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  • miR32-5p promoted vascular smooth muscle cell calcification by upregulating TNFα in the microenvironment
    BMC Immunol. (IF 2.186) Pub Date : 2020-01-17
    Jingsong Cao; Ling Chen; Xiaoling Zhong; Yingying Shen; Yan Gao; Qian Chen; Xuyu Zu; Jianghua Liu

    Vascular calcification is often associated with chronic inflammation and is a risk factor for brain arterial stiffness. Our previous results showed that miR32-5p was positively correlated with vascular smooth muscle cells (VSMC) calcification, but it is unclear whether miR32-5p promoted VSMC calcification by regulating inflammatory factor production. In this study, bioinformatics analysis was used to select tumour necrosis factor α (TNFα) as a candidate inflammatory factor associated with calcification. Moreover, alizarin red staining and qRT-PCR analysis revealed that TNFα produced by BV2 cells was the key promoting factor of VSMC calcification. Interestingly, the expression of TNFα was significantly increased at the mRNA and protein levels after miR32-5p mimic treatment but significantly decreased after miR32-5p antagomir treatment. To explore the mechanism of the regulation of TNFα expression by miR32-5p, bioinformatics analysis indicated that PIKfyve was a candidate target gene of miR32-5p, and luciferase assays verified that the expression of PIKfyve was significantly repressed by miR32-5p mimics. Importantly, rescue experiments showed that the expression of TNFα in BV2 cells treated with miR32-5p antagomir and the PIKfyve inhibitor YM201636 was significantly increased. The production of TNFα in microglia could be affected by miR32-5p targeting PIKfyve, and these results will be beneficial to reveal the mechanism of brain arterial calcification.

    更新日期:2020-01-17
  • Diagnostic value of serum soluble triggering expressed receptor on myeloid cells 1 (sTREM-1) in suspected sepsis: a meta-analysis
    BMC Immunol. (IF 2.186) Pub Date : 2020-01-13
    Wei Chang; Fei Peng; Shan-Shan Meng; Jing-Yuan Xu; Yi Yang

    We aim to synthesize the up-to-date studies to investigate the diagnostic value of serum soluble triggering expressed receptor on myeloid cells 1 (sTREM-1) in suspected sepsis. A total of 19 studies with 2418 patients were finally enrolled in the meta-analysis. The pooled sensitivity was 0.82 (95% CI 0.73 to 0.89), specificity 0.81 (95% CI 0.75 to 0.86), positive likelihood ratio 4.3 (95% CI 3.02 to 6.12), negative likelihood ratio 0.22 (95% CI 0.24 to 0.35), diagnostic odds ratio 20 (95% CI 9 to 41) and AuROC 0.88 (95% CI 0.85 to 0.91). The meta-regression analysis revealed that the sample size, reference standard description, prevalence of sepsis in the trials and consecution of patient recruitment might be the source of heterogeneity. The serum sTREM-1 had a moderate ability in diagnosis in suspected sepsis based on the current studies. However, more large-scale studies were needed to further evaluate the diagnostic accuracy of sTREM-1.

    更新日期:2020-01-14
  • A software package for immunologists to learn simulation modeling
    BMC Immunol. (IF 2.186) Pub Date : 2020-01-02
    Andreas Handel

    As immunology continues to become more quantitative, increasingly sophisticated computational tools are commonly used. One useful toolset are simulation models. Becoming familiar with such models and their uses generally requires writing computer code early in the learning process. This poses a barrier for individuals who do not have prior coding experience. To help reduce this barrier, I wrote software that teaches the use of mechanistic simulation models to study infection and immune response dynamics, without the need to read or write computer code. The software, called Dynamical Systems Approach to Immune Response Modeling (DSAIRM), is implemented as a freely available package for the R programming language. The target audience are immunologists and other scientists with no or little coding experience. DSAIRM provides a hands-on introduction to simulation models, teaches the basics of those models and what they can be used for. Here, I describe the DSAIRM R package, explain the different ways the package can be used, and provide a few introductory examples. Working through DSAIRM will equip individuals with the knowledge needed to critically assess studies using simulation models in the published literature and will help them understand when such a modeling approach might be suitable for their own research. DSAIRM also provides users a potential starting point towards development and use of simulation models in their own research.

    更新日期:2020-01-02
  • Amentoflavone ameliorates cold stress-induced inflammation in lung by suppression of C3/BCR/NF-κB pathways
    BMC Immunol. (IF 2.186) Pub Date : 2019-12-30
    Jiayi Cai; Chunyang Zhao; Yajie Du; Yuan Huang; Qingchun Zhao

    Cold stress, which may lead to local and systemic injury, is reported to be related to the immune system, especially the complement system. At present, the lack of effective treatment is a critical issue. Amentoflavone (AF), which can inhibit cold stress-induced inflammation in lung by multiple mechanisms, is the main therapeutic ingredient in plants of the genus Selaginella. In the current study, we found that cold could induce lung inflammation related to the complement system and its downstream pathways. AF treatment significantly inhibited lung inflammation from cold exposure. We presented evidence that AF can bind to complement component 3 (C3) to regulate inflammation-related pathways involving Lck/Yes novel tyrosine kinase (Lyn), protein kinase B (Akt), nuclear factor-κB (NF-κB) and immune factors. Moreover, 30 mg/kg of AF caused significantly greater improvement than 15 mg/kg in reducing the level of C3 in lung tissue. AF can protect lung tissue from cold exposure. The protective effect may be achieved by inhibition of C3 and negative regulation of the B cell receptor (BCR)/NF-κB signaling pathways and high mobility group box 1 (HMGB1), which ultimately ameliorates the inflammatory response.

    更新日期:2019-12-31
  • Interactions between Yersinia pestis V-antigen (LcrV) and human Toll-like receptor 2 (TLR2) in a modelled protein complex and potential mechanistic insights
    BMC Immunol. (IF 2.186) Pub Date : 2019-12-16
    Tiandi Wei; Jing Gong; Guojing Qu; Mingyu Wang; Hai Xu

    Yersinia pestis, the etiological pathogen of plague, is capable of repressing the immune response of white blood cells to evade phagocytosis. The V-antigen (LcrV) was found to be involved in this process by binding to human Toll-like Receptor 2 (TLR2). The detailed mechanism behind this LcrV and TLR2 mediated immune response repression, however, is yet to be fully elucidated due to the lack of structural information. In this work, with protein structure modelling, we were able to construct a structure model of the heterotetramer of Y. pestis LcrV and human TLR2. Molecular dynamics simulation suggests the stability of this structure in aquatic environment. The LcrV model has a dumbbell-like structure with two globule domains (G1 at N-terminus and G2 away from membrane) connected with a coiled-coil linker (CCL) domain. The two horseshoe-shape TLR2 subunits form a V-shape structure, are not in direct contact with each other, and are held together by the LcrV homodimer. In this structure model, both the G1 and CCL domains are involved in the formation of LcrV homodimer, while all three domains are involved in LcrV-TLR2 binding. A mechanistic model was proposed based on this heterotetrameric structure model: The LcrV homodimer separates the TLR2 subunits to inhibit the dimerization of TLR2 and subsequent signal transfer for immune response; while LcrV could also inhibit the formation of heterodimers of TLR2 with other TLRs, and leads to immune response repression. A heterotetrameric structure of Y. pestis LcrV and human TLR2 was modelled in this work. Analysis of this modelled structure showed its stability in aquatic environments and the role of LcrV domains and residues in protein-protein interaction. A mechanistic model for the role of LcrV in Y. pestis pathogenesis is raised based on this heterotetrameric structure model. This work provides a hypothesis of LcrV function, with which further experimental validation may elucidate the role of LcrV in human immune response repression.

    更新日期:2019-12-17
  • NK cell predicts the severity of acute graft-versus-host disease in patients after allogeneic stem cell transplantation using antithymocyte globulin (ATG) in pretreatment scheme
    BMC Immunol. (IF 2.186) Pub Date : 2019-12-09
    Ping Zhang; Shujun Yang; Yujing Zou; Xiao Yan; Hao Wu; Miao Zhou; Yong Cheng Sun; Yi Zhang; Huiling Zhu; Kaihong Xu; Yi Wang; Li Xia Sheng; Qitian Mu; Liguang Sun; Guifang Ouyang

    Graft-versus-host disease (GVHD) is one of the most complex complications after allogeneic stem cell transplantation. Current standard of grading system is based on clinical symptoms in skin, liver and intestinal. However, it’s difficult to differ GVHD and its extent just by clinical manifestation. Here we retrospectively analyzed cell immune function in patients implemented allogeneic stem cell transplantation in Ningbo first Hospital from Jan 2013 to Jan 2018. the data are collected from 51 patients (mean age was 42; 45.1% women). The average NK cell percentage was 39.31% in severe GVHD (Grade III-IV), was 16.98% in mild GVHD (GradeI-II), while was 21.15% in No GVHD group. The statistical analysis showed difference among each grade. Further analysis was performed in Antithymocyte globulin (ATG) treated group and control group. We showed NK Cell percentage was sharply different in ATG treated group: 47.34% in severe GVHD, 11.98% in mild GVHD group, while 18.3% in no GVHD group. However, in control group, the average percentage of NK cells was 23.27% in severe GVHD, was 23.22%in mild GVHD group, while was 21.13% in no GVHD group. The data supports that ATG can prevent GVHD by increasing NK cell percentage. The percentage of NK cell seemed to be a useful probe to evaluate the severity of GVHD in allogeneic stem cell transplantation patients using ATG in pretreatment.

    更新日期:2019-12-11
  • ILC2 transfers to apolipoprotein E deficient mice reduce the lipid content of atherosclerotic lesions
    BMC Immunol. (IF 2.186) Pub Date : 2019-12-10
    Polyxeni T. Mantani; Pontus Dunér; Irena Ljungcrantz; Jan Nilsson; Harry Björkbacka; Gunilla Nordin Fredrikson

    Expansion of type 2 innate lymphoid cells (ILC2s) in hypercholesterolaemic mice protects against atherosclerosis while different ILC2 subsets have been described (natural, inflammatory) based on their suppression of tumorigenicity 2 (ST2) and killer-cell lectin like receptor G1 (KLRG1) expression. The aim of the current study is to characterize the interleukin 25 (IL25)-induced splenic ILC2 population (Lin−CD45+IL17RB+ICOS+IL7raintermediate) and address its direct role in experimental atherosclerosis by its adoptive transfer to hypercholesterolaemic apolipoprotein E deficient (apoE−/−) mice. Immunomagnetically enriched, FACS-sorted ILC2s from the spleens of IL-25 treated apoE−/− mice were stained for KLRG1 and ST2 directly upon cell obtainment or in vitro cell expansion for flow cytometric analysis. IL25-induced splenic ILC2s express high levels of both KLRG1 and ST2. However, both markers are downregulated upon in vitro cell expansion. In vitro expanded splenic ILC2s were intraperitoneally transferred to apoE−/− recipients on high fat diet. ApoE−/− mice that received in vitro expanded splenic ILC2s had decreased lipid content in subvalvular heart and brachiocephalic artery (BCA) plaques accompanied by increased peritoneal B1 cells, activated eosinophils and alternatively activated macrophages (AAMs) as well as anti-phosphorylcholine (PC) immunoglobulin (Ig) M in plasma. With the current data we designate the IL25-induced ILC2 population to decrease the lipid content of atherosclerotic lesions in apoE−/− mice and we directly link the induction of B1 cells and the atheroprotective anti-PC IgM antibodies with ILC2s.

    更新日期:2019-12-11
  • The effect of tuberculosis on immune reconstitution among HIV patients on highly active antiretroviral therapy in Adigrat general hospital, eastern Tigrai, Ethiopia; 2019: a retrospective follow up study
    BMC Immunol. (IF 2.186) Pub Date : 2019-12-05
    Hadush Negash; Haftom Legese; Mebrahtu Tefera; Fitsum Mardu; Kebede Tesfay; Senait Gebresilasie; Berhane Fseha; Tsega Kahsay; Aderajew Gebrewahd; Brhane Berhe

    Ethiopia initiated antiretroviral therapy early in 2005. Managing and detecting antiretroviral treatment response is important to monitor the effectiveness of medication and possible drug switching for low immune reconstitution. There is less recovery of CD4+ T cells among human immunodeficiency virus patients infected with tuberculosis. Hence, we aimed to assess the effect of tuberculosis and other determinant factors of immunological response among human immunodeficiency virus patients on highly active antiretroviral therapy. A retrospective follow up study was conducted from October to July 2019. A total of 393 participants were enrolled. An interviewer based questionnaire was used for data collection. Patient charts were used to extract clinical data and follow up results of the CD4+ T cell. Current CD4+ T cell counts of patients were performed. STATA 13 software was used to analyze the data. A p-value ≤0.05 was considered a statistically significant association. The mean age of study participants was 39.2 years (SD: + 12.2 years) with 8.32 mean years of follow up. The overall prevalence of immune reconstitution failure was 24.7% (97/393). Highest failure rate occurred within the first year of follow up time, 15.7 per 100 Person-year. Failure of CD4+ T cells reconstitution was higher among tuberculosis coinfected patients (48.8%) than mono-infected patients (13.7%). Living in an urban residence, baseline CD4+ T cell count ≤250 cells/mm3, poor treatment adherence and tuberculosis infection were significantly associated with the immunological failure. There was a high rate of CD4+ T cells reconstitution failure among our study participants. Tuberculosis infection increased the rate of failure. Factors like low CD4+ T cell baseline count, poor adherence and urban residence were associated with the immunological failure. There should be strict monitoring of CD4+ T cell counts among individuals with tuberculosis coinfection.

    更新日期:2019-12-05
  • Using the K/BxN mouse model of endogenous, chronic, rheumatoid arthritis for the evaluation of potential immunoglobulin-based therapeutic agents, including IVIg and Fc-μTP-L309C, a recombinant IgG1 Fc hexamer
    BMC Immunol. (IF 2.186) Pub Date : 2019-12-04
    Bonnie J. B. Lewis; Jade Ville; Megan Blacquiere; Selena Cen; Rolf Spirig; Adrian W. Zuercher; Fabian Käsermann; Donald R. Branch

    High-dose intravenous immunoglobulin (IVIg), and more recently, subcutaneously-delivered Ig (SCIg), are used to treat a variety of autoimmune diseases; however, there are challenges associated with product production, availability, access and efficacy. These challenges have provided incentives to develop a human recombinant Fc as a more potent alternative to IVIg and SCIg for the treatment of autoimmune diseases. Recently, a recombinant human IgG1 Fc hexamer (Fc-μTP-L309C) was shown to be more efficacious than IVIg in a variety of autoimmune mouse models. We have now examined its efficacy compared to IVIg and SCIg in the K/BxN mouse model of endogenous, chronic rheumatoid arthritis (RA). Using the serum-transfer K/BxN model and the endogenous autoimmune model, amelioration of the arthritis was achieved. Effective treatment required high and frequent doses of IVIg, SCIg and Fc-μTP-L309C. However, Fc-μTP-L309C was efficacious at 10-fold lower doses that IVIg/SCIg. Also, arthritis could be prevented when Fc-μTP-L309C was given prior to onset of the arthritis in both the endogenous model and in the serum transfer model. Our results show that Fc-μTP-L309C is a powerful treatment for the prevention and amelioration of severe, chronic arthritis in a true autoimmune mouse model of RA. Thus, the K/BxN endogenous arthritis model should be useful for testing potential therapeutics for RA. Our findings provide rationale for further examination of the treatment efficacy of immunoglobulin-based therapeutics in rheumatoid arthritis.

    更新日期:2019-12-04
  • Prevalence and associated factors of treatment failure among HIV/AIDS patients on HAART attending University of Gondar Referral Hospital Northwest Ethiopia
    BMC Immunol. (IF 2.186) Pub Date : 2018-12-17
    Gizachew Ayele; Belay Tessema; Anteneh Amsalu; Getachew Ferede; Gizachew Yismaw

    The initiation of highly active antiretroviral therapy (HAART) plays a significant role in the clinical management of HIV infected people by preventing morbidity and mortality. This benefit becomes, the most terrible when treatment failure develops. Thus, this research aims to assess the prevalence and associated factors of treatment failure among HIV/AIDS patients on HAART attending University of Gondar Referral Hospital Northwest Ethiopia. Patients on ART with a minimum of 6 months and up to 12 years of treatment were being enrolled. The prevalence of treatment failure, immunological failure and virological failure among people living with HIV/AIDS attending University of Gondar referral hospital were 20.3, 13.2, and 14.7%, respectively. Patients who had no formal education (Adjusted odds ratio (AOR): 3.8; 95% CI, 1.05–13.77), primary level education (AOR: 4.2; 95% CI, 1.16–15.01) and duration on ART < 6 years (AOR: 2.1; 95%CI, 1.12–3.81) were a significant risk factor. However, initial adult regimen D4T + 3TC+ EFV (AOR: 0.025; 95% CI, 0.002–0.36), AZT +3TC + NVP (AOR: 0.07; 95% CI, 0.01–0.71), AZT + 3TC + EFV (AOR: 0.046; 95% CI, 0.004–0.57) andTDF+3TC + EFV (AOR: 0.04; 95% CI, 0.004–0.46) were significantly protective for treatment failure. Timely and early identification of associated factors and monitoring antiretroviral therapy treatment failure should be done to enhance the benefit and to prevent further complication of the patients. It is preferable to initiate ART using any one of the following ART regimens: AZT +3TC + NVP, AZT + 3TC + EFV and TDF + 3TC + EFV to prevent treatment failure. Since the prevalence of this treatment failure and its associated factor may be different from other ART centers and community in Ethiopia, further national representative institutional based cross-sectional researches are needed across all ART centers of Ethiopia in order to determine the prevalence of treatment failure and its associated factors.

    更新日期:2019-11-28
  • Anti-SIRT1 autoantibody is elevated in ankylosing spondylitis: a potential disease biomarker
    BMC Immunol. (IF 2.186) Pub Date : 2018-12-17
    Qiongyi Hu; Yue Sun; Yuan Li; Hui Shi; Jialin Teng; Honglei Liu; Xiaobing Cheng; Junna Ye; Yutong Su; Yufeng Yin; Mengru Liu; Jiucun Wang; Chengde Yang

    Little is known about the presence of specific autoantibodies in ankylosing spondylitis (AS), an immune-mediated inflammatory disease. The object of this study was to explore potential autoantibody profiles in AS patients. Levels of anti-SIRT1 autoantibodies were significantly higher in AS (P < 0.001) and psoriatic arthritis (PsA) (P < 0.01) patients but not rheumatoid arthritis (RA) patients compared with healthy controls. Additionally, titers of anti-NAD-dependent protein deacetylase sirtuin-1(SIRT1) antibodies were significantly higher in AS patients than in RA (P < 0.05) and PsA (P < 0.05) patients. Moreover, levels of anti-SIRT1 (P < 0.001) antibodies were significantly higher during the first year in patients with hip joint involvement. The anti-SIRT1 antibody positivity rate was 18.9% in AS patients. Our findings indicate that anti-SIRT1 autoantibodies may serve as a marker for diagnosing AS and predicting hip joint involvement at an early stage.

    更新日期:2019-11-28
  • Human NK cells adapt their immune response towards increasing multiplicities of infection of Aspergillus fumigatus
    BMC Immunol. (IF 2.186) Pub Date : 2018-12-18
    Lothar Marischen; Anne Englert; Anna-Lena Schmitt; Hermann Einsele; Juergen Loeffler

    The saprophytic fungus Aspergillus fumigatus reproduces by generation of conidia, which are spread by airflow throughout nature. Since humans are inhaling certain amounts of spores every day, the (innate) immune system is constantly challenged. Even though macrophages and neutrophils carry the main burden, also NK cells are regarded to contribute to the antifungal immune response. While NK cells reveal a low frequency, expression and release of immunomodulatory molecules seem to be a natural way of their involvement. In this study we show, that NK cells secrete chemokines such as CCL3/MIP-1α, CCL4/MIP-1β and CCL5/RANTES early on after stimulation with Aspergillus fumigatus and, in addition, adjust the concentration of chemokines released to the multiplicity of infection of Aspergillus fumigatus. These results further corroborate the relevance of NK cells within the antifungal immune response, which is regarded to be more and more important in the development and outcome of invasive aspergillosis in immunocompromised patients after hematopoietic stem cell transplantation. Additionally, the correlation between the multiplicity of infection and the expression and release of chemokines shown here may be useful in further studies for the quantification and/or surveillance of the NK cell involvement in antifungal immune responses.

    更新日期:2019-11-28
  • Oncolytic herpes simplex virus and immunotherapy
    BMC Immunol. (IF 2.186) Pub Date : 2018-12-18
    Wenqing Ma; Hongbin He; Hongmei Wang

    Oncolytic viruses have been proposed to be employed as a potential treatment of cancer. Well targeted, they will serve the purpose of cracking tumor cells without causing damage to normal cells. In this category of oncolytic viral drugs human pathogens herpes simplex virus (HSV) is especially suitable for the cause. Although most viral infection causes antiviral reaction in the host, HSV has multiple mechanisms to evade those responses. Powerful anti-tumor effect can thus be achieved via genetic manipulation of the HSV genes involved in this evading mechanism, namely deletions or mutations that adapt its function towards a tumor microenvironment. Currently, oncolytic HSV (oHSV) is widely use in clinical; moreover, there’s hope that its curative effect will be further enhanced through the combination of oHSV with both traditional and emerging therapeutics. In this review, we provide a summary of the HSV host antiviral response evasion mechanism, HSV expresses immune evasion genes such as ICP34.5, ICP0, Us3, which are involved in inducing and activating host responses, so that the virus can evade the immune system and establish effective long-term latent infection; we outlined details of the oHSV strains generated by removing genes critical to viral replication such as ICP34.5, ICP0, and inserting therapeutic genes such as LacZ, granulocyte macrophage colony-stimulating factor (GM-CSF); security and limitation of some oHSV such G207, 1716, OncoVEX, NV1020, HF10, G47 in clinical application; and the achievements of oHSV combined with immunotherapy and chemotherapy. We reviewed the immunotherapy mechanism of the oHSV and provided a series of cases. We also pointed out that an in-depth study of the application of oHSV in cancer treatment will potentially benefits cancer patients more.

    更新日期:2019-11-28
  • 5-Aminolevulinic acid regulates the immune response in LPS-stimulated RAW 264.7 macrophages
    BMC Immunol. (IF 2.186) Pub Date : 2018-12-19
    Yuta Sugiyama; Yukari Hiraiwa; Yuichiro Hagiya; Motowo Nakajima; Tohru Tanaka; Shun-ichiro Ogura

    Macrophages are crucial players in a variety of inflammatory responses to environmental cues. However, it has been widely reported that macrophages cause chronic inflammation and are involved in a variety of diseases, such as obesity, diabetes, metabolic syndrome, and cancer. In this study, we report the suppressive effect of 5-aminolevulinic acid (ALA), via the HO-1-related system, on the immune response of the LPS-stimulated mouse macrophage cell line RAW264.7. RAW264.7 cells were treated with LPS with or without ALA, and proinflammatory mediator expression levels and phagocytic ability were assessed. ALA treatment resulted in the attenuation of iNOS and NO expression and the downregulation of proinflammatory cytokines (TNF-α, cyclooxygenase2, IL-1β, IL-6). In addition, ALA treatment did not affect the phagocytic ability of macrophages. To our knowledge, this study is the first to investigate the effect of ALA on macrophage function. Our findings suggest that ALA may have high potential as a novel anti-inflammatory agent. In the present study, we showed that exogenous addition of ALA induces HO-1 and leads to the downregulation of NO and some proinflammatory cytokines. These findings support ALA as a promising anti-inflammatory agent.

    更新日期:2019-11-28
  • Correction to: blood handling and leukocyte isolation methods impact the global transcriptome of immune cells
    BMC Immunol. (IF 2.186) Pub Date : 2018-12-21
    Brittany A. Goods; Jacqueline M. Vahey; Arthur F. Steinschneider; Michael H. Askenase; Lauren Sansing; J. Christopher Love

    It has been highlighted that the original article [1] contained a typesetting mistake in the middle name of Arthur F. Steinschneider.

    更新日期:2019-11-28
  • Variation in IL-21-secreting circulating follicular helper T cells in Kawasaki disease
    BMC Immunol. (IF 2.186) Pub Date : 2018-12-27
    Meng Xu; Yanfang Jiang; Jian Zhang; Yan Zheng; Deying Liu; Lishuang Guo; Sirui Yang

    Circulating follicular helper T (cTfh) cells are a specialized subset of CD4+ T cells that express the CXC-chemokine receptor 5 (CXCR5). These cells exhibit immune activities by inducing B cell differentiation and proliferation via the secretion of interleukin (IL)-21. Multiple studies have demonstrated that cTfh cells are associated with the progression and severity of numerous diseases. To investigate the role of cTfh cells in the development of Kawasaki disease (KD), we analyzed the distinct subpopulations of cTfh cells and serum IL-21 levels in different phases of KD. According to the differential expression of inducible co-stimulator (ICOS) and programmed cell death protein 1 (PD-1), cTfh cells were divided into distinct subsets. We used flow cytometry and flow cytometric bead arrays (CBA) to analyze subsets of CD4+CXCR5+ T cells and serum IL-21 levels. The samples were collected from control subjects and Kawasaki disease patients in the acute and remission phases. In the acute phase (AP), the percentages of ICOShighPD-1high, ICOS+PD-1+, ICOS−PD-1+, CD45RA−IL-21+ cTfh cells and serum IL-21 levels significantly increased. Furthermore, the percentages of ICOShighPD-1high and ICOS+PD-1+ cTfh cells positively correlated with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values, whereas the percentage of ICOS−PD-1+ cTfh cells indicated negative correlations. The percentages of ICOS+PD-1+, ICOShighPD-1high and CD45RA−IL-21+ cTfh cells correlated positively with serum IL-21 levels. In the remission phase (RP), the percentages of ICOS−PD-1+, CD45RA−IL-21+ cTfh cells and serum IL-21 levels were significantly decreased. In contrast, the percentages of ICOS+PD-1+, ICOShighPD-1high, and ICOS+PD-1− cTfh cells were further increased. Among these subsets, only CD45RA−IL-21+ cTfh cells correlated positively with serum IL-21 levels. The present study is the first investigation that examined the distribution of circulating cTfh cell subsets in Kawasaki disease. Both cTfh cells and serum IL-21 are essential to the pathogenesis of KD. Our study provides further understanding of the immune response involved in KD and offers novel insights in the pathogenetic mechanism of this disease.

    更新日期:2019-11-28
  • Mannose-binding lectin concentrations in people living with HIV/AIDS infected by HHV-8
    BMC Immunol. (IF 2.186) Pub Date : 2019-01-03
    Viviane Martha Santos de Morais; Juliana Prado Gonçales; Georgea Gertrudes de Oliveira Mendes Cahú; Tania Regina Tozetto-Mendoza; Maria Rosângela Cunha Duarte Coêlho

    Mannose-binding lectin (MBL) plays an important role in the innate immune response by activating the complement system via the lectin pathway, and it has been studied in several viral infections; however, the influence of MBL in PLWHA infected with HHV-8 is unknown. The objective of this study was to verify the association of MBL deficient plasma concentrations in HIV/HHV-8 coinfected and HIV monoinfected patients and to correlate these concentrations with HIV viral load and CD4 counts in both groups. This was an analytical study of case-controls consisting of PLWHA monitored at the medical outpatient of Infectious and Parasitic Diseases of the clinical hospital in the Federal University of Pernambuco. Plasma concentrations of MBL were obtained by an enzyme-linked immunosorbent assay (ELISA) using a commercial Human Mannose Binding Lectin kit (MyBioSource, Inc.) that was performed according to the manufacturer’s guidelines, with values < 100 ng/ml considered deficient. A total of 245 PLWHA samples were analysed; 118 were HIV/HHV-8 coinfected and 127 were HIV monoinfected; 5.1% (6/118) of the coinfected patients and 3.2% (4/127) of the monoinfected patients (p = 0.445) were considered plasma concentration deficient. The median of the plasma concentrations of MBL in the coinfected patients was 2803 log10 ng/ml and was 2.959 log10 ng/ml in the monoinfected patients (p = 0.001). There was an inverse correlation between the plasma concentrations of MBL and the HIV viral load in both groups, but no correlation with the CD4 count. Although the plasma concentrations considered deficient in MBL were not associated with HHV-8 infection in PLWHA, the coinfected patients showed lower MBL concentrations and an inverse correlation with HIV viral load, suggesting that there may be consumption and reduction of MBL due to opsonization of HIV and HHV-8, leading to the reduction of plasma MBL and non-accumulation in the circulation.

    更新日期:2019-11-28
  • Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human lymphocytes and sensitivity to HIV-1 infection
    BMC Immunol. (IF 2.186) Pub Date : 2019-01-07
    Raghubendra Singh Dagur; Amanda Branch-Woods; Saumi Mathews; Poonam S. Joshi; Rolen M. Quadros; Donald W. Harms; Yan Cheng; Shana M. Miles; Samuel J. Pirruccello; Channabasavaiah B. Gurumurthy; Santhi Gorantla; Larisa Y. Poluektova

    The use of immunodeficient mice transplanted with human hematopoietic stem cells is an accepted approach to study human-specific infectious diseases such as HIV-1 and to investigate multiple aspects of human immune system development. However, mouse and human are different in sialylation patterns of proteins due to evolutionary mutations of the CMP-N-acetylneuraminic acid hydroxylase (CMAH) gene that prevent formation of N-glycolylneuraminic acid from N-acetylneuraminic acid. How changes in the mouse glycoproteins’ chemistry affect phenotype and function of transplanted human hematopoietic stem cells and mature human immune cells in the course of HIV-1 infection are not known. We mutated mouse CMAH in the NOD/scid-IL2Rγc−/− (NSG) mouse strain, which is widely used for the transplantation of human cells, using the CRISPR/Cas9 system. The new strain provides a better environment for human immune cells. Transplantation of human hematopoietic stem cells leads to broad B cells repertoire, higher sensitivity to HIV-1 infection, and enhanced proliferation of transplanted peripheral blood lymphocytes. The mice showed no effect on the clearance of human immunoglobulins and enhanced transduction efficiency of recombinant adeno-associated viral vector rAAV2/DJ8. NSG-cmah−/− mice expand the mouse models suitable for human cells transplantation, and this new model has advantages in generating a human B cell repertoire. This strain is suitable to study different aspects of the human immune system development, provide advantages in patient-derived tissue and cell transplantation, and could allow studies of viral vectors and infectious agents that are sensitive to human-like sialylation of mouse glycoproteins.

    更新日期:2019-11-28
  • Treatment of established TH2 cells with 4μ8c, an inhibitor of IRE1α, blocks IL-5 but not IL-4 secretion
    BMC Immunol. (IF 2.186) Pub Date : 2019-01-10
    Cody Poe; Cheyanne Youngblood; Karissa Hodge; Kyeorda Kemp

    T cell activation induces ER stress and upregulates Inositol Requiring Enzyme 1 alpha (IRE1α), an activator of the unfolded protein response (UPR) pathway. Inhibition of IRE1α RNase activity in activated CD4+ splenocytes from naïve mice, via treatment of the cells with the commercially available drug 4μ8c upon activation, results in the reduction of the secretion of proteins IL-5, IL-4, and IL-13. Prior to this work, it was unknown if 4μ8c could inhibit TH2 cytokines in established TH2 cells, cells that are crucial in promoting disease in severe asthma. Treatment of a mouse T helper (TH)2 cell line and differentiated human TH2 cells with 4μ8c resulted in inhibition of IL-5, but not IL-4, as measured by ELISA. The reduced cytokine expression was not due to differences in mRNA stability or mRNA levels; it appears to be due to a defect in secretion, as the cells produce cytokines IL-5 as measured by flow cytometry and western blot. These data suggest that the inhibition of IL-5 was due to post-translational processes. IL-5 promotes chronic, inflammatory asthma, and 4μ8c blocks its expression in T cells in vitro. Future studies will determine if 4μ8c treatment can ameliorate the effects of the cytokine IL-5 in a disease model.

    更新日期:2019-11-28
  • Correlate tumor mutation burden with immune signatures in human cancers
    BMC Immunol. (IF 2.186) Pub Date : 2019-01-11
    Xiaosheng Wang; Mengyuan Li

    Tumor mutation burden (TMB) has been associated with cancer immunotherapeutic response and cancer prognosis. Although many explorations have revealed that high TMB may yield many neoantigens to incite antitumor immune response, a systematic exploration of the correlation between TMB and immune signatures in different cancer types is lacking. We classified cancer into the lower-TMB subtype and the higher-TMB subtype for each of 32 cancer types based on their somatic mutation data from the Cancer Genome Atlas (TCGA), and compared the expression levels of immune-related genes and gene-sets between both subtypes of cancers in each cancer type. In some cancer types most of the immune signatures analyzed were upregulated in the lower-TMB subtype, while in some other cancer types the immune signatures were prone to be upregulated in the higher-TMB subtype. However, the regulatory T cells, immune cell infiltrate, tumor-infiltrating lymphocytes, and cytokine signatures tended to be upregulated in the lower-TMB subtype, and the cancer-testis antigen (CTA) and pro-inflammatory signatures were inclined to be upregulated in the higher-TMB subtype. Importantly, high TMB was associated with elevated expression of PD-L1 in diverse prevailing cancers. Furthermore, we found that higher TMB was associated with better survival prognosis in numerous cancer types while was associated with worse prognosis in a few cancer types. High TMB may inhibit immune cell infiltrations while promote CTAs expression and inflammatory response in cancer. In many common cancer types, higher TMB may respond favorably to anti-PD-1/PD-L1 immunotherapy. Our data implicate that higher-TMB patients could gain a more favorable prognosis in diverse cancer types if treated with immunotherapy, otherwise would have a poorer prognosis compared to lower-TMB patients.

    更新日期:2019-11-28
  • Phenotypic and functional stability of leukocytes from human peripheral blood samples: considerations for the design of immunological studies
    BMC Immunol. (IF 2.186) Pub Date : 2019-01-18
    Adriana Navas; Lina Giraldo-Parra; Miguel Darío Prieto; Juliana Cabrera; María Adelaida Gómez

    Human peripheral blood mononuclear cells (PBMCs) are extensively used for research of immune cell functions, identification of biomarkers and development of diagnostics and therapeutics for human diseases, among others. The assumption that “old blood samples” are not appropriate for isolation of PBMCs for functional assays has been a dogma in the scientific community. However, partial data on the impact of time after phlebotomy on the quality and stability of human PBMCs preparations impairs the design of studies in which time-controlled blood sampling is challenging such as field studies involving multiple sampling centers/sites. In this study, we evaluated the effect of time after phlebotomy over a 24 h time course, on the stability of human blood leukocytes used for immunological analyses. Blood samples from eight healthy adult volunteers were obtained and divided into four aliquots, each of which was left in gentle agitation at room temperature (24 °C) for 2 h (control), 7 h, 12 h and 24 h post phlebotomy. All samples at each time point were independently processed for quantification of mononuclear cell subpopulations, cellular viability, gene expression and cytokine secretion. A 24 h time delay in blood sample processing did not affect the viability of PBMCs. However, a significantly lower frequency of CD3+ T cells (p < 0.05) and increased LPS-induced CXCL10 secretion were observed at 12 h post-phlebotomy. Alterations in TNFα, CCL8, CCR2 and CXCL10 gene expression were found as early as 7 h after blood sample procurement. These data reveal previously unrecognized early time-points for sample processing control, and provide an assay-specific time reference for the design of studies that involve immunological analyses of human blood samples.

    更新日期:2019-11-28
  • Monoclonal antibody against EV71 3Dpol inhibits the polymerase activity of RdRp and virus replication
    BMC Immunol. (IF 2.186) Pub Date : 2019-01-22
    Yaoming Li; Jie Yu; Xiuwen Qi; Huimin Yan

    Enterovirus A 71 (EV71) is a neurotropic virus that may lead to acute flaccid paralysis, encephalitis, cardiopulmonary failure or even death. No vaccine and defensive drug controlling EV71 is currently available, novel and efficient antiviral drug or vaccine is therefore urgently needed. 3Dpol (RNA-dependent RNA polymerase (RdRp)) has been an important target for anti-EV71 drug development. A panel of monoclonal IgG antibodies (mAbs) against EV71 3Dpol were generated by traditional cell fusion methods. And the antibody affinity and specificity to EV71 3Dpol were evaluated by Enzyme-linked Immunosorbent Assay (ELISA), Indirect Fluorescent Assay (IFA) and Western blotting. Antiviral activities of these antibodies were also determined in vitro and in vivo. Two mAbs towards EV71 3Dpol were able to effectively suppress EV71 replication in Vero-1008 cell when intracellarly delivered. And they also dampened the RNA polymerase activity of 3Dpol in vitro. More importantly, these mAbs provided partial protection in EV71-challenged neonatal murine challenge model. These results showed that two of mAbs against EV71 3Dpol inhibited EV71 replication and could be utilized as promising therapeutic drug candidate.

    更新日期:2019-11-28
  • CEACAM1 regulates the IL-6 mediated fever response to LPS through the RP105 receptor in murine monocytes
    BMC Immunol. (IF 2.186) Pub Date : 2019-01-23
    Zhifang Zhang; Deirdre La Placa; Tung Nguyen; Maciej Kujawski; Keith Le; Lin Li; John E. Shively

    Systemic inflammation and the fever response to pathogens are coordinately regulated by IL-6 and IL-1β. We previously showed that CEACAM1 regulates the LPS driven expression of IL-1β in murine neutrophils through its ITIM receptor. We now show that the prompt secretion of IL-6 in response to LPS is regulated by CEACAM1 expression on bone marrow monocytes. Ceacam1−/− mice over-produce IL-6 in response to an i.p. LPS challenge, resulting in prolonged surface temperature depression and overt diarrhea compared to their wild type counterparts. Intraperitoneal injection of a 64Cu-labeled LPS, PET imaging agent shows confined localization to the peritoneal cavity, and fluorescent labeled LPS is taken up by myeloid splenocytes and muscle endothelial cells. While bone marrow monocytes and their progenitors (CD11b+Ly6G−) express IL-6 in the early response (< 2 h) to LPS in vitro, these cells are not detected in the bone marrow after in vivo LPS treatment perhaps due to their rapid and complete mobilization to the periphery. Notably, tissue macrophages are not involved in the early IL-6 response to LPS. In contrast to human monocytes, TLR4 is not expressed on murine bone marrow monocytes. Instead, the alternative LPS receptor RP105 is expressed and recruits MD1, CD14, Src, VAV1 and β-actin in response to LPS. CEACAM1 negatively regulates RP105 signaling in monocytes by recruitment of SHP-1, resulting in the sequestration of pVAV1 and β-actin from RP105. This novel pathway and regulation of IL-6 signaling by CEACAM1 defines a novel role for monocytes in the fever response of mice to LPS.

    更新日期:2019-11-28
  • Expression of ligands for activating natural killer cell receptors on cell lines commonly used to assess natural killer cell function
    BMC Immunol. (IF 2.186) Pub Date : 2019-01-29
    Alexandra Tremblay-McLean; Sita Coenraads; Zahra Kiani; Franck P. Dupuy; Nicole F. Bernard

    Natural killer cell responses to virally-infected or transformed cells depend on the integration of signals received through inhibitory and activating natural killer cell receptors. Human Leukocyte Antigen null cells are used in vitro to stimulate natural killer cell activation through missing-self mechanisms. On the other hand, CEM.NKr.CCR5 cells are used to stimulate natural killer cells in an antibody dependent manner since they are resistant to direct killing by natural killer cells. Both K562 and 721.221 cell lines lack surface major histocompatibility compatibility complex class Ia ligands for inhibitory natural killer cell receptors. Previous work comparing natural killer cell stimulation by K562 and 721.221 found that they stimulated different frequencies of natural killer cell functional subsets. We hypothesized that natural killer cell function following K562, 721.221 or CEM.NKr.CCR5 stimulation reflected differences in the expression of ligands for activating natural killer cell receptors. K562 expressed a higher intensity of ligands for Natural Killer G2D and the Natural Cytotoxicity Receptors, which are implicated in triggering natural killer cell cytotoxicity. 721.221 cells expressed a greater number of ligands for activating natural killer cell receptors. 721.221 expressed cluster of differentiation 48, 80 and 86 with a higher mean fluorescence intensity than did K562. The only ligands for activating receptor that were detected on CEM.NKr.CCR5 cells at a high intensity were cluster of differentiation 48, and intercellular adhesion molecule-2. The ligands expressed by K562 engage natural killer cell receptors that induce cytolysis. This is consistent with the elevated contribution that the cluster of differentiation 107a function makes to total K562 induced natural killer cell functionality compared to 721.221 cells. The ligands expressed on 721.221 cells can engage a larger number of activating natural killer cell receptors, which may explain their ability to activate a larger frequency of these cells to become functional and secrete cytokines. The few ligands for activating natural killer cell receptors expressed by CEM.NKr.CCR5 may reduce their ability to activate natural killer cells in an antibody independent manner explaining their relative resistance to direct natural killer cell cytotoxicity.

    更新日期:2019-11-28
  • Active immunization with norovirus P particle-based amyloid-β chimeric protein vaccine induces high titers of anti-Aβ antibodies in mice
    BMC Immunol. (IF 2.186) Pub Date : 2019-02-12
    Ping Yang; Yongqing Guo; Yao Sun; Bin Yu; Haihong Zhang; Jiaxin Wu; Xianghui Yu; Hui Wu; Wei Kong

    Active immunotherapy targeting amyloid-β (Aβ) is a promising treatment for Alzheimer’s disease (AD). Numerous preclinical studies and clinical trials demonstrated that a safe and effective AD vaccine should induce high titers of anti-Aβ antibodies while avoiding the activation of T cells specific to Aβ. An untagged Aβ1–6 chimeric protein vaccine against AD based on norovirus (NoV) P particle was expressed in Escherichia coli and obtained by sequential chromatography. Analysis of protein characteristics showed that the untagged Aβ1–6 chimeric protein expressed in soluble form exhibited the highest particle homogeneity, with highest purity and minimal host cell protein (HCP) and residual DNA content. Importantly, the untagged Aβ1–6 chimeric soluble protein could induce the strongest Aβ-specific humoral immune responses without activation of harmful Aβ-specific T cells in mice. The untagged Aβ1–6 chimeric protein vaccine is safe and highly immunogenic. Further research will determine the efficacy in cognitive improvement and disease progression delay.

    更新日期:2019-11-28
  • Patients with idiopathic recurrent miscarriage have abnormally high TGFß+ blood NK, NKT and T cells in the presence of abnormally low TGFß plasma levels
    BMC Immunol. (IF 2.186) Pub Date : 2019-03-04
    Li Zhu; Mostafa Aly; Ruben Jeremias Kuon; Bettina Toth; Haihao Wang; Hristos Karakizlis; Rolf Weimer; Christian Morath; Eman Ibrahim; Naruemol Ekpoom; Gerhard Opelz; Volker Daniel

    Previously, we demonstrated up-regulated activated CD4+ and CD8+ T lymphocytes as well as up-regulated cytotoxic NK cells in the blood of patients with idiopathic recurrent miscarriage. In the present study, we tried to identify deficiencies in counter-regulating immune mechanisms of these patients. Cytokines were determined in NK cells and in plasma samples of 35 healthy controls, 33 patients with idiopathic recurrent miscarriage, 34 patients with end stage renal disease, 10 transplant patients early and 37 transplant patients late post-transplant using flow-cytometry and luminex. In addition, cytokines were studied in supernatants of cell cultures with peripheral blood mononuclear cells stimulated in-vitro with tumor cell line K562. Patients with idiopathic recurrent miscarriage exhibited the highest absolute cell counts of circulating TGFß1+ NK, NKT and T lymphocytes and the lowest TGFß1 plasma levels of all study groups (for all p < 0.050). In-vitro, peripheral blood mononuclear cells of patients with idiopathic recurrent miscarriage showed high spontaneous TGFß1 production that could not be further increased by stimulation with K562, indicating increased consumption of TGFß1 by activated cells in the cell culture. Moreover, patients with idiopathic recurrent miscarriage had abnormally high IL4+ as well as abnormally high IFNy+ NK cells (p < 0.010) but similar IL10+ NK cell numbers as female healthy controls and showed the lowest plasma levels of IL10, TGFß3, IL1RA, IL1ß, IL5, IL6, IL8, IL17, TNFα, GM-CSF, TPO and VEGF and the highest plasma levels of G-CSF, FGF-basic, CCL3 and CXCL5 as compared to female HC and female transplant recipients (for all p < 0.050). Patients with idiopathic recurrent miscarriage show an activated immune system that can hardly be stimulated further and cannot be efficiently down-regulated by up-regulated TGFß1+ and IL4+ NK, NKT and T lymphocytes which are present concomitantly in these patients. The strongly decreased TGFß and IL10 plasma levels indicate deficient down-regulation and reflect a dysbalance of the immune system in patients with idiopathic recurrent miscarriage. These findings may be relevant for explaining the pathogenesis of idiopathic recurrent miscarriage.

    更新日期:2019-11-28
  • A novel approach reveals that HLA class 1 single antigen bead-signatures provide a means of high-accuracy pre-transplant risk assessment of acute cellular rejection in renal transplantation
    BMC Immunol. (IF 2.186) Pub Date : 2019-04-27
    Nicole Wittenbrink; Sabrina Herrmann; Arturo Blazquez-Navarro; Chris Bauer; Eric Lindberg; Kerstin Wolk; Robert Sabat; Petra Reinke; Birgit Sawitzki; Oliver Thomusch; Christian Hugo; Nina Babel; Harald Seitz; Michal Or-Guil

    Acute cellular rejection (ACR) is associated with complications after kidney transplantation, such as graft dysfunction and graft loss. Early risk assessment is therefore critical for the improvement of transplantation outcomes. In this work, we retrospectively analyzed a pre-transplant HLA antigen bead assay data set that was acquired by the e:KID consortium as part of a systems medicine approach. The data set included single antigen bead (SAB) reactivity profiles of 52 low-risk graft recipients (negative complement dependent cytotoxicity crossmatch, PRA < 30%) who showed detectable pre-transplant anti-HLA 1 antibodies. To assess whether the reactivity profiles provide a means for ACR risk assessment, we established a novel approach which differs from standard approaches in two aspects: the use of quantitative continuous data and the use of a multiparameter classification method. Remarkably, it achieved significant prediction of the 38 graft recipients who experienced ACR with a balanced accuracy of 82.7% (sensitivity = 76.5%, specificity = 88.9%). The resultant classifier achieved one of the highest prediction accuracies in the literature for pre-transplant risk assessment of ACR. Importantly, it can facilitate risk assessment in non-sensitized patients who lack donor-specific antibodies. As the classifier is based on continuous data and includes weak signals, our results emphasize that not only strong but also weak binding interactions of antibodies and HLA 1 antigens contain predictive information. ClinicalTrials.gov NCT00724022 . Retrospectively registered July 2008.

    更新日期:2019-11-28
  • Immunoglobulin G responses against falciparum malaria specific antigens are higher in children with homozygous sickle cell trait than those with normal hemoglobin
    BMC Immunol. (IF 2.186) Pub Date : 2019-04-27
    George Msema Bwire; Mtebe Majigo; Robert Makalla; Lillian Nkinda; Akili Mawazo; Mucho Mizinduko; Julie Makani

    High Immunoglobulin G (IgG) response to Plasmodium falciparum antigens is associated with partial malaria protection in sickle hemoglobin (HbS) children. However, this response has been more studied in children with heterozygous sickle cell trait (HbAS) but little explored in those with homozygous sickle cell trait (HbSS). The current study was conducted to determine the IgG responses against specific Plasmodium falciparum antigens in children with homozygous sickle cell trait (HbSS) by comparing to those with normal hemoglobin (HbAA). A cross sectional study was conducted between April and July 2018 in Dar es Salaam tertiary hospitals. Parents were consented for their child to give about 5 ml of venous blood. IgG concentration from the blood plasma of 220 children (110 HbAA vs. 110 HbSS) were determined using indirect Enzyme Linked Immunosorbent Assay (ELISA). Then IgG medians were compared between the groups with prism 5 software (GraphPad) using Mann Whitney U test. Where the differences in age, hemoglobin levels and body weight between the groups was analyzed using independent sample t test. Multiple linear regressions were used to control cofounding variables such as body weight, age and hemoglobin level using statistical package for social sciences software (SPSS version 23). P value <0.05 was considered statistically significant. The median IgG concentration to PfEBA-175, Pfg27, yPfs28C antigens were HbSS; 20.7 ng/ml (IQR; 18.1–25.6) vs. HbAA; 2.3 ng/ml (IQR; 1.21–3.04), HbSS; 2.76 ng/ml (IQR: 2.08–5.69) vs. HbAA; 1.36 ng/ml (IQR: 1.28–1.76), and HbSS; 26,592 ng/ml (IQR: 10817–41,462) vs. HbAA; 14,164 ng/ml (IQR; 3069–24,302) respectively (p < 0.0001 for all IgG). In both groups; age, body weight and hemoglobin level had no impact on the levels of IgG responses to Plasmodium falciparum antigens except for HbAA group which showed a significant increase in IgG against Pfg27 by 0.004 ng/ml with 1 g/dl increase in Hb level (p = 0.028). This study found significant higher levels of specific Plasmodium falciparum IgG responses in children with homozygous sickle cell trait than those with normal hemoglobin.

    更新日期:2019-11-28
  • Tristetraprolin specifically regulates the expression and alternative splicing of immune response genes in HeLa cells
    BMC Immunol. (IF 2.186) Pub Date : 2019-05-02
    Yafang Tu; Xiongfei Wu; Fengyun Yu; Jianzhong Dang; Juan Wang; Yaxun Wei; Zhitao Cai; Zhipeng Zhou; Wenliang Liao; Lian Li; Yi Zhang

    Tristetraprolin (TTP) is an RNA binding protein that plays a critical role in regulating proinflammatory immune responses by destabilizing target mRNAs via binding to their AU-rich elements (AREs) in the 3′-UTRs of mRNAs. A recent CLIP-seq study revealed that TTP-binding sites are enriched in the intronic regions of RNA. TTP is also a nuclear protein that exhibits putative DNA-binding activity. These features suggested that TTP might regulate gene transcription and/or alternative splicing of pre-mRNAs in the absence of stimulation. To elucidate the regulatory pattern of TTP, we cloned and overexpressed the human TTP-encoding gene, ZFP36, in HeLa cells in the absence of inflammatory stimuli. The transcriptomes of the control and ZFP36-overexpressing cells were sequenced and subjected to analysis and validation. Upon ZFP36 overexpression, the expression of genes associated with innate immunity, including those in the type I interferon signaling pathway and viral response, were specifically upregulated, implying a transcriptional regulatory mechanism associated with the predicted DNA binding activity of TTP. TTP preferentially regulated the alternative splicing of genes involved in the positive regulation of the I-κB/NF-κB cascade and the TRIF-dependent toll-like receptor, MAPK, TNF, and T cell receptor signaling pathways. Our findings indicated that TTP may regulate the immune response via the regulation of alternative splicing and potentially transcription, which greatly expands the current understanding of the mechanisms of TTP-mediated gene regulation.

    更新日期:2019-11-28
  • Identification and characterisation of transient receptor potential melastatin 2 and CD38 channels on natural killer cells using the novel application of flow cytometry
    BMC Immunol. (IF 2.186) Pub Date : 2019-05-10
    Cassandra Balinas; Helene Cabanas; Donald Staines; Sonya Marshall-Gradisnik

    Natural Killer (NK) cells are effector lymphocytes of the innate immune system and are subclassed into CD56BrightCD16Dim/− and CD56DimCD16+ NK cells. Intracellular calcium (Ca2+) is fundamental to regulate a number of intracellular signalling pathways and functions in NK cells, which are essential in mediating their natural cytotoxic function. Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable non-selective cation channel that possesses a critical role in calcium-dependent cell signalling to maintain cellular homeostasis. TRPM2 and CD38 protein surface expression has yet to be determined on NK cells using flow cytometry. Characterisation of TRPM2 has been previously identified by in vivo models, primarily using methods such as genetic remodification, immunohistochemistry and whole cell electrophysiology. The aim of this study was to develop an in vitro methodology to characterise TRPM2 and CD38 surface expression on NK cell subsets using an antibody that has not been previously applied using flow cytometry. At 2 h/1 h, TRPM2 (Fig. 2 A, B, p < 0.05) and TRPM2/CD38 (Fig. 3A, B, p < 0.05) surface expression significantly increased between 1:300 and 1:50 at 2 h/1 h. TRPM2/CD38 surface expression furthermore increased between 1:100 and 1:50 at 2 h/1 h (Fig. 3A, p < 0.05). Interestingly, TRPM2/CD38 surface expression significantly decreased from 1:50 to 1:5 on CD56BrightCD16Dim/− NK cells. These consistent findings highlight that 1:50 is the optimal antibody dilution and threshold to measure TRPM2 and TRPM2/CD38 surface expression on NK subsets. 2 h/1 h was determined as the optimal incubation period to ensure a sufficient timeframe for maximal antibody binding and surface expression. For the first time, we describe an in vitro methodology to characterise TRPM2 and CD38 surface expression on NK cells in healthy participants. Finally, using an antibody that has not been previously applied in flow cytometry, we determined an antibody concentration and incubation time that is robust, rapid and sensitive for the application of flow cytometry.

    更新日期:2019-11-28
  • Clinical and laboratory associations of mannose-binding lectin in 219 adults with IgG subclass deficiency
    BMC Immunol. (IF 2.186) Pub Date : 2019-05-22
    James C. Barton; Jackson C. Barton; Luigi F. Bertoli

    Mannose-binding lectin (MBL) deficiency may increase risk of respiratory tract infection in adults unselected for IgG or IgG subclass levels. In a retrospective study, we sought to determine associations of serum MBL levels with clinical and laboratory characteristics of unrelated non-Hispanic white adults at diagnosis of IgG subclass deficiency (IgGSD). We computed the correlation of first and second MBL levels expressed as natural logarithms (ln) in a patient subgroup. We compared these characteristics of all adults with and without MBL ≤50 ng/mL: age; sex; body mass index; upper/lower respiratory tract infection; diabetes; autoimmune condition(s); atopy; other allergy; corticosteroid therapy; and subnormal serum IgG subclasses, IgA, and IgM. We performed logistic regression on MBL ≤50 ng/mL (dichotomous) using the three independent variables with the lowest values of p in univariate comparisons. There were 219 patients (mean age 51 ± 13 y; 82.5% women). Thirty-six patients (16.4%) had MBL ≤50 ng/mL. Two MBL measurements were available in 14 patients. The median interval between the first and second measurements was 125 d (range 18–1031). For ln-transformed data, we observed adjusted r2 = 0.9675; Pearson correlation coefficient 0.9849; and p < 0.0001. Characteristics of patients with and without MBL ≤50 ng/mL did not differ significantly in univariate comparisons. We performed a regression on MBL ≤50 ng/mL using: subnormal IgM (p = 0.0565); upper respiratory tract infection (p = 0.1094); and body mass index (p = 0.1865). This regression revealed no significant associations. Conclusions: We conclude that the proportion of the present IgGSD patients with serum MBL ≤50 ng/mL is similar to that of healthy European adults. MBL ≤50 ng/mL was not significantly associated with independent variables we studied.

    更新日期:2019-11-28
  • Distinct variations of antibody secreting cells and memory B cells during the course of Kawasaki disease
    BMC Immunol. (IF 2.186) Pub Date : 2019-06-03
    Meng Xu; Yanfang Jiang; Jinghua Wang; Jinxiang Liu; Congcong Liu; Deying Liu; Sirui Yang

    Both antibody secreting cells (ASCs) and memory B cells are essential for the maintenance of humoral immunity. To date, limit studies have focused on the two populations in Kawasaki disease (KD). To address the status of humoral immunity during KD, our current concentration is on the variations of ASCs and memory B cells, as well as their subsets in both acute and remission stages of KD. ASCs were defined as the population with high expressions of CD27 and CD38 among CD3-CD20- lymphocytes. Based on the expression of surface marker CD138 and intracellular marker IgG, ASCs were further divided into two subsets. Memory B cells were characterized by the expressions of IgD, CD27 and IgM, upon which memory B cells were further categorized into CD27 + IgD- (switched memory, Sm), CD27-IgD- (Double negative, DN) and CD27 + IgD + IgM+ (marginal zone, MZ) B cells. Collectively, six populations were analyzed using flow cytometry. The blood samples were collected from KD patients in different stages and healthy controls. In the acute stage, the percentages of ASCs, CD138+ ASCs, and IgG+ ASCs were significantly increased. In contrast, the percentages of memory B cells including Sm and MZ B cells were significantly decreased. Correlation analysis found ASCs positively correlated with the level of serum IgM, whereas MZ B cells not only positively correlated with the level of serum IgG, IgA, and IgM, but also positively correlated with the level of serum complement C3 and C4 and negatively correlated with the value of C-reactive protein (CRP). In the remission stage, the percentages of IgG+ ASCs and MZ B cells were significantly reduced, whereas other subsets presented heterogeneous variations. Our study provided direct evidence that ASCs contributed to the pathogenesis of KD, and it was the first time to describe the variation of memory B cells in this disease. Among the subsets, only IgG+ ASCs presented a significant increase in the acute stage and decreased after IVIG administration, indicating the involvement of IgG+ ASCs in the inflammation of KD and also suggesting that IVIG played an inhibitory role in the expression of cytoplasmic IgG.

    更新日期:2019-11-28
  • Soluble CD14 subtype (sCD14-ST) as biomarker in neonatal early-onset sepsis and late-onset sepsis: a systematic review and meta-analysis
    BMC Immunol. (IF 2.186) Pub Date : 2019-06-03
    Iris van Maldeghem; Charlotte M. Nusman; Douwe H. Visser

    Early diagnosis of bacterial sepsis in neonates is hampered by non-specific symptoms and the lack of rapid responding laboratory measures. The biomarker soluble CD14 subtype (sCD14-ST) seems promising in the diagnostic process of neonatal sepsis. In order to evaluate the differences in diagnostic accuracy of sCD14-ST between early onset sepsis (EOS) and late onset sepsis (LOS) we assessed this systematic review and meta-analysis. Twelve articles were included in the systematic review and 10 in the meta-analysis. There was a high risk of bias on patient selection, index test and/or flow and timing. The overall quality of the included studies was moderate. At sepsis onset a consequently higher level of sCD14-ST was found in septic neonates compared to healthy controls with significant higher levels in LOS compared to EOS. In the first 24 h after sepsis onset a significant increase in pooled means of plasma sCD14-ST levels was seen in EOS (t(71.6) = 7.3, p < .0001) while this was not seen in LOS or healthy controls. Optimal cut-off values ranged from 305 to 672 ng/l for EOS cases versus healthy controls. The pooled sensitivity was 81% (95%CI: 0.76–0.85), the pooled specificity was 86% (0.81–0.89) with an AUC of 0.9412 (SE 0.1178). In LOS optimal cut-off values ranged from 801 to 885 ng/l with a pooled sensitivity of 81% (0.74–0.86) and a pooled specificity of 100% (0.98–1.00). An AUC and SROC was not estimable in LOS because of the low number of studies. sCD14-ST is a promising and rapid-responding diagnostic biomarker for EOS and LOS. The difference in pooled means between EOS and LOS underlines the importance to consider EOS and LOS as two different disease entities, requiring separate analysis in original articles and systematic reviews.

    更新日期:2019-11-28
  • Similar immune mechanisms control experimental airway eosinophilia elicited by different allergens and treatment protocols
    BMC Immunol. (IF 2.186) Pub Date : 2019-06-04
    Evelyn J. Hyde; Kirsty A. Wakelin; Naomi J. Daniels; Sayani Ghosh; Franca Ronchese

    Mouse models have been extremely valuable in identifying the fundamental mechanisms of airway inflammation that underlie human allergic asthma. Several models are commonly used, employing different methods and routes of sensitisation, and allergens of varying clinical relevance. Although all models elicit similar hallmarks of allergic airway inflammation, including airway eosinophilia, goblet cell hyperplasia and cellular infiltration in lung, it is not established whether they do so by involving the same mechanisms. We compared the impact of inactivation of various innate or adaptive immune genes, as well as sex, in different models of allergic airway inflammation in mice of C57BL/6 background. Chicken ovalbumin (OVA) and house dust mite (HDM) were used as allergens in settings of single or multiple intranasal (i.n.) challenges, after sensitisation in adjuvant or in adjuvant-free conditions. Eosinophil numbers in the broncho-alveolar lavage and lung histopathology were assessed in each model. We found that Major Histocompatibility Complex Class II (MHCII) deficiency and lack of conventional CD4+ T cells had the most profound effect, essentially ablating airway eosinophilia and goblet cell hyperplasia in all models. In contrast, Thymic stromal lymphopoietin receptor (TSLPR) deficiency greatly reduced eosinophilia but had a variable effect on goblet cells. CD1d deficiency and lack of Natural Killer T (NKT) cells moderately impaired inflammation in OVA models but not HDM, whereas sex affected the response to HDM but not OVA. Lastly, defective Toll-like receptor (TLR)4 expression had only a relatively modest overall impact on inflammation. All the models studied were comparably dependent on adaptive CD4+ T cell responses and TSLP. In contrast, sex, NKT cells and TLR4 appeared to play subtler and more variable roles that were dependent on the type of allergen and mode of immunization and challenge. These results are consistent with clinical data suggesting a key role of CD4+ T cells and TSLP in patients with allergic asthma.

    更新日期:2019-11-28
  • Longitudinal immunosequencing in healthy people reveals persistent T cell receptors rich in highly public receptors
    BMC Immunol. (IF 2.186) Pub Date : 2019-06-21
    Nathaniel D. Chu; Haixin Sarah Bi; Ryan O. Emerson; Anna M. Sherwood; Michael E. Birnbaum; Harlan S. Robins; Eric J. Alm

    The adaptive immune system maintains a diversity of T cells capable of recognizing a broad array of antigens. Each T cell’s specificity for antigens is determined by its T cell receptors (TCRs), which together across all T cells form a repertoire of millions of unique receptors in each individual. Although many studies have examined how TCR repertoires change in response to disease or drugs, few have explored the temporal dynamics of the TCR repertoire in healthy individuals. Here we report immunosequencing of TCR β chains (TCRβ) from the blood of three healthy individuals at eight time points over one year. TCRβ repertoires of all peripheral-blood T cells and sorted memory T cells clustered clearly by individual, systematically demonstrating that TCRβ repertoires are specific to individuals across time. This individuality was absent from TCRβs from naive T cells, suggesting that the differences resulted from an individual’s antigen exposure history, not genetic background. Many characteristics of the TCRβ repertoire (e.g., diversity, clonality) were stable across time, although we found evidence of T cell expansion dynamics even within healthy individuals. We further identified a subset of “persistent” TCRβs present across all time points. These receptors were rich in clonal and highly public receptors and may play a key role in immune system maintenance. Our results highlight the importance of longitudinal sampling of the immune system, providing a much-needed baseline for TCRβ dynamics in healthy individuals. Such a baseline will improve interpretation of changes in the TCRβ repertoire during disease or treatment.

    更新日期:2019-11-28
  • Lack of the hyaluronan receptor CD44 affects the course of bacterial otitis media and reduces leukocyte recruitment to the middle ear
    BMC Immunol. (IF 2.186) Pub Date : 2019-06-21
    Hyun Woo Lim; Kwang Pak; Arwa Kurabi; Allen F. Ryan

    CD44 is a multifunctional molecule that plays major roles in both leukocyte recruitment and tissue proliferation. Since mucosal hyperplasia and leukocyte infiltration of the middle ear cavity are major features of otitis media, we evaluated the role of CD44 in the pathophysiology and course of this disease in a mouse model of middle ear infection. Expression of genes related to CD44 function were evaluated using gene arrays in wild-type mice. The middle ears of mice deficient in CD44 were inoculated with non-typeable Haemophilus influenzae. Histopathology and bacterial clearance were compared to that seen in wild-type controls. We observed strong up-regulation of CD44 and of genes related to its role in leukocyte extravasation into the middle ear, during the course of acute otitis media. Mice deficient in CD44 exhibited reduced early mucosal hyperplasia and leukocyte recruitment, followed by delayed resolution of infection and persistent inflammation. CD44 plays an important role in OM pathogenesis by altering the mucosal growth and neutrophil enlistment. Targeted therapies based on CD44 could be useful adjuncts to the treatment of middle ear infections.

    更新日期:2019-11-28
  • A comprehensive autoantigen-ome of autoimmune liver diseases identified from dermatan sulfate affinity enrichment of liver tissue proteins
    BMC Immunol. (IF 2.186) Pub Date : 2019-06-26
    Wei Zhang; Jung-hyun Rho; Michael H. Roehrl; Julia Y. Wang

    Autoimmune diseases result from aberrant immune attacks by the body itself. It is mysterious how autoantigens, a large cohort of seemingly unconnected molecules expressed in different parts of the body, can induce similar autoimmune responses. We have previously found that dermatan sulfate (DS) can form complexes with molecules of apoptotic cells and stimulate autoreactive CD5+ B cells to produce autoantibodies. Hence, autoantigenic molecules share a unique biochemical property in their affinity to DS. This study sought to further test this uniform principle of autoantigenicity. Proteomes were extracted from freshly collected mouse livers. They were loaded onto columns packed with DS-Sepharose resins. Proteins were eluted with step gradients of increasing salt strength. Proteins that bound to DS with weak, moderate, or strong affinity were eluted with 0.4, 0.6, and 1.0 M NaCl, respectively. After desalting, trypsin digestion, and gel electrophoresis, proteins were sequenced by mass spectrometry. To validate whether these proteins have been previously identified as autoantigens, an extensive literature search was conducted using the protein name or its alternative names as keywords. Of the 41 proteins identified from the strong DS-affinity fraction, 33 (80%) were verified autoantigens. Of the 46 proteins with moderate DS-affinity, 27 (59%) were verified autoantigens. Of the 125 proteins with weak DS-affinity, 44 (35%) were known autoantigens. Strikingly, these autoantigens fell into the classical autoantibody categories of autoimmune liver diseases: ANA (anti-nuclear autoantibodies), SMA (anti-smooth muscle autoantibodies), AMA (anti-mitochondrial autoantibodies), and LKM (liver-kidney microsomal autoantigens). This study of DS-affinity enrichment of liver proteins establishes a comprehensive autoantigen-ome for autoimmune liver diseases, yielding 104 verified and 108 potential autoantigens. The liver autoantigen-ome sheds light on the molecular origins of autoimmune liver diseases and further supports the notion of a unifying biochemical principle of autoantigenicity.

    更新日期:2019-11-28
  • Macrophage migration inhibitory factor is involved in antineutrophil cytoplasmic antibody-mediated activation of C5a-primed neutrophils
    BMC Immunol. (IF 2.186) Pub Date : 2019-06-27
    Jian Hao; Tiegang Lv; Liping Xu; Mao Ran; Kaili Wu

    C5a is important for antineutrophil cytoplasmic antibody (ANCA)-mediated activation of neutrophils. The present study aimed to assess the role of macrophage migration inhibitory factor (MIF) in ANCA-mediated activation of C5a-primed neutrophils. The effects of MIF on ANCA-mediated neutrophil respiratory burst and degranulation were determined. In addition, the effect of a MIF antagonist on the activation of C5a-primed neutrophils was assessed. MIF treatment resulted in increased membrane proteinase-3 (mPR3) expression on neutrophils and enhanced myeloperoxidase (MPO) amounts in neutrophil culture supernatants. The concentration of MIF was significantly higher in the neutrophils supernatant primed with C5a (negative control: 14.2 ± 1.16 ng/ml; C5a: 45.8 ± 2.8 ng/ml, P < 0.001 vs. negative control; C5a + IgG: 44.8 ± 1.93 ng/ml, P < 0.001 vs. negative control; C5a + MPO-ANCA: 73.0 ± 5.5 ng/ml, P < 0.001 vs. C5a; and C5a + PR3-ANCA: 69.4 ± 5.35 ng/ml, P < 0.001 vs. C5a). MIF primed neutrophils to undergo respiratory burst and degranulation in response to ANCA. Indeed, mean fluorescence intensity (a measure of respiratory burst) was significantly higher in MIF-primed neutrophils activated with MPO-ANCA-positive IgG or PR3-ANCA-positive IgG compared with non-primed neutrophils. Meanwhile, a MIF antagonist reduced oxygen radical production in C5a-primed neutrophils treated with patient-derived ANCA-positive IgG. MIF can prime neutrophils to undergo ANCA-mediated respiratory burst and degranulation. Blocking MIF resulted in reduced ANCA-mediated activation of C5a-primed neutrophils. These findings indicated that the interaction between MIF and C5a may contribute to ANCA-mediated neutrophil activation.

    更新日期:2019-11-28
  • Association of proinflammatory genes expression with serum interleukin 1β and free fatty acids in metabolically healthy and unhealthy abdominally obese individuals: a case-control study
    BMC Immunol. (IF 2.186) Pub Date : 2019-07-04
    Parichehr Amiri; Behzad Baradaran; Maryam Saghafi-Asl; Mahsa Naghizadeh; Dariush Shanehbandi; Nahid Karamzad; Sepideh Zununi Vahed

    Proinflammatory genes are highly expressed in several metabolic disorders associated with obesity. But it is not clarified whether gene expression levels and downstream inflammatory markers are related to the metabolic state or the presence of obesity. Hence, the present study aimed to compare Toll-Like Receptor 2 (TLR2), Myeloid Differentiation Factor 88 (MyD88), and NFĸB mRNA expression levels between metabolically healthy abdominally obese (MHAO) and metabolically unhealthy abdominally obese (MUAO) individuals. We compared mRNA expression levels of the genes as well as serum FFAs and IL-1β in MUAO (n = 36) and MHAO (n = 34) groups. Serum FBS, TG, and HDL-C in addition to systolic and diastolic blood pressure were significantly higher in MUAO than MHAO groups (p < 0.05). The odds of MUAO was significantly decreased with high HDL-C (OR = 0.22, 95%CI: 0.08–0.63) and increased with high FBS (OR = 7.04, 95%CI: 1.42–34.69) and TG (OR = 30.55, 95%CI: 7.48–60.67). There were no significant differences in proinflammatory genes as well as serum FFAs and IL-1β between the two groups. No associations were found between the genes expression and serum markers. However, NFĸB expression was significantly correlated with TLR2 and MyD88 (r = 0.747; p < 0.001). Significant correlations were also noticed between TLR2 and MyD88 expression as well as between serum FFAs and IL-1β in each group (p < 0.001). Serum concentration of IL-1β, FFAs, and mRNA expression levels of TLR2, MyD88, and NFĸB may be resulted from abdominal obesity and not be related to the presence or absence of metabolic health.

    更新日期:2019-11-28
  • Changes of B cell subsets in central pathological process of autoimmune encephalomyelitis in mice
    BMC Immunol. (IF 2.186) Pub Date : 2019-07-08
    Yingqiong Xiong; Shaomin Cheng; Xiaomu Wu; Yue Ren; Xufang Xie

    Multiple sclerosis is a demyelinating and autoimmune disease and its immune response is not fully elucidated. This study was conducted to examine the pathological changes and B cell subsets in experimental autoimmune encephalomyelitis (EAE) mice, and analyze the expression of triosephosphate isomerase (TPI) and GADPH to define the role of B cell subsets in the disease. Female C57BL/6 mice were randomly divided into EAE group (n = 18) and control (n = 18). During the experiments, the weight and nerve function scores were determined. The proportions of B cell subsets in the peripheral blood were measured by flow cytometry. Seven, 18 and 30 days after immunization, the brain and spinal cord tissues were examined for the infiltration of inflammatory cells using hematoxylin-eosin (HE) HE staining and the demyelination using Luxol fast blue staining. The expression of B cell-related proteins was detected immunohistochemistrially and the expression of antigenic TPI and GADPH was analyzed using enzyme-linked immunosorbent assay (ELISA). HE staining showed that mice had more severe EAE 18 d than 7 d after modelling, while the symptoms were significantly relieved at 30 d. The results were consistent with the weight measurements and neural function scores. Immunohistochemistry studies showed that B cells aggregated in the spinal cord, but not much in the brain. Flow cytometry studies showed that there were more B cells in control than in EAE models from day 7 and the difference was narrowed at day 30. The level of plasma cells increased continuously, reached the top at day 21 and obviously declined at day 30. On other hand, the numbers of memory B cells increased gradually over the experimental period. The numbers of plasma and memory B cells were similar between the control and EAE mice. ELISA data revealed that the brain contents of TPI and GAPDH were higher in EAE mice than in control at day 7, while at day 18, the levels were reversed. In the central pathological process of EAE mice, B cells exert role through the mechanism other than producing antibodies and the levels of brain TPI and GADPH are related to the severity of autoimmune induced-damage.

    更新日期:2019-11-28
  • Identification of adjuvants for clinical trials performed with Plasmodium falciparum AMA1 in rabbits
    BMC Immunol. (IF 2.186) Pub Date : 2019-07-30
    Sumera Younis; Bart W. Faber; Clemens H.M. Kocken; Edmond J. Remarque

    In this study, seven adjuvants were compared for use with Plasmodium falciparum DiCo-Apical Membrane Antigen 1 (Pf-DiCo-AMA1), with the aim to identify an ideal adjuvant which yields high antibody titres and potentially broadens the responses in clinical trials. The following adjuvant formulations were evaluated: SE, SE-GLA, Liposomes, Liposomes-GLA, CoVaccine HT™, ImSaVac-P and ImSaVac-P o/w. The study was performed in rabbits, which were immunized with FVO-AMA1 in combination with one of the seven adjuvants. Antibody levels (humoral responses) and functional activity of the antibodies induced against malaria vaccine candidate AMA1 were evaluated. Thus, in this study the ideal adjuvant is expected to induce high functional antibody levels, a long-lived response, and a broad cross-strain activity. AMA1 formulated in all adjuvants was immunogenic. However, the magnitude of the immune responses differed between the seven adjuvants. The highest IgG levels were observed for the CoVaccine HT™ group, this was statistically significant for all four AMA1 variants versus all other adjuvant groups. No differences were observed in the breadth of the humoral response, i.e., increased recognition of AMA1 variants. Also, Growth Inhibition Activity (GIA) for both Plasmodium falciparum strains (FCR3 – homologous to FVO AMA1 protein and NF54 – heterologous to FVO AMA1 protein) were significantly higher in the CoVaccine HT™ group as compared to the other adjuvant groups. In brief, all seven vaccine – adjuvant formulations were immunogenic. The magnitude of the immune responses differed between the seven adjuvants. No statistically significant differences were observed in the breadth of the humoral response, nor in longevity of the response. Nevertheless, AMA1 formulated in CoVaccine HT™ appeared as the best adjuvant for use in clinical trials.

    更新日期:2019-11-28
  • Increased circulating Tfh to Tfr ratio in chronic renal allograft dysfunction: a pilot study
    BMC Immunol. (IF 2.186) Pub Date : 2019-08-05
    Lin Yan; Yamei Li; Yi Li; Xiaojuan Wu; Xianding Wang; Lanlan Wang; Yunying Shi; Jiangtao Tang

    T follicular helper (Tfh) cells play a control role in contribution of B cell differentiation and antibody production. T follicular regulatory (Tfr) cells inhibit Tfh-B cell interaction. To identify whether circulating Tfh (cTfh) and Tfr (cTfr) cells contribute to chronic renal allograft dysfunction (CAD), 67 kidney transplant recipients (34 recipients with CAD, 33 recipients with stable function) were enrolled. The frequency of cTfh and cTfr cells, the level of serum CXCL13 were measured. The frequency of cTfr cells in CAD group was significantly lower than that in stable group (0.31% vs 0.68%, P = 0.002). The cTfh to cTfr ratio in CAD group was significantly higher than that in stable group (55.4 vs 25.3, P = 0.013). Serum CXCL13 in CAD group was significantly higher than stable group (30.4 vs 21.9 ng/ml, P = 0.025). After linear regression analysis, the cTfh to cTfr ratio was an independent risk factor for estimated glomerular filtration rate (eGFR) in recipients (standardized coefficient = − 0.420, P = 0.012). After logistic regression analysis, the cTfh to cTfr ratio was an independent risk factor for CAD (OR = 1.043, 95%CI = 1.004–1.085, P = 0.031). The imbalance between cTfh and cTfr cells contribute to the development of CAD.

    更新日期:2019-11-28
  • CD4+ T cell exhaustion revealed by high PD-1 and LAG-3 expression and the loss of helper T cell function in chronic hepatitis B
    BMC Immunol. (IF 2.186) Pub Date : 2019-08-07
    Yuejiao Dong; Xuefen Li; Lu Zhang; Qiaoyun Zhu; Chunlei Chen; Jiaqi Bao; Yu Chen

    Immune inhibitory receptors play an important role in chronic infections. However, little is known about their role in hepatitis B virus (HBV) infection. Here, we analyzed the relationship between programmed death-1 (PD-1) and lymphocyte activation gene-3 (LAG-3) expression on CD4+ T cells and HBV disease progression. PD-1 and LAG-3 expression was significantly higher on CD4+ T cells from HBV patients than on those from the HCs. In addition, a significant positive correlation was found between the PD-1 and LAG-3 expression levels and the ALT(alanine aminotransferase) level. CD4+ T cell function was inhibited by high PD-1 and LAG-3 levels, and CD4+ T cells with high PD-1 and LAG-3 expression lost the ability to secrete IFN-γ, IL-2 and TNF-α. Furthermore, blockade of the PD-1 and LAG-3 pathways reversed the damage to CD4+ T cell proliferation and cytokine secretion. CD4+ T cell exhaustion during chronic HBV had high PD-1 and LAG-3 expression and the absence of helper T cell cytokines, including IFN-γ, IL-2 and TNF-α. After blocking PD-L1 and LAG-3, CD4+ T cell function in chronic hepatitis B patients was partially restored.

    更新日期:2019-11-28
  • Comprehensive analyses of long non-coding RNA expression profiles by RNA sequencing and exploration of their potency as biomarkers in psoriatic arthritis patients
    BMC Immunol. (IF 2.186) Pub Date : 2019-08-07
    Tao Yue; Mei Ji; Huanru Qu; Mengru Guo; Fengmin Bai; Zhanming Zhang; Weifeng Wang; Xuming Gong; Zhenghua Zhang

    The aim of the current study was to investigate the long non-coding RNA (lncRNA) expression profiles in psoriatic arthritis (PSA) patients by RNA sequencing, and to further explore potential biomarkers that were able to predict PSA risk and activity. LncRNA and mRNA expression profiles in peripheral blood mononuclear cells (PBMC) of 4 PSA patients and 4 normal controls (NCs) were detected by RNA sequencing, followed by comprehensive bioinformatic analyses. Subsequently, 3 top upregulated and 2 top downregulated lncRNAs were chosen for further validation in 93 PSA patients and 93 NCs by quantitative polymerase chain reaction (qPCR) assay. Totally 76 upregulated and 54 downregulated lncRNAs, as well as 231 upregulated and 102 downregulated mRNAs were discovered in PSA patients compared with NCs. Enrichment analyses revealed that they were mostly associated with nucleosome, extracellular exosome and extracellular matrix, and the top enriched pathways were systemic lupus erythematosus (SLE), alcoholism and viral carcinogenesis. qPCR assay showed that lnc-RP11-701H24.7 and lnc-RNU12 were upregulated in PSA patients compared with NCs, and they could predict PSA risk with high area under curves. Besides, lnc-RP11-701H24.7 was positively associated with ESR, SJC, TJC and pain VAS score while lnc-RNU12 was positively correlated with PASI score, CRP and PGA score, implying that both of them were positively correlated with disease activity. Our study facilitates comprehensive understanding of lncRNA expression profiles in PSA pathogenesis, and discovers that lnc-RP11-701H24.7 and lnc-RNU12 might be served as novel biomarkers for PSA risk and activity.

    更新日期:2019-11-28
  • Pneumococcal vaccination responses in adults with subnormal IgG subclass concentrations
    BMC Immunol. (IF 2.186) Pub Date : 2019-08-20
    Antony R. Parker; Markus Skold; Stephen Harding; J. Clayborn Barton; Luigi F. Bertoli; James C. Barton

    We sought to compare Pneumovax®23 responses in adults with subnormal IgG subclass concentrations. We studied adults with normal total IgG, frequent/severe respiratory infection, and subnormal IgG1, IgG3, or IgG1 + IgG3 before and after Pneumovax®23. We defined response as serotype-specific IgG > 1.3 μg/mL and aggregate response as IgG > 1.3 μg/mL for ≥70% of all serotypes tested. We compared patients with and without serotype-specific responses and performed logistic regression on aggregate responses using: age; male sex; body mass index; autoimmune condition(s); atopy; other allergies; subnormal IgGSc immunophenotypes; IgA; and IgM. There were 59 patients (mean age 44 ± 13 (SD) years; 83.1% women). Median days between pre- and post-Pneumovax®23 testing was 33 (range 19–158). The median post-vaccination summated concentration of serotype-specific IgG was higher in patients with subnormal IgG1 than subnormal IgG3 (responders and non-responders). All subnormal IgG1 + IgG3 non-responders responded to serotypes 8, 9 and 26, unlike other non-responders. Subnormal IgG3 responders had lower responses to serotypes 1, 4, 12, 23, 26, and 51. Subnormal IgG3 non-responders had higher responses to serotypes 1, 3, 8, 9, 12, 14, 19, 51, and 56. Response rates decreased with increasing age. Aggregate responders were: subnormal IgG1, 54%; IgG3, 46%; and IgG1 + IgG3, 46%. Regression on aggregate response revealed lower response with male sex (odds ratio 0.09 [95% CI 0.01, 0.77]) and atopy (0.17 [0.03, 0.83]). Serotype-specific IgG responses to Pneumovax®23 were greater in patients with subnormal IgG1 than subnormal IgG3. Male sex and atopy were associated with lower aggregate responses.

    更新日期:2019-11-28
  • Genetic polymorphisms and epigenetic regulation of survivin encoding gene, BIRC5, in multiple sclerosis patients
    BMC Immunol. (IF 2.186) Pub Date : 2019-08-22
    Dariush Rahban; Forogh Mohammadi; Mehdi Alidadi; Taha Ghantabpour; Pedram Abbasi Ghasem Kheyli; Majid Ahmadi

    The persistent the inflammatory condition in multiple sclerosis (MS) may due to the aberrant regulation of the elimination of the pathogenic autoreactive lymphocytes through apoptosis. Survivin, encoded by the BIRC5 gene, has been indicated to be involved in the regulation of apoptosis. This survey intended to investigate the genetic and microRNA mediated regulation of survivin in relapsing-remitting MS (RRMS) disease. It was observed that the C allele (OR = 1.38, 95% CI = 1.05–1.348, P = 0.022) and CC genotype (OR = 1.84, 95% CI = 1.06–3.19; P = 0.029) in the rs9904341 polymorphism increased the disease risk. Furthermore, miR-34a was significantly downregulated (Fold change = 0.41, P = 0.001) in the PBMCs from RRMS subjects. Survivin mRNA expression in PBMCs and serum survivin level were increased in RRMS patients in comparison to the controls. Downregulation of miR-34a was negatively correlated with increased survivin level. Although the genetic polymorphism of BIRC5 gene was associated with the disease risk, miR-34a was suggested to be involved in the regulation of survivin in the RRMS patients.

    更新日期:2019-11-28
  • The predictive role of CD4+ cell count and CD4/CD8 ratio in immune reconstitution outcome among HIV/AIDS patients receiving antiretroviral therapy: an eight-year observation in China
    BMC Immunol. (IF 2.186) Pub Date : 2019-08-28
    Chong-Xi Li; Yu-Ye Li; Li-Ping He; Jing Kou; Jin-Song Bai; Jun Liu; Bo Tian; Li-Juan Cao; Kun-Hua Wang; Yi-Qun Kuang

    The immune reconstitution after initiation of highly active antiretroviral therapy (HAART) among HIV-infected individuals substantially affects patients’ prognosis. However, the dynamic characteristics and predictors of reconstitution outcome remain unclear. In this study, the HIV/AIDS patients with sustained virological suppression (viral load < 50 copies/ml) after HAART were enrolled. The patients were subgrouped into immunological non-responders (INRs) (< 200 cells/μl), immunological inadequate responders (IIRs) (200 ~ 500 cells/μl) and immunological responders (IRs) (> 500 cells/μl) according to the CD4 cell count after two-year HAART. The immune reconstitution data based on the CD4+ and CD8+ cell counts with 8-year follow-up were collected for analysis. The CD4+ cell counts in the immunological responders (IRs) were significantly higher than in the immunological non-responders (INRs) and immunological inadequate responders (IIRs) (P < 0.001). The overall CD4+ cell count and CD4/CD8 ratio in the IRs increased faster than the IIRs and INRs. The CD4+ cell count growth at 0.5 year and 1 year after HAART in the IRs was significantly higher than the IIRs and INRs. The ROC curve demonstrated that 1 year CD4+ cell count had the highest predictive value, with the best cut-off value of 188 cells/μl, the predictive sensitivity was 81.0%, the predictive specificity was 85.2%, false positive rate was 14.8%, false negative rate was 19.0%, positive predictive value (IR) was 63.0%, negative predictive value (INR) was 93.5%. Taken together, our findings suggest that early initiation of HAART can reduce the immune reconstitution failure. The combination of baseline CD4+ cell count and baseline CD4/CD8 ratio may serve as a valid predictor of immune reconstitution prognosis after HAART.

    更新日期:2019-11-28
  • Low dose of IL-2 combined with rapamycin restores and maintains the long-term balance of Th17/Treg cells in refractory SLE patients
    BMC Immunol. (IF 2.186) Pub Date : 2019-09-04
    Chunmiao Zhao; Yanfang Chu; Zhaoyun Liang; Bingying Zhang; Xuxia Wang; Xiaona Jing; Meihua Hao; Yiqi Wang; Jia An; Xingzhe Zhang; Liguang Sun; Junwei Chen

    The development of Systemic lupus erythematosus (SLE) has been associated with the balance of Th17 and Treg cells. IL-2 and rapamycin can influence the populations of both Th17 and Treg cells. However, it is unclear whether low dose of IL-2 and rapamycin can relieve the symptoms of SLE patients and what is the mechanisms. In this study, we aim to analyze the effect of low dose of IL-2 plus rapamycin on the number of Tregs, Th17 cells and the ratio of Th17/Treg cells, as well as to evaluate its therapeutic efficacy in refractory SLE patients. Fifty refractory SLE patients and 70 healthy controls were enrolled and followed up for 24 weeks. We found that compared with HC, the refractory SLE patients had a lower number of Tregs, a similar number of Th17 cells, but an increased ratio of Th17/Treg. After the treatment, the number of Tregs of the patients at 12th and 24th week was significantly increased. While the number of Th17 cells was unchanged, the ratio of Th17/Treg was significantly decreased at both 6 weeks and 24 weeks. After 6, 12 and 24 weeks of treatment, the SLEDAI score was significantly reduced. The prednison dosage at 6th,12th and 24th week post treatment was significantly decreased. Our results support that the reduction of Tregs and the imbalance of Th17/Treg cells were correlated with the occurrence and development of refractory SLE. Low dose of IL-2 combined with rapamycin was able to restore the number of Tregs and the balance of Th17/Treg cells. As a result, this approach was able to induce immune tolerance and promote disease remission, allowing for the reduction in prednisone dosage. ChiCTR-IPR-16009451 Registration date: 2016/10/16

    更新日期:2019-11-28
  • Biological variation of immunological blood biomarkers in healthy individuals and quality goals for biomarker tests
    BMC Immunol. (IF 2.186) Pub Date : 2019-09-14
    Najib Aziz; Roger Detels; Joshua J. Quint; David Gjertson; Timothy Ryner; Anthony W. Butch

    Cytokines, chemokines, adipocytokines, soluble cell receptors, and immune activation markers play an important role in immune responsiveness and can provide prognostic value since they reflect underlying conditions and disease states. This study was undertaken to investigate the components of biological variation for various laboratory tests of blood immunological biomarkers. Estimates of intra-individual coefficient of variation (CVI) and inter-individual coefficient of variation (CVG) were examined for blood immunological biomarkers. Biomarkers with CVI < 10% for both genders were CD3, CD4, and CD8 T-cells, serum levels of soluble cluster of differentiation 14 (sCD14), sCD163, and soluble glycoprotein 130 (sgp130). The CVI for serum levels of adiponectin, interleukin-1 receptor antagonist (IL-1Ra), macrophage inflammatory protein 1 beta (MIP-1β), soluble CD40 Ligand (sCD40L), soluble interleukin-2 receptor alpha (sIL-2Rα), soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor receptor II (sTNF-RII), and tumor necrosis factor alpha (TNF-α) were between 11 and 20%. Biomarkers with CVG < 20% were CD3 T-cell, and serum concentrations of sCD14, sCD40L, and sgp130. The biomarkers with CVG > 40% were adiponectin, IL-1ra, leptin, MIP-1β, sCD163, and sIL-2Rα. The biological variations of biomarkers have important monitoring value for longitudinal investigation and are essential for quality specification of tests that are performed in the laboratory. The CVI was relatively small while CVG was comparatively large and mean values of each biomarker vary between subjects. The individuality of biomarkers significantly influences reference interval values. A majority of the biomarkers in this study had strong individuality and the result of each biomarker should be cautiously interpreted if using established reference interval values. Comparison of a patient’s test result with previous ones may be more useful than the usage of conventional reference values.

    更新日期:2019-11-28
  • Simple propagation method for resident macrophages by co-culture and subculture, and their isolation from various organs
    BMC Immunol. (IF 2.186) Pub Date : 2019-09-18
    Kazushige Ogawa; Mayu Tsurutani; Aya Hashimoto; Miharu Soeda

    Resident macrophages (Mø) originating from yolk sac Mø and/or foetal monocytes colonise tissues/organs during embryonic development. They persist into adulthood by self-renewal at a steady state, independent of adult monocyte inputs, except for those in the intestines and dermis. Thus, many resident Mø can be propagated in vitro under optimal conditions; however, there are no specific in vitro culture methods available for the propagation of resident Mø from diverse tissues/organs. We provided a simple method for propagating resident Mø derived from the liver, spleen, lung, and brain of ICR male mice by co-culture and subculture along with the propagation of other stromal cells of the respective organs in standard culture media and successfully demonstrated the propagation of resident Mø colonising these organs. We also proposed a simple method for segregating Mø from stromal cells according to their adhesive property on bacteriological Petri dishes, which enabled the collection of more than 97.6% of the resident Mø from each organ. Expression analyses of conventional Mø markers by flow cytometry showed similar expression patterns among the Mø collected from the organs. This is the first study to clearly provide a practical Mø propagation method applicable to resident Mø of diverse tissues and organs. Thus, this novel practical Mø propagation method can offer broad applications for the use of resident Mø of diverse tissues and organs.

    更新日期:2019-11-28
  • Enhanced IFN-γ, but not IL-2, response to Mycobacterium tuberculosis antigens in HIV/latent TB co-infected patients on long-term HAART
    BMC Immunol. (IF 2.186) Pub Date : 2019-10-11
    Girmay Desalegn; Aster Tsegaye; Dawit Gebreegziabiher; Abraham Aseffa; Rawleigh Howe

    HIV-infected individuals with latent TB infection are at increased risk of developing active TB. HAART greatly reduces the incidence rate of TB in HIV-infected patients and reconstitutes Mycobacterium tuberculosis (M. tuberculosis)-specific immune response in the first 12 months of therapy. The durability of the anti-mycobacterial immune restoration after a year of HAART however remains less investigated. A cross-sectional study was conducted to evaluate M. tuberculosis-specific functional immune responses in HIV/latent TB co-infected patients who were on HAART for at least 1.5 up to 9 years as compared to HAART-naïve patients. Three-hundred sixteen HIV-infected patients without active TB were screened by tuberculin skin testing for M. tuberculosis infection and peripheral blood mononuclear cells (PBMCs) were isolated from 61 HIV/latent TB co-infected patients (30 HAART-naïve and 31 HAART-treated). IFN-γ and IL-2 ELISPOT as well as CFSE cell proliferation assays were performed after stimulation with M. tuberculosis antigens PPD and ESAT-6. The median frequency of PPD and ESAT-6 specific IFN-γ secreting cells was significantly higher in the HAART-treated patients as compared to HAART-naïve patients, p = 0.0021 and p = 0.0081 respectively. However, there was no significant difference in the median frequency of IL-2 secreting cells responding to PPD (p = 0.5981) and ESAT-6 (p = 0.3943) antigens between HAART-naïve and-treated groups. Both IFN-γ and IL-2 responses were independent of CD4+ T cell count regardless of the HAART status. Notably, the frequency of PPD and ESAT-6 specific IL-2 secreting cells was positively associated with CD4+ T cell proliferation while inversely correlated with duration of HAART, raising the possibility that M. tuberculosis-specific IL-2 response that promote the antigen-specific CD4+ T cell proliferation diminish with time on antiretroviral therapy in HIV/latent TB co-infected patients. This study shows an increased M. tuberculosis-specific IFN-γ, but not IL-2, response in HIV/latent TB co-infected patients with long-term HAART, consistent with only partial immune restoration. Future studies should, therefore, be done to prospectively define the rate and extent to which functional immune responses to M. tuberculosis are restored after long-term HAART.

    更新日期:2019-11-28
  • IgA and IgG antibody detection of mycobacterial antigens in pleural fluid and serum from pleural tuberculous patients
    BMC Immunol. (IF 2.186) Pub Date : 2019-10-17
    Renan Jeremias da Silva; Raquel da Silva Corrêa; Isabela Gama Sardella; Ana Carla de Paulo Mulinari; Thiago Thomaz Mafort; Ana Paula Santos; Rogério Rufino; Luciana Silva Rodrigues; Maria Helena Féres Saad

    A previous study demonstrated pleural fluid (PF) IgA immunodominance for the fused MT10.3:MPT64 protein in pleural tuberculosis (PLTB) cases. However, no clue on the role of IgA and IgG against this and other antigens in PF and serum concerning improved diagnosis is available. Thus, the aim of the present study was to validate PF IgA-MT10.3:MPT64 and evaluate PF and serum IgA and IgG reactivity against this protein, its peptides (F2) and single MPT64, MT10.3 and the PPE59 mycobacterial specific antigens. IgA and IgG ELISA were measured against the antigen in PLTB (n = 29) and other non-TB pleurisy (n = 39) patient samples. The immunodominance of PF IgA-MT10.3:MPT64 was confirmed in PLTB (86.2%) followed by PPE59 (62%), while serum IgA-F2 exhibited 51.7% sensitivity. PF and serum IgG-MT10.3:MPT64 led to 65.5 and 51.7% sensitivity, respectively. However, MT10.3 and MPT64 displayed overall lower sensitivity (≤34.5) for both antibodies. All results at 95% fixed specificity. Combinatory results indicated 93.1% sensitivity for PF IgA-MT10.3:MPT64/−PPE59 and IgA/IgG-MT10.3:MPT64 at 92.3% specificity, followed by IgA-MT10.3:MPT64/−MPT64 or /−F2 (89.6%) without jeopardizing specificity (94.9%). The combinatory results of the PF adenosine deaminase test (ADA) and IgA-MT10.3:MPT64/−F2 demonstrated the highest sensitivity (96.6%), with a specificity of 92.3%. The PF IgA-MT10:MPT64 immune dominance was validated in PLTB, and its combinatory results with PPE59 or MPT64 or F2 antigens as well as with IgG, are reported herein for the first time, improving their potential to assist diagnosis. Combining PF-ADA and IgA-MT10.3:MPT64/−F2 results achieved better accuracy. Moreover, serum IgG, although less accurate, displays potential beyond microbiological tests.

    更新日期:2019-11-28
  • Immune cell infiltration characteristics and related core genes in lupus nephritis: results from bioinformatic analysis
    BMC Immunol. (IF 2.186) Pub Date : 2019-10-21
    Yiling Cao; Weihao Tang; Wanxin Tang

    Lupus nephritis (LN) is a common complication of systemic lupus erythematosus that presents a high risk of end-stage renal disease. In the present study, we used CIBERSORT and gene set enrichment analysis (GSEA) of gene expression profiles to identify immune cell infiltration characteristics and related core genes in LN. Datasets from the Gene Expression Omnibus, GSE32591 and GSE113342, were downloaded for further analysis. The GSE32591 dataset, which included 32 LN glomerular biopsy tissues and 14 glomerular tissues from living donors, was analyzed by CIBERSORT. Different immune cell types in LN were analyzed by the Limma software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis based on GSEA were performed by clusterProfiler software. Lists of core genes were derived from Spearman correlation between the most significant GO term and differentially expressed immune cell gene from CIBERSORT. GSE113342 was employed to validate the association between selected core genes and clinical manifestation. Five types of immune cells revealed important associations with LN, and monocytes emerged as having the most prominent differences. GO and KEGG analyses indicated that immune response pathways are significantly enriched in LN. The Spearman correlation indicated that 15 genes, including FCER1G, CLEC7A, MARCO, CLEC7A, PSMB9, and PSMB8, were closely related to clinical features. This study is the first to identify immune cell infiltration with microarray data of glomeruli in LN by using CIBERSORT analysis and provides novel evidence and clues for further research of the molecular mechanisms of LN.

    更新日期:2019-11-28
  • Foxp3+Helios+ regulatory T cells are associated with monocyte subsets and their PD-1 expression during acute HIV-1 infection
    BMC Immunol. (IF 2.186) Pub Date : 2019-10-24
    Lifeng Liu; Qiuyue Zhang; Peng Chen; Na Guo; Aixin Song; Xiaojie Huang; Wei Xia; Li Li; Christiane Moog; Hao Wu; Bin Su; Tong Zhang

    Helios has been reported to stabilize regulatory T (Treg) suppressive function. Programmed cell death protein 1 (PD-1) expression in three human monocyte subsets modulates immune responses. Recently, our team reported that three monocyte subsets are associated with T helper cell differentiation in HIV-1-infected patients. Until now, the effects of monocyte subsets and their PD-1 expression on Foxp3+Helios+ Treg cells have not been fully characterized, especially during acute HIV-1 infection. The frequency of Foxp3+Helios+CD45RA+ Treg cells is significantly higher in patients with acute HIV-1 infection than those of healthy controls and chronic HIV-1-infected patients undergoing combined antiretroviral therapy. The frequency of Foxp3+Helios+CD45RA+ Treg cells is inversely correlated with CD4 T-cell counts and the CD4/CD8 ratio in chronic HIV-1-infected patients. During acute HIV-1 infection, the frequency of Foxp3+Helios+CD45RA+ Treg cells is inversely correlated with the frequency of the intermediate CD14++CD16+ monocyte subset, but positively correlated with PD-1 expression in both intermediate CD14++CD16+ and non-classical CD14+CD16++ monocyte subsets. In this study, the perturbations of Foxp3+Helios+ Treg cells were characterized, and the association between monocyte subsets and their PD-1 expression and Foxp3+Helios+ Treg cells was evaluated during HIV-1 infection. Our observations provide new evidence of the roles for Foxp3+Helios+ Treg cells and PD-1 expression on monocyte subsets in HIV pathogenesis.

    更新日期:2019-11-28
  • Circulating monocyte subsets in multiple myeloma patients receiving autologous stem cell transplantation – a study of the preconditioning status and the course until posttransplant reconstitution for a consecutive group of patients
    BMC Immunol. (IF 2.186) Pub Date : 2019-11-08
    Ida Marie Rundgren; Elisabeth Ersvær; Aymen Bushra Ahmed; Anita Ryningen; Øystein Bruserud

    Induction therapy of multiple myeloma patients prior to autologous stem cell transplantation has changed from conventional chemotherapy to treatment based on proteasome inhibitors or immunomodulatory drugs. We used flow cytometry to analyze total monocyte and monocyte subset (classical, intermediate and non-classical monocytes) peripheral blood levels before and following auto-transplantation for a consecutive group of myeloma patients who had received the presently used induction therapy. The patients showed normal total monocyte concentrations after induction/stem cell mobilization, but the concentrations of classical monocytes were increased compared with healthy controls. Melphalan conditioning reduced the levels of total CD14+ as well as classical and non-classical monocytes, whereas intermediate monocytes were not affected. Thus, melphalan has a non-random effect on monocyte subsets. Melphalan had a stronger effect on total and classical monocyte concentrations for those patients who had received induction therapy including immunomodulatory drugs. Total monocytes and monocyte subset concentrations decreased during the period of pancytopenia, but monocyte reconstitution occurred before hematopoietic reconstitution. However, the fractions of various monocyte subsets varied considerably between patients. The total level of circulating monocytes is normalized early after auto-transplantation for multiple myeloma, but pre- and post-transplant levels of various monocyte subsets show considerable variation between patients.

    更新日期:2019-11-28
  • Low pre-transplant levels of mannose-binding lectin are associated with viral infections and mortality after haematopoietic allogeneic stem cell transplantation
    BMC Immunol. (IF 2.186) Pub Date : 2019-11-09
    M. Puente; C. Fariñas-Alvarez; A. Moreto; P. Sánchez-Velasco; J. G. Ocejo-Vinyals; M. C. Fariñas

    Mannose-binding lectin (MBL) is a key component of innate immunity. Low serum MBL levels, related to promoter polymorphism and structural variants, have been associated with an increased risk of infection. The aim of this work was to analyse the incidence and severity of infections and mortality in relation to the MBL2 genotype and MBL levels in patients underwent allogeneic haematopoietic stem cell transplantation (Allo-HSCT). This was a prospective cohort study of 72 consecutive patients underwent Allo-HSCT between January 2007 and June 2009 in a tertiary referral centre. Three periods were considered in the patients’ follow-up: the early period (0–30 days after Allo-HSCT), the intermediate period (30–100 days after Allo-HSCT) and the late period (> 100 days after Allo-HSCT). A commercial line probe assay for MBL2 genotyping and an ELISA Kit were used to measure MBL levels. A total of 220 episodes of infection were collected in the 72 patients. No association between donor or recipient MBL2 genotype and infection was found. The first episode of infection presented earlier in patients with pre-transplant MBL levels of < 1000 ng/ml (median 6d vs 8d, p = 0.036). MBL levels < 1000 ng/ml in the pre-transplant period (risk ratio (RR) 2.48, 95% CI 1.00–6.13), neutropenic period (0–30 days, RR 3.28, 95% CI 1.53–7.06) and intermediate period (30–100 days, RR 2.37, 95% CI 1.15–4.90) were associated with increased risk of virus infection. No association with bacterial or fungal disease was found. Mortality was associated with pre-transplant MBL levels < 1000 ng/ml (hazard ratio 5.55, 95% CI 1.17–26.30, p = 0.03) but not with MBL2 genotype. Patients who underwent Allo-HSCT with low pre-transplant MBL levels presented the first episode of infection earlier and had an increased risk of viral infections and mortality in the first 6 months post-transplant. Thus, pre-transplant MBL levels would be important in predicting susceptibility to viral infections and mortality and might be considered a biomarker to be included in the pre-transplantation risk assessment.

    更新日期:2019-11-28
  • The effect of pneumococcal immunization on total and antigen-specific B cells in patients with severe chronic kidney disease
    BMC Immunol. (IF 2.186) Pub Date : 2019-11-12
    Gabrielle Nicole Gaultier; William McCready; Marina Ulanova

    While the 23-valent pneumococcal polysaccharide vaccine (PPV23) is routinely used in Canada and some other countries to prevent pneumococcal infection in adults with chronic kidney disease (CKD), patients develop a suboptimal antibody response to PPV23 due to their immune dysfunction. The 13-valent pneumococcal conjugate vaccine (PCV13) has superior immunogenicity in some categories of immunocompromised adults; however, its effect on the immune response in CKD patients has only been addressed by two recent studies with conflicting results. The effect of PPV23 or PCV13 on B cells in these patients has not been previously studied. We studied the absolute numbers and proportions of B cells and subpopulations in two groups of adult patients with severe CKD pre- and 7 days post-immunization with PCV13: pneumococcal vaccine naïve and previously immunized with PPV23 (over one year ago). PPV23 immunized patients had significantly lower proportions and absolute numbers of class switched memory (CD19 + CD27 + IgM-), as well as lower absolute numbers of IgM memory (CD19 + CD27 + IgM+) and class switched B cells (CD19 + CD27-IgM-) compared to PPV23 naïve patients. Following PCV13 immunization, the differences in absolute numbers of B-cell subpopulations between groups remained significant. The PPV23 immunized group had higher proportions of CD5- B cells along with lower proportions and absolute numbers of CD5+ B cells compared to PPV23 naïve patients both pre- and post-immunization with PCV13. However, previous PPV23 immunization did not have a noticeable effect on the numbers of total IgG or serotype 6B and 14 specific antibody-secreting cells detected 7 days post-immunization with PCV13. Nevertheless, fold increase in anti-serotype 14 IgG concentrations 28 days post-PCV13 was greater in PPV23 naïve than in previously immunized patients. The results suggest that immunization with PPV23 may result in long-term changes in B-cell subpopulations such as increased prevalence of CD5- B cells and decreased prevalence of class switched memory B cells in the peripheral blood. Because previous immunization with PPV23 in patients with CKD is associated with a significant decrease in the total class switched memory B cells in response to subsequent immunization with PCV13, this may reduce PCV13 immunogenicity in the setting of PPV23 followed by PCV13. Registered February 24, 2015 at ClinicalTrials.gov (NCT 02370069).

    更新日期:2019-11-28
  • Subsets of mononuclear phagocytes are enriched in the inflamed colons of patients with IBD
    BMC Immunol. (IF 2.186) Pub Date : 2019-11-12
    Hong Liu; Suryasarathi Dasgupta; Yu Fu; Brandi Bailey; Christian Roy; Eric Lightcap; Benjamin Faustin

    Myeloid cells, especially mononuclear phagocytes, which include monocytes, macrophages and dendritic cells (DC), play vital roles in innate immunity, and in the initiation and maintenance of adaptive immunity. While T cell-associated activation pathways and cytokines have been identified and evaluated in inflammatory bowel disease (IBD) patients (Neurath, Nat Rev Gastroenterol Hepatol 14:269–78, 1989), the role of mononuclear phagocytes are less understood. Recent reports support the crucial role of DC subsets in the development of acute colitis models (Arimura et al., Mucosal Immunol 10:957–70, 2017), and suggest they may contribute to the pathogenesis of ulcerative colitis (UC) by inducing Th1/Th2/Th17 responses (Matsuno et al., Inflamm Bowel Dis 23:1524–34, 2017). We performed in silico analysis and evaluated the enrichment of immune cells, with a focus on mononuclear phagocytes in IBD patient colonic biopsies. Samples were from different gut locations, with different levels of disease severity, and with treatment response to current therapies. We observe enrichment of monocytes, M1 macrophages, activated DCs (aDCs) and plasmacytoid dendritic cells (pDCs) in inflamed tissues from various gut locations. This enrichment correlates with disease severity. Additionally, the same mononuclear phagocytes subsets are among the top enriched cell types in both infliximab and vedolizumab treatment non-responder samples. We further investigated the enrichment of selected DC and monocyte subsets based on gene signatures derived from a DC- and monocyte-focused single cell RNA-seq (scRNA-seq) study (Villani et al., Science 356:eaah4573, 2017), and verified enrichment in both inflamed tissues and those with treatment resistance. Moreover, we validated an increased mononuclear phagocyte subset abundance in a Dextran Sulphate Sodium (DSS) induced colitis model in C57Bl/6 mice representative of chronic inflammation. We conducted an extensive analysis of immune cell populations in IBD patient colonic samples and identified enriched subsets of monocytes, macrophages and dendritic cells in inflamed tissues. Understanding how they interact with other immune cells and other cells in the colonic microenvironment such as epithelial and stromal cells will help us to delineate disease pathogenesis.

    更新日期:2019-11-28
  • Immunogenicity of Del19 EGFR mutations in Chinese patients affected by lung adenocarcinoma
    BMC Immunol. (IF 2.186) Pub Date : 2019-11-13
    Deng Pan; Dapeng Zhou; Weijing Cai; Weibo Wu; Wen Ling Tan; Caicun Zhou; Yanyan Lou

    Mutant peptides presented by cancer cells are superior vaccine candidates than self peptides. The efficacy of mutant K-Ras, P53 and EGFR (Epidermal Growth Factor Receptor) peptides have been tested as cancer vaccines in pancreatic, colorectal, and lung cancers. The immunogenicity of EGFR Del19 mutations, frequent in Chinese lung adenocarcinoma patients, remains unclear. We predicted the HLA binding epitopes of Del19 mutations of EGFR in Chinese lung adenocarcinoma patients with NetMHC software. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the EGFR-reactive IgG in lung cancer patients. Del19 mutations may be presented by multiple HLA Class I molecules, with delE746_A750 presented by 37.5% of Chinese population. For HLA Class II molecules, Del19 mutations of EGFR may be presented by multiple HLA-DRB1 molecules, with delE746_A750 presented by 58.1% of Chinese population. Serum reactivity to wild type EGFR protein was significantly higher in patients with Del19 EGFR mutations than those with EGFR L858R point mutation or with EGFR wild type genotype. These findings suggest that Del19 mutations of EGFR, with an estimated frequency of 40% in Chinese lung adenocarcinoma patients, may serve as unique targets for immunotherapy in Chinese lung cancer patients.

    更新日期:2019-11-28
  • GPR30, but not estrogen receptor-alpha, is crucial in the treatment of experimental autoimmune encephalomyelitis by oral ethinyl estradiol.
    BMC Immunol. (IF 2.186) Pub Date : 2010-04-21
    Melissa A Yates,Yuexin Li,Peter J Chlebeck,Halina Offner

    BACKGROUND Remission of multiple sclerosis during periods of high ovarian hormone secretion (such as pregnancy) has led to a great deal of interest in the potential for estrogens to treat autoimmune disease. Previous work has established that 17beta-estradiol can inhibit onset of experimental autoimmune encephalomyelitis (EAE), while ethinyl estradiol (EE) can reduce the severity of established disease. In the current study, the influence of estrogen receptor-alpha (ERalpha) and the G-protein coupled estrogen receptor (GPR30 or GPER) on EE's ability to treat EAE was explored. RESULTS EE reduced disease severity in wild-type and ERalpha knockout (ERKO) mice, but did not alter disease in the GPR30KO group. Production of anti-inflammatory IL-10 increased in EE-ERKO mice (which showed reduced disease) but not in EE-GPR30KO mice (who did not have improved disease). CONCLUSIONS Differential production of IL-10 following EE treatment in ERKO and GPR30KO animals may be responsible for the distinctly different effects on disease severity. Increased IL-10 in ERKO-EE compared to ERKO-Controls is likely to be an important factor in reducing established disease. The inability of EE to reduce disease in GPR30KO mice indicates an important but still undefined role for GPR30 in regulating immune reactivity.

    更新日期:2019-11-01
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