Cytokines, growth factors and proteases in medium and large vessel vasculitis Clin. Immunol. (IF 3.557) Pub Date : 2019-02-14 Cornelia M. Weyand, Ryu Watanabe, Hui Zhang, Mitsuhiro Akiyama, Gerald J. Berry, Jörg J. Goronzy
Giant cell arteritis and Takayasu arteritis are autoimmune vasculitides that cause aneurysm formation and tissue infarction. Extravascular inflammation consists of an intense acute phase response. Deeper understanding of pathogenic events in the vessel wall has highlighted the loss of tissue protective mechanisms, the intrusion of immune cells into “forbidden territory”, and the autonomy of self-renewing vasculitic infiltrates. Adventitial vasa vasora critically control vessel wall access and drive differentiation of tissue-invasive T cells. Selected T cells establish tissue residency and build autonomous, self-sufficient inflammatory lesions. Pathogenic effector T cells intrude and survive due to failed immune checkpoint inhibition. Vasculitis-sustaining T cells and macrophages provide a broad portfolio of effector functions, involving heterogeneous populations of pro-inflammatory T cells and diverse macrophage subsets that ultimately induce wall capillarization and intimal hyperplasia. Redirecting diagnostic and therapeutic strategies from control of extravascular inflammatory markers to suppression of vascular inflammation will improve disease management.
Elevated kynurenine levels in diffuse cutaneous and anti-RNA polymerase III positive systemic sclerosis Clin. Immunol. (IF 3.557) Pub Date : 2019-02-14 Corrado Campochiaro, Simon Lytton, Svetlana Nihtyanova, Dietmar Fuchs, Voon H. Ong, Christopher P. Denton
Systemic sclerosis (SSc) is a systemic disease characterized by vasculopathy, progressive fibrosis and autoimmune activation. Tryptophan (Trp) metabolism has been linked to altered immune cell function and to malignancy. We have investigated the role of Trp metabolic pathway in SSc measuring serum Trp, Kynurenine (Kyn) and Trp/Kyn ratio in a cohort of 97 SSc patients and 10 healthy controls. Association with disease characteristics was evaluated. We found that Trp levels in SSc patients were significantly lower compared to HCs. We also found that patients with diffuse cutaneous (dcSSc) had lower levels of Trp compared to limited cutaneous (lcSSc). These results were paralleled by higher levels of Kyn found in SSc patients compared to HCs and significantly lower levels in dcSSc compared to lcSSc. The autoantibody profile was also found to be significantly associated with Kyn and Trp levels as anti-RNA-polymerase III (ARA) positive patients were shown to have lower Trp levels and higher Kyn levels compared with anti-centromere and anti-topoisomerase I positive patients. Moreover, the highest Trp/Kyn was found in ARA+ patients with dcSSc, suggesting that an activation of the Kyn pathway, is more specifically associated with this subset of SSc patients. Stability over time makes these markers of Trp metabolism feasible for SSc stratification.
BCG-induced formation of neutrophil extracellular traps play an important role in bladder cancer treatment Clin. Immunol. (IF 3.557) Pub Date : 2019-02-13 Kangkang Liu, Erlin Sun, Mingde Lei, Limin Li, Jingda Gao, Xuewu Nian, Lining Wang
Bacillus Calmette-Guerin (BCG) is one of the most effective treatments for bladder cancer. Little attention has been paid to the possible role of neutrophils in BCG immunotherapy. In this study, we examined neutrophil extracellular traps (NETs) formation induced by BCG stimulation, and found that BCG-induced NETs exerted cytotoxicity, induced apoptosis and cell-cycle arrest, and inhibited migration in bladder tumor cells. BCG-activated tumor cells but not non-activated ones elicited NETs formation, in which IL-8 and TNF-α from activated tumor cells both took effect. Moreover, NETs activated peripheral blood mononuclear cells (PBMCs) exhibited a higher expression of CD4 and Th1 cytokines. Additionally, the role of NETs in vivo contributed to the recruitment of T cells and monocytes-macrophages and tissue damage, thus preventing tumor growth. NETs proteins mainly caused these effects on tumor and cellular immunity. In conclusion, we demonstrated a novel immunoregulatory role for NETs in the early stages of BCG immunotherapy.
CD25 deficiency: A new conformational mutation prevents the receptor expression on cell surface Clin. Immunol. (IF 3.557) Pub Date : 2019-02-08 Marina Vignoli, Sara Ciullini Mannurita, Antonella Fioravanti, Manuela Tumino, Alessia Grassi, Graziella Guariso, Claudio Favre, Mario M. D'Elios, Eleonora Gambineri
CD25 deficiency is a very rare autosomal recessive disorder that shows a clinical phenotype highly overlapping IPEX syndrome with an increased susceptibility to viral, bacterial, and fungal infections. It is due to mutations in the IL2Rα gene that codes for the α subunit of the IL2 receptor complex.Here we report the characterization of a novel IL2Rα gene mutation leading to a severe protein conformational alteration that abrogates its cell surface expression in a child presenting with early-onset IPEX-like disorder. Cytofluorimetric analysis revealed the total absence of CD25 cell surface expression and addressed IL2Rα molecular investigation.The early clinical and molecular diagnosis of CD25 deficiency in this patient promptly led to hematopoietic stem cell transplantation (HSCT), allowing complete resolution of the symptoms and definitive cure of the disease.
Genetic and inflammatory factors associated with psoriatic arthritis: Relevance to diagnosis and management Clin. Immunol. (IF 3.557) Pub Date : 2019-02-06 Daniel E. Furst, Jennifer Belasco, James S. Louie
Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory musculoskeletal condition with complex pathophysiology. In recent years, understanding of the pathogenesis of PsA has improved substantially. Several genetic and inflammatory factors have been identified and studied as targets for new biologic disease-modifying therapies. This review presents findings from a detailed literature assessment conducted to identify genes and biomarkers associated with PsA and its most common comorbidities. This literature assessment identifies genes and biomarkers that may be predictive of the onset and severity of PsA, places them in the context of our understanding of PsA pathogenesis, and explores potential connections between the pathways involved in PsA and current biologic therapeutics used to treat PsA. Knowledge of the genetics and inflammatory factors associated with disease pathogenesis can support the targeted development of new biologic therapies and biomarkers for PsA.
Immune aging in diabetes and its implications in wound healing Clin. Immunol. (IF 3.557) Pub Date : 2019-02-05 J. Moura, P. Madureira, E.C. Leal, A.C. Fonseca, E. Carvalho
Immune systems have evolved to recognize and eliminate pathogens and damaged cells. In humans, it is estimated to recognize 109 epitopes and natural selection ensures that clonally expanded cells replace unstimulated cells and overall immune cell numbers remain stationary. But, with age, it faces continuous repertoire restriction and concomitant accumulation of primed cells. Changes shaping the aging immune system have bitter consequences because, as inflammatory responses gain intensity and duration, tissue-damaging immunity and inflammatory disease arise. During inflammation, the glycolytic flux cannot cope with increasing ATP demands, limiting the immune response's extent. In diabetes, higher glucose availability stretches the glycolytic limit, dysregulating proteostasis and increasing T-cell expansion. Long-term hyperglycemia exerts an accumulating effect, leading to higher inflammatory cytokine levels and increased cytotoxic mediator secretion upon infection, a phenomenon known as diabetic chronic inflammation. Here we review the etiology of diabetic chronic inflammation and its consequences on wound healing.
Caspse-11-GSDMD pathway is required for serum ferritin secretion in sepsis Clin. Immunol. (IF 3.557) Pub Date : 2019-02-05 Dan Wang, Songlin Yu, Yening Zhang, Lingmin Huang, Yiting Tang, Kai Zhao, Ben Lu
Ferritin is the major iron storage molecule of vertebrates, which can be detected in serum under numerous conditions, including inflammatory, neurodegenerative, and malignant diseases. Given this character, serum ferritin is frequently used as a biomarker in clinical settings. How the ferritin secreted to the serum has attracted much attention. Although some studies have found ferritin was mediated via the endoplasmic reticulum (ER)-Golgi secretion pathway or secretory lysosomes trafficking pathway under normal conditions, the secretion pathway of ferritin under pathological conditions, especially in sepsis is not very clear. In this report, we adopt a murine sepsis model to study the secretion pathway of ferritin in sepsis. We demonstrated caspase-11-GSDMD pathway and associated pyroptosis are required for secretion of ferritin in vitro and in vivo in sepsis. Moreover, our work connects pyroptosis to serum ferritin secretion and suggests a passive release process of ferritin, enhancing our understanding of the mechanism of ferritin secretion.
HLA- and genotype-based risk assessment model to identify infantile onset pompe disease patients at high-risk of developing significant anti-drug antibodies (ADA) Clin. Immunol. (IF 3.557) Pub Date : 2019-01-31 A.S. De Groot, Z.B. Kazi, R.F. Martin, F.E. Terry, A.K. Desai, W.D. Martin, P.S. Kishnani
In Pompe disease, anti-drug antibodies (ADA) to acid alpha-glucosidase (GAA) enzyme replacement therapy contribute to early mortality. Assessing individual risk for ADA development is notoriously difficult in (CRIM-positive) patients expressing endogenous GAA. The individualized T cell epitope measure (iTEM) scoring method predicts patient-specific risk of developing ADA against therapeutic recombinant human GAA (rhGAA) using individualized HLA-binding predictions and GAA genotype. CRIM-negative patients were six times more likely to develop high ADA titers than CRIM-positive patients in this retrospective study, whereas patients with high GAA-iTEM scores were 50 times more likely to develop high ADA titers than patients with low GAA-iTEM scores. This approach identifies high-risk IOPD patients requiring immune tolerance induction therapy to prevent significant ADA response to rhGAA leading to a poor clinical outcome and can assess ADA risk in patients receiving replacement therapy for other enzyme or blood factor deficiency disorders.
Precursor B-cell development in bone marrow of Good syndrome patients Clin. Immunol. (IF 3.557) Pub Date : 2019-01-25 Lucía del Pino Molina, Marjolein Wentink, Marcel van Deuren, Martin van Hagen, C.I. Edvard Smith, Mirjam van der Burg
Good syndrome is an immunodeficiency presenting with thymoma, hypogammaglobulinemia and almost absent B cells. To investigate the origin of the B-cell lymphopenia in these patients, we studied B cell differentiation in the bone marrow of Good syndrome patients. We found very low numbers of precursor B cells in bone marrow of Good syndrome patients and a differentiation arrest after the pro-B-cell stage; this is different from other agammaglobulinemia patients with a defect in pre B-cell receptor signaling.
Hydroxyfasudil alleviates demyelination through the inhibition of MOG antibody and microglia activation in cuprizone mouse model Clin. Immunol. (IF 3.557) Pub Date : 2019-01-17 Jing Wang, Ruo-Xuan Sui, Qiang Miao, Qing Wang, Li-Juan Song, Jie-Zhong Yu, Yan-Hua Li, Bao-Guo Xiao, Cun-Gen Ma
Dissecting alterations in human CD8+ T cells with aging by high-dimensional single cell mass cytometry Clin. Immunol. (IF 3.557) Pub Date : 2019-01-16 Min Sun Shin, Kristina Yim, Kevin Moon, Hong-Jai Park, Subhasis Mohanty, Joseph W. Kim, Ruth R. Montgomery, Albert C. Shaw, Smita Krishnaswamy, Insoo Kang
We investigated the effect of aging on the multi-dimensional characteristics and heterogeneity of human peripheral CD8+ T cells defined by the expression of a set of molecules at the single cell level using the recently developed mass cytometry or Cytometry by Time-Of-Flight (CyTOF) and computational algorithms. CD8+ T cells of young and older adults had differential expression of molecules, especially those related to cell activation and migration, permitting the clustering of young and older adults through an unbiased approach. The changes in the expression of individual molecules were collectively reflected in the altered high-dimensional profiles of CD8+ T cells in older adults as visualized by the dimensionality reduction analysis tools principal component analysis (PCA) and t-distributed stochastic neighbor embedding (t-SNE). A combination of PhenoGraph clustering and t-SNE analysis revealed heterogeneous subsets of CD8+ T cells that altered with aging. Furthermore, intermolecular quantitative relationships in CD8+ T cells appeared to change with age as determined by the computational algorithm conditional-Density Resampled Estimate of Mutual Information (DREMI). The results of our study showed that heterogeneity, multidimensional characteristics, and intermolecular quantitative relationships in human CD8+ T cells altered with age, distinctively clustering young and older adults through an unbiased approach.
In seroconverted rheumatoid arthritis patients a multi-reactive anti-herpes IgM profile is associated with disease activity Clin. Immunol. (IF 3.557) Pub Date : 2019-01-11 Regina V. Larionova, Marina I. Arleevskaya, Olga A. Kravtsova, Shamil Validov, Yves Renaudineau
Conflicting results have been reported regarding human herpes virus (HHV) reactivation in patients with rheumatoid arthritis (RA). To explore this link, 74 RA patients were selected and compared to 42 first degree relatives (FDR) from probands with RA and 25 healthy controls from the Tatarstan women cohort. The serological analysis was done by testing anti-HSV/CMV/EBV IgM, IgG, plus the IgG avidity index, and completed by evaluating HSV/CMV/EBV DNA by PCR. Results from these analyses reveal: (i) a long lasting infection of HHV in RA, FDR and healthy controls (IgG seroconversion >97%); (ii) an elevated IgM anti-HHV response in seroconverted RA patients which is related to HSV1/2 reactivation (HSV1/2 PCR+); and (iii) a multi-reactive IgM HHV burden profile associated with disease activity (DAS28). In conclusion, HSV1/2 reactivation in seroconverted RA patients is associated with an abnormal anti-HHV immune response, which was reflected in IgM HHV burden, and in activity disease profile.
A novel ATM mutation associated with elevated atypical lymphocyte populations, hyper-IgM, and cutaneous granulomas Clin. Immunol. (IF 3.557) Pub Date : 2019-01-09 Heather Minto, Kofi A. Mensah, Paul R. Reynolds, Eric Meffre, Kira Rubtsova, Erwin W. Gelfand
Ataxia-Telangiectasia (AT) is an immunodeficiency most often associated with T cell abnormalities. We describe a patient with a hyper-IgM phenotype and immune cell abnormalities that suggest a distinct clinical phenotype. Significant B cell abnormalities with increased unswitched memory B cells, decreased naive transitional B cells, and an elevated frequency of CD19+CD38loCD27−CD10−CD21−/low B cells expressing high levels of T-bet and Fas were demonstrated. The B cells were hyporesponsive to in vitro stimulation through the B cell receptor, Toll like receptors (TLR) 7 and 9, and CD40. T cell homeostasis was also disturbed with a significant increase in γδ T cells, circulating T follicular helper cells (Tfh), and decreased numbers of T regulatory cells. The ATM mutations in this patient are posited to have resulted in the perturbations in the frequencies and distributions of B and T cell subsets, resulting in the phenotype in this patient. Key messages A novel mutation creating a premature stop codon and a nonsense mutation in the ATM gene are postulated to have resulted in the unique clinical picture characterized by abnormal B and T cell populations, lymphocyte subset dysfunction, granuloma formation, and a hyper-IgM phenotype. Capsule summary A patient presented with ataxia-telangiectasia, cutaneous granulomas, and a hyper-IgM phenotype; a novel combination of mutations in the ATM gene was associated with abnormal distributions, frequencies, and function of T and B lymphocyte subsets.
A novel monoallelic gain of function mutation in p110δ causing atypical activated phosphoinositide 3-kinase δ syndrome (APDS-1) Clin. Immunol. (IF 3.557) Pub Date : 2019-01-09 Vassilios Lougaris, Manuela Baronio, Daniele Moratto, Giacomo Tampella, Luisa Gazzurelli, Mattia Facchetti, Baldasssarre Martire, Fabio Cardinale, Francesco Lanzarotto, Maria Pia Bondioni, Vincenzo Villanacci, Bodo Grimbacher, Alessandro Plebani
This study reports on a novel activating p110δ mutation causing adult-onset hypogammaglobulinemia with lymphopenia without the classical presentation of atypical Activated phosphoinositide 3-kinase δ syndrome (ADPS-1), underlining thus the heterogeneous clinical and immunological presentation of p110δ mutated individuals and offers additional data on the role of p110δ in early and late B cell development in humans.
Severe combined immunodeficiency (SCID) presenting in childhood, with agammaglobulinemia, associated with novel compound heterozygous mutations in DCLRE1C Clin. Immunol. (IF 3.557) Pub Date : 2019-01-07 Mikael Sundin, Per Marits, Kim Ramme, Antonios G.A. Kolios, Jakob Nilsson
Severe combined immunodeficiency (SCID) can be caused by deleterious mutations in DCLRE1C, leading to deficient non-homologous end joining by compromising the function of the Artemis protein. This impairs the process of V(D)J recombination of the T- and B-cell receptors and typically results in radiosensitive T−, B−, NK+ SCID presenting during the first months of life. We present a case of a 3-year-old girl with two novel compound heterozygous variants in DCLRE1C (c.58G>C and c.374A>C) that were associated with marked reduced numbers of peripheral T- and B-cells and undetectable total serum IgG. Despite the severe laboratory phenotype, the patient had a normal development, albeit failure to thrive (−2.5 to −3 SD), during her first years of life including day-care attendance at preschool for 1.5 years. After being diagnosed with pneumonia the clinical picture of SCID was recognized and the girl successfully underwent hematopoietic stem-cell transplantation.
High levels of antibodies to citrullinated α-enolase peptide-1 (CEP-1) identify erosions and interstitial lung disease (ILD) in a Chinese rheumatoid arthritis cohort Clin. Immunol. (IF 3.557) Pub Date : 2019-01-03 Yudong Liu, Chenxi Liu, Liubing Li, Fengchun Zhang, Yongzhe Li, Shulan Zhang
We evaluated the clinical performance of anti-CEP-1 in a Chinese rheumatoid arthritis (RA) cohort. A total of 264 subjects were tested, including 101 RA patients, 38 juvenile idiopathic arthritis (JIA) patients, 46 disease control (DC) and 79 healthy controls (HC). The presence of anti-CEP-1 in patients with RA, JIA, DCs and HC were 61.4%, 13.2%, 15.2% and 5.1%, respectively. Anti-CCP2 demonstrated the highest positive likelihood ratio of 10.11 in the diagnosis of RA, followed by RF (8.88) and anti-CEP-1 (5.82). Anti-CEP-1 positive RA patients displayed significantly higher DAS28 compared to anti-CEP-1 negative RA patients (p = .045). Significant associations were identified between anti-CEP-1 and joint erosions at anti-CEP-1 value of >124.78 U/ml (p = .0026) and between anti-CEP-1 and ILD at anti-CEP-1 value of >185.91 U/ml (p = .0222). Our findings indicate that anti-CEP-1 may not be able to replace anti-CCP2 for routine diagnosis for RA, but they may be helpful for subtyping of the disease.
Autoimmunity-associated intronic SNP (rs2281808) detected by a simple phenotypic assay: Unique case or broader opportunity? Clin. Immunol. (IF 3.557) Pub Date : 2018-12-21 Sushmita Sinha, Pranav S. Renavikar, Michael P. Crawford, Jake W. Rodgers, Eva Tsalikian, Michael Tansey, Nitin J. Karandikar
Multiple genome-wide association studies have shown that the single-nucleotide polymorphism (SNP) rs2281808 TT variant, present within the signal regulatory protein gamma (SIRPG) gene, is associated with autoimmune diseases, such as type 1 diabetes. SIRPγ is the only SIRP expressed on T cells. The role of SIRPγ in human T-cells or the effect of the TT variant are poorly understood. In this short report, we demonstrate the rather unusual finding that this intronic SNP is associated with a reduction of SIRPγ expression on T cells, both in healthy subjects as well as patients with type 1 diabetes. Using this information, we propose that a simple flow cytometric detection of SIRPγ could be a potential diagnostic testing approach for the presence of SNP in the appropriate clinical context.
Type I and II interferons commit to abnormal expression of chemokine receptor on B cells in patients with systemic lupus erythematosus Clin. Immunol. (IF 3.557) Pub Date : 2018-12-19 Maiko Yoshikawa, Shingo Nakayamada, Satoshi Kubo, Aya Nawata, Yukihiro Kitanaga, Shigeru Iwata, Kei Sakata, Ma Xiaoxue, Sheau Pey Wang, Kazuhisa Nakano, Kazuyoshi Saito, Yoshiya Tanaka
Memory B cells are increased in systemic lupus erythematosus (SLE) cases, but the qualitative abnormalities and induction mechanism of these cells are unclear. Here, we subclassified B cells by their chemokine receptor expression and investigated their induction mechanism. The peripheral blood of patients with SLE showed higher levels of CXCR5− and CXCR3+ B cells. CXCR5−CXCR3+ B cell levels were elevated in patients with active SLE, which decreased with improving disease conditions. Interferon (IFN)-γ stimulation increased CXCR3 expression, whereas IFN-β stimulation reduced CXCR5 expression in B cells. Furthermore, CXCR5−CXCR3+ B cells were induced by a combination of IFN-β and IFN-γ stimulation. Renal tissue examination of patients with active lupus nephritis confirmed the presence of CD19+CXCR3+ B cells. Collectively, the results revealed qualitative abnormalities accompanying reduced CXCR5 expression via type I IFN and enhanced CXCR3 expression via type II IFN in SLE, suggesting their involvement in B cell infiltration into tissues and inflammatory pathogenesis.
Management of XLP-1 and ITK deficiency: The challenges posed by PID with an unpredictable spectrum of disease manifestations Clin. Immunol. (IF 3.557) Pub Date : 2018-12-17 B. Shadur, O. Abu Zaitoun, A. NaserEddin, E. Even-Or, I. Zaidman, P. Stepensky
The incorporation of next generation sequencing into routine immunological practice has enabled the identification of novel inborn errors of disease, helped define new categories of immune deficiency and extended the clinical spectrum associated with many long-recognised diseases. The family of EBV (Epstein Barr Virus)-sensitive primary immune deficiencies is one such group and in this paper we describe three families: two with X-linked lymphoproliferative disease type-1 (XLP-1) and one with deficiency of Interleukin-2 Inducible T-cell Kinase (ITK). Both diseases have a wide range of clinical manifestations and are united by an exquisite predisposition to EBV, dysgammaglobulinemia, hemophagocytic lymphohistiocytosis, and lymphoma. We detail our approach to diagnosis, treatment, and risk stratification in these diseases where both clinicians and patients must grapple with constant uncertainty.
IgE blockade in autoimmunity: Omalizumab induced remission of bullous pemphigoid Clin. Immunol. (IF 3.557) Pub Date : 2018-12-14 Talia James, Sam Salman, Brittany Stevenson, Christine Bundell, Gavin Kelly, David Nolan, Mina John
Bullous pemphigoid (BP) is a blistering dermopathy and a prototypic antibody-mediated autoimmune disease. Detection of IgG autoantibodies against hemidesmosomal proteins BP180 and/or BP230 are diagnostic and levels can correlate with disease activity. Therapies include corticosteroids and oral immunosuppressants, while intravenous immunoglobulin and rituximab are reserved for treatment resistant cases. Here we describe a patient with severe BP which was refractory to standard first line therapy, intravenous immunoglobulin and rituximab induced depletion of peripheral B cells. Use of the monoclonal anti-IgE antibody omalizumab resulted in rapid resolution of blistering despite ongoing high levels of anti-skin IgG antibodies. To our knowledge this is the first case of BP responsive to omalizumab after failure of rituximab to be reported. This case adds to emerging data on omalizumab as a novel BP treatment as well as providing new evidence of an independent role for autoreactive IgE-mediated inflammation in the formation of BP skin lesions.
The role of synthetic manufactured peptides containing common citrullinated epitopes in rheumatoid arthritis diagnosis Clin. Immunol. (IF 3.557) Pub Date : 2018-12-10 Saeed Darawshe, Abdulla Watad, Nicola L. Bragazzi, Smadar Gertel, Howard Amital
Background: Anti-citrullinated peptide antibodies (ACPA) play an important role in rheumatoid arthritis (RA) diagnosis. In our study, we sought to assess the potential diagnostic value of synthetically manufactured peptides that contain epitopes believed to have a pathogenic role in RA. Methods: Serum samples from RA patients and healthy controls were obtained. Two synthetic peptides were manufactured containing the common epitopes considered to play a pivotal role in the RA pathogenesis including the antigenic epitopes of filaggrin, beta-fibrinogen, collagen, vimentin and enolase. Three different ELISA kits for citrullinated peptides (namely: CCP3, Cit-ME-Vim and Cit-ME-Eno) were tested and compared. To assess the diagnostic value of the three ELISA tests, for each test the optical densities (OD) were recorded. The statistical power of each test was calculated measuring the area under the curve (AUC) corresponding with each peptide. Results: Serum levels of ACPA recognized by the commercial CCP3 in RA and healthy controls were 1.31 ± 0.88 optic density units (ODU) and 0.21 ± 0.11 ODU, respectively. Cit-ME-Vim levels were 0.55 ± 0.46 ODU in RA subjects and 0.17 ± 0.182 ODU in healthy controls whereas Cit-ME-Eno was 0.61 ± 0.65 ODU in RA subjects and 0.22 ± 0.20 ODU in healthy controls. AUC results were as follows: CCP3, 0.89 [95%CI 0.75–0.87]; Cit-ME-Vim, 0.76 [95%CI 0.69–0.82]; Cit-ME-Eno, 0.73 [95%CI 0.65–0.79]. Statistical significance for all results was achieved (p < .0001). Sensitivity values for each kit are as follow: CCP3 70.42%; Cit-ME-Vim 63.38%; Cit-ME-Eno 40.85%, and specificity 91% for all tests. Conclusion: Our study supports the presence of an added value for the Cit-ME-Vim peptides in the diagnosis of RA. Further studies are needed to replicate such findings.
Autoimmune and angiogenic biomarkers in autoimmune atherosclerosis Clin. Immunol. (IF 3.557) Pub Date : 2018-12-10 Emese Balogh, Anita Pusztai, Attila Hamar, Edit Végh, Szilvia Szamosi, György Kerekes, Jennifer McCormick, Monika Biniecka, Sándor Szántó, Gabriella Szűcs, Zoltán Nagy, Ursula Fearon, Douglas J. Veale, Zoltán Szekanecz
Several inflammatory, proteolytic, angiogenic and bone-associated factors play a role in the development of autoimmune, accelerated atherosclerosis in rheumatic diseases. Some of these may serve as biomarkers of vascular pathology and may be useful in the follow-up of vascular damage and outcome. Multi-biomarker profiles rather than a single markers would likely be optimal in this respect.
Microbial transglutaminase: A new potential player in celiac disease Clin. Immunol. (IF 3.557) Pub Date : 2018-12-10 Lerner Aaron, Matthias Torsten
Microbial transglutaminase is heavily used in the food processing industries to improve food qualities. Being a protein's glue, by cross-linking it creates neoepitope complexes that are immunogenic and potentially pathogenic in celiac disease. Despite low sequence identity, it imitates functionally its family member, the endogenous tissue transglutaminase, which is the autoantigen of celiac disease. The present comprehensive review highlights the enzyme characteristics, endogenous and exogenous intestinal sources, its cross-talks with gluten and gliadin, its immunogenicity and potential pathogenicity and risks for the gluten induced conditions. If substantiated, it might represent a new environmental inducer of celiac disease. The present findings might affect nutritional product labeling, processed food additive policies and consumer health education.
Autoimmune interstitial lung disease in Latin-America Clin. Immunol. (IF 3.557) Pub Date : 2018-12-10 F. Vivero, F. Campins, D. Lancellotti, P. Malfante, S. Babini, J. Sebastiani, V. Basso, A. Gaser, J. Enghelmayer, E. Gandara,
Information about the prognosis and natural history of autoimmune interstitial lung diseases (Ai-ILD) is limited. The aim of the study was to evaluate the characteristics of patients diagnosed with Ai-ILD in Latin-America. We conducted an ambispective multicenter cohort study in 25 centers of Argentina, Colombia, and Uruguay between January 2015 and April 2018. Participants were included in the study if they had diagnosis of Ai-ILD performed by a multidisciplinary team. Patients were classified into the following sub-groups: connective tissue disease-associated ILD (ILD-CTD), interstitial pneumonia with autoimmune features (IPAF), and positive antineutrophils cytoplasmatic antibodies associated ILD (ILD-ANCA). All images were reviewed by a blinded thoracic radiologist. Out of the 381 patients included during the study period, 282 (74%; 95% CI; 69.39–78.16) were women. Mean age was 58 years old (DS 16). Three-hundred and twenty-five (85.1%; 95% CI 81.39–88.5) patients were classified as ILD-CTD (rheumatoid arthritis 31%, systemic sclerosis 29%, dermatomyositis 15%). Thirty-six patients were classified as IPAF (9.5%; 95% CI 6.9–12.8), and 13 (3.5%; 95% CI 2–5.75) as ILD-ANCA. Fifty percent of patients (95% CI 45.12–55.43) had a mild decrease of the forced vital capacity at the time of diagnosis. The most common treatment strategy was the combination of steroids and cyclophosphamide (30.1%; 95% CI 25.32–35.34) followed by azathioprine (20,3%; 95% CI 16.32–25.14). In conclusion, to the best of our knowledge, this is the first study to evaluate the characteristics and treatment strategies used in patients affected by Ai-ILD in Latin-America. Future studies should to evaluate the prognosis and impact of current treatment strategies in patients with Ai-ILD.
Relapsing Evans syndrome and systemic lupus erythematosus with antiphospholipid syndrome treated with Bortezomib in combination with plasma exchange Clin. Immunol. (IF 3.557) Pub Date : 2018-12-10 Olga Tkachenko, Sergey Lapin, Alexey Maslyansky, Valentina Myachikova, Liya Mikhailova, Boris Gilburd
Relapsing Evans syndrome (ES) and systemic lupus erythematosus (SLE) with secondary antiphospholipid syndrome (APS) is very rare association. Coexistence of these syndromes is potentially fatal and require high-dose combined immunosuppressive therapy. We describe a case of successful use of Bortezomib and plasma exchange in a patient with ES and APS refractory to standard therapy. Thirty-two-year-old male who presented episodes of relapsing hemolytic anemia, pancytopenia and multiple thrombosis with positive direct and indirect antiglobulin test result, lupus anticoagulant and medium titer of anti-beta-2-glycoprotein 1 and anti-cardiolipin antibodies was diagnosed with ES and SLE with secondary APS. High-dose therapy by steroids and Cyclosporin A were started with temporary improvement. There was also no stable improvement with Rituximab and Cyclophosphamide. Bortezomib in combination with cyclosporine A and plasma exchange was introduced. He had stable improvement in hematological parameters with no evidence of relapse of hemolytic crisis or thrombosis during a follow-up for 1 year.
T cell receptor revision and immune repertoire changes in autoimmune diseases Clin. Immunol. (IF 3.557) Pub Date : 2018-12-10 Xi Jia, Bing Wang, Tianyu Zhai, Qiuming Yao, Qian Li, Jin-an Zhang
Autoimmune disease (AID) is a condition in which the immune system breaks down and starts to attack the body. Some common AIDs include rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus and so forth. The changes in T-cell receptor (TCR) repertoire have been found in several autoimmune diseases, and may be responsible for the breakdown of peripheral immune tolerance. In this review, we discussed the processes of TCR revision in peripheral immune environment, the changes in TCR repertoire that occurred in various AIDs, and the specifically expanded T cell clones. We hope our discussion can provide insights for the future studies, helping with the discovery of disease biomarkers and expanding the strategies of immune-targeted therapy.
The long-term prognostic significance of sarcoidosis-associated pulmonary hypertension – A cohort study Clin. Immunol. (IF 3.557) Pub Date : 2018-12-10 Shmuel Tiosano, Mathilde Versini, Lior Dar Antaki, Liron Spitzer, Yarden Yavne, Abdulla Watad, Omer Gendelman, Doron Comaneshter, Arnon D. Cohen, Howard Amital
Background Sarcoidosis is a multisystem, chronic, progressive, granulomatous disease. Sarcoidosis-associated pulmonary hypertension is a well described, but not common, complication of sarcoidosis. In small scale studies, it has been previously described as manifestation of advanced disease and was found to be associated increased morbidity and mortality. This study sought to assess the long-term prognostic significance of sarcoidosis-associated pulmonary hypertension (SAPH) by using data obtained from a large population-based registry which contains longitudinal follow-up data. Methods Utilizing the records of the largest healthcare provider in Israel, we extracted a cohort consisting of sarcoidosis patients and age-and-sex matched controls. Dates of sarcoidosis registration, pulmonary hypertension and death, as well as anthropometric information and medical comorbidities, were extracted from the database. A multivariate logistic regression model was used to find variables associated with pulmonary hypertension. Cox proportional hazards method and log-rank test were used for survival analysis. Results The cohort included 3993 sarcoidosis patients and 19,856 controls. Pulmonary hypertension was observed among 269 sarcoidosis patients (6.74%) vs. 400 controls (2.01%). Sarcoidosis was found as independently associated with pulmonary hypertension (OR 3.17). After a mean follow-up of 7.49 years (median 7.24, maximum 17.88 years), 710 (17.8%) of the sarcoidosis patients and 2121 (10.7%) of the controls had died. Both sarcoidosis and pulmonary hypertension were found to be significantly associated with an increased risk of all-cause mortality (HR 1.82 and HR 2.31, respectively). Conclusions SAPH is associated with a poor prognosis. Proper screening methods may assess whether early identification and treatment improve life expectancy.
Intravenous Immunoglobulin (IVIG) in the vanguard therapy of Systemic Sclerosis Clin. Immunol. (IF 3.557) Pub Date : 2018-12-10 João Pedro Gomes, Lèlita Santos, Yehuda Shoenfeld
Systemic Sclerosis (SSc) is a rare autoimmune disease that is characterized by a progressive skin fibrosis, an obliteration of the microvasculature and an exaggerated extracellular matrix deposition, which lead to a multisystemic dysfunction. Various pathogenetic mechanisms were described. The lack of a successful therapy make SSc a disease with a poor prognosis. The intravenous immunoglobulin (IVIG) has been used for a long time in different autoimmune diseases, and firstly used in SSc patients in 2000. IVIG has multiple non-specific mechanisms of action and, beyond an impressive improvement in muscle symptoms, a French nationwide cohort demonstrated that IVIG ameliorates the skin disease and systemic inflammation, and helps the daily dose corticosteroid's tapering at the end of the treatment. The benefits on gastrointestinal symptoms of IVIG was reported by a recent English article, in which the patients consistently reported a decrease in the gastro-esophageal reflux disease symptoms and their frequencies. The impact on the lung involvement still remains unclear. One of the advantages of IVIG is its safe profile. Few adverse effects were reported and most of them are mild, and can be managed and usually they do not relapse. Harmful effects were described, but they can be avoid with cautious and judicious use of this therapy.
The loss of tolerance to CHI3L1 – A putative role in inflammatory bowel disease? Clin. Immunol. (IF 3.557) Pub Date : 2018-12-10 Claudia Deutschmann, Dirk Roggenbuck, Peter Schierack
The incidence of inflammatory bowel disease (IBD) is steadily increasing. IBD is characterized by a chronic inflammation of the gastrointestinal tract and is classified into the two main groups Crohn's disease (CD) and ulcerative colitis (UC). Genetic predispositions, environmental factors and a dysregulated immune response are known to part take in the onset of IBD. However, their etiopathogenesis is still not fully understood. In the last decade, there is growing evidence of the involvement of the 18- glycosylhydrolase family member Chitinase-3-like protein 1 (CHI3L1) in IBD. CHI3L1 is associated with various diseases including cancer and chronic inflammatory conditions like rheumatoid arthritis, IBD and even neurological disorders where it can act as a chemotractant, mitogen or growth factor. In this review will focus on the role of autoimmunity to CHI3L1 in IBD in the context of its expression in inflamed colonic epithelia and interaction with intestinal microbiota. It will further provide insight into the interaction of CHI3L1 with different mechanisms of the innate and adaptive immune response in IBD.
A large screen for paraneoplastic neurological autoantibodies; diagnosis and predictive values Clin. Immunol. (IF 3.557) Pub Date : 2018-12-10 Lior Seluk, Alisa Taliansky, Hagith Yonath, Boris Gilburd, Howard Amital, Yehuda Shoenfeld, Shaye Kivity
Background Paraneoplastic neurological syndromes (PNS) are a group of syndromes that affect the central and peripheral neuromuscular system in association with cancer. Specific antibodies may assist in the diagnosis of PNS. The antibodies tested can be classified into those directed against intracellular neuronal proteins (“well characterized” PNS: Hu, Yo, RI, CV2, amphiphysin, Ma1, Ma2) and those directed against neural surface antigens (autoimmune encephalitis syndromes: NMDA, AMPA, LGI1, CASPR2, GABAR). We aimed to characterize patients with unexplained neuropsychiatric symptoms, in whom positive PNS antibodies were detected in the Sheba medical center, a large referral hospital. Methods Clinical and demographic data of patients with positive PNS antibodies were collected during the years 2002–2016. Antibodies were tested by either Line immunoassay or by cell-based indirect immunofluorscent assay. Results During the follow up of 14 years, 4010 PNS tests were performed in patients with unexplained neuropsychiatric symptoms. Seventy-two were found to be positive; among them we had full clinical data access to 44. The most frequent antibodies were anti-Hu (31.8%), anti-Yo (18.2%), anti-CV2 (13.6%), and anti-NMDA (9.1%), and the most common cancers were small-cell lung (SCLC) and ovarian cancers. In the well characterized paraneoplastic group, cancer was diagnosed in 55.9% of the patients, and in the autoimmune encephalitis group, 40.0% were diagnosed with cancer. A positive correlation between antibody titer and the presence of cancer was found. Ninety percent of the tests in patients who were found positive were ordered by a neurologist or neuro-oncologist. Conclusions The titers of PNS auto-antibodies can predict cancer in patients whom anti-PNS antibodies are tested. In addition, consultation with a specialist should be considered before this test is ordered.
Mesenchymal stem cells participate in oral mucosa carcinogenesis by regulating T cell proliferation Clin. Immunol. (IF 3.557) Pub Date : 2018-12-04 Yichen Chen, Xi Wang, Juan Fang, Jingjing Song, Da Ma, Liqun Luo, Bailin He, Juan Xia, Vivian Wai Yan Lui, Bin Cheng, Zhi Wang
Recent evidences suggested that Mesenchymal stem cells (MSCs) may be involved in tumor formation by modulating of the tumor microenvironment, but it is still unclear the potential of MSCs in the malignant transformation of oral mucosa. Using a chemically-induced oral carcinogenesis model by 4-nitroquinoline-1-oxide (4NQO), we generated precancerous lesions and cancerous lesions in the oral cavity of rats. Flow cytometric analysis on lesions derived single cell suspension revealed an increase in the proportion of MSCs and a decreased proportion of T cell during oral mucosa malignancy. Moreover, MSCs showed increased immunosuppression capacity on T cell proliferation during mucosa malignancy. At last, we demonstrated that higher frequency of lesions resident MSCs was correlated with more Ki67 expression in the lesion, which indicated higher cellular proliferative status in the lesions. Our study demonstrated that MSCs may play an important role in oral mucosa malignant transformation through regulating T cell proliferation.
Plasma CXCL13 is a predictive factor for HBsAg loss and clinical relapse after discontinuation of nucleos(t)ide analogue treatment Clin. Immunol. (IF 3.557) Pub Date : 2018-11-30 Muye Xia, Guichan Liao, Hongjie Chen, Yin Wu, Rong Fan, Xiaoyong Zhang, Jie Peng
In this study, we investigated whether plasma cytokine/chemokine levels could predict HBsAg loss or clinical relapse (CR) after stopping nucleos(t)ides analogue (NA) treatment. Theplasma cytokines/chemokines levels were measured at 0, 4, 8, 12, 24 and 48 weeks after NA discontinuation by using the enzyme-linked immunoassay (ELISA) kit. Cox regression analysis revealed that CXCL13 level at the end of treatment (EOT) was an independent predictor for CR (HR 0.26, p < 0.001) and HBsAg loss (HR 3.01, p = 0.008) after treatment cessation. Among the patients with EOT CXCL13 level < 80 pg/ml, the cumulative incidences of CR and HBsAg loss were 65% and 0% at 4 years, respectively. As for the patients with EOT CXCL13 level ≥ 1000 pg/ml, 47.5% cases had HBsAg loss. Our study showed that EOT CXCL13 level was associated with off-treatment response, which may be used to guide cessation of NA treatment in clinical practice.
Reprint of "The interaction between environmental triggers and epigenetics in autoimmunity" Clin. Immunol. (IF 3.557) Pub Date : 2018-11-30 Bruce Richardson
Systemic lupus erythematosus flares when genetically predisposed people encounter environmental agents that cause oxidative stress, such as infections and sunlight. How these modify the immune system to initiate flares is unclear. Drug induced lupus models demonstrate that CD4+ T cells epigenetically altered with DNA methylation inhibitors cause lupus in animal models, and similar T cells are found in patients with active lupus. How infections and sun exposure inhibit T cell DNA methylation is unclear. DNA methylation patterns are replicated each time a cell divides in a process that requires DNA methyltransferase one (Dnmt1), which is upregulated as cells enter mitosis, as well as the methyl donor S-adenosylmethionine, created from dietary sources. Reactive oxygen species that inhibit Dnmt1 upregulation, and a diet poor in methyl donors, combine to cause lupus in animal models. Similar changes are found in patients with active lupus, indicating a mechanism contributing to lupus flares.
Epigenetic editing: How cutting-edge targeted epigenetic modification might provide novel avenues for autoimmune disease therapy Clin. Immunol. (IF 3.557) Pub Date : 2018-02-06 Matlock A. Jeffries
Autoimmune diseases are enigmatic and complex, and most been associated with epigenetic changes. Epigenetics describes changes in gene expression related to environmental influences mediated by a variety of effectors that alter the three-dimensional structure of chromatin and facilitate transcription factor or repressor binding. Recent years have witnessed a dramatic change and acceleration in epigenetic editing approaches, spurred on by the discovery and later development of the CRISPR/Cas9 system as a highly modular and efficient site-specific DNA binding domain. The purpose of this article is to offer a review of epigenetic editing approaches to date, with a focus on alterations of DNA methylation, and to describe a few prominent published examples of epigenetic editing. We will also offer as an example work done by our laboratory demonstrating epigenetic editing of the FOXP3 gene in human T cells. Finally, we discuss briefly the future of epigenetic editing in autoimmune disease.
Mechanistic aspects of epigenetic dysregulation in SLE Clin. Immunol. (IF 3.557) Pub Date : 2018-02-06 Christian Michael Hedrich
Epigenetic events have been linked with disease expression in individuals genetically predisposed to the development of systemic lupus erythematosus (SLE), a severe systemic autoimmune/inflammatory disease. Altered DNA methylation and hydroxymethylation as well as histone modifications mediate changes in chromatin accessibility and gene expression in immune cells from SLE patients. Defective epigenetic control contributes to uncontrolled expression of inflammatory mediators, including cytokines and co-receptors, resulting in systemic inflammation and tissue damage. While the pathophysiological involvement of epigenetic changes in SLE has been accepted for some time, we only recently started to investigate and understand molecular events contributing to epigenetic dysregulation. Here, epigenetic alterations will be discussed with a focus on underling molecular events that may be target of preventative measures or future treatment strategies.
Treatment of antiphospholipid syndrome beyond anticoagulation Clin. Immunol. (IF 3.557) Pub Date : 2018-03-03 Chrisanna Dobrowolski, Doruk Erkan
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder marked by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). At the present time, treatment is primarily focused on anticoagulation. However, there is increasing awareness of the mechanisms involved in APS pathogenesis, which has led to the trial of novel therapies targeting those mechanisms. Following a brief review of the etiopathogenesis of and current management strategies in APS, this paper focuses on the evidence for these potential, targeted APS treatments, e.g., hydroxychloroquine, statins, rituximab, belimumab, eculizumab, defibrotide, sirolimus, and peptide therapy.
Epigenetic interplay between immune, stromal and cancer cells in the tumor microenvironment Clin. Immunol. (IF 3.557) Pub Date : 2018-03-06 Antonio Garcia-Gomez, Javier Rodríguez-Ubreva, Esteban Ballestar
Compelling evidences highlight the critical role of the tumor microenvironment as mediator of tumor progression and immunosuppression in several types of cancer. The reciprocal interplay between neoplastic and non-tumoral host cells is mediated by direct cell-to-cell contact, soluble factors and exosomes that result in differential gene expression patterns that are driven by epigenetic mechanisms. In this regard, extensive literature has described the abnormalities in the DNA methylation status and histone modification profiles in tumor cells. However, little is known about the mechanisms of epigenetic dysregulation that participate as a consequence of the intricate crosstalk among the cells within the tumor niche. This review summarizes the current knowledge on epigenetic changes that result from the interactions between myeloid, stromal and cancer cells in the tumor microenvironment and its functional impact in both tumorigenesis and tumor progression. We also discuss potential niche-specific epigenetic biomarkers to improve the prognosis and clinical treatment of cancer patients.
Biological therapies in inflammatory bowel disease: Beyond anti-TNF therapies Clin. Immunol. (IF 3.557) Pub Date : 2018-03-12 Konstantinos H. Katsanos, Konstantinos Papamichael, Joseph D. Feuerstein, Dimitrios K. Christodoulou, Adam S. Cheifetz
The pharmacological management of inflammatory bowel disease (IBD) over the last two decades has transitioned from reliance on aminosalycilates, corticosteroids and immunomodulators to earlier treatment with anti-tumor necrosis factor (anti-TNF) therapy. Nevertheless, 20–30% of patients discontinue anti-TNF therapy for primary non-response and another 30–40% for losing response within one year of treatment. These undesirable therapeutic outcomes can be attributed to pharmacokinetic (anti-drug antibodies and/or low drug concentrations) or pharmacodynamic issues characterized by a non-TNF driven inflammation. The latter issues necessitate the use of medications with different mechanisms of action. Besides the biologics natalizumab, vedolizumab and ustekinumab that have already been approved for the treatment of IBD new non-anti-TNF therapies are currently under investigation including small molecule drugs against Janus kinase and sphingosine-1-phosphate receptors. This manuscript will review the medications that are in the later stages of development for the treatment of IBD and directed against immune targets other than TNF.
Epigenetics as biomarkers in autoimmune diseases Clin. Immunol. (IF 3.557) Pub Date : 2018-03-21 Haijing Wu, Jieyue Liao, Qianwen Li, Ming Yang, Ming Zhao, Qianjin Lu
Autoimmune diseases are immune system disorders in which immune cells cannot distinguish self-antigens from foreign ones. The current criteria for autoimmune disease diagnosis are based on clinical manifestations and laboratory tests. However, none of these markers shows both high sensitivity and specificity. In addition, some autoimmune diseases, for example, systemic lupus erythematosus (SLE), are highly heterogeneous and often exhibit various manifestations. On the other hand, certain autoimmune diseases, such as Sjogren's syndrome versus SLE, share similar symptoms and autoantibodies, which also causes difficulties in diagnosis. Therefore, biomarkers that have both high sensitivity and high specificity for diagnosis, reflect disease activity and predict drug response are necessary. An increasing number of publications have proposed the abnormal epigenetic modifications as biomarkers of autoimmune diseases. Therefore, this review will comprehensively summarize the epigenetic progress in the pathogenesis of autoimmune disorders and unearth potential biomarkers that might be appropriate for disease diagnosis and prediction.
Epigenome-wide association studies for systemic autoimmune diseases: The road behind and the road ahead Clin. Immunol. (IF 3.557) Pub Date : 2018-03-29 Elena Carnero-Montoro, Marta E. Alarcón-Riquelme
Epigenetics is known to be an important mechanism in the pathogenesis of autoimmune diseases. Epigenetic variations can act as integrators of environmental and genetic exposures and propagate activated states in immune cells. Studying epigenetic alterations by means of genome-wide approaches promises to unravel novel molecular mechanisms related to disease etiology, disease progression, clinical manifestations and treatment responses. This paper reviews what we have learned in the last five years from epigenome-wide studies for three systemic autoimmune diseases, namely systemic lupus erythematosus, primary Sjögren's syndrome, and rheumatoid arthritis. We examine the degree of epigenetic sharing between different diseases and the possible mediating role of epigenetic associations in genetic and environmental risks. Finally, we also shed light into the use of epigenetic markers towards a better precision medicine regarding disease prediction, prevention and personalized treatment in systemic autoimmunity.
Epigenetic alterations in primary Sjögren's syndrome – an overview Clin. Immunol. (IF 3.557) Pub Date : 2018-04-09 Juliana Imgenberg-Kreuz, Johanna K. Sandling, Gunnel Nordmark
Primary Sjögren's syndrome (pSS) is a chronic autoimmune rheumatic disease characterized by inflammation of exocrine glands, mainly salivary and lacrimal glands. In addition, pSS may affect multiple other organs resulting in systemic manifestations. Although the precise etiology of pSS remains elusive, pSS is considered to be a multi-factorial disease, where underlying genetic predisposition, environmental factors and epigenetic mechanisms contribute to disease development. Epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNAs, may constitute a dynamic link between genome, environment and phenotypic manifestation by their modulating effects on gene expression. A growing body of studies reporting altered epigenetic landscapes in pSS suggests that epigenetic mechanisms play a role in the pathogenesis of pSS, and the reversible nature of epigenetic modifications suggests therapeutic strategies targeting epigenetic dysregulation in pSS. This article reviews our current understanding of epigenetic mechanisms in pSS and discusses implications for novel diagnostic and therapeutic approaches.
Immune senescence, epigenetics and autoimmunity Clin. Immunol. (IF 3.557) Pub Date : 2018-04-11 Donna Ray, Raymond Yung
Aging of the immune system in humans and animals is characterized by a decline in both adaptive and innate immune responses. Paradoxically, aging is also associated with a state of chronic inflammation (“inflammaging”) and an increased likelihood of developing autoimmune diseases. Epigenetic changes in non-dividing and dividing cells, including immune cells, due to environmental factors contribute to the inflammation and autoimmunity that characterize both the state and diseases of aging. Here, we review the epigenetic mechanisms involved in the development of immune senescence and autoimmunity in old age.
Oxidative stress and dietary micronutrient deficiencies contribute to overexpression of epigenetically regulated genes by lupus T cells Clin. Immunol. (IF 3.557) Pub Date : 2018-04-11 Donna Ray, Faith M. Strickland, Bruce C. Richardson
Patients with active lupus have altered T cells characterized by low DNA methyltransferase levels. We hypothesized that low DNA methyltransferase levels synergize with low methionine levels to cause greater overexpression of genes normally suppressed by DNA methylation. CD4+ T cells from lupus patients and controls were stimulated with PHA then cultured in custom media with normal or low methionine levels. Oxidative stress was induced by treating the normal CD4+ T cells with peroxynitrite prior to culture. Methylation sensitive gene expression was measured by flow cytometry. Results showed low methionine levels caused greater overexpression of methylation sensitive genes in peroxynitrite treated T cells relative to untreated T cells, and in T cells from lupus patients relative to T cells from healthy controls. In conclusion, low dietary transmethylation micronutrient levels and low DNA methyltransferase levels caused either by oxidative stress or lupus, have additive effects on methylation sensitive T cell gene expression.
CD14+ monocytes contribute to inflammation in chronic nonbacterial osteomyelitis (CNO) through increased NLRP3 inflammasome expression Clin. Immunol. (IF 3.557) Pub Date : 2018-04-30 D. Brandt, E. Sohr, J. Pablik, A. Schnabel, F. Kapplusch, K. Mäbert, J.H. Girschick, H. Morbach, F. Thielemann, S.R. Hofmann, C.M. Hedrich
The pathophysiology of chronic nonbacterial osteomyelitis (CNO) remains incompletely understood. Increased NLRP3 inflammasome activation and IL-1β release in monocytes from CNO patients was suggested to contribute to bone inflammation. Here, we dissect immune cell infiltrates and demonstrate the involvement of monocytes across disease stages. Differences in cell density and immune cell composition may help to discriminate between BOM and CNO. However, differences are subtle and infiltrates vary in CNO. In contrast to other cells involved, monocytes are a stable element during all stages of CNO, which makes them a promising candidate in the search for “drivers” of inflammation. Furthermore, we link increased expression of inflammasome components NLRP3 and ASC in monocytes with site-specific DNA hypomethylation around the corresponding genes NLRP3 and PYCARD. Our observations deliver further evidence for the involvement of pro-inflammatory monocytes in the pathophysiology of CNO. Cellular and molecular alterations may serve as disease biomarkers and/or therapeutic targets.
Association of high 5-hydroxymethylcytosine levels with Ten Eleven Translocation 2 overexpression and inflammation in Sjögren's syndrome patients Clin. Immunol. (IF 3.557) Pub Date : 2018-06-09 Carolina Lagos, Patricia Carvajal, Isabel Castro, Daniela Jara, Sergio González, Sergio Aguilera, María-José Barrera, Andrew F.G. Quest, Verónica Bahamondes, Claudio Molina, Ulises Urzúa, Marcela A. Hermoso, Cecilia Leyton, María-Julieta González
Here, we determined the 5-hydroxymethylcytosine (5hmC), 5-methylcytosine (5mC), Ten Eleven Translocation (TETs), and DNA methyltransferases (DNMTs) levels in epithelial and inflammatory cells of labial salivary glands (LSG) from Sjögren's syndrome (SS)-patients and the effect of cytokines on HSG cells. LSG from SS-patients, controls and HSG cells incubated with cytokines were analysed. Levels of 5mC, 5hmC, DNMTs, TET2 and MeCP2 were assessed by immunofluorescence. In epithelial cells from SS-patients, an increase in TET2, 5hmC and a decrease in 5mC and MeCP2 were observed, additionally, high levels of 5mC and DNMTs and low levels of 5hmC were detected in inflammatory cells. Cytokines increased TET2 and 5hmC and decreased 5mC levels. Considering that the TET2 gene.promoter contains response elements for transcription factors activated by cytokines, together to in vitro results suggest that changes in DNA hydroxymethylation, resulting from altered levels of TET2 are likely to be relevant in the Sjögren's syndrome etiopathogenesis.
Single-cell epigenetics – Chromatin modification atlas unveiled by mass cytometry Clin. Immunol. (IF 3.557) Pub Date : 2018-06-28 Peggie Cheung, Francesco Vallania, Mai Dvorak, Sarah E. Chang, Steven Schaffert, Michele Donato, Aditya M. Rao, Rong Mao, Paul J. Utz, Purvesh Khatri, Alex J. Kuo
Modifications of histone proteins are fundamental to the regulation of epigenetic phenotypes. Dysregulations of histone modifications have been linked to the pathogenesis of diverse human diseases. However, identifying differential histone modifications in patients with immune-mediated diseases has been challenging, in part due to the lack of a powerful analytic platform to study histone modifications in the complex human immune system. We recently developed a highly multiplexed platform, Epigenetic landscape profiling using cytometry by Time-Of-Flight (EpiTOF), to analyze the global levels of a broad array of histone modifications in single cells using mass cytometry. In this review, we summarize the development of EpiTOF and discuss its potential applications in biomedical research. We anticipate that this platform will provide new insights into the roles of epigenetic regulation in hematopoiesis, immune cell functions, and immune system aging, and reveal aberrant epigenetic patterns associated with immune-mediated diseases.
Autosomal Recessive Agammaglobulinemia - first case with a novel TCF3 mutation from Pakistan Clin. Immunol. (IF 3.557) Pub Date : 2018-07-29 Sonia Qureshi, Muhammad Dawood Amir Sheikh, Farah Naz Qamar
Autosomal Recessive Agammaglobulinemia (ARA) is an uncommon type of primary immunodeficiency characterized by mutations in genes responsible for early B cell differentiation and function. One such gene is the TCF3 gene, which encodes a transcription factor important for immunoglobulin gene expression. We present the case of a 9 year old girl with history of diarrhea and recurrent pneumonias. Laboratory investigation showed significantly reduced levels of immunoglobulins along with a significant fall in the number of CD19+ cells. Genetic analysis identified a TCF3 gene base deletion covering exons 5–11.
The role and clinical significance of programmed cell death- ligand 1 expressed on CD19+B-cells and subsets in systemic lupus erythematosus Clin. Immunol. (IF 3.557) Pub Date : 2018-11-28 Xiao-Yun Jia, Qing-qing Zhu, Yuan-Yuan Wang, Yang Lu, Zhi-Jun Li, Bai-Qing Li, Jie Tang, Hong-Tao Wang, Chuan-Wang Song, Chang-Hao Xie, Lin-Jie Chen
Background Programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1)-targeted therapies have enhanced T-cell response and demonstrated efficacy in the treatment of multiple cancers. However, the role and clinical significance of PD-L1 expression on CD19+ B-cells and their subsets, with particular reference to systemic lupus erythematosus (SLE), have not yet been studied in detail. Objective The present study aimed to investigate PD-L1 expression on CD19+ B-cells and their subsets, in addition to exploring its possible role in Tfh-cell activation and B-cell differentiation in SLE. Methods Frequencies of CD19+ B-cells, their subsets, PD-L1 and Tfh cells in the peripheral blood of SLE patients and healthy controls (HCs) were determined using cytometry. The clinical data of SLE patients were recorded in detail, and the correlation between their laboratory parameters, clinical parameters and disease activity indices was statistically analyzed. CD19+PD-L1+B-cells and CD19+PD-L1− B-cells were sorted and cultured with a stimulant, following which the supernatants were collected for immunoglobulin G and anti-double stranded DNA detection via enzyme-linked immunosorbent assay. Results In SLE patients, CD19+B-cells and partial subgroups were enriched in peripheral blood. Also, the observed increase in the frequency of CD19+PD-L1+B-cells was significantly associated with a higher disease activity index. An in vitro culture test demonstrated that the amounts of anti-dsDNA and immunoglobulin G secreted by the CD19+PD-L1+B-cells of SLE patients and HCs were vastly different. In addition, a strong correlation existed between the frequencies of CD19+PD-L1+B-cells and defined Tfh cells of SLE patients. Conclusion This study demonstrated that the expression of CD19+PD-L1+B-cells in the peripheral blood of SLE patients was abnormal, and that disease-related laboratory parameters and clinical indicators were correlated. CD19+PD-L1+B-cells were enriched and played a critical role in activating the pathogenic T-cell and B-cell responses in patients with SLE.
Early B cell developmental impairment with progressive B cell deficiency in NFKB2 mutated CVID disease without autoimmunity Clin. Immunol. (IF 3.557) Pub Date : 2018-11-28 Vassilios Lougaris, Daniele Moratto, Manuela Baronio, Tiziana Lorenzini, Stefano Rossi, Luisa Gazzurelli, Maria Pia Bondioni, Alessandro Plebani
This study provides evidence for a novel role for NFKB2 in human B cell development in the bone marrow and in the periphery, leading to progressive peripheral B cell deficiency not always combined with autoimmune phenomena, broadening thus the clinical spectrum of NFKB2 mutated CVID disease and implying an essential role for NFKB2 in early human B cell development.
Taming hemodialysis-induced inflammation: Are complement C3 inhibitors a viable option? Clin. Immunol. (IF 3.557) Pub Date : 2018-11-22 Dimitrios C. Mastellos, Edimara S. Reis, Ali-Reza Biglarnia, Meryl Waldman, Richard J. Quigg, Markus Huber-Lang, Marc A. Seelen, Mohamed R. Daha, John D. Lambris
Owing to an increasing shortage of donor organs, the majority of patients with end-stage kidney disease remains reliant on extracorporeal hemodialysis (HD) in order to counter the lifelong complications of a failing kidney. While HD remains a life-saving option for these patients, mounting evidence suggests that it also fuels a vicious cycle of thromboinflammation that can increase the risk of cardiovascular disease. During HD, blood-borne innate immune systems become inappropriately activated on the biomaterial surface, instigating proinflammatory reactions that can alter endothelial and vascular homeostasis. Complement activation, early during the HD process, has been shown to fuel a multitude of detrimental thromboinflammatory reactions that collectively contribute to patient morbidity. Here we discuss emerging aspects of complement's involvement in HD-induced inflammation and put forth the concept that targeted intervention at the level of C3 might constitute a promising therapeutic approach in HD patients.
Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils Clin. Immunol. (IF 3.557) Pub Date : 2018-11-22 Emma Weeding, Patrick Coit, Srilakshmi Yalavarthi, Mariana J. Kaplan, Jason S. Knight, Amr H. Sawalha
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thromboembolic events and pregnancy loss. We sought to characterize the DNA methylation profile of primary APS in comparison to healthy controls and individuals with SLE. In primary APS neutrophils compared to controls, 17 hypomethylated and 25 hypermethylated CpG sites were identified. Notable hypomethylated genes included ETS1, a genetic risk locus for SLE, and PTPN2, a genetic risk locus for other autoimmune diseases. Gene ontology analysis of hypomethylated genes revealed enrichment of genes involved in pregnancy. None of the differentially methylated sites in primary APS were differentially methylated in SLE neutrophils, and there was no demethylation of interferon signature genes in primary APS as is seen in SLE. Hypomethylation within a single probe in the IFI44L promoter (cg06872964) was able to distinguish SLE from primary APS with a sensitivity of 93.3% and specificity of 80.0% at a methylation fraction of 0.329.
SLAMF receptors on normal and malignant B cells Clin. Immunol. (IF 3.557) Pub Date : 2018-11-15 Idit Shachar, Avital Barak, Hadas Lewinsky, Lital Sever, Lihi Radomir
The Signaling Lymphocyte Activation Molecule family (SLAMF) is a collection of nine surface receptors expressed mainly on hematopoietic cells, and was found to modulate the behavior of immune cells. SLAMF receptors are expressed on B cells in health and disease. Each SLAM receptor has a unique differential expression pattern during the development and activation of B cells. Furthermore, recent findings have revealed a principal role for this family of receptors in B cell malignancies, emphasizing their importance in the control of malignant cell survival, cell to cell communication within the tumor microenvironment, retention in the supporting niches and regulation of T cell anti-tumor response. This review summarizes the latest studies regarding SLAMF expression and behavior in B cells and in B cell pathologies, and discusses the therapeutic potential of these receptors.
Association of anti-nuclear matrix protein 2 antibody with complications in patients with idiopathic inflammatory myopathies: A meta-analysis of 20 cohorts Clin. Immunol. (IF 3.557) Pub Date : 2018-11-13 Linqing Zhong, Zhongxun Yu, Hongmei Song
Background Several complications like calcinosis, interstitial lung disease (ILD) or malignancy, are primary causes leading to poor outcomes in idiopathic inflammatory myopathies (IIM) patients. Specific antibodies might help to indicate the occurrence or absence of these complications. Objective The aim of this study was to evaluate the association of anti-nuclear matrix protein 2 antibody (anti-NXP2) with calcinosis, ILD and malignancy in IIM patients. Methods Two investigators independently searched literature about the relation of anti-NXP2 with calcinosis, ILD, malignancy in IIM patients in PubMed, EMBASE, Web of Science databases, then selected eligible articles and extracted data from the included studies. The association between anti-NXP2 and these complications was assessed by odds ratios (OR) and 95% confidence intervals (95% CI). Further quantitative meta-analysis, subgroup analysis, sensitivity analysis and publication bias analysis were conducted with STATA 14.0 software (Stata Corp.; College Station, Texas, USA). A fixed-effects model (the Mantel-Haenszel method) was employed when I2 < 25%, otherwise a random-effects model (the Mantel-Haenszel method) was used. Results Twenty cohorts with 3064 IIM patients were included in this meta-analysis, among which 9 were about calcinosis in adults, 6 about calcinosis in juvenile patients, 9 about ILD in adults, 3 about ILD in juvenile patients, while 13 about malignancy in adult patients. Anti-NXP2 was more common in patients with calcinosis than those without calcinosis (pooled OR = 4.00, 95% CI: 2.65–6.06 in adults; pooled OR = 1.62, 95% CI: 1.14–2.30 in juvenile patients). On the contrary, this antibody was less common in adult patients with ILD than those without ILD (pooled OR: 0.33, 95% CI: 0.19–0.56). No significant difference concerning the incidence of anti-NXP2 antibody was found in IIM patients between those with and without cancer (pooled OR = 1.42, 95% CI: 0.69–2.91). Conclusion The present study indicates that anti-NXP2 autoantibody is a risk factor for development into calcinosis both in adult and juvenile patients, while a protective factor for ILD in adult patients. Anti-NXP2 had no relation with malignancy in adult patients.
The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management Clin. Immunol. (IF 3.557) Pub Date : 2018-11-13 Reza Yazdani, Saba Fekrvand, Sepideh Shahkarami, Gholamreza Azizi, Bobak Moazzami, Hassan Abolhassani, Asghar Aghamohammadi
Hyper Immunoglobulin M syndrome (HIGM) is a rare primary immunodeficiency disorder characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM. Various X-linked and autosomal recessive/dominant mutations have been reported as the underlying cause of the disease. Based on the underlying genetic defect, the affected patients present a variety of clinical manifestations including pulmonary and gastrointestinal complications, autoimmune disorders, hematologic abnormalities, lymphoproliferation and malignancies which could be controlled by multiple relevant therapeutic approaches. Herein, the epidemiology, pathogenesis, clinical manifestations, diagnosis, management, prognosis and treatment in patients with HIGM syndrome have been reviewed.
New insights into immune cells cross-talk during IgG4-related disease Clin. Immunol. (IF 3.557) Pub Date : 2018-11-10 Fahd Touzani, Agnieszka Pozdzik
Immunoglobulin G4-related disease (IgG4-RD) is a newly acknowledged entity, characterized by an immune-mediated fibro-inflammatory process affecting virtually all organs, with infiltration of IgG4+ bearing plasma cells. Until today the pathogenesis of IgG4-RD remains unknown. Treatment with anti-CD20 monoclonal antibodies efficiently induced remission and attenuated the secretory phenotype of myofibroblasts responsible of uncontrolled collagen deposition. This supports the pathogenic role of the adaptive immunity, particularly B cell compartment and B cell/T cell interaction. Latest studies have also highlighted the importance of innate immune system that has been underestimated before and the key role of a specific T cell subset, T follicular helper cells that are involved in IgG4-class-switching and plasmablast differentiation. In this review, we aim to review the most recent knowledge of innate immunity, T and B cells involvement in IgG4-RD, and introduce tertiary lymphoid organs (TLO) as a potential marker of relapse in this condition.
Signaling lymphocyte activation molecule family in systemic lupus erythematosus Clin. Immunol. (IF 3.557) Pub Date : 2018-11-08 Denis Comte, Maria P. Karampetsou, Morgane Humbel, George C. Tsokos
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by a breakdown in immune tolerance leading to the development of auto-reactive lymphocytes and autoantibodies. Recent findings have provided new insight on the role of the signaling lymphocytic activation molecule family (SLAMF) receptors, a group of nine co-regulatory molecules involved in the activation of hematopoietic cells, and their downstream protein SLAM-associated protein (SAP), into the pathogenesis of SLE. This review summarizes the current knowledge on SLAMF in human SLE immunopathogenesis, and the importance of SLAMF molecules as new therapeutic targets.
Natural and modified IL-2 for the treatment of cancer and autoimmune diseases Clin. Immunol. (IF 3.557) Pub Date : 2018-11-08 Masayuki Mizui
Interleukin-2 (IL-2) is a pleiotropic cytokine required for both effector lymphocyte proliferation/differentiation and regulatory T cell expansion/survival. Ability to receive IL-2 signals is defined by the affinity to distinct IL-2-receptor-complexes on each subset of cells. While IL-2 targets anti-tumor cytotoxic lymphocytes (CTLs) for the treatment of patients with melanoma or renal cell carcinoma, IL-2 directed at regulatory T (Treg) cells has value in several immune-related diseases including chronic graft-versus-host disease (cGVHD), type 1 diabetes (T1D) and systemic lupus erythematosus (SLE). A variety of IL-2 alteration has been made to deliver IL-2 to the proper target, including mutant IL-2, IL-2-fusion proteins and anti-IL-2 antibodies. Experimental and clinical trials with IL-2 are spreading for diverse group of diseases. Although the sustainability and efficiency of IL-2-responding cells in controlling disease activity are still not fully understood, the results of clinical trials will provide a basis of the most effective regimen for each disease.
A Markov Multi-State model of lupus nephritis urine biomarker panel dynamics in children: Predicting changes in disease activity Clin. Immunol. (IF 3.557) Pub Date : 2018-11-02 E.M.D. Smith, A. Eleuteri, B. Goilav, L. Lewandowski, A. Phuti, T. Rubinstein, D. Wahezi, C.A. Jones, S.D. Marks, R. Corkhill, C. Pilkington, K. Tullus, C. Putterman, C. Scott, A.C. Fisher, M.W. Beresford
Background A urine ‘biomarker panel’ comprising alpha-1-acid-glycoprotein, ceruloplasmin, transferrin and lipocalin-like-prostaglandin-D synthase performs to an ‘excellent’ level for lupus nephritis identification in children cross-sectionally. The aim of this study was to assess if this biomarker panel predicts lupus nephritis flare/remission longitudinally. Methods The novel urinary biomarker panel was quantified by enzyme linked immunoabsorbant assay in participants of the United Kingdom Juvenile Systemic Lupus Erythematosus (UK JSLE) Cohort Study, the Einstein Lupus Cohort, and the South African Paediatric Lupus Cohort. Monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 were also quantified in view of evidence from other longitudinal studies. Serial urine samples were collected during routine care with detailed clinical and demographic data. A Markov Multi-State model of state transitions was fitted, with predictive clinical/biomarker factors assessed by a corrected Akaike Information Criterion (AICc) score (the better the model, the lower the AICc score). Results The study included 184 longitudinal observations from 80 patients. The homogeneous multi-state Markov model of lupus nephritis activity AICc score was 147.85. Alpha-1-acid-glycoprotein and ceruloplasmin were identified to be the best predictive factors, reducing the AICc score to 139.81 and 141.40 respectively. Ceruloplasmin was associated with the active-to-inactive transition (hazard ratio 0.60 (95% confidence interval [0.39, 0.93])), and alpha-1-acid-glycoprotein with the inactive-to-active transition (hazard ratio 1.49 (95% confidence interval [1.10, 2.02])). Inputting individual alpha-1-acid-glycoprotein/ceruloplasmin values provides 3, 6 and 12 months probabilities of state transition. Conclusions Alpha-1-acid-glycoprotein was predictive of active lupus nephritis flare, whereas ceruloplasmin was predictive of remission. The Markov state-space model warrants testing in a prospective clinical trial of lupus nephritis biomarker led monitoring.
2B4 dysfunction in XLP1 NK cells: More than inability to control EBV infection Clin. Immunol. (IF 3.557) Pub Date : 2018-11-02 Daniela Pende, Raffaella Meazza, Stefania Marcenaro, Maurizio Aricò, Cristina Bottino
X-linked lymphoproliferative disease 1 (XLP1) is a monogenic disorder caused by mutations in SH2D1A, resulting in the absence/dysfunction of the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). Consequently, SLAM receptors as 2B4 (CD244) and NTB-A (SLAMF6), upon ligand engagement, exert inhibitory instead of activating function. This causes an immune dysfunction that is worsened by the selective inability of NK and T cells to kill EBV-infected B cells with dramatic clinical sequelae (e.g. fulminant mononucleosis, hyperinflammation, lymphoma). Here we outline recent findings on the interplay between inhibitory 2B4 and the various activating receptors in NK cells. 2B4 engagement selectively blocks ITAM-dependent activating receptors as NCR and CD16, while it does not affect NKG2D and DNAM-1. Furthermore, inhibitory 2B4 participates to NK cell education, as highlighted by the existence in XLP1 patients of a large subset of fully functional NK cells that lack self-HLA specific inhibitory receptors and exert autoreactivity against mature dendritic cells.
Clinical presentation, immunologic features, and hematopoietic stem cell transplant outcomes for IKBKB immune deficiency Clin. Immunol. (IF 3.557) Pub Date : 2018-10-31 Geoffrey D.E. Cuvelier, Tamar S. Rubin, Anne Junker, Roona Sinha, Alan M. Rosenberg, Donna A. Wall, Marlis L. Schroeder
IKBKB deficiency is a rare but life-threatening primary immunodeficiency disorder, involving activation defects in adaptive and innate immunity. We present sixteen cases of a homozygous IKBKB mutation (c.1292dupG) in infants characterized by early-onset bacterial, viral, fungal and Mycobacterial infections. In most cases, T- and B-cells were quantitatively normal, but phenotypically naïve, with severe hypogammaglobulinemia. T-cell receptor excision circles were normal, meaning newborn screening by TREC analysis would miss IKBKB cases. Although IKBKB deficiency does not meet traditional laboratory based definitions for SCID, this combined immune deficiency appears to be at least as profound. Urgent HSCT, performed in eight patients, remains the only known curative therapy, although only three patients are survivors. Ongoing infections after transplant remain a concern, and may be due to combinations of poor social determinants of health, secondary graft failure, and failure of HSCT to replace non-hematopoietic cells important in immune function and dependent upon IKK/NF-κB pathways.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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