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  • cDC2 and plasmacytoid dendritic cells diminish from tissues of patients with non‐Hodgkin orbital lymphoma and idiopathic orbital inflammation
    Eur. J. Immunol. (IF 4.695) Pub Date : 2020-01-16
    Kamil G. Laban; Rianne Rijken; Sanne Hiddingh; Jorre S. Mertens; Rob L. P. van der Veen; Christine A.E. Eenhorst; Aridaman Pandit; Timothy R.D.J. Radstake; Joke H. de Boer; Rachel Kalmann; Jonas J. W. Kuiper
    更新日期:2020-01-16
  • Overexpression of GILZ in macrophages limits systemic inflammation while increasing bacterial clearance in sepsis in mice
    Eur. J. Immunol. (IF 4.695) Pub Date : 2020-01-16
    Mehdi Ellouze; Lola Vigouroux; Colas Tcherakian; Paul‐Louis Woerther; Aurélie Guguin; Olivier Robert; Mathieu Surenaud; Thi Tran; Joseph Calmette; Thomas Barbin; Gabriel Perlemuter; Anne‐Marie Cassard; Pierre Launay; Virginie Maxime; Djillali Annane; Yves Levy; Véronique Godot
    更新日期:2020-01-16
  • Neutrophils suppress mucosal‐associated invariant T cells in humans
    Eur. J. Immunol. (IF 4.695) Pub Date : 2020-01-16
    Marion Schneider; Rachel F. Hannaway; Rajesh Lamichhane; Sara M. de la Harpe; Joel DA Tyndall; Andrea J. Vernall; A Tony; James Edgeworth Ussher

    Mucosal‐associated invariant T (MAIT) cells are innate‐like T lymphocytes that are abundant in mucosal tissues and the liver where they can respond rapidly to a broad range of riboflavin producing bacterial and fungal pathogens. Neutrophils, which are recruited early to sites of infection, play a non‐redundant role in pathogen clearance and are crucial for controlling infection. The interaction of these two cell types is poorly studied. Here, we investigated both the effect of neutrophils on MAIT cell activation and the effect of activated MAIT cells on neutrophils. We show that neutrophils suppress the activation of MAIT cells by a cell‐contact and hydrogen peroxide dependent mechanism. Moreover, highly activated MAIT cells were able to produce high levels of TNFα that induced neutrophil death. We therefore provide evidence for a negative regulatory feedback mechanism in which neutrophils prevent over‐activation of MAIT cells and, in turn, MAIT cells limit neutrophil survival.

    更新日期:2020-01-16
  • Impaired T cell receptor signaling and development of T cell–mediated autoimmune arthritis
    Immunol. Rev. (IF 11.292) Pub Date : 2020-01-16
    Yusuke Takeuchi; Keiji Hirota; Shimon Sakaguchi

    Mutations of the genes encoding T‐cell receptor (TCR)‐proximal signaling molecules, such as ZAP‐70, can be causative of immunological diseases ranging from T‐cell immunodeficiency to T‐cell–mediated autoimmune disease. For example, SKG mice, which carry a hypomorphic point mutation of the Zap‐70 gene, spontaneously develop T‐cell–mediated autoimmune arthritis immunopathologically similar to human rheumatoid arthritis (RA). The Zap‐70 mutation alters the sensitivity of developing T cells to thymic positive/negative selection by self‐peptides/MHC complexes, shifting self‐reactive TCR repertoire to include a dominant arthritogenic specificity and also affecting thymic development and function of autoimmune suppressive regulatory T (Treg) cells. Polyclonal self‐reactive T cells, including potentially arthritogenic T cells, thus produced by the thymus recognize self‐peptide/MHC complexes on antigen‐presenting cells (APCs) in the periphery and stimulate them to produce cytokines including IL‐6 to drive the arthritogenic T cells to differentiate into arthritogenic T‐helper 17 (Th17) cells. Insufficient Treg suppression or activation of APCs via microbial and other environmental stimuli evokes arthritis by activating granulocyte‐macrophage colony‐stimulating factor‐secreting effector Th17 cells, mediating chronic bone‐destructive joint inflammation by activating myeloid cells, innate lymphoid cells, and synoviocytes in the joint. These findings obtained from the study of SKG mouse arthritis are instrumental in understanding how arthritogenic T cells are produced, become activated, and differentiate into effector T cells mediating arthritis, and may help devising therapeutic measures targeting autoimmune pathogenic Th17 cells or autoimmune‐suppressing Treg cells to treat and prevent RA.

    更新日期:2020-01-16
  • Inflammasomes contributing to inflammation in arthritis
    Immunol. Rev. (IF 11.292) Pub Date : 2020-01-16
    Lotte Spel; Fabio Martinon

    Inflammasomes are intracellular multiprotein signaling platforms that initiate inflammatory responses in response to pathogens and cellular damage. Active inflammasomes induce the enzymatic activity of caspase‐1, resulting in the induction of inflammatory cell death, pyroptosis, and the maturation and secretion of inflammatory cytokines IL‐1β and IL‐18. Inflammasomes are activated in many inflammatory diseases, including autoinflammatory disorders and arthritis, and inflammasome‐specific therapies are under development for the treatment of inflammatory conditions. In this review, we outline the different inflammasome platforms and recent findings contributing to our knowledge about inflammasome biology in health and disease. In particular, we discuss the role of the inflammasome in the pathogenesis of arthritic diseases, including rheumatoid arthritis, gout, ankylosing spondylitis, and juvenile idiopathic arthritis, and the potential of newly developed therapies that specifically target the inflammasome or its products for the treatment of inflammatory diseases.

    更新日期:2020-01-16
  • Impairment of agonist-induced M2 muscarinic receptor activation by autoantibodies from chagasic patients with cardiovascular dysautonomia
    Clin. Immunol. (IF 3.548) Pub Date : 2020-01-16
    Sabrina P. Beltrame; Laura C. Carrera Páez; Sergio R. Auger; Ahmad H. Sabra; Claudio R. Bilder; Claudia I. Waldner; Juan C. Goin
    更新日期:2020-01-16
  • egc Superantigens Impair Monocytes/Macrophages Inducing Cell Death and Inefficient Activation
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-09
    Sofia Noli Truant; Mauricio C. De Marzi; María B. Sarratea; María B. Antonoglou; Ana P. Meo; Laura V. Iannantuono López; María J. Fernández Lynch; Marcos Todone; Emilio L. Malchiodi; Marisa M. Fernández

    Bacterial superantigens (SAgs) are enterotoxins that bind to MHC-II and TCR molecules, activating as much as 20% of the T cell population and promoting a cytokine storm which enhances susceptibility to endotoxic shock, causing immunosuppression, and hindering the immune response against bacterial infection. Since monocytes/macrophages are one of the first cells SAgs find in infected host and considering the effect these cells have on directing the immune response, here, we investigated the effect of four non-classical SAgs of the staphylococcal egc operon, namely, SEG, SEI, SEO, and SEM on monocytic–macrophagic cells, in the absence of T cells. We also analyzed the molecular targets on APCs which could mediate SAg effects. We found that egc SAgs depleted the pool of innate immune effector cells and induced an inefficient activation of monocytic–macrophagic cells, driving the immune response to an impaired proinflammatory profile, which could be mediated directly or indirectly by interactions with MHC class II. In addition, performing surface plasmon resonance assays, we demonstrated that non-classical SAgs bind the gp130 molecule, which is also present in the monocytic cell surface, among other cells.

    更新日期:2020-01-16
  • Association of Soluble HLA-G Plasma Level and HLA-G Genetic Polymorphism With Pregnancy Outcome of Patients Undergoing in vitro Fertilization Embryo Transfer
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-04
    Izabela Nowak; Karolina Wilczyńska; Paweł Radwan; Andrzej Wiśniewski; Rafał Krasiński; Michał Radwan; Jacek R. Wilczyński; Andrzej Malinowski; Piotr Kuśnierczyk

    Infertility is currently a growing problem observed around the world and is estimated to affect between 8 and 12% of reproductive-aged couples worldwide. Artificial reproductive techniques are the last chance for couples seeking their own child. Human leukocyte antigen (HLA)-G expression has been suggested as an immunomodulatory molecule that influences pregnancy outcome. The HLA-G gene encodes either membrane-bound or/and soluble proteins. The aim of this study was the evaluation of the role of soluble HLA-G (sHLA-G) and its gene polymorphism in successful implantation after in vitro fertilization embryo transfers (IVF-ETs) in different clinical protocols. We tested the HLA-G polymorphism in three positions: rs1632947: c.-964G>A; rs1233334: c.-725G>C/T in promoter region; rs371194629: c.*65_*66insATTTGTTCATGCCT in 3′ untranslated region of exon 8, in 389 patients who underwent IVF-ETs and 320 women with healthy children born after natural conception. Among the patient group, 239 women were with recurrent implantation failure and 117 women had an ongoing pregnancy or a child born after IVF-ET. We found that certain rs1632947-rs1233334-rs371194629 HLA-G haplotypes and diplotypes were associated with infertility, while others were protective. The lowest secretors of sHLA-G were G-C-ins haplotype carriers (37.21 IU/ml), while the highest -G-C-del carriers (73.80 IU/ml). Other haplotype carriers were intermediate secretors. In our study, regardless of possessed haplotype by the patient, 59.73 IU/ml sHLA-G was the threshold value with the best sensitivity (58.82%) and specificity (66.10%) to discriminate patients who achieved and maintained pregnancy from those who did not conceive or they had miscarriage (p = 0.0085; likelihood ratio, 1.74; 95% CI = 0.55–0.78). However, we do not exclude that factors other than sHLA-G may also contribute to complications in pregnancy. In addition, we found that IVF patients in cycles when frozen/thawed embryo was transferred secreted higher soluble HLA-G levels than patients with fresh embryo transferred (p = 0.021). Moreover, correlation analysis of sHLA-G concentration measured before and after embryo transfer for particular patients indicated short ovarian stimulation with gonadotropin-releasing hormone antagonist as more beneficial than long protocol with gonadotropin-releasing hormone agonist. Our study confirms a role of HLA-G polymorphism in infertility and soluble HLA-G in the early stages of pregnancy.

    更新日期:2020-01-16
  • Effects of Vitamin D2 (Ergocalciferol) and D3 (Cholecalciferol) on Atlantic Salmon (Salmo salar) Primary Macrophage Immune Response to Aeromonas salmonicida subsp. salmonicida Infection
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-09
    Manuel Soto-Dávila; Katherinne Valderrama; Sabrina M. Inkpen; Jennifer R. Hall; Matthew L. Rise; Javier Santander

    Vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are fat-soluble secosteroid hormones obtained from plant and animal sources, respectively. Fish incorporates vitamin D2 and D3 through the diet. In mammals, vitamin D forms are involved in mineral metabolism, cell growth, tissue differentiation, and antibacterial immune response. Vitamin D is an essential nutrient in aquafeeds for finfish. However, the influence of vitamin D on fish cell immunity has not yet been explored. Here, we examined the effects of vitamin D2 and vitamin D3 on Salmo salar primary macrophage immune response to A. salmonicida subspecies salmonicida infection under in vitro conditions. We determined that high concentrations of vitamin D2 (100,000 ng/ml) and D3 (10,000 ng/ml) affect the growth of A. salmonicida and decrease the viability of S. salar primary macrophages. In addition, we determined that primary macrophages pre-treated with a biologically relevant concentration of vitamin D3 for 24 h showed a decrease of A. salmonicida infection. In contrast, vitamin D2 did not influence the antibacterial activity of the S. salar macrophages infected with A. salmonicida. Vitamin D2 and D3 did not influence the expression of canonical genes related to innate immune response. On the other hand, we found that A. salmonicida up-regulated the expression of several canonical genes and suppressed the expression of leukocyte-derived chemotaxin 2 (lect-2) gene, involved in neutrophil recruitment. Primary macrophages pre-treated for 24 h with vitamin D3 counteracted this immune suppression and up-regulated the transcription of lect-2. Our results suggest that vitamin D3 affects A. salmonicida attachment to the S. salar primary macrophages, and as a consequence, the A. salmonicida invasion decreased. Moreover, our study shows that the positive effects of vitamin D3 on fish cell immunity seem to be related to the lect-2 innate immunity mechanisms. We did not identify positive effects of vitamin D2 on fish cell immunity. In conclusion, we determined that the inactive form of vitamin D3, cholecalciferol, induced anti-bacterial innate immunity pathways in Atlantic salmon primary macrophages, suggesting that its utilization as a component of a healthy aquafeed diet in Atlantic salmon could enhance the immune response against A. salmonicida.

    更新日期:2020-01-16
  • Fcγ Receptor IIB Controls Skin Inflammation in an Active Model of Epidermolysis Bullosa Acquisita
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-09
    Balint Kovacs; Jenny Tillmann; Lisa-Christin Freund; Falk Nimmerjahn; Christian D. Sadik; Katja Bieber; Ralf J. Ludwig; Christian M. Karsten; Jörg Köhl

    Epidermolysis bullosa acquisita (EBA) is an autoimmune skin blistering disease characterized by IgG autoantibodies (aAb) against type VII collagen (COL7). The mechanisms controlling the formation of such aAbs and their effector functions in the skin tissue are incompletely understood. Here, we assessed whether the inhibitory IgG Fc receptor, FcγRIIB, controls the development of autoimmune skin blistering disease in an active model of EBA. For this purpose, we immunized congenic EBA-susceptible B6.SJL-H2s (B6.s) and B6.s-Fcgr2b−/− mice with the immunodominant vWFA2 region of COL7. B6.s-Fcgr2b−/− mice developed a strong clinical phenotype with 15 ± 3.3% of affected body surface area at week 4. In contrast, the body surface area in B6.s mice was affected to a maximum of 5% at week 6 with almost no disease signs at week 4. Surprisingly, we already found strong but similar COL7-specific serum IgG1 and IgG2b aAb production at week 2. Further, aAb and C3b deposition in the skin of B6.s and B6.s-Fcgr2b−/− mice increased between weeks 2 and 6 after vWFA2 immunization. Importantly, neutrophil skin infiltration and activation was much stronger in B6s-Fcgr2b−/− than in B6.s mice and already present at week 2. Also, the early aAb response in B6.s-Fcgr2b−/− mice was more diverse than in wt B6.s mice. Reactive oxygen species (ROS) release from infiltrating neutrophils play a crucial role as mediator of skin inflammation in EBA. In line, sera from B6.s and B6.s-Fcgr2b−/− mice induced strong ROS release from bone marrow-neutrophils in vitro. In contrast to the antibody-transfer-induced EBA model, individual targeting of FcγRIII or FcγRIV decreased ROS release to 50%. Combined FcγR blocking abrogated ROS release from BM neutrophils. Also, ROS release induced by COL7-specific serum IgG aAbs was significantly higher using BM neutrophils from B6.s-Fcgr2b−/− than from B6.s mice. Together, our findings identified FcγRIIB as a suppressor of skin inflammation in the active EBA model through inhibition of early epitope spreading, protection from strong early neutrophil infiltration to and activation of neutrophils in the skin and suppression of FcγRIII activation by IgG1 aAbs which drive strong ROS release from neutrophils leading to tissue destruction at the dermal-epidermal junction.

    更新日期:2020-01-16
  • Bacterial Exposure Mediates Developmental Plasticity and Resistance to Lethal Vibrio lentus Infection in Purple Sea Urchin (Strongylocentrotus purpuratus) Larvae
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-09
    Nicholas W. Schuh; Tyler J. Carrier; Catherine S. Schrankel; Adam M. Reitzel; Andreas Heyland; Jonathan P. Rast

    Exposure to and colonization by bacteria during development have wide-ranging beneficial effects on animal biology but can also inhibit growth or cause disease. The immune system is the prime mediator of these microbial interactions and is itself shaped by them. Studies using diverse animal taxa have begun to elucidate the mechanisms underlying the acquisition and transmission of bacterial symbionts and their interactions with developing immune systems. Moreover, the contexts of these associations are often confounded by stark differences between “wild type” microbiota and the bacterial communities associated with animals raised in conventional or germ-free laboratories. In this study, we investigate the spatio-temporal kinetics of bacterial colonization and associated effects on growth and immune function in larvae of the purple sea urchin (Strongylocentrotus purpuratus) as a model for host-microbe interactions and immune system development. We also compare the host-associated microbiota of developing embryos and larvae raised in natural seawater or exposed to adult-associated bacteria in the laboratory. Bacteria associated with zygotes, embryos, and early larvae are detectable with 16S amplicon sequencing, but 16S-FISH indicates that the vast majority of larval bacterial load is acquired after feeding begins and is localized to the gut lumen. The bacterial communities of laboratory-cultured embryos are significantly less diverse than the natural microbiota but recapitulate its major components (Alphaproteobacteria, Gammaproteobacteria, and Bacteroidetes), suggesting that biologically relevant host-microbe interactions can be studied in the laboratory. We also demonstrate that bacterial exposure in early development induces changes in morphology and in the immune system. In the absence of bacteria, larvae grow larger at the 4-arm stage. Additionally, bacteria-exposed larvae are significantly more resistant to lethal infection with the larva-associated pathogen Vibrio lentus suggesting that early exposure to high levels of microbes, as would be expected in natural conditions, affects the immune state in later larvae. These results expand our knowledge of microbial influences on early sea urchin development and establish a model in which to study the interactions between the developing larval immune system and the acquisition of larval microbiota.

    更新日期:2020-01-16
  • DNA Methylation in Anopheles albimanus Modulates the Midgut Immune Response Against Plasmodium berghei
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-10
    Fabiola Claudio-Piedras; Benito Recio-Tótoro; Renaud Condé; Juan M. Hernández-Tablas; Gerardo Hurtado-Sil; Humberto Lanz-Mendoza

    Epigenetic mechanisms such as DNA methylation and histone post-translational modifications are fundamental for the phenotypic plasticity of insects during their interaction with the environment. In response to environmental cues, the methylation pattern in DNA is dynamically remodeled to achieve an epigenetic control of gene expression. DNA methylation is the focus of study in insects for its evolutionarily conserved character; however, there is scant knowledge about the epigenetic regulation in vector mosquitoes, especially during their infection by parasites. The aim of the present study was to evaluate the participation of DNA methylation in the immune response of Anopheles albimanus to a Plasmodium infection. For this, we first investigated the presence of a fully functional DNA methylation system in A. albimanus by assessing its potential role in larval development. Subsequently, we evaluated the transcriptional response to Plasmodium berghei of two mosquito phenotypes with different degrees of susceptibility to the parasite, in a scenario where their global DNA methylation had been pharmacologically inhibited. Our study revealed that A. albimanus has a functional DNA methylation system that is essential to larval viability, and that is also responsive to feeding and parasite challenges. The pharmacological erasure of the methylome with azacytidine or decitabine abolished the divergent responses of both mosquito phenotypes, leading to a transcriptionally similar response upon parasite challenge. This response was more specific, and the infection load in both phenotypes was lowered. Our findings suggest that DNA methylation may constitute a key factor in vector competence, and a promising target for preventing malaria transmission.

    更新日期:2020-01-16
  • Identifying the inheritable component of human thymic T cell repertoire generation in monozygous twins
    Eur. J. Immunol. (IF 4.695) Pub Date : 2020-01-14
    Nelli Heikkilä; Reetta Vanhanen; Dawit A. Yohannes; Päivi Saavalainen; Seppo Meri; T. Sakari Jokiranta; Hanna Jarva; Ilkka P. Mattila; David Hamm; Silja Sormunen; Jari Saramäki; T. Petteri Arstila
    更新日期:2020-01-15
  • CD5 blockade enhances ex vivo CD8+ T cell activation and tumour cell cytotoxicity
    Eur. J. Immunol. (IF 4.695) Pub Date : 2020-01-15
    Faizah Alotaibi; Mateusz Rytelewski; Rene Figueredo; Ronak Zareardalan; Meng Zhang; Peter J Ferguson; Saman Maleki Vareki; Yousef Najajreh; Mikal El‐Hajjar; Xiufen Zheng; Wei‐ping Min; James Koropatnick

    CD5 is expressed on T cells and a subset of B cells (B1a). It can attenuate T‐cell receptor (TCR) signalling and impair cytotoxic T lymphocyte (CTL) activation and is a therapeutic targetable tumour antigen expressed on leukemic T and B cells. However, the potential therapeutic effect of functionally blocking CD5 to increase T cell anti‐tumour activity against tumours (including solid tumours) has not been explored. CD5 knockout mice show increased anti‐tumour immunity: reducing CD5 on CTLs may be therapeutically beneficial to enhance the anti‐tumour response. Here we show that ex vivo administration of a function‐blocking anti‐CD5 monoclonal antibody (MAb) to primary mouse CTLs of both tumour‐naïve mice and mice bearing murine 4T1 breast tumour homografts enhanced their capacity to respond to activation by treatment with anti‐CD3/anti‐CD28 MAbs or 4T1 tumour cell lysates. Furthermore, it enhanced TCR signalling (ERK activation) and increased markers of T cell activation, including proliferation, CD69 levels, interferon‐γ production, apoptosis, and Fas receptor and Fas ligand levels. Finally, CD5 function‐blocking MAb treatment enhanced the capacity of CD8+ T cells to kill 4T1‐mouse tumour cells in an ex vivo assay. These data support the potential of blockade of CD5 function to enhance T cell‐mediated anti‐tumour immunity.

    更新日期:2020-01-15
  • CRISPR gene-engineered CYBBko THP-1 cell lines highlight the crucial role of NADPH-induced reactive oxygen species for regulating inflammasome activation
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-15
    Aissa Benyoucef; Lorie Marchitto; Fabien Touzot

    CRISPR-Cas9 engineered CYBBko THP-1 cell lines display an inflammatory profile with increased IL-1β, IL-6 and TNF-α secretion as consequence of NADPH-induced ROS deficiency. This phenotype is reminiscent of the one observed in phagocytes from CGD patients.

    更新日期:2020-01-15
  • The role of Astakine in Scylla paramamosain against Vibrio alginolyticus and white spot syndrome virus infection
    Fish Shellfish Immun. (IF 3.298) Pub Date : 2020-01-15
    Jing Wang; Wenjing Hong; Fei Zhu

    Astakine is a crucial factor in the proliferation and differentiation of hematopoietic stem cells and is directly involved in hematopoiesis in crustaceans. To assess the role of Astakine in the innate immune system of Scylla paramamosain, the immune responses in healthy and Astakine-inhibited S. paramamosain were investigated in the present study. The RNA transcripts of Astakine were widely distributed in all examined tissues, with significantly higher levels of expression in hemocytes of both healthy and challenged S. paramamosain with Vibrio alginolyticus and WSSV. When Astakine was knocked down by RNA interference technology, immune-related genes, including Janus kinase, prophenoloxidase, hemocyanin, β-actin, myosin II essential light chain-like protein, signal transducer and activator of transcription, Relish, and C-type-lectin, were significantly down-regulated in hemocytes. The levels of phenoloxidaseactivity (PO), total hemocyte counts (THC) and hemocyte proliferation decreased significantly in hemocytes of Astakine-dsRNA treated S. paramamosain. After being challenged with V. alginolyticus and WSSV, the THC decreased significantly and the levels of hemocyte apoptosis increased significantly in Astakine-dsRNA treated S. paramamosain in comparison with those in infected groups without Astakine-dsRNA treatment. After being challenged with WSSV, the WSSV copies were significantly lower in Astakine-dsRNA treated groups than those in the WSSV infection group, which suggested that knockdown of Astakine was not conductive to WSSV replication and this might be associated with the decreasing THC. The results of survival analysis showed that the survival rate of V. alginolyticus or WSSV infected S. paramamosain decreased significantly following Astakine knockdown. These results suggested that RNA interference of Astakine might weaken the resistance of S. paramamosain to V. alginolyticus or WSSV infection. The weaken resistivity after knockdown Astakine might be related to the changes of important immune-related gene expression, THC, PO activity, proliferation and apoptosis of hemocytes.

    更新日期:2020-01-15
  • Clone, identification and functional characterization of a novel toll (Shtoll1) from the freshwater crab Sinopotamon henanense in response to cadmium exposure and Aeromonas hydrophila infection
    Fish Shellfish Immun. (IF 3.298) Pub Date : 2020-01-15
    Lang Lang; Minnan Bao; Weixin Jing; Wei Chen; Lan Wang

    Toll is essential in innate immune system which is important for defense against bacterial, fungal and viral infections in invertebrates. Our previous study showed that cadmium (Cd) could change the expression pattern of ShToll3 in the epithelium (gills and midgut from the freshwater crab Sinopotamon henanense) infected by Aeromonas hydrophila. To investigate the diverse innate immune roles of crustacean homolog Tolls, in this study, we cloned Shtoll1 from S. henanense. The full-length cDNA of Shtoll1 was 4746 bp, with an ORF of 3033 bp encoding a putative protein of 111 amino acids, a 5′-untranslated region of 255 bp and a 3′-untranslated region of 1713 bp. Phylogenetic analysis showed that ShToll1 was clustered into the group of DmToll1, DmToll 4 and DmToll 5. In addition, the tissue distribution results showed that Shtoll1 was expressed widely in different tissues, with the highest expression in heamocytes. Besides, Shtoll1 expressions were upregulated in heamocytes and hepatopancreas after A. hydrophila infection. At the same time, the increase of Shtoll1 expressions were examined in heamocytes in response to Cd exposure and A. hydrophila infection in combination. Through western blotting and immunohistochemical analysis, the ShToll1 expressions in heamocytes were increased in response to A. hydrophila and Cd independently as well as in combination. Moreover, the mRNA level of three antimicrobial peptides (AMPs) alf5, alf6, and c-lys, which possibly responded to Cd and A. hydrophila stimulation through Shtoll1, were analyzed. Thus, we conclude that Cd expand the susceptibility of ShToll1 to A. hydrophila infection in heamocytes. This suggest that ShToll1 may contribute to the innate immune defense of S. henanense against A. hydrophila and Cd in heamocytes.

    更新日期:2020-01-15
  • Function characterization and expression regulation of two different-sized 3’ untranslated region-containing interferon genes from clone F of gibel carp Carassius auratus gibelio
    Mol. Immunol. (IF 3.064) Pub Date : 2020-01-15
    Zhao-Xing Zang; Cheng Dan; Li Zhou; Qi-Ya Zhang; Jian-Fang Gui; Yi-Bing Zhang

    Fish interferon (IFN)-mediated antiviral innate immunity is the first line of defense against virus invasion. In the present study, we identify two fish IFN genes (here tentatively named IFNa and IFNc) with different-sized 3′ UTRs from clone F strain of gibel carp Carassius auratus gibelio. Carp IFNa has a relatively short 3′UTR without AU-rich elements (AREs) but IFNc has a long one with 9 AREs. Functionally, carp IFNa and IFNc display significantly antiviral potential to viral infection, likely through induction of downstream IFN-stimulated genes (ISGs). Both carp IFN genes are induced by viral infection, poly(I:C) treatment and IRF3/7, which are ascribed to the IFN-sensitive response elements (ISRE) within their promoters. Carp IFN genes are also induced by each other and by themselves, indicating existence of a positive feedback loop in fish IFN-mediated antiviral immune response. Comparative analyses of 3′UTR-mediated expression regulation at mRNA and protein levels show that the ARE-containing 3′UTR of carp IFNc rather than the short 3′UTR of carp IFNa promotes mRNA decay but instead results in high-level protein expression, indicating that 3′UTR of fish IFN mRNAs might be a potential factor for regulation of IFN-mediated antiviral immune response. Considering a fact that a given protein function is largely related to its protein level, these results suggest that both promoter and 3′UTR contribute to the transcription and translation of fish IFN genes, thus shaping their eventually antiviral potential.

    更新日期:2020-01-15
  • Baseline derived neutrophil-to-lymphocyte ratio as a prognostic biomarker for non-colorectal gastrointestinal cancer patients treated with immune checkpoint blockade
    Clin. Immunol. (IF 3.548) Pub Date : 2020-01-15
    Shuang Li; Jianling Zou; Chang Liu; Xi Jiao; Jifang Gong; Jian Li; Zhenghang Wang; Ming Lu; Zhihao Lu; Lin Shen

    Background Biomarkers in non-colorectal gastrointestinal (GI) cancer patients receiving immune checkpoint blockades (ICBs) are still limited. Methods Data were prospectively collected from a discovery cohort (n = 53) and a validation cohort (n = 107) in patients with non-colorectal GI cancer receiving ICB, as well as a chemotherapy-only cohort (n = 171). System inflammatory markers and derived neutrophil-to-lymphocyte ratio (dNLR) were determined as biomarkers by univariate and multivariate analyses. Results A higher level of dNLR (cutoff = 3) was associated with shorter overall survival (OS) in discovery and validation cohorts. In pooled cohort, disease control rate (DCR) (28% vs. 48.1%) was associated with dNLR (p = .017). In univariate analysis, original tumor site, tumor histopathology, number of metastases, and dNLR were correlated with OS. In multivariate analysis, higher dNLR level was correlated with reduced OS (10.43 months vs. 4.20 months, p < .001). In chemotherapy-only cohort, dNLR was also correlated with DCR and OS. Conclusion Higher dNLR level was correlated with worse outcomes, suggesting that dNLR may help risk-group stratification and assist disease management strategies as a prognostic biomarker for non-colorectal GI patients receiving ICB.

    更新日期:2020-01-15
  • EZH2 deficiency attenuates Treg differentiation in rheumatoid arthritis
    J. Autoimmun. (IF 7.543) Pub Date : 2020-01-15
    Xin-yue Xiao; Yue-ting Li; Xu Jiang; Xin Ji; Xin Lu; Bo Yang; Li-jun Wu; Xiao-han Wang; Jing-bo Guo; Li-dan Zhao; Yun-yun Fei; Hua-xia Yang; Wen Zhang; Feng-chun Zhang; Fu-lin Tang; Jian-min Zhang; Wei He; Hua Chen; Xuan Zhang

    The chromatin modifier enhancer of zeste homolog 2 (EZH2) methylates lysine 27 of histone H3 (H3K27) and regulates T cell differentiation. However, the potential role of EZH2 in the pathogenesis of rheumatoid arthritis (RA) remains elusive. We analyzed EZH2 expression in PBMC, CD4+ T cells, CD19+ B cell, and CD14+ monocytes from active treatment-naïve RA patients and healthy controls (HC). We also suppressed EZH2 expression using EZH2 inhibitor GSK126 and measured CD4+ T cell differentiation, proliferation and apoptosis. We further examined TGFβ-SMAD and RUNX1 signaling pathways in EZH2-suppressed CD4+ T cells. Finally, we explored the regulation mechanism of EZH2 by RA synovial fluid and fibroblast-like synoviocyte (FLS) by neutralizing key proinflammatory cytokines. EZH2 expression is lower in PBMC and CD4+ T cells from RA patients than those from HC. EZH2 inhibition suppressed regulatory T cells (Tregs) differentiation and FOXP3 transcription, and downregulated RUNX1 and upregulated SMAD7 expression in CD4+ T cells. RA synovial fluid and fibroblast-like synoviocytes suppressed EZH2 expression in CD4+ T cells, which was partially neutralized by anti-IL17 antibody. Taken together, EZH2 in CD4+ T cells from RA patients was attenuated, which suppressed FOXP3 transcription through downregulating RUNX1 and upregulating SMAD7 in CD4+ T cells, and ultimately suppressed Tregs differentiation. IL17 in RA synovial fluid might promote downregulation of EZH2 in CD4+ T cells. Defective EZH2 in CD4+ T cells might contribute to Treg deficiency in RA.

    更新日期:2020-01-15
  • To TAP or not to TAP: alternative peptides for immunotherapy of cancer
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2020-01-14
    Koen A. Marijt; Thorbald van Hall

    Intracellular processing of antigens is crucial for the generation of T cell immunity towards cancers, since cleaved protein products are the molecular targets of these adaptive lymphocytes. The majority of antigenic peptides requires the TAP transporter to gain access to the peptide loading complex in the ER lumen where they bind MHC class I (MHC-I). This pivotal role of TAP in antigen processing makes the system vulnerable for modifications in cancer cells and indeed human cancers frequently silence this gene epigenetically. Interestingly, TAP-independent processing pathways then become apparent and partly restore MHC class I presentation with alternative peptides. In this review we discuss recent insights on how TAP-independent processing of immunogenic peptides occurs, and how these antigens can be exploited for cancer immunotherapy.

    更新日期:2020-01-15
  • Prediction of cancer neoepitopes needs new rules
    Semin. Immunol. (IF 7.358) Pub Date : 2020-01-14
    Cory A. Brennick; Mariam M. George; Pramod K. Srivastava; Sukrut H. Karandikar

    Tumors are immunogenic and the non-synonymous point mutations harbored by tumors are a source of their immunogenicity. Immunologists have long been enamored by the idea of synthetic peptides corresponding to mutated epitopes (neoepitopes) as specific “vaccines” against tumors presenting those neoepitopes in context of MHC I. Tumors may harbor hundreds of point mutations and it would require effective prediction algorithms to identify candidate neoepitopes capable of eliciting potent tumor-specific CD8+ T cell responses. Our current understanding of MHC I-restricted epitopes come from the observance of CD8+ T cell responses against viral (vaccinia, lymphocytic choriomeningitis etc.) and model (chicken ovalbumin, hen egg lysozyme etc.) antigens. Measurable CD8+ T cell responses elicited by model or viral antigens are always directed against epitopes possessing strong binding affinity for the restricting MHC I alleles. Immense collective effort to develop methodologies combining genomic sequencing, bioinformatics and traditional immunological techniques to identify neoepitopes with strong binding affinity to MHC I has only yielded inaccurate prediction algorithms. Additionally, new evidence has emerged suggesting that neoepitopes, which unlike the epitopes of viral or model antigens have closely resembling wild-type counterparts, may not necessarily demonstrate strong affinity to MHC I. Our bearing need recalibration.

    更新日期:2020-01-15
  • MUCIN-4 (MUC4) is a novel tumor antigen in pancreatic cancer immunotherapy
    Semin. Immunol. (IF 7.358) Pub Date : 2020-01-14
    Shailendra K. Gautam; Sushil Kumar; Vi Dam; Dario Ghersi; Maneesh Jain; Surinder K. Batra

    Pancreatic cancer (PC) is a highly lethal malignancy with a dismal five-year survival rate. This is due to its asymptomatic nature, lack of reliable biomarkers, poor resectability, early metastasis, and high recurrence rate. Limited efficacies of current treatment modalities treatment-associated toxicity underscore the need for the development of immunotherapy-based approaches. For non-resectable, locally advanced metastatic PC, immunotherapy-based approaches including vaccines, antibody-targeted, immune checkpoint inhibition, CAR-T-cells, and adoptive T-cell transfer could be valuable additions to existing treatment modalities. Thus far, the vaccine candidates in PC have demonstrated modest immunological responses in different treatment modalities. The identification of tumor-associated antigens (TAA) and their successful implication in PC treatment is still a challenge. MUC4, a high molecular weight glycoprotein that functionally contributes to PC pathogenesis, is an attractive TAA. It is not detected in the normal pancreas; however, it is overexpressed in mouse and human pancreatic tumors. The recombinant MUC4 domain, as well as predicted immunogenic T-cell epitopes, elicited cellular and humoral anti-MUC4 response, suggesting its ulility as a vaccine candidate for PC therapy. Existence of PC-associated MUC4 splice variants, autoantibodies against overexpressed and aberrantly glycosylated MUC4 and presence of T-cell clones against the mutations present in MUC4 further reinforce its significance as a tumor antigen for vaccine development. Herein, we review the significance of MUC4 as a tumor antigen in PC immunotherapy and discuss both, the development and challenges associated with MUC4 based immunotherapy. Lastly, we will present our perspective on MUC4 antigenicity for the future development of MUC4-based PC immunotherapy.

    更新日期:2020-01-15
  • Cytokine Production and NET Formation by Monosodium Urate-Activated Human Neutrophils Involves Early and Late Events, and Requires Upstream TAK1 and Syk
    Front. Immunol. (IF 4.716) Pub Date : 
    Olga Tatsiy; Thomas Z. Mayer; Vanessa de Carvalho Oliveira; Stéphanie Sylvain-Prévost; Marilyn Isabel; Claire M. Dubois; Patrick P. McDonald

    Gout is a prevalent and incapacitating disease triggered by the deposition of monosodium urate (MSU) crystals in joints, which are also massively infiltrated by neutrophils. The interaction of the latter with MSU crystals triggers several responses, including the generation of inflammatory mediators and of neutrophil extracellular traps (NETs). Though some of the signaling events mobilized by MSU in neutrophils have been described (e.g., Src family kinases, Syk, PKC, PI3K), the picture remains fragmentary. Likewise, the impact of these signaling events on cellular responses is incompletely understood. In this study, we examined transcriptomic changes triggered by MSU in neutrophils and their impact on the corresponding proteins, as well as the role of various signaling pathways in prominent functional responses. We report for the first time that neutrophils can secrete the monocyte chemoattractant, CCL4, in response to MSU. Accordingly, we found that transcription factors NF-κB, CREB, and C/EBP are belatedly activated by MSU crystals, and at least the former is involved in chemokine generation. Moreover, we show that MAPKs and Akt are activated by MSU in neutrophils, that they are under the control of TAK1 and Syk, and that they participate in cytokine generation and NETosis. In the latter instance, we found the phenomenon to be independent of endogenous ROS, but under the control of PAD4. We finally provide evidence that endogenous factors contribute to the belated phosphorylation of kinases and transcription factors in response to MSU. Collectively, our findings unveil potentially important therapeutic targets for gouty arthritis.

    更新日期:2020-01-15
  • Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release
    Front. Immunol. (IF 4.716) Pub Date : 
    Iwona Cichon; Weronika Ortmann; Aleksandra Bednarz; Malgorzata Lenartowicz; Elzbieta Kolaczkowska

    Neutrophil extracellular traps (NETs) contribute to pathological disorders, and their release was directly linked to numerous diseases. With intravital microscopy (IVM), we showed previously that NETs also contribute to the pathology of systemic inflammation and are strongly deposited in liver sinusoids. Over a decade since NET discovery, still not much is known about the metabolic or microenvironmental aspects of their formation. Copper is a vital trace element essential for many biological processes, albeit its excess is potentially cytotoxic; thus, copper levels are tightly controlled by factors such as copper transporting ATPases, ATP7A, and ATP7B. By employing IVM, we studied the impact of copper on NET formation during endotoxemia in liver vasculature on two mice models of copper excess or deficiency, Wilson (ATP7B mutants) and Menkes (ATP7A mutants) diseases, respectively. Here, we show that respective ATP7 mutations lead to diminished NET release during systemic inflammation despite unaltered intrinsic capacity of neutrophils to cast NETs as tested ex vivo. In Menkes disease mice, the in vivo effect is mostly due to diminished neutrophil infiltration of the liver as unmutated mice with a subchronic copper deficiency release even more NETs than their controls during endotoxemia, whereas in Wilson disease mice, excess copper directly diminishes the capacity to release NETs, and this was further confirmed by ex vivo studies on isolated neutrophils co-cultured with exogenous copper and a copper-chelating agent. Taken together, the study extends our understanding on how microenvironmental factors affect NET release by showing that copper is not a prerequisite for NET release but its excess affects the trap casting by neutrophils.

    更新日期:2020-01-15
  • DGK α and ζ Activities Control TH1 and TH17 Cell Differentiation
    Front. Immunol. (IF 4.716) Pub Date : 
    Jialong Yang; Hong-Xia Wang; Jinhai Xie; Lei Li; Jinli Wang; Edwin C. K. Wan; Xiao-Ping Zhong

    CD4+ T helper (TH) cells are critical for protective adaptive immunity against pathogens, and they also contribute to the pathogenesis of autoimmune diseases. How TH differentiation is regulated by the TCR's downstream signaling is still poorly understood. We describe here that diacylglycerol kinases (DGKs), which are enzymes that convert diacylglycerol (DAG) to phosphatidic acid, exert differential effects on TH cell differentiation in a DGK dosage-dependent manner. A deficiency of either DGKα or ζ selectively impaired TH1 differentiation without obviously affecting TH2 and TH17 differentiation. However, simultaneous ablation of both DGKα and ζ promoted TH1 and TH17 differentiation in vitro and in vivo, leading to exacerbated airway inflammation. Furthermore, we demonstrate that dysregulation of TH17 differentiation of DGKα and ζ double-deficient CD4+ T cells was, at least in part, caused by increased mTOR complex 1/S6K1 signaling.

    更新日期:2020-01-15
  • Innate Lymphoid Cells in Colorectal Cancers: A Double-Edged Sword
    Front. Immunol. (IF 4.716) Pub Date : 
    Qiutong Huang; Wang Cao; Lisa Anna Mielke; Cyril Seillet; Gabrielle T. Belz; Nicolas Jacquelot

    The immune system plays a fundamental role at mucosal barriers in maintaining tissue homeostasis. This is particularly true for the gut where cells are flooded with microbial-derived signals and antigens, which constantly challenge the integrity of the intestinal barrier. Multiple immune cell populations equipped with both pro- and anti-inflammatory functions reside in the gut tissue and these cells tightly regulate intestinal health and functions. Dysregulation of this finely tuned system can progressively lead to autoimmune disease and inflammation-driven carcinogenesis. Over the last decade, the contribution of the adaptive immune system in controlling colorectal cancer has been studied in detail, but the role of the innate system, particularly innate lymphoid cells (ILCs), have been largely overlooked. By sensing their microenvironment, ILCs are essential in supporting gut epithelium repair and controling bacterial- and helminth-mediated intestinal infections, highlighting their important role in maintaining tissue integrity. Accumulating evidence also suggests that they may play an important role in carcinogenesis including intestinal cancers. In this review, we will explore the current knowledge about the pro- and anti-tumor functions of ILCs in colorectal cancer.

    更新日期:2020-01-15
  • Natural Killer Cells in Systemic Autoinflammatory Diseases: A Focus on Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome
    Front. Immunol. (IF 4.716) Pub Date : 
    Jessica Vandenhaute; Carine H. Wouters; Patrick Matthys

    Natural killer (NK) cells are innate immune lymphocytes with potent cytolytic and immune-regulatory activities. NK cells are well-known for their ability to kill infected and malignant cells in a fast and non-specific way without prior sensitization. For this purpose, NK cells are equipped with a set of cytotoxic molecules such as perforin and apoptosis-inducing proteins. NK cells also have the capacity to produce large amounts of cytokines and chemokines that synergize with their cytotoxic function and that ensure interaction with other immune cells. A less known feature of NK cells is their capacity to kill non-infected autologous cells, such as immature dendritic cells and activated T cells and monocytes. Via the release of large amounts of TNF-α and IFN-γ, NK cells may contribute to disease pathology. Conversely they may exert a regulatory role through secretion of immuno-regulatory cytokines such as GM-CSF, IL-13, and IL-10. Thus, NK cells may be important target and effector cells in the pathogenesis of autoinflammatory diseases, in particular in those disorders associated with a cytokine storm or in conditions where immune cells are highly activated. Key examples of such diseases are systemic juvenile idiopathic arthritis (sJIA) and its well-associated complication, macrophage activation syndrome (MAS). sJIA is a chronic childhood immune disorder of unknown etiology, characterized by arthritis and systemic inflammation, including a daily spiking fever and evanescent rash. MAS is a potentially fatal complication of autoimmune and autoinflammatory diseases, and most prevalently associated with sJIA. MAS is considered as a subtype of hemophagocytic lymphohistiocytosis (HLH), a systemic hyperinflammatory disorder characterized by defective cytotoxic pathways of cytotoxic T and NK cells. In this review, we describe the established features of NK cells and provide the results of a literature survey on the reported NK cell abnormalities in monogenic and multifactorial autoinflammatory disorders. Finally, we discuss the role of NK cells in the pathogenesis of sJIA and MAS.

    更新日期:2020-01-15
  • Lymphoid Aggregates in the CNS of Progressive Multiple Sclerosis Patients Lack Regulatory T Cells
    Front. Immunol. (IF 4.716) Pub Date : 
    Luisa Bell; Alexander Lenhart; Andreas Rosenwald; Camelia M. Monoranu; Friederike Berberich-Siebelt

    In gray matter pathology of multiple sclerosis, neurodegeneration associates with a high degree of meningeal inflammatory activity. Importantly, ectopic lymphoid follicles (eLFs) were identified at the inflamed meninges of patients with progressive multiple sclerosis. Besides T lymphocytes, they comprise B cells and might elicit germinal center (GC)-like reactions. GC reactions are controlled by FOXP3+ T-follicular regulatory cells (TFR), but it is unknown if they participate in autoantibody production in eLFs. Receiving human post-mortem material, gathered from autopsies of progressive multiple sclerosis patients, indeed, distinct inflammatory infiltrates enriched with B cells could be detected in perivascular areas and deep sulci. CD35+ cells, parafollicular CD138+ plasma cells, and abundant expression of the homing receptor for GCs, CXCR5, on lymphocytes defined some of them as eLFs. However, they resembled GCs only in varying extent, as T cells did not express PD-1, only few cells were positive for the key transcriptional regulator BCL-6 and ongoing proliferation, whereas a substantial number of T cells expressed high NFATc1 like GC-follicular T cells. Then again, predominant cytoplasmic NFATc1 and an enrichment with CD3+CD27+ memory and CD4+CD69+ tissue-resident cells implied a chronic state, very much in line with PD-1 and BCL-6 downregulation. Intriguingly, FOXP3+ cells were almost absent in the whole brain sections and CD3+FOXP3+ TFRs were never found in the lymphoid aggregates. This also points to less controlled humoral immune responses in those lymphoid aggregates possibly enabling the occurrence of CNS-specific autoantibodies in multiple sclerosis patients.

    更新日期:2020-01-15
  • Immune Suppression Mediated by STAT4 Deficiency Promotes Lymphatic Metastasis in HNSCC
    Front. Immunol. (IF 4.716) Pub Date : 
    Kelvin Anderson; Nathan Ryan; Greta Volpedo; Sanjay Varikuti; Abhay R. Satoskar; Steve Oghumu

    Head and neck squamous cell carcinoma (HNSCC) is a prevalent form of cancer with 5-years survival rates around 57%, and metastasis is a leading cause of mortality. Host-derived immunological factors that affect HNSCC tumor development and metastasis are not completely understood. We investigated the role of host-derived signal transducer and activator of transcription 4 (STAT4) during experimental HNSCC using an aggressive and metastatic HNSCC cell line, LY2, which was orthotopically injected into the buccal sulcus of wild type (WT) and STAT4 deficient (Stat4−/−) BALB/c mice. Necropsies performed at terminal sacrifice revealed that Stat4−/− mice displayed comparable primary tumor growth to the WT mice. However, the rate and extent of lymph node and lung metastasis among Stat4−/− mice was significantly higher. Downstream analyses performed on primary tumors, draining lymph nodes, spleens and bone marrow revealed significant upregulation of lymphocytic immunosuppressive biomarkers as well as an accumulation of granulocytic MDSC subpopulations in draining lymph nodes of metastatic Stat4−/− mice. Further, we observed a significant decrease in TH1, TH17, and cytotoxic activity in tumor bearing Stat4−/− compared to WT mice. Our results demonstrate that STAT4 mediates resistance to HNSCC metastasis, and activation of STAT4 could potentially mitigate lymphatic metastasis in HNSCC patients.

    更新日期:2020-01-15
  • IL-17A in Psoriasis and Beyond: Cardiovascular and Metabolic Implications
    Front. Immunol. (IF 4.716) Pub Date : 
    Esther von Stebut; Wolf-Henning Boehncke; Kamran Ghoreschi; Tommaso Gori; Ziya Kaya; Diamant Thaci; Andreas Schäffler

    Interleukin 17A (IL-17A) is one of the currently known six members of the IL-17 cytokine family and is implicated in immune responses to infectious pathogens and in the pathogenesis of inflammatory autoimmune diseases like psoriasis. Psoriatic skin is characterized by high expression of IL-17A and IL-17F, which act on immune and non-immune cell types and strongly contribute to tissue inflammation. In psoriatic lesions, IL-17A, IL-17E, and IL-17F are involved in neutrophil accumulation, followed by the formation of epidermal micro abscesses. IL-17A together with other Th17 cytokines also upregulates the production of several chemokines that are implicated in psoriasis pathogenesis. IL17A-targeting antibodies show an impressive clinical efficacy in patients with psoriasis. Studies have reported an improvement of at least 75% as measured by the psoriasis area and severity index (PASI) in >80% of patients treated with anti-IL-17A therapy. Psoriasis skin manifestations, cardiovascular as well as metabolic disease in psoriasis appear to share pathogenic mechanisms evolving around IL-17A and its proinflammatory role. Thus, anti-IL-17A therapy not only improves skin manifestations of psoriasis, but also cardiovascular inflammation as well as metabolic factors and different domains of psoriatic arthritis (PsA) including peripheral arthritis, enthesitis, dactylitis, and axial involvement. This review summarizes the biological role of IL-17A, before reviewing currently available data on its role in the physiology and pathophysiology of the skin, as well as the cardiovascular and the metabolic system. In conclusion, clinical recommendations for patients with moderate to severe psoriasis based on the current available data are given.

    更新日期:2020-01-15
  • Dysregulation of Complement Activation and Placental Dysfunction: A Potential Target to Treat Preeclampsia?
    Front. Immunol. (IF 4.716) Pub Date : 
    E. Pierik; Jelmer R. Prins; Harry van Goor; Gustaaf A. Dekker; Mohamed R. Daha; Marc A. J. Seelen; Sicco A. Scherjon

    Preeclampsia is one of the leading causes of maternal and neonatal mortality and morbidity worldwide, affecting 2–8% of all pregnancies. Studies suggest a link between complement activation and preeclampsia. The complement system plays an essential role in the innate immunity, leading to opsonization, inflammation, and elimination of potential pathogens. The complement system also provides a link between innate and adaptive immunity and clearance of immune complexes and apoptotic cells. During pregnancy there is increased activity of the complement system systemically. However, locally at the placenta, complement inhibition is crucial for the maintenance of a normal pregnancy. Inappropriate or excessive activation of the complement system at the placenta is likely involved in placental dysfunction, and is in turn associated with pregnancy complications like preeclampsia. Therefore, modulation of the complement system could be a potential therapeutic target to prevent pregnancy complications such as preeclampsia. This review, based on a systematic literature search, gives an overview of the complement system and its activation locally in the placenta and systemically during healthy pregnancies and during complicated pregnancies, with a focus on preeclampsia. Furthermore, this review describes results of animal and human studies with a focus on the complement system in pregnancy, and the role of the complement system in placental dysfunction. Various clinical and animal studies provide evidence that dysregulation of the complement system is associated with placental dysfunction and therefore with preeclampsia. Several drugs are used for prevention and treatment of preeclampsia in humans and animal models, and some of these drugs work through complement modulation. Therefore, this review further discusses these studies examining pharmaceutical interventions as treatment for preeclampsia. These observations will help direct research to generate new target options for prevention and treatment of preeclampsia, which include direct and indirect modulation of the complement system.

    更新日期:2020-01-15
  • Using Precisely Defined in vivo Microbiotas to Understand Microbial Regulation of IgE
    Front. Immunol. (IF 4.716) Pub Date : 
    Madeleine Wyss; Kirsty Brown; Carolyn A. Thomson; Mia Koegler; Fernanda Terra; Vina Fan; Francesca Ronchi; Dominique Bihan; Ian Lewis; Markus B. Geuking; Kathy D. McCoy

    Early life exposure to microbes plays an important role in immune system development. Germ-free mice, or mice colonized with a low-diversity microbiota, exhibit high serum IgE levels. An increase in microbial richness, providing it occurs in a critical developmental window early in life, leads to inhibition of this hygiene-induced IgE. However, whether this inhibition is dependent solely on certain microbial species, or is an additive effect of microbial richness, remains to be determined. Here we report that mice colonized with a combination of bacterial species with specific characteristics is required to inhibit IgE levels. These defined characteristics include the presence in early life, acetate production and immunogenicity reflected by induction of IgA. Suppression of IgE did not correlate with production of the short chain fatty acids propionate and butyrate, or induction of peripherally induced Tregs in mucosal tissues. Thus, inhibition of IgE induction can be mediated by specific microbes and their associated metabolic pathways and immunogenic properties.

    更新日期:2020-01-15
  • Enhanced Cell Division Is Required for the Generation of Memory CD4 T Cells to Migrate Into Their Proper Location
    Front. Immunol. (IF 4.716) Pub Date : 
    Jana Sarkander; Shintaro Hojyo; Mathias Mursell; Yuzuru Yamasaki; Tsung-Yen Wu; Damon J. Tumes; Kosuke Miyauchi; Cam Loan Tran; Jinfang Zhu; Max Löhning; Andreas Hutloff; Mir-Farzin Mashreghi; Masato Kubo; Andreas Radbruch; Koji Tokoyoda

    CD4 T cell memory is fundamental for long-lasting immunity and effective secondary responses following infection or vaccination. We have previously found that memory CD4 T cells specific for systemic antigens preferentially reside in the bone marrow (BM) and arise from splenic CD49b+T-bet+ CD4 T cells. However, how BM-homing memory precursors are generated during an immune reaction is unknown. We show here that BM memory precursors are generated via augmented rates of cell division throughout a primary immune response. Treatment with the cytostatic drug cyclophosphamide or blockade of the CD28/B7 co-stimulatory pathway at the beginning of the contraction phase abrogates the generation of BM memory precursors. We determine that, following a critical number of cell divisions, memory precursors downregulate CCR7 and upregulate IL-2Rβ, indicating that loss of CCR7 and gain of IL-2 signal are required for the migration of memory precursors toward the BM.

    更新日期:2020-01-15
  • Endogenous T Cell Receptor Rearrangement Represses Aggressive Central Nervous System Autoimmunity in a TcR-Transgenic Model on the Non-Obese Diabetic Background
    Front. Immunol. (IF 4.716) Pub Date : 
    Asmita Pradeep Yeola; Prenitha Mercy Ignatius Arokia Doss; Joanie Baillargeon; Irshad Akbar; Benoit Mailhot; Mohammad Balood; Sébastien Talbot; Ana Carrizosa Anderson; Steve Lacroix; Manu Rangachari

    The T cell response to central nervous system (CNS) antigen in experimental autoimmune encephalomyelitis (EAE) permits one to model the immune aspects of multiple sclerosis. 1C6 transgenic mice on the non-obese diabetic (NOD) background possess a class II-restricted T cell receptor (TcR; Vα5-Vβ7) specific for the encephalitogenic peptide myelin oligodendrocyte glycoprotein (MOG)[35−55]. It remains to be determined what role is played by allelic inclusion in shaping the TcR repertoire of these mice. Here, we show that 1C6 T cells display substantial promiscuity in their expression of non-transgenically derived Vα chains. Further, enforced expression of the transgenic TcR in 1C6 × Rag1−/− mice profoundly disrupted thymic negative selection and led to a sharp decrease in the number of mature peripheral T cells. 1C6 × Rag1−/− mice developed spontaneous EAE at a significant frequency and rapidly developed fatal EAE upon immunization with myelin oligodendrocyte glycoprotein (MOG)[35−55]. Passive transfer of 1C6 × Rag1+/+ CD4+ T cells, but not CD8+ T cells or B cells, partially rescued 1C6 × Rag1−/− mice from severe EAE. FoxP3+ CD4+ Treg cells were present in the CNS of immunized 1C6 mice, as well as immunized 1C6 × Rag1−/− that had been supplemented with 1C6 CD4+ T cells. However, they were not observed in 1C6 × Rag1−/− that did not receive Rag1-sufficient 1C6 CD4+. Further, in vivo blockade of Treg accelerated the onset of symptoms in 1C6 mice immunized with MOG[35−55], indicating the pertinence of Treg-mediated control of autoimmune inflammation in this model. Thus, TcR allelic inclusion is crucial to the generation of FoxP3+ CD4+ T cells necessary for the suppression of severe CNS autoimmunity.

    更新日期:2020-01-15
  • Qualitative Changes in Cortical Thymic Epithelial Cells Drive Postpartum Thymic Regeneration
    Front. Immunol. (IF 4.716) Pub Date : 
    Maude Dumont-Lagacé; Tariq Daouda; Lucyle Depoërs; Jérémie Zumer; Yahya Benslimane; Sylvie Brochu; Lea Harrington; Sébastien Lemieux; Claude Perreault

    During gestation, sex hormones cause a significant thymic involution which enhances fertility. This thymic involution is rapidly corrected following parturition. As thymic epithelial cells (TECs) are responsible for the regulation of thymopoiesis, we analyzed the sequential phenotypic and transcriptomic changes in TECs during the postpartum period in order to identify mechanisms triggering postpartum thymic regeneration. In particular, we performed flow cytometry analyses and deep RNA-sequencing on purified TEC subsets at several time points before and after parturition. We report that pregnancy-induced involution is not caused by loss of TECs since their number does not change during or after pregnancy. However, during pregnancy, we observed a significant depletion of all thymocyte subsets downstream of the double-negative 1 (DN1) differentiation stage. Variations in thymocyte numbers correlated with conspicuous changes in the transcriptome of cortical TECs (cTECs). The transcriptomic changes affected predominantly cTEC expression of Foxn1, its targets and several genes that are essential for thymopoiesis. By contrast, medullary TECs (mTECs) showed very little transcriptomic changes in the early postpartum regenerative phase, but seemed to respond to the expansion of single-positive (SP) thymocytes in the late phase of regeneration. Together, these results show that postpartum thymic regeneration is orchestrated by variations in expression of a well-defined subset of cTEC genes, that occur very early after parturition.

    更新日期:2020-01-15
  • Immunomodulatory Protective Effects of Rb9 Cyclic-Peptide in a Metastatic Melanoma Setting and the Involvement of Dendritic Cells
    Front. Immunol. (IF 4.716) Pub Date : 
    Fabrício C. Machado; Natália Girola; Vera S. C. Maia; Patrícia C. Bergami-Santos; Alice S. Morais; Ricardo A. Azevedo; Carlos R. Figueiredo; José A. M. Barbuto; Luiz R. Travassos

    The cyclic VHCDR3-derived peptide (Rb9) from RebMab200 antibody, directed to a NaPi2B phosphate-transport protein, displayed anti-metastatic melanoma activity at 50–300 μg intraperitoneally injected in syngeneic mice. Immune deficient mice failed to respond to the peptide protective effect. Rb9 induced increased CD8+ T and low Foxp3+ T cell infiltration in lung metastases and high IFN-γ and low TGF-β in lymphoid organs. The peptide co-localized with F-actin and a nuclear site in dendritic cells and specifically bound to MIF and CD74 in a dot-blot setting. Murine bone-marrow dendritic cells preincubated with Rb9 for 6 h were treated with MIF for short time periods. The modulated responses showed stimulation of CD74 and inhibition of pPI3K, pERK, and pNF-κB as compared to MIF alone. Rb9 in a melanoma-conditioned medium, stimulated the M1 type conversion in bone marrow-macrophages. Functional aspects of Rb9 in vivo were studied in therapeutic and prophylactic protocols using a melanoma metastatic model. In both protocols Rb9 exhibited a marked anti-melanoma protection. Human dendritic cells were also investigated showing increased expression of surface markers in response to Rb9 incubation. Rb9 either stimulated or slightly inhibited moDCs submitted to inhibitory (TGF-β and IL-10) or activating (LPS) conditions, respectively. Lymphocyte proliferation was obtained with moDCs stimulated by Rb9 and tumor cell lysate. In moDCs from cancer patients Rb9 exerted immunomodulatory activities depending on their functional status. The peptide may inhibit over-stimulated cells, stimulate poorly activated and suppressed cells, or cause instead, little phenotypic and functional alterations. Recently, the interaction MIF-CD74 has been associated to PD-L1 expression and IFN-γ, suggesting a target for melanoma treatment. The effects described for Rb9 and the protection against metastatic melanoma may suggest the possibility of a peptide reagent that could be relevant when associated to modern immunotherapeutic procedures.

    更新日期:2020-01-15
  • Lymph Flow Induces the Postnatal Formation of Mature and Functional Meningeal Lymphatic Vessels
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-12
    László Bálint; Zsombor Ocskay; Bálint András Deák; Petra Aradi; Zoltán Jakus

    Recently, the presence of lymphatics has been demonstrated and characterized in the dura mater, which is in contrast to the well-accepted view indicating the lack of a classical lymphatic drainage system of the central nervous system (CNS). Moreover, the role of meningeal lymphatics in the pathogenesis of Alzheimer's disease and multiple sclerosis was suggested. However, the possible regulators of the developmental program and function of meningeal lymphatics remain unclear. Here, we aimed at characterizing the lymph flow dependence of the developmental program and function of the meningeal lymphatics. First, we demonstrated that lymphatics present in the dura mater are involved in the uptake and transport of macromolecules from the CNS. Meningeal lymphatics develop during the postnatal period which process involves the maturation of the vessels. The formation of mature meningeal lymphatics coincides with the increase of the drainage of macromolecules from the CNS to the deep cervical lymph nodes. Importantly, the structural remodeling and maturation of meningeal lymphatics is impaired in Plcγ2−/− mice with reduced lymph flow. Furthermore, macromolecule uptake and transport by the meningeal lymphatics are also affected in Plcγ2−/− mice. Collectively, lymph flow-induced mechanical forces are required for the postnatal formation of mature and functional meningeal lymphatic vessels. Defining lymph flow-dependence of the development and function of meningeal lymphatics may lead to better understanding of the pathogenesis of neurological diseases including Alzheimer's disease and multiple sclerosis.

    更新日期:2020-01-15
  • (Sterol)ized Immunity: Could PI3K/AKT3 Be the Answer?
    Immunity (IF 21.522) Pub Date : 2020-01-14
    Xun Chi; Steven J. Bensinger

    Type I interferons (IFNs) can reprogram the cholesterol biosynthetic pathway to facilitate innate immune responses. In this issue of Immunity, Xiao et al. (2020) reveal that type I IFN signaling and 7-dehydrocholesterol (7-DHC) accumulation form a positive feedback loop to amplify innate immune responses to control viral infections by activating AKT3.

    更新日期:2020-01-15
  • Clec2d Joins the Cell Death Sensor Ranks
    Immunity (IF 21.522) Pub Date : 2020-01-14
    Carlos del Fresno; David Sancho

    Sensing tissue damage is an ancient function of immune cells that is central to the regulation of inflammation, tissue repair, and immunity. In this issue of Immunity, Lai et al. (2020) uncover a role for the C-type lectin receptor Clec2d as a sensor of cell death, which directly detects histones released during necrosis and thus contributes to inflammation and immunopathology.

    更新日期:2020-01-15
  • Keeping T-he Killers at Bay via FcγRIIb
    Immunity (IF 21.522) Pub Date : 2020-01-14
    Falk Nimmerjahn

    Understanding how cytotoxic T cells are regulated is key for enhancing or suppressing their activity in tumor or transplantation settings. A study by Morris et al. (2020) in this issue of Immunity shows that crosslinking of inhibitory Fc receptor FcγRIIb by the suppressive cytokine Fgl2 limits cytotoxic CD8+ T cell responses by inducing T cell apoptosis.

    更新日期:2020-01-15
  • That Wasn’t a Complement—Too Much C3 in Demyelinating Disease
    Immunity (IF 21.522) Pub Date : 2020-01-14
    Wendy Xin; Jonah R. Chan

    Multiple sclerosis is a chronic inflammatory disease characterized by demyelination in the central nervous system. In this issue of Immunity, Werneberg et al. report a striking loss of synapses driven by excessive microglial pruning early in demyelinating disease, which can be rescued by inhibiting the complement component C3.

    更新日期:2020-01-15
  • Mutant KRAS at the Heart of Tumor Immune Evasion
    Immunity (IF 21.522) Pub Date : 2020-01-14
    Febe van Maldegem; Julian Downward

    In the search for therapeutic combinations for the treatment of cancer, the pairing of targeted inhibitors of oncogenic driver pathways with immunotherapy has largely been overlooked. In Nature, Canon et al. (2019) describe how the novel KRAS-G12C inhibitor AMG 510 can potentiate immune rejection in combination with immune checkpoint blockade.

    更新日期:2020-01-15
  • Top 10 Challenges in Cancer Immunotherapy
    Immunity (IF 21.522) Pub Date : 2020-01-14
    Priti S. Hegde; Daniel S. Chen

    Cancer immunotherapy is a validated and critically important approach for treating patients with cancer. Given the vast research and clinical investigation efforts dedicated to advancing both endogenous and synthetic immunotherapy approaches, there is a need to focus on crucial questions and define roadblocks to the basic understanding and clinical progress. Here, we define ten key challenges facing cancer immunotherapy, which range from lack of confidence in translating pre-clinical findings to identifying optimal combinations of immune-based therapies for any given patient. Addressing these challenges will require the combined efforts of basic researchers and clinicians, and the focusing of resources to accelerate understanding of the complex interactions between cancer and the immune system and the development of improved treatment options for patients with cancer.

    更新日期:2020-01-15
  • Human Anti-tumor Immunity: Insights from Immunotherapy Clinical Trials
    Immunity (IF 21.522) Pub Date : 2020-01-14
    Jackson G. Egen; Wenjun Ouyang; Lawren C. Wu

    Therapeutics that target the T cell inhibitory checkpoint proteins CTLA-4 and PD(L)1 are efficacious across a broad range of cancers, resulting in reductions in tumor burden and increased long-term survival in subsets of patients. The significant and wide-ranging effects of these immunotherapies have prompted the clinical investigation of additional therapies that modulate anti-tumor immunity through effects on T cells, myeloid cells, and other cell types within the tumor microenvironment. The clinical activity of these newer investigational therapies has been mixed, with some therapeutics showing promise but others not exhibiting appreciable efficacy. In this review, we summarize the results of select recent clinical studies of cancer immunotherapies beyond anti-CTLA-4 and anti-PD(L)1 and discuss how these results are providing new insights into the regulation of human anti-tumor immunity.

    更新日期:2020-01-15
  • Tumor Immunology and Tumor Evolution: Intertwined Histories
    Immunity (IF 21.522) Pub Date : 2020-01-14
    Jérôme Galon; Daniela Bruni

    Cancer is a complex disease whose outcome depends largely on the cross-talk between the tumor and its microenvironment. Here, we review the evolution of the field of tumor immunology and the advances, in lockstep, of our understanding of cancer as a disease. We discuss the involvement of different immune cells at distinct stages of tumor progression and how immune contexture determinants shaping tumor development are being exploited therapeutically. Current clinical stratification schemes focus on the tumor histopathology and the molecular characteristics of the tumor cell. We argue for the importance of revising these stratification systems to include immune parameters so as to address the immediate need for improved prognostic and/or predictive information to guide clinical decisions.

    更新日期:2020-01-15
  • Signaling through the Inhibitory Fc Receptor FcγRIIB Induces CD8+ T Cell Apoptosis to Limit T Cell Immunity
    Immunity (IF 21.522) Pub Date : 2020-01-14
    Anna B. Morris; Clara R. Farley; David F. Pinelli; Layne E. Adams; Mark S. Cragg; Jeremy M. Boss; Christopher D. Scharer; Miguel Fribourg; Paolo Cravedi; Peter S. Heeger; Mandy L. Ford
    更新日期:2020-01-15
  • Ex vivo expansion of regulatory T cells from long-term Belatacept-treated kidney transplant patients restores their phenotype and suppressive function but not their FOXP3 TSDR demethylation status
    Cell. Immunol. (IF 3.291) Pub Date : 2020-01-14
    A. Cortés-Hernández; E. Alvarez-Salazar; S. Arteaga-Cruz; J. Alberú Gómez; G. Soldevila

    We recently reported that Tregs from long-term Belatacept-treated kidney transplant patients displayed an altered phenotype and impaired suppressive function compared to Tregs from healthy controls. However, it remains unknown whether ex vivo expansion of Tregs from patients who underwent long-term immunosuppression may be feasible to be used in their treatment. In this work, Tregs from Belatacept-treated patients were polyclonally expanded in vitro in the presence of rapamycin and IL-2. After four weeks of expansion, Tregs from patients expressed high levels of FOXP3, CD25, CTLA-4, Helios and CCR7, and showed strong suppressive activity, even in the presence of pro-inflammatory cytokines. However, FOXP3 TSDR demethylation remained lower in expanded Tregs from Belatacept-treated patients compared to healthy control Tregs. These data suggest that ex vivo expansion of Tregs from patients undergoing long-term immunosuppression may require the use of epigenetic modifying agents to stabilize FOXP3 expression to be considered as treatment in kidney transplant patients.

    更新日期:2020-01-14
  • Nrf2 expression driven by Foxp3 specific deletion of Keap1 results in loss of immune tolerance in mice
    Eur. J. Immunol. (IF 4.695) Pub Date : 2020-01-14
    Patricia Klemm; Anandhi Rajendiran; Athanassios Fragoulis; Christoph Wruck; Angela Schippers; Norbert Wagner; Tobias Bopp; Klaus Tenbrock; Kim Ohl
    更新日期:2020-01-14
  • Nasal DNA methylation profiling of asthma and rhinitis
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-14
    Cancan Qi; Yale Jiang; Ivana V. Yang; Erick Forno; Ting Wang; Judith M. Vonk; Ulrike Gehring; Henriëtte A. Smit; Edith B. Milanzi; Orestes A. Carpaij; Marijn Berg; Laura Hesse; Sharon Brouwer; Jonathan Cardwell; Cornelis J. Vermeulen; Edna Acosta-Pérez; Glorisa Canino; Nadia Boutaoui; Gerard H. Koppelman

    Background Epigenetic signatures in the nasal epithelium, which is a primary interface with the environment and an accessible proxy for the bronchial epithelium, might provide insights into mechanisms of allergic disease. Objective We aimed to identify and interpret methylation signatures in nasal epithelial brushes associated with rhinitis and asthma. Methods Nasal epithelial brushes were obtained from 455 children at the 16 year follow-up of the Dutch PIAMA birth cohort study. Epigenome-wide association studies (EWAS) were performed on asthma, rhinitis and asthma and/or rhinitis (AsRh) using logistic regression, and top results were replicated in two independent cohorts of African American and Puerto Rican children. Significant CpG sites (CpGs) were related to environmental exposures (pets, active and passive smoking and molds) during secondary school, and correlated to gene expression by RNA-sequencing (n=244). Results The EWAS identified CpGs significantly associated with rhinitis (n=81) and AsRh (n=75), but not with asthma. We significantly replicated 62 /81 CpGs with rhinitis, and 60/75 with AsRh, as well as one CpG with asthma. Methylation of cg03565274 was negatively associated with AsRh, and positively associated with pets exposure during secondary school. DNA methylation signals associated with AsRh were mainly driven by specific IgE positive subjects. DNA methylation related to gene transcripts that were enriched for immune pathways, and expressed in immune and epithelial cells. Nasal CpGs performed well in predicting AsRh. Conclusions We identified replicable DNA methylation profiles of asthma and rhinitis in nasal brushes. Pets exposure may affect nasal epithelial methylation in relation to asthma and rhinitis.

    更新日期:2020-01-14
  • Complement Receptor-Mediated Phagocytosis Induces Proinflammatory Cytokine Production in Murine Macrophages
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-12
    Durga Acharya; Xiao Rui (Lisa) Li; Rebecca Emily-Sue Heineman; Rene E. Harrison

    Macrophages are professional phagocytes that are uniquely situated between the innate and adaptive arms of immunity with a high capacity for phagocytosis and proinflammatory cytokine production as well as antigen presentation. Phagocytosis is a critical process to eliminate microbes, apoptotic cells and other foreign particles and is accelerated by host-generated opsonins, such as antibodies and complement. Early phagocytosis studies established the paradigm that FcγR-mediated phagocytosis was more proinflammatory than Complement Receptor (CR)-mediated uptake in macrophages. Using qPCR, cytokine antibody arrays and ELISA, we revisited this research question in primary macrophages. Using qPCR we determined that CR-mediated phagocytosis increases levels of TNF-α, IL-1β, IL-6, and MMP-9, compared to FcγR-mediated phagocytosis and control unstimulated cells. We confirmed these findings at the protein level using cytokine antibody arrays and ELISAs. We next investigated the mechanism behind upregulated cytokine production during CR-mediated phagocytosis. IκBα protein levels were reduced after phagocytosis of both IgG- and C3bi-sRBCs indicating proteolytic degradation and implicating NF-κB activation. Inhibition of NF-κB activation impacted IL-6 production during phagocytosis in macrophages. Due to the roles of calpain in IκBα and integrin degradation, we hypothesized that CR-mediated phagocytosis may utilize calpain for proinflammatory mediator enhancement. Using qPCR and cytokine antibody array analysis, we saw significant reduction of cytokine expression during CR-mediated phagocytosis following the addition of the calpain inhibitor, PD150606, compared to untreated cells. These results suggest that the upregulation of proinflammatory mediators during CR-mediated phagocytosis is potentially dependent upon calpain-mediated activation of NF-κB.

    更新日期:2020-01-14
  • Intercellular Adhesion Molecule-1 (ICAM-1) and ICAM-2 Differentially Contribute to Peripheral Activation and CNS Entry of Autoaggressive Th1 and Th17 Cells in Experimental Autoimmune Encephalomyelitis
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-16
    Neda Haghayegh Jahromi; Luca Marchetti; Federica Moalli; Donovan Duc; Camilla Basso; Heidi Tardent; Elisa Kaba; Urban Deutsch; Caroline Pot; Federica Sallusto; Jens V. Stein; Britta Engelhardt

    In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), myelin-specific T cells are activated in the periphery and differentiate in T helper (Th) 1 and Th17 effector cells, which cross the blood-brain barrier (BBB) to reach the central nervous system (CNS), where they induce neuroinflammation. Here, we explored the role of intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 in the activation of naïve myelin-specific T cells and in the subsequent migration of differentiated encephalitogenic Th1 and Th17 cells across the BBB in vitro and in vivo. While on antigen-presenting cells ICAM-1, but not ICAM-2 was required for the activation of naïve CD4+ T cells, endothelial ICAM-1 and ICAM-2 mediated both Th1 and Th17 cell migration across the BBB. ICAM-1/-2-deficient mice developed ameliorated typical and atypical EAE transferred by encephalitogenic Th1 and Th17 cells, respectively. Our study underscores important yet cell-specific contributions for ICAM-1 and ICAM-2 in EAE pathogenesis.

    更新日期:2020-01-14
  • IL8 and PMA Trigger the Regulation of Different Biological Processes in Granulocyte Activation
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-16
    Roxane L. Degroote; Maria Weigand; Stefanie M. Hauck; Cornelia A. Deeg

    The molecular mechanisms driving specific regulation of neutrophils are not completely understood to date. In order to characterize fundamental granulocyte features on protein level, we analyzed changes in proteome composition as reaction to stress from cell activation processes. For this purpose, we isolated primary granulocytes from equine whole blood through density gradient centrifugation followed by sodium chloride lysis and stimulated cells for 30 min with interleukin-8 (IL8) due to its role as a chemotactic factor for neutrophils. We additionally used phorbol 12-myristate 13-acetate (PMA) and lipopolysaccharide (LPS), which are primarily associated to neutrophil extracellular trap formation and release of reactive oxygen species. From mass spectrometry analysis, we identified a total of 2,032 proteins describing the whole granulocyte proteome, including 245 proteins (12% of identified proteome) newly associated to in vivo expression in primary equine granulocytes (hypothetical proteins). We also found distinct and different changes in protein abundance (ratio ≥ 2) after short stimulation of cells with various stimuli, pointing to rapid and differentiated reaction pattern. IL8 stimulation resulted in increased protein abundance of 58 proteins (3% of proteome), whereas PMA induced changed protein abundance of 207 (10 % of proteome) and LPS of 46 proteins (2% of proteome). Enrichment analyses clearly showed fundamental differences between stimuli, with primary association of IL8 stimulation to processes in immune response, receptor signaling and signal transduction. Top enrichment for PMA on the other hand pointed to vesicle mediated transport and exocytosis. Stimulation with LPS did not result in any significant enrichment. Although we detected 43% overlap of enrichment categories for IL8 and PMA stimulation, indicating that activation of neutrophils with different stimuli partly induces some similar biological processes and pathways, hierarchical clustering showed clear differences in distribution and biological relevance of clusters between the chosen stimuli. Our studies provide novel information on the granulocyte proteome and offer insights into early, differentiated granulocyte reaction to stimuli, which contribute to a better understanding of molecular mechanisms involved in activation and recruitment of neutrophils, through inflammatory stimuli.

    更新日期:2020-01-14
  • Cytoskeletal Protein 4.1R Is a Positive Regulator of the FcεRI Signaling and Chemotaxis in Mast Cells
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-16
    Lubica Draberova; Helena Draberova; Lucie Potuckova; Ivana Halova; Monika Bambouskova; Narla Mohandas; Petr Draber

    Protein 4.1R, a member of the 4.1 family, functions as a bridge between cytoskeletal and plasma membrane proteins. It is expressed in T cells, where it binds to a linker for activation of T cell (LAT) family member 1 and inhibits its phosphorylation and downstream signaling events after T cell receptor triggering. The role of the 4.1R protein in cell activation through other immunoreceptors is not known. In this study, we used 4.1R-deficient (4.1R-KO) and 4.1R wild-type (WT) mice and explored the role of the 4.1R protein in the high-affinity IgE receptor (FcεRI) signaling in mast cells. We found that bone marrow mast cells (BMMCs) derived from 4.1R-KO mice showed normal growth in vitro and expressed FcεRI and c-KIT at levels comparable to WT cells. However, 4.1R-KO cells exhibited reduced antigen-induced degranulation, calcium response, and secretion of tumor necrosis factor-α. Chemotaxis toward antigen and stem cell factor (SCF) and spreading on fibronectin were also reduced in 4.1R-KO BMMCs, whereas prostaglandin E2-mediated chemotaxis was not affected. Antibody-induced aggregation of tetraspanin CD9 inhibited chemotaxis toward antigen in WT but not 4.1R-KO BMMCs, implying a CD9-4.1R protein cross-talk. Further studies documented that in the absence of 4.1R, antigen-mediated phosphorylation of FcεRI β and γ subunits was not affected, but phosphorylation of SYK and subsequent signaling events such as phosphorylation of LAT1, phospholipase Cγ1, phosphatases (SHP1 and SHIP), MAP family kinases (p38, ERK, JNK), STAT5, CBL, and mTOR were reduced. Immunoprecipitation studies showed the presence of both LAT1 and LAT2 (LAT, family member 2) in 4.1R immunocomplexes. The positive regulatory role of 4.1R protein in FcεRI-triggered activation was supported by in vivo experiments in which 4.1R-KO mice showed the normal presence of mast cells in the ears and peritoneum, but exhibited impaired passive cutaneous anaphylaxis. The combined data indicate that the 4.1R protein functions as a positive regulator in the early activation events after FcεRI triggering in mast cells.

    更新日期:2020-01-14
  • Granzyme A in Chikungunya and Other Arboviral Infections
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-17
    Alessandra S. Schanoski; Thuy T. Le; Dion Kaiserman; Caitlin Rowe; Natalie A. Prow; Diego D. Barboza; Cliomar A. Santos; Paolo M. A. Zanotto; Kelly G. Magalhães; Luigi Aurelio; David Muller; Paul Young; Peishen Zhao; Phillip I. Bird; Andreas Suhrbier

    Granzyme A (GzmA) is secreted by cytotoxic lymphocytes and has traditionally been viewed as a mediator of cell death. However, a growing body of data suggests the physiological role of GzmA is promotion of inflammation. Here, we show that GzmA is significantly elevated in the sera of chikungunya virus (CHIKV) patients and that GzmA levels correlated with viral loads and disease scores in these patients. Serum GzmA levels were also elevated in CHIKV mouse models, with NK cells the likely source. Infection of mice deficient in type I interferon responses with CHIKV, Zika virus, or dengue virus resulted in high levels of circulating GzmA. We also show that subcutaneous injection of enzymically active recombinant mouse GzmA was able to mediate inflammation, both locally at the injection site as well as at a distant site. Protease activated receptors (PARs) may represent targets for GzmA, and we show that treatment with PAR antagonist ameliorated GzmA- and CHIKV-mediated inflammation.

    更新日期:2020-01-14
  • Treg Heterogeneity, Function, and Homeostasis
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-18
    Daniil Shevyrev; Valeriy Tereshchenko

    T-regulatory cells (Tregs) represent a unique subpopulation of helper T-cells by maintaining immune equilibrium using various mechanisms. The role of T-cell receptors (TCR) in providing homeostasis and activation of conventional T-cells is well-known; however, for Tregs, this area is understudied. In the last two decades, evidence has accumulated to confirm the importance of the TCR in Treg homeostasis and antigen-specific immune response regulation. In this review, we describe the current view of Treg subset heterogeneity, homeostasis and function in the context of TCR involvement. Recent studies of the TCR repertoire of Tregs, combined with single-cell gene expression analysis, revealed the importance of TCR specificity in shaping Treg phenotype diversity, their functions and homeostatic maintenance in various tissues. We propose that Tregs, like conventional T-helper cells, act to a great extent in an antigen-specific manner, which is provided by a specific distribution of Tregs in niches.

    更新日期:2020-01-14
  • Distribution of Bacterial α1,3-Galactosyltransferase Genes in the Human Gut Microbiome
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-06
    Emmanuel Montassier; Gabriel A. Al-Ghalith; Camille Mathé; Quentin Le Bastard; Venceslas Douillard; Abel Garnier; Rémi Guimon; Bastien Raimondeau; Yann Touchefeu; Emilie Duchalais; Nicolas Vince; Sophie Limou; Pierre-Antoine Gourraud; David A. Laplaud; Arnaud B. Nicot; Jean-Paul Soulillou; Laureline Berthelot

    Because of a loss-of-function mutation in the GGTA1 gene, humans are unable to synthetize α1,3-Galactose (Gal) decorated glycans and develop high levels of circulating anti-α1,3-Galactose antibodies (anti-Gal Abs). Anti-Gal Abs have been identified as a major obstacle of organ xenotransplantation and play a role in several host-pathogen relationships including potential susceptibility to infection. Anti-Gal Abs are supposed to stem from immunization against the gut microbiota, an assumption derived from the observation that some pathogens display α1,3-Gal and that antibiotic treatment decreases the level of anti-Gal. However, there is little information to date concerning the microorganisms producing α1,3-Gal in the human gut microbiome. Here, available α1,3-Galactosyltransferase (GT) gene sequences from gut bacteria were selectively quantified for the first time in the gut microbiome shotgun sequences of 163 adult individuals from three published population-based metagenomics analyses. We showed that most of the gut microbiome of adult individuals contained a small set of bacteria bearing α1,3-GT genes. These bacteria belong mainly to the Enterobacteriaceae family, including Escherichia coli, but also to Pasteurellaceae genera, Haemophilus influenza and Lactobacillus species. α1,3-Gal antigens and α1,3-GT activity were detected in healthy stools of individuals exhibiting α1,3-GT bacterial gene sequences in their shotgun data.

    更新日期:2020-01-14
  • Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-10
    Martin Villalba; Catherine Alexia; Anais Bellin-Robert; Alexis Fayd'herbe de Maudave; Delphine Gitenay

    The innate lymphocyte lineage natural killer (NK) is now the target of multiple clinical applications, although none has received an agreement from any regulatory agency yet. Transplant of naïve NK cells has not proven efficient enough in the vast majority of clinical trials. Hence, new protocols wish to improve their medical use by producing them from stem cells and/or modifying them by genetic engineering. These techniques have given interesting results but these improvements often hide that natural killers are mainly that: natural. We discuss here different ways to take advantage of NK physiology to improve their clinical activity without the need of additional modifications except for in vitro activation and expansion and allograft in patients. Some of these tactics include combination with monoclonal antibodies (mAb), drugs that change metabolism and engraftment of specific NK subsets with particular activity. Finally, we propose to use specific NK cell subsets found in certain patients that show increase activity against a specific disease, including the use of NK cells derived from patients.

    更新日期:2020-01-14
  • Neutralizing Anti-Rituximab Antibodies and Relapse in Membranous Nephropathy Treated With Rituximab
    Front. Immunol. (IF 4.716) Pub Date : 2019-12-16
    Sonia Boyer-Suavet; Marine Andreani; Maël Lateb; Benjamin Savenkoff; Vesna Brglez; Sylvia Benzaken; Ghislaine Bernard; Patrick H. Nachman; Vincent Esnault; Barbara Seitz-Polski

    Membranous Nephropathy (MN) is an autoimmune disease associated with antibodies against podocyte proteins: M-type phospholipase A2 receptor (PLA2R1) or thrombospondin type-1 domain-containing 7A (THSD7A) in 70 and 3% of patients, respectively. Antibody titer is correlated with disease activity: rising during active disease and decreasing before remission. Therefore, decreasing PLA2R1-Antibodies titer has become an important goal of therapy. Rituximab a chimeric monoclonal antibody induces remission in 60–80% of primary MN patients. All monoclonal antibodies such as rituximab can elicit antidrug antibodies, which may interfere with therapeutic response. We aim to analyze the relevance of anti-rituximab antibodies on the outcome of MN after a first course of rituximab. Forty-four MN patients were included and treated with two 1 g infusions of rituximab at 2-weeks interval. Anti-rituximab antibodies, CD19 count, and clinical response were analyzed. Then, we (i) analyzed the association of anti-rituximab antibodies at month-6 with response to treatment: remission, relapse and the need for another rituximab course; (ii) confirmed if anti-rituximab antibodies could neutralize rituximab B-cells depletion; and (iii) tested whether anti-rituximab antibodies could cross-inhibit new humanized anti-CD20 therapies. Anti-rituximab antibodies were detected in 10 patients (23%). Seventeen patients received a second rituximab course after a median time of 12 months (7–12), following nine cases of resistance and eight relapses. Anti-rituximab antibodies were significantly associated with faster B-cell reconstitution at month-6 (75 [57–89] vs. 2 [0–41] cells/μl, p = 0.006), higher proteinuria 12 months after rituximab infusion (1.7 [0.7; 5.8] vs. 0.6 [0.2; 3.4], p = 0.03) and before treatment modification (3.5 [1.6; 7.1] vs. 1.7 [0.2; 1.7] p = 0.0004). Remission rate 6 months after rituximab was not different according to anti-rituximab status (p > 0.99) but the rate of relapse was significantly higher for patients with anti-rituximab antibodies (p < 0.001). These patients required more frequently a second course of rituximab infusions (7/10 vs. 10/34, p = 0.03). Anti-rituximab antibodies neutralized rituximab activity in 8/10 patients and cross-reacted with other humanized monoclonal antibodies in only two patients. Three patients with anti-rituximab antibodies were successfully treated with ofatumumab. Anti-rituximab antibodies could neutralize rituximab B cells cytotoxicity and impact clinical outcome of MN patients. Humanized anti-CD20 seems to be a satisfying therapeutic alternative for patients with anti-rituximab antibodies and resistant or relapsing MN.

    更新日期:2020-01-14
  • Neonatal Antibiotic Treatment Is Associated With an Altered Circulating Immune Marker Profile at 1 Year of Age
    Front. Immunol. (IF 4.716) Pub Date : 2019-11-29
    Berthe C. Oosterloo; Belinda van't Land; Wilco de Jager; Nicole B. Rutten; Margot Klöpping; Johan Garssen; Arine M. Vlieger; Ruurd M. van Elburg

    Background: Neonatal antibiotics disturb the developing gut microbiome and are therefore thought to influence the developing immune system, but exact mechanisms and health consequences in later life still need to be elucidated. Therefore, we investigated whether neonatal antibiotics influence inflammatory markers at 1 year of age. In addition, we determined whether health problems during the first year of life, e.g., allergic disorders (eczema and wheezing) or infantile colics, were associated with changes in the circulating immune marker profile at 1 year of age. Methods: In a subgroup (N = 149) of the INCA-study, a prospective birth-cohort study, a blood sample was drawn from term born infants at 1 year of age and analyzed for 84 immune related markers using Luminex. Associations of antibiotic treatment, eczema, wheezing, and infantile colics with immune marker concentrations were investigated using a linear regression model. The trial is registered as NCT02536560. Results: The use of broad-spectrum antibiotics in the first week of life, was significantly associated with different levels of inflammatory markers including sVCAM-1, sCD14, sCD19, sCD27, IL-1RII, sVEGF-R1, and HSP70 at 1 year of age. Eczema was associated with decreased concentrations of IFNα, IFNγ, TSLP, CXCL9, and CXCL13, but increased concentrations of CCL18 and Galectin-3. Wheezing, independent of antibiotic treatment, was positively associated to TNF-R2 and resistin. Infantile colics were positively associated to IL-31, LIGHT, YKL-40, CXCL13, sPD1, IL1RI, sIL-7Ra, Gal-1, Gal-9, and S100A8 at 1 year of age, independent of early life antibiotic treatment. Conclusion: In this explorative study, we identified that neonatal antibiotics are associated with immunological alterations at 1 year of age and that, independent of the antibiotic treatment, infantile colics were associated with alterations within gut associated markers. These findings support the importance of the first host microbe interaction in early life immune development.

    更新日期:2020-01-14
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