Development Of Systemic Autoimmunity Research Articles

Silicosis and silica-induced autoimmunity in multiple Collaborative Cross strains.

Abstract Background: The connection between pulmonary silica dust exposure and the development of systemic autoimmunity is well established. However, the extent to which genetic differences influence the severity of silica-induced autoimmunity remains unclear. Objective: Investigate the role of silica exposure on disease biomarkers (cytokines/chemokines and antinuclear antibodies (ANA)) and systemic autoimmune disease in genetically diverse Collaborative Cross recombinant inbred (CC RI) mice. Methods: Baseline serum ANA and chemokines/cytokines were assessed from 61 CC RI strains. Six CC RI strains, chosen to represent different baseline immune phenotypes, were exposed to 5 mg crystalline silica or PBS and examined 12 weeks later for serum ANA, bronchoalveolar lavage fluid cell counts, tracheobronchial lymph node and spleen weights, and histological assessment of silicosis and lupus nephritis. Results: All strains developed silicosis; however, two strains with low baseline immune activity did not develop silica-induced autoimmunity. In contrast, strains with higher baseline immune activity developed elevated ANA levels with strain variation in ANA types. One strain developed lupus nephritis, with significantly greater severity compared to controls. Conclusion: Baseline immune activity significantly influences the development of silica-induced autoimmunity and lung inflammation; however, genetics may be mediating silicosis and systemic autoimmunity independently.

Influence of periodontitis on levels of autoantibodies in rheumatoid arthritis patients: A systematic review.

Periodontitis (PD) is a dysbiotic disease of tooth-supporting structures that has been associated with various systemic diseases including rheumatoid arthritis (RA). To date, evidence demonstrated increased prevalence of RA among PD patients and postulated PD to have a role in the development of autoantibodies in RA patients. Therefore, a systematic review was conducted to assess the available evidence to ascertain the effect of PD on levels of autoantibodies in the serum, saliva and gingival crevicular fluid (GCF) of RA patients. The systematic review was conducted in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. Relevant literature was searched from PubMed, Web of Science, Scopus and Ebscohost databases from inception until 31 August 2020. The risk of bias in each study was determined based on the Newcastle-Ottawa Scale tool. Results from random-effect meta-analyses were presented as summary estimates of odds ratios (ORs) for seropositivity and standardised mean difference (SMD) of autoantibody levels with 95% confidence intervals. Sensitivity tests and meta-regression were performed to assess the robustness of the results and potential cause of heterogeneity. The electronic and manual searches gathered 932 articles. Following screening and full-text assessment, a total of 29 studies were included in the analysis. Twenty-eight published observational studies were included in the quantitative analysis in the form of random-effect meta-analysis which revealed that PD was associated with anti-citrullinated proteins autoantibodies (ACPAs) and Rheumatoid Factor (RF) seropositive RA patients (OR for ACPA seropositivity: 1.82; 95% CI: 1.13-2.93) (OR for RF seropositivity: 1.53; 95% CI: 1.05-2.24). Also, RA patients with PD had increased serum levels of ACPA and RF. However, high heterogeneity among studies' results, partially ascribed to the unstandardised case definition of PD and laboratory testing of autoantibodies. Apart from ACPA and RF in serum, studies which reported on other RA-related autoantibodies, as well as autoantibody levels in saliva and GCF were scarce. RA patients with PD tend to have greater ACPA and RF levels in their serum when compared with the RA patients without PD supporting the plausible role of PD in the development of systemic autoimmunity in RA patients.

Inborn errors of immunity and immunodeficiencies: Antibody-mediated pathology and autoimmunity as a consequence of impaired immune reactions.

B-cell tolerance to self-antigen is an active process that requires the temporal and spatial integration of signals of defined intensity. In common variable immune deficiency disorders, CTLA-4 deficiency, autoimmune lymphoproliferative syndrome, or in collagen VII deficiency, genetic defects in molecules regulating development, activation, maturation, and ECM composition alter the generation of B cells, resulting in immunodeficiency. Paradoxically, at the same time, the defective immune processes favor autoantibody production and immunopathology through impaired establishment of tolerance. The development of systemic autoimmunity in the framework of defective BCR signaling is relatively unusual in genetic mouse models. In sharp contrast, such reduced signaling in humans is clearly linked to pathological autoimmunity. The molecular mechanisms by which tolerance is broken in these settings are only starting to be explored resulting in novel therapeutic interventions. For instance, in CTLA-4 deficiency, homeostasis can be restored by CTLA-4 Ig treatment. Following this example, the identification of the molecular targets causing the reduced signals and their restoration is a visionary way to reestablish tolerance and develop novel therapeutic avenues for immunopathologies.

+3179G/A Insulin-Like Growth Factor-1 Receptor Polymorphism: A Novel Susceptibility Contributor in Anti-Ro/SSA Positive Patients with Sjögren's Syndrome: Potential Clinical and Pathogenetic Implications.

Background: Alterations of the insulin-like growth factor (IGF) pathway along with genetic variations of the IGF1 receptor (IGF1R) gene have been linked to the development of systemic autoimmunity, possibly through apoptosis induction. This study aims to investigate whether genetic variations of the IGF1R contribute to Sjögren’s syndrome (SS) pathogenesis and explores potential functional implications. Methods: DNA extracted from whole peripheral blood derived from 277 primary SS patients, complicated or not by lymphoma, and 337 Healthy controls (HC) was genotyped for the rs2229765 IGF1R polymorphism using the RFLP-PCR assay. Gene expression of IGF1R and IGF1 isoforms, caspases 1, 4, and 5, and inflammasome components NLRP3, ASC, IL1β, IL18, IL33, IGFBP3, and IGFBP6 were quantitated by RT-PCR in total RNA extracted from minor salivary gland biopsies (MSGs) of 50 SS patients and 13 sicca controls (SCs). In addition, IGF1R immunohistochemical (IHC) expression was assessed in formalin-fixed, paraffin-embedded MSG tissue sections derived from 10 SS patients and 5 SCs. Results: The prevalence of the A/A genotype of the rs2229765 IGF1R polymorphism was significantly higher in the anti-Ro/SSA positive SS population compared to healthy controls (24.8% vs. 10.7%, p = 0.001). Moreover, IGF1Rs at both mRNA and protein levels were reduced in SS-derived MSGs compared to SCs and were negatively associated with caspase 1 transcripts. The latter were positively correlated with NLRP3, ASC, and IL1β at the salivary gland tissue level. IGF1R expression in peripheral blood was negatively correlated with ESR and IgG serum levels and positively correlated with urine-specific gravity values. Conclusions: The rs2229765 IGF1R variant confers increased susceptibility for seropositive primary SS. Dampened IGF1R mRNA and protein expression in salivary gland tissues could be related to increased apoptosis and subsequently to the activation of inflammasome pathways.

Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation.

ABSTRACTMyeloid-derived cells, in particular macrophages, are increasingly recognized as critical regulators of the balance of immunity and tolerance. However, whether they initiate autoimmune disease or perpetuate disease progression in terms of epiphenomena remains undefined.Here, we show that depletion of MCPIP1 in macrophages and granulocytes (Mcpip1fl/fl-LysMcre+ C57BL/6 mice) is sufficient to trigger severe autoimmune disease. This was evidenced by the expansion of B cells and plasma cells and spontaneous production of autoantibodies, including anti-dsDNA, anti-Smith and anti-histone antibodies. Consequently, we document evidence of severe skin inflammation, pneumonitis and histopathologic evidence of glomerular IgG deposits alongside mesangioproliferative nephritis in 6-month-old mice. These phenomena are related to systemic autoinflammation, which secondarily induces a set of cytokines such as Baff, Il5, Il9 and Cd40L, affecting adaptive immune responses. Therefore, abnormal macrophage activation is a key factor involved in the loss of immune tolerance.Overall, we demonstrate that deficiency of MCPIP1 solely in myeloid cells triggers systemic lupus-like autoimmunity and that the control of myeloid cell activation is a crucial checkpoint in the development of systemic autoimmunity.

T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy.

T cell subsets are critically involved in the development of systemic autoimmunity and organ inflammation in systemic lupus erythematosus (SLE). Each T cell subset function (such as effector, helper, memory or regulatory function) is dictated by distinct metabolic pathways requiring the availability of specific nutrients and intracellular enzymes. The activity of these enzymes or nutrient transporters influences the differentiation and function of T cells in autoimmune responses. Data are increasingly emerging on how metabolic processes control the function of various T cell subsets and how these metabolic processes are altered in SLE. Specifically, aberrant glycolysis, glutaminolysis, fatty acid and glycosphingolipid metabolism, mitochondrial hyperpolarization, oxidative stress and mTOR signalling underwrite the known function of T cell subsets in patients with SLE. A number of medications that are used in the careof patients with SLE affect cell metabolism, and the development of novel therapeutic approaches to control the activity of metabolic enzymes in T cell subsets represents a promising endeavour in the search for effective treatment of systemic autoimmune diseases.

Lifetime Pesticide Use and Antinuclear Antibodies in Male Farmers From the Agricultural Health Study.

Farming and pesticide use have been associated with systemic autoimmune diseases, and while certain organochlorine insecticides and other pesticides are suspected to influence risk, the role of specific pesticides in the development of systemic autoimmunity is not known. We measured serum antinuclear autoantibodies (ANA) by immunofluorescence on Hep-2 cells in 668 male farmers in the study of Biomarkers of Exposure and Effect in Agriculture (BEEA; 2010–2013), an Agricultural Health Study (AHS) subcohort. We examined ANA in relation to lifetime use of 46 pesticides first reported at AHS enrollment (1993–1997) and updated at intervals through BEEA enrollment. Odds ratios (OR) and 95% confidence intervals (CI) were estimated after adjusting for age, state, education, season of blood draw, current pesticide use, and correlated pesticides. Having ANA antibodies (3 or 4+ intensity at a 1:80 dilution, 21% of study participants) was associated with a reported history of seeking medical care due to exposure to pesticides (OR 2.15; 95%CI 1.17, 3.95), use of the fumigant methyl bromide (OR 3.16; 95%CI 1.05, 9.5), and use of petroleum oil/distillates (OR 1.50; 95%CI 1.00, 2.25). Using a higher threshold (3 or 4+ at a 1:160 dilution, 9%) ANA positivity was associated with the carbamate insecticide aldicarb (OR 4.82; 95%CI 1.33, 17.5) and greater combined use of four cyclodiene organochlorine insecticides (top tertile of intensity-weighted lifetime days vs. no use; OR T3 3.20; 95%CI 1.10, 9.27). By contrast, greater use of non-cyclodiene organochlorine insecticides was inversely associated with ANA (1:80 dilution 3 or 4+, OR T3 0.24; 95%CI 0.08, 0.72). Specific autoantibodies (to extractable nuclear antigens and anti-dsDNA), measured on those with ANA detected at the 1:80 dilution 3 or 4+, were seen in 15 individuals (2%), and were associated with use of two or more cyclodiene organochlorine insecticides and several other pesticides (e.g., carbofuran, ethylene dibromide). These findings suggest that specific pesticide exposures may have long-term effects on ANA prevalence and support the hypothesis that certain organochlorine insecticides may increase the risk of developing systemic autoimmunity.

DNGR1-mediated deletion of A20/Tnfaip3 in dendritic cells alters T and B-cell homeostasis and promotes autoimmune liver pathology

Dendritic cells (DCs) are central regulators of tolerance versus immunity. The outcome depends amongst others on DC subset and activation status. Whereas CD11b+ type 2 conventional DCs (cDC2s) initiate proinflammatory helper T (Th)-cell responses, CD103+ cDC1s are crucial for regulatory T-cell (Treg) induction and CD8+ T-cell activation. DC activation is controlled by the transcription factor NF-κB. Ablation of A20/Tnfaip3, a critical regulator of NF-κB activation, in DCs leads to constitutive DC activation and development of systemic autoimmunity. We hypothesized that the activation status of cDCs controls the development of autoimmunity.To target cDCs, DNGR1(Clec9a)-cre-mediated excision of A20/Tnfaip3 was used through generation of Tnfaip3fl/flxClec9a+/cre (Tnfaip3DNGR1−KO) mice. Immune cell activation was evaluated at 31-weeks of age.We found that DNGR1-cre-mediated deletion of A20/Tnfaip3 resulted in liver pathology characterized by inflammatory infiltrates adjacent to the portal triads. Both cDC subsets as well as monocyte-derived DCs (moDCs) in Tnfaip3DNGR1−KO livers harbored an activated phenotype. Specifically, the costimulatory molecule CD40 in liver cDCs and moDCs was regulated by A20/Tnfaip3 expression. Livers from Tnfaip3DNGR1−KO mice had augmented proportions of Th1, Th17, Treg, and follicular Th (Tfh)-cells compared to control mice, accompanied by an increase in IgA-producing plasma cells. Serum IgA from Tnfaip3DNGR1−KO mice recognized self-proteins, specifically cytoplasmic proteins in liver periportal regions.These data show that enhanced activation of cDCs and moDCs, due to A20/Tnfaip3 ablation, promotes the development of organ-specific autoimmunity but not systemic autoimmunity. This model could be useful to examine the pathobiological processes contributing to autoimmune liver diseases.

Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity

Eos (lkzf4) is a member of the Ikaros family of transcription factors and is preferentially expressed in T-regulatory (Treg) cells. However, the role of Eos in Treg function is controversial. One study using siRNA knock down of Eos demonstrated that it was critical for Treg suppressor function. In contrast, Treg from mice with a global deficiency of Eos had normal Treg function in vitro and in vivo. To further dissect the function of Eos in Tregs, we generated mice with a conditional knock out of Eos in Treg cells (lkzf4fl/fl X Foxp3YFP−cre, Eos cKO). Deletion of Eos in Treg resulted in activation of CD4+Foxp3- and CD8+ T cells at the age of 3 months, cellular infiltration in non-lymphoid tissues, hyperglobulinemia, and anti-nuclear antibodies. While Tregs from Eos cKO mice displayed normal suppressive function in vitro, Eos cKO mice developed severe Experimental Autoimmune Encephalomyletis (EAE) following immunization with myelin oligodendrocyte glycoprotein (MOG) and Eos cKO Treg were unable to suppress Inflammatory Bowel Disease (IBD). Eos cKO mice had decreased growth of the transplantable murine adenocarcinoma MC38 tumor accompanied by enhanced IFN-γ/TNF-α production by CD8+ T cells in tumor draining lymph nodes. Mice with a global deficiency of Eos or a deficiency of Eos only in T cells developed autoimmunity at a much older age (12 months or 7–8 months, respectively). Taken together, Eos appears to play an essential role in multiple aspects of Treg suppressor function, but also plays an as yet unknown role in the function of CD4+Foxp3- and CD8+ T cells and potentially in non-T cells.

Review: Transcriptional Regulation of CD4+ T Cell Differentiation in Experimentally Induced Arthritis and Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of the joint synovium and infiltration by activated inflammatory cells. CD4+ T cells form a large proportion of the inflammatory cells invading the synovial tissue, and are involved in the RA pathologic process. In general, CD4+ T cells differentiate into various T helper cell subsets and acquire the functional properties to respond to specific pathogens, and also mediate some autoimmune disorders such as RA. Because the differentiation of T helper cell subsets is determined by the expression of specific transcription factors in response to the cytokine environment, these transcription factors are considered to have a role in the pathology of RA. Treg cells control an excess of T cell–mediated immune response, and the transcription factor FoxP3 is critical for the differentiation and function of Treg cells. Treg cell dysfunction can result in the development of systemic autoimmunity. In this review, we summarize how the expression of transcription factors modulates T helper cell immune responses and the development of autoimmune diseases, especially in RA. Understanding the role of transcription factors in the pathogenesis of autoimmunity may lead to novel therapeutic strategies to control the differentiation and function of both T helper cells and Treg cells.

MicroRNA control in the development of systemic autoimmunity

Mammalian immune responses are intended to eradicate microbial pathogens and thus protect individuals from the harmful effects of such infections. However, unresolved inflammation can be devastating to the host and cause tissue damage and organ malfunction. Immune responses can even mistakenly target self-antigens and mediate autoimmune inflammation. Consequently, a variety of cellular and molecular mechanisms have evolved to control the inflammatory responses, and many of these safeguards or triggers are perturbed in the setting of autoimmunity. In this review, we discuss the emerging roles of cellular non-coding RNAs, and in particular microRNAs (miRNAs), in the regulation of autoimmune inflammation. How miRNAs function to impact the onset, magnitude, and resolution of inflammatory responses and recent observations regarding links between miRNAs and specific autoimmune disorders will be addressed. Finally, the diagnostic and therapeutic relevance of miRNAs involved in autoimmunity will be considered. It is clear that, taken together, mammalian miRNAs are integral to the pathogenesis of mammalian autoimmune diseases and may be effective targets of next-generation therapeutics aimed at eradicating tissue inflammation.

Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice

Tim-1, a type I transmembrane glycoprotein, consists of an IgV domain and a mucin domain. The IgV domain is essential for binding Tim-1 to its ligands, but little is known about the role of the mucin domain, even though genetic association of TIM-1 with atopy/asthma has been linked to the length of mucin domain. We generated a Tim-1-mutant mouse (Tim-1(Δmucin)) in which the mucin domain was deleted genetically. The mutant mice showed a profound defect in IL-10 production from regulatory B cells (Bregs). Associated with the loss of IL-10 production in B cells, older Tim-1(Δmucin) mice developed spontaneous autoimmunity associated with hyperactive T cells, with increased production of IFN-γ and elevated serum levels of Ig and autoantibodies. However, Tim-1(Δmucin) mice did not develop frank systemic autoimmune disease unless they were crossed onto the Fas-mutant lpr mice on a C57BL/6 background. Tim-1(Δmucin)lpr mice developed accelerated and fulminant systemic autoimmunity with accumulation of abnormal double-negative T cells and autoantibodies to a number of lupus-associated autoantigens. Thus, Tim-1 plays a critical role in maintaining suppressive Breg function, and our data also demonstrate an unexpected role of the Tim-1 mucin domain in regulating Breg function and maintaining self-tolerance.

Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells

AbstractThe antiphospholipid syndrome (APS) is an autoimmune disease characterized by thromboembolic events and/or fetal loss in the presence of antiphospholipid antibodies (aPLs). The mechanisms underlying the pathogenicity of aPLs are still poorly understood. Here we show that 3 human monoclonal aPLs as well as IgG fractions from patients with the APS increase mRNA expression of the intracellular toll-like receptor (TLR) 7 in plasmacytoid dendritic cells and TLR8 in monocytes. Simultaneously they induce the translocation of TLR7 or TLR8 from the endoplasmic reticulum to the endosome. These effects depend on the uptake of aPLs into the endosome, subsequent activation of endosomal NADPH oxidase, and generation of superoxide. As a consequence cells are dramatically sensitized to ligands for TLR7 and TLR8. This observation delineates a novel signal transduction pathway in innate immunity originating from the endosome. Because the overexpression of TLR7 can also be detected in plasmacytoid dendritic cells from patients with the APS ex vivo, our results provide an explanation for proinflammatory and procoagulant effects of aPLs. Because inappropriate expression of TLR7 has been implicated in the development of systemic autoimmunity, these findings may also be relevant for the understanding of autoimmunity.

The Ubiquitin-Editing Protein A20 Prevents Dendritic Cell Activation, Recognition of Apoptotic Cells, and Systemic Autoimmunity

Dendritic cells (DCs) regulate both immunity and tolerance. Here we have shown that the ubiquitin editing enzyme A20 (Tnfaip3) determines the activation threshold of DCs, via control of canonical NF-κB activation. Tnfaip3(fl/fl)Cd11c-cre(+) mice lacking A20 in DCs demonstrated spontaneous proliferation of conventional and double-negative Tcells, their conversion to interferon-γ (IFN-γ)-producing effector cells, and expansion of plasma cells. They developed ds-DNA antibodies, nephritis, the antiphospholipid syndrome, and lymphosplenomegaly-features of systemic lupus erythematosus-and extramedullary hematopoiesis. A20-deficient DCs were resistant to apoptosis, caused by increased sensitivity to CD40L and RANKL prosurvival signals and upregulation of antiapoptotic proteins Bcl-2 and Bcl-x. They captured injected apoptotic cells more efficiently, resisted the inhibitory effects of apoptotic cells, and induced self-reactive effector lymphocytes. Because genetic polymorphisms in TNFAIP3 are associated with human autoimmune disorders, these findings identify A20-mediated control of DC activation as a crucial checkpoint in the development of systemic autoimmunity.

Deficiency of gelatinase B/MMP-9 aggravates lpr-induced lymphoproliferation and lupus-like systemic autoimmune disease

Gelatinase B/matrix metalloproteinase-9 (MMP-9) is a key enzyme involved in inflammatory, hematological, vascular and neoplastic diseases. In previous studies, we explored the intracellular substrate set or ‘degradome’ of MMP-9 and found many systemic autoantigens as novel intracellular gelatinase B substrates. Little is known, however, about the functional role of MMP-9 in the development of systemic autoimmunity in vivo. B6lpr/lpr mice with defective Fas-mediated apoptosis were used to investigate the functions of MMP-9 in lymphocyte proliferation and in the development of systemic autoimmunity. Combined Fas and gelatinase B deficiency resulted in extreme lymphoproliferative disease with enhanced lymphadenopathy and splenomegaly, and significantly reduced survival compared with single Fas deficiency. At the cellular level, this was corroborated by increased lymph node accumulation of ‘double negative’ T cells, B cells and myeloid cells. In addition, higher autoantibody titers and more pronounced autoimmune tissue injury were found in the absence of MMP-9, culminating in chronically enhanced systemic lupus erythematosus (SLE)-like autoimmunity. After cleavage by MMP-9 the SLE autoantigens U1snRNP A and ribosomal protein P0 were hardly recognized by plasma samples of both B6lpr/lpr.MMP-9−/− and B6lpr/lpr.MMP-9+/+ mice, pointing to a destruction of B cell epitopes by MMP-9-mediated proteolysis. In addition, the same loss of immunodominant epitopes was observed with plasma samples from SLE patients, suggesting that MMP-9 suppresses systemic antibody-mediated autoimmunity by clearance of autoepitopes in immunogenic substrates. Thus, new protective functions for MMP-9 were revealed in the suppression of lymphoproliferation and dampening of systemic autoimmunity, cautioning against the long-term use of MMP inhibitors in autoimmune lymphoproliferative syndrome (ALPS) and SLE.

Thrombotic Microangiopathic Hemolytic Anemia With Reduction of ADAMTS13 Activity

Severe manifestations of systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and thrombotic thrombocytopenic purpura (TTP) are characterized by multiorgan thrombotic microangiopathy. We describe reduction of ADAMTS13 activity and the development of systemic autoimmunity in all 8 children initially diagnosed with acquired noncongenital TTP during an 8.5-year period. Median age at diagnosis was 12.0 years (range, 2.6-17.3 years). ADAMTS13 activity was absent (<5%) in 6 patients; 3 patients had a detected inhibitor. SLE was diagnosed concurrently in 3 patients, and 4 patients were diagnosed within 5 years. Six of the children diagnosed with SLE had absent ADAMTS13 activity at diagnosis. In 6 patients with SLE, immune-mediated nephritis developed by 46 months. All surviving patients with SLE developed antiphospholipid antibodies, including some with a lupus anticoagulant. Patients with SLE did not have TTP recurrences once daily immunosuppressive regimens were started. An evaluation for SLE/APS is warranted in children and adolescents with reduced ADAMTS13 activity and thrombotic microangiopathy.

Manifestations of systemic autoimmunity in vaccinated salmon

The development of systemic autoimmunity may result as an undesired side-effect following vaccination, and this condition was recently shown to occur in farmed salmon ( Salmo salar). Several of previously reported side-effects following vaccination of fish should therefore be reviewed in the light of this condition. Here, organs and pathological changes in three separate groups of fish severely affected by vaccination were investigated by different morphological methods ( n = 84). Granulomas or microgranulomas were observed at the injection site and in several organs. Mott cells were observed in all tissues examined. Pannus-like changes with lymphocyte infiltrates were observed in spines. In conclusion, the reactions following vaccination were of a systemic nature that may be explained by a pathogenetic mechanism caused by systemic autoimmunity.

The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells

Mechanisms linking innate immunity and autoimmune responses are poorly understood. Myeloid-related protein-8 (Mrp8) and Mrp14 are damage-associated molecular pattern molecules (DAMPs) highly upregulated in various autoimmune disorders. We show in a mouse autoimmune model that local Mrp8 and Mrp14 production is essential for the induction of autoreactive CD8+ T cells and the development of systemic autoimmunity. This effect is mediated via Toll-like receptor 4 (TLR4) signaling leading to increased interleukin-17 (IL-17) expression. Notably, expression of Mrp8 and Mrp14 was upregulated in cutaneous lupus erythematosus, and stimulation of CD8+ T cells from individuals with lupus erythematosus with MRP proteins resulted in an upregulation of IL-17, suggesting a key role for MRP8 and MRP14 for the development of autoreactive lymphocytes during human autoimmunity as well. These results demonstrate a link between local expression of DAMP molecules and the development of systemic autoimmunity.

Sex hormone-independent capacities of female hematopoietic cells from lupus-prone mice (83.23)

Abstract Many systemic autoimmune diseases are more commonly found in females than in males. This is evident in Systemic Lupus Erythromatosis (SLE), a prototypic systemic autoimmune disorder, where the ratio of females to males is 9:1. Our current understanding of the etiology of SLE implies important roles for genes and environmental factors such as sex hormones. Analyses of mouse models of SLE have proven good models for both; however, the relative importance of genes versus sex hormones is still largely unresolved. Using the (NZB x NZW)F1 mouse model system of SLE we have created a system in which we can segregate the effects of genes and hormones on the immune system in vivo. Briefly, male or female (NZB x NZW)F1 mice were lethally irradiated and reconstituted by age-matched male or female bone marrow (BM) or fetal liver (FL) cells. The resulting chimera mice were followed for the development of lupus-like disease. We found that female BM and FL cells express an intrinsic capacity to drive accelerated lupus-like disease development even in the presence of male pubertal sex hormones. Interestingly, chimera mice receiving female cells also presented with increased serum cytokine and immunoglobulin levels, suggesting that activation of both T and B cells happened more easily in female than male cells. These data represent a new system in which to investigate intrinsic differences between male and female immune mechanisms during the development of systemic autoimmunity.

IL-21 and T follicular helper cells

Upon encounter with antigen, CD4(+) T cells differentiate into effector T(h) subsets with distinctive functions that are related to their unique cytokine profiles and anatomical locations. One of the most important T(h) functions is to provide signals to developing B cells that induce specific and appropriate antibody responses. The major CD4(+) T cell subset that helps B cells is the T follicular helper (T(FH)) cell, whose expression of the chemokine receptor CXCR5 [chemokine (C-X-C motif) receptor 5] serves to localize this cell to developing germinal centers (GCs) where it provides instructive signals leading to Ig class switching and somatic mutation. T(FH) cells produce high levels of IL-21, a cytokine that is critical for GC formation and also for the generation of T(FH) cells. Although T(FH) cells have been found to produce cytokines characteristic of other T(h) subsets, they represent a distinct lineage whose development is driven by the transcription factor B-cell CLL lymphoma-6 (BCL6). Consistent with their critical role in the generation of antibody responses, dysregulated T(FH) function has been associated with the development of systemic autoimmunity. Here, we review the role of IL-21 in the regulation of normal T(FH) development and function as well as in progression of autoimmune responses.