Epistasis and immunity: the role of genetic interactions in autoimmune diseases

Autoimmune disorders are a complex and varied group of diseases that are caused by breakdown of self-tolerance. The aetiology of autoimmunity is multi-factorial, with both environmental triggers and genetically determined risk factors. In recent years, it has been increasingly recognized that genetic risk factors do not act in isolation, but rather the combination of individual additive effects, gene-gene interactions and gene-environment interactions determine overall risk of autoimmunity. The importance of gene-gene interactions, or epistasis, has been recently brought into focus, with research demonstrating that many autoimmune diseases, including rheumatic arthritis, autoimmune glomerulonephritis, systemic lupus erythematosus and multiple sclerosis, are influenced by epistatic interactions. This review sets out to examine the basic mechanisms of epistasis, how epistasis influences the immune system and the role of epistasis in two major autoimmune conditions, systemic lupus erythematosus and multiple sclerosis.     

Toll-like receptor 8 deletion accelerates autoimmunity in a mouse model of lupus through a Toll-like receptor 7-dependent mechanism

Systemic lupus erythematosus is an autoimmune disorder characterized by increased levels of lymphocyte activation, antigen presentation by dendritic cells, and the formation of autoantibodies. This leads to immune complex-mediated glomerulonephritis. Toll-like receptor 7 (T7) and TLR9 localize to the endosomal compartment and play important roles in the generation of autoantibodies against nuclear components, as they recognize RNA and DNA, respectively. In contrast, very little is known about endogenous TLR8 activation in mice. We therefore tested whether TLR8 could affect autoimmune responses in a murine model of lupus. We introduced a Tlr8 null mutation into C57BL/6 mice congenic for the Nba2 (NZB autoimmunity 2) locus and bearing the Yaa (Y-linked autoimmune acceleration) mutation containing a tlr8 duplicated gene, and monitored disease development, autoantibody production, and glomerulonephritis-associated mortality. Cellular responses were investigated in female Nba2.TLR8^−/− mice bearing no copy of tlr8. The TLR8 deficiency accelerated disease progression and mortality, increased the number of circulating antibodies and activated monocytes, and heightened cellular responses to TLR7 ligation. TLR8-deficient antigen-presenting cells exhibited increased levels of MHC class II expression. The ability of dendritic cells to present antigens to allogeneic T cells after TLR7 ligation was also improved by TLR8 deficiency. TLR8 deletion accelerated autoimmunity in lupus-prone mice in response to TLR7 activation. Antigen-presenting cell function seemed to play a key role in mediating the effects of TLR8 deficiency.     

Relationship between natural and infection‐induced antibodies in systemic autoimmune diseases (SAD): SLE,SSc and RA

Infection or vaccine‐induced T cell‐dependent immune response and the subsequent high‐affinity neutralizing antibody production have been extensively studied, while the connection between natural autoantibodies (nAAbs) and disease‐specific antibodies has not been thoroughly investigated. Our goal was to find the relationship between immunoglobulin (Ig)M and IgG isotype nAAbs and infection or vaccine‐induced and disease‐related autoantibody levels in systemic autoimmune diseases (SAD). A previously described indirect enzyme‐linked immunosorbent assay (ELISA) test was used for detection of IgM/IgG nAAbs against citrate synthase (anti‐CS) and F4 fragment (anti‐F4) of DNA topoisomerase I in 374 SAD samples, with a special focus on systemic lupus erythematosus (SLE) (n = 92), rheumatoid arthritis (n = 73) and systemic sclerosis (n = 157) disease groups. Anti‐measles IgG and anti‐dsDNA IgG/IgM autoantibodies were measured using commercial and in‐house indirect ELISA tests. In all SAD groups the anti‐measles IgG‐seropositive cases showed significantly higher anti‐CS IgG titers (P = 0·011). In anti‐dsDNA IgG‐positive SLE patients, we detected significantly higher levels of anti‐CS and anti‐F4 IgG nAAbs (P = 0·001 and < 0·001, respectively). Additionally, we found increased levels of IgM isotypes of anti‐CS and anti‐F4 nAAbs in anti‐dsDNA IgM‐positive SLE patients (P = 0·002 and 0·016, respectively). The association between IgG isotypes of pathogen‐ or autoimmune disease‐related antibodies and the IgG nAAbs may underscore the immune response‐inducible nature of the diseases investigated. The relationship between protective anti‐dsDNA IgM and the IgM isotype of anti‐F4 and anti‐CS may provide immunoserological evidence for the beneficial roles of nAAbs in SLE patients.     

Toll样受体7及I型干扰素通路在系统性红斑狼疮中的作用研究

探讨Toll样受体7(TLR7)及I型干扰素(IFN-α)通路在系统性红斑狼疮(SLE)发病中的作用。采用实时荧光定量PCR方法检测42例SLE患者和34例正常人外周血TLR7mRNA以及4个干扰素调节基因mRNA的表达水平,同时观察TLR7mRNA的表达量与SLE疾病活动相关指标和干扰素积分(IFN score)的关系。结果,SLE患者外周血TLR7mRNA的表达水平显著增高;TLR7mRNA的表达水平与SLEDAI积分、肾脏损伤指数、抗双链DNA(dsDNA)抗体、抗RNA相关抗体水平及干扰素积分呈正相关;与补体C3、C4、白细胞数呈负相关。TLR7—IFN-α通路可能参与了SLE的病理过程。     

dsRNA sensors and plasmacytoid dendritic cells in host defense and autoimmunity

The innate immune system detects viruses through molecular sensors that trigger the production of type I interferons (IFN-I) and inflammatory cytokines. As viruses vary tremendously in size, structure, genomic composition, and tissue tropism, multiple sensors are required to detect their presence in various cell types and tissues. In this review, we summarize current knowledge of the diversity, specificity, and signaling pathways downstream of viral sensors and ask whether two distinct sensors that recognize the same viral component are complementary, compensatory, or simply redundant. We also discuss why viral sensors are differentially distributed in distinct cell types and whether a particular cell type dominates the IFN-I response during viral infection. Finally, we review evidence suggesting that inappropriate signaling through viral sensors may induce autoimmunity. The picture emerging from these studies is that disparate viral sensors in different cell types form a dynamic and integrated molecular network that can be exploited for improving vaccination and therapeutic strategies for infectious and autoimmune diseases.     

半乳凝素-1与自身免疫疾病

 自身免疫性疾病是机体对自身抗原发生免疫反应而导致自身组织损害的一系列疾病,其发病机制复杂,T辅助细胞亚群失衡在其中发挥重要作用。半乳凝素-1是一种内源性糖结合蛋白,在T细胞的凋亡、信号传导及细胞因子的分泌等发挥重要的调节作用,有大量研究表明gal-1参与了自身免疫性疾病的发病机制,给予重组gal-1干预可以改善疾病的严重程度,延缓疾病进展,提示其有望成为一个新的自身免疫性疾病的治疗靶点。     

DNA甲基化与自身免疫性疾病

DNA甲基化及其调节酶是近年来表观遗传学研究的热点。 DNA甲基化异常可影响某些基因的表达,导致自身免疫性疾病的发生发展。深入研究DNA甲基化在自身免疫性疾病中的作用, 有利于阐明自身免疫性疾病的发病机制,为治疗这些疾病提供新的线索。     

A model for lupus brain disease

Systemic lupus erythematosus is an autoimmune disease characterized by antibodies that bind target autoantigens in multiple organs in the body. In peripheral organs, immune complexes engage the complement cascade, recruiting blood-borne inflammatory cells and initiating tissue inflammation. Immune complex-mediated activation of Fc receptors on infiltrating blood-borne cells and tissue resident cells amplifies an inflammatory cascade with resulting damage to tissue function, ultimately leading to tissue destruction. This pathophysiology appears to explain tissue injury throughout the body, except in the central nervous system. This review addresses a paradigm we have developed for autoantibody-mediated brain damage. This paradigm suggests that antibody-mediated brain disease does not depend on immune complex formation but rather on antibody-mediated alterations in neuronal activation and survival. Moreover, antibodies only access brain tissue when blood-brain barrier integrity is impaired, leading to a lack of concurrence of brain disease and tissue injury in other organs. We discuss the implications of this model for lupus and for identifying other antibodies that may contribute to brain disease.     

An MRL/MpJ-lpr/lpr substrain with a limited expansion of lpr double-negative T cells and a reduced autoimmune syndrome

The autosomal recessive mutant gene, lpr, has been shown toaccelerate the progression of lupus-like autoimmune disease,which is associated with a massive expansion of a unique CD4^–CD8^–double-negative T cell subset, in MRL/MpJ mice. Here we reporta substrain of MRL/MpJ-lpr/lpr (MRL-lpr) mice which live almosttwice as long with delayed development of glomerulonephritis,compared with conventional MRL-lpr mice. This substrain, termedMRL-lpr.II (II for long-lived), develops generalized lymphadenopathycharacteristically seen in MRL-lpr mice. However, the expansionof a double negative lpr T cell subset is markedly limited witha mean value of 15% in their lymph nodes compared to about 70%in conventional MRL-lpr mice. Overall production of autoantibodies,such as anti-DNA and rheumatoid factors, does not significantlydiffer between the two MRL-lpr mice. However, serum levels ofcryoglobulins, whose major component is lgG3, are markedly diminishedin MRL-lpr.ll mice with a parallel decrease in lgG3. Since MRL-lpr.llmice still carry the lpr mutation, as documented by the presenceof defects in the Fas antigen, a possible new mutation in thissubstrain may play a significant role in the pathogenesls oflupus-like autoimmune syndrome.     

Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease resulting from dysregulation of the immune system. Interleukin-6 (IL-6) is a multifunctional cytokine produced by macrophages, monocytes and T and B cells. It stimulates B-cell differentiation/maturation, immunoglobulin secretion, and T-cell functions. Elevated levels of IL-6 in serum, urine and renal glomeruli were detected in patients with active SLE and in murine models of SLE. Our study investigated the role of IL-6 in an SLE-like disease in New Zealand Black/White (NZB/W) F1 mice by administration of an anti-murine IL-6 monoclonal antibody (mAb). Intraperitoneal administration of the anti-IL-6 mAb suppressed the production of anti-dsDNA autoantibody. B-cell proliferation induced by anti-IgM and anti-CD40 was lower in the anti-IL-6 mAb-treated mice, ex vivo studies demonstrated that anti-IL-6 mAb treatment inhibited anti-dsDNA production. Anti-CD3-induced T-cell proliferation and mixed lymphocyte reactions were inhibited by anti-IL-6 mAb treatment, indicating a partial down-regulation of T cells. Histological analysis showed that treatment with anti-IL-6 mAb prevented the development of severe kidney disease. These results suggest that treatment with anti-IL-6 mAb has a beneficial effect on autoimmunity in murine SLE and that autoreactive B cells may be the primary target for anti-IL-6 mAb treatment; its effect on autoreactive T cells is also indicated.     

Combined steroid-cyclosporin treatment of chronic autoimmune diseases

Summary Twenty-one patients suffering from different autoimmune diseases (14 from systemic lupus erythematosus, 4 from rheumatoid arthritis, one from Sjögren's syndrome, one from systemic hypersensitivity vasculitis, and one from diffuse proliferative glomerulonephritis) were treated with a combined immuno-suppressive regimen. Cyclosporin was given at a dose of 5 mg/kg/day together with steroids. In addition, the rheumatoid arthritis patients also received methotrexate. In all patients a kidney biopsy was performed after a treatment period of 17 to 42 months (mean duration 21.7 months). The cumulative cyclosporin dose at the time of biopsy varied from 1.071 to 4.587 mg/kg. Patients suffering from systemic lupus erythematosus and rheumatoid arthritis were assessed according to a scoring system set up for this purpose. The combined therapy proved useful in these patients as reflected in the diminution of the respective activity scores, improvement of kidney function, and diminution of proteinuria. Histological examination of the kidney biopsy specimens showed only minimal activity in patients with systemic lupus erythematosus. No unequivocal signs of renal toxicity could be detected. In the last group, the condition of the patient with Sjögren's syndrome was stabilized and the patient with systemic vasculitis improved clinically. Neither patient had signs of kidney lesions. The patient with diffuse proliferative glomerulonephritis, in whom kidney biopsy was performed before and after treatment, showed improvement of kidney function, diminution of proteinuria, and diminution of inflammatory activity within the kidney, and no signs of cyclosporin toxicity.Abbreviations CyA Cyclosporin - MTX Methotrexate - NSAID Nonsteroidal antiinflammatory drugs - RA Rheumatoid arthritis - SLE Systemic lupus erythematosus - TFA index Index of extent of tubular atrophy, intersitital fibrosis, and arteriolopathy     

Human B-cell subset identification and changes in inflammatory diseases

Open in a separate windowGraphical Abstract     

Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases

Summary:  The molecular apparatus that protects us against infection can also injure us by causing autoimmune or autoinflammatory disease. It now seems that at times, defects within the sensing arm of innate immunity contribute to diseases of this type. The initiation of an immune response is often microbe dependent and, in many cases, Toll-like receptor (TLR) dependent. Positive feedback loops triggering immune activation may occur when TLR signaling pathways stimulate host cells in an unchecked manner. Or, immune activation may persist because of failure to eradicate an inciting infection. Or on occasion, endogenous DNA may trigger specific immune responses that beget further responses in a TLR-dependent autoamplification loop. Specific biochemical defects that cause loop-related autoimmunity have been revealed by random germline mutagenesis and by gene targeting. We have also developed some insight into critical points at which feedback loops can be interrupted.     

长链非编码RNA在自身免疫性疾病中的研究进展

长链非编码RNA(LncRNAs)是转录本长度大于等于200 nt的,不具备编码蛋白功能的RNA。LncRNAs具有基因转录、蛋白质转运及染色质重塑等功能。LncRNAs参与多种免疫性疾病的发生、发展与转归,在自身免疫性疾病中发挥重要的作用。     

Haemodialysis as a model for studying endogenous plasma DNA: oligonucleosome-like structure and clearance.

The rate of clearance of extracellular plasma DNA in man has important implications for pathogenetic mechanisms in systemic lupus erythematosus (SLE), as well as for certain other clinical states. Present knowledge of this parameter is derived exclusively from studies of injected, naked DNA in animals. Recent information indicates that the physiologic form of plasma DNA in SLE is that of oligonucleosome-like molecules rather than of naked DNA and consists of multimeric complexes of DNA bound to histone, probably arising from an apoptotic process. In order to study the rate at which these oligonucleosome-like complexes are removed from plasma and to do so in man rather than experimental animals, we exploited the observation that during haemodialysis large amounts of DNA are released, apparently within the dialysis coil, into the patient's plasma. Since this release appears to cease promptly with termination of the procedure, it offered the potential for estimating the rate of removal of such DNA from human plasma. Moreover, if that DNA, as postulated, were shown to possess an oligonucleosome-like structure resembling that found endogenously in human SLE, the relevance of such information to the human disease state would be further enhanced. The present results support the conclusion that DNA released into plasma during haemodialysis possesses such an oligonucleosome-like structure. The plasma half-life of that DNA in man was found not to exceed 4 min. The highly dynamic state thus implied for extracellular endogenous plasma DNA in man has important implications for pathogenetic mechanisms dependent on dsDNA in SLE. Moreover, individuals undergoing chronic haemodialysis, who are thereby exposed to a very large cumulative amount of such DNA, might serve as models for studying its long-term sequelae.     

IL-17: A new actor in IFN-driven systemic autoimmune diseases

Systemic autoimmune diseases such as systemic lupus erythematosus are type I IFN-driven diseases with exaggerated B-cell responses and autoantibody production. Th17 cells, a T-helper-cell subset with high inflammatory capacity, was initially discovered and characterized in the context of experimental autoimmune encephalomyelitis - an animal model of multiple sclerosis. There is now emerging evidence that Th17 cells, and more generally IL-17 and IL-17-producing cells, may play a role in the pathogenesis of type I IFN-driven systemic autoimmune diseases such as lupus. Here, we review the different studies suggesting a role for IL-17 and IL-17-producing cells in systemic autoimmune diseases, both in humans and in animal models, and we consider the possible mechanisms by which these cells may contribute to disease. We also discuss the hypothesis that type I IFN and IL-17 act in concert to sustain and amplify autoimmune and inflammatory responses, making them a dangerous combination involved in the pathogenesis of systemic autoimmune diseases.     

Carbonic anhydrase III: A new target for autoantibodies in autoimmune diseases

The objective of this study was to identify new autoantibodies that could be useful for the diagnosis of rheumatoid arthritis (RA) using immunoblotting on synovial membrane proteins which represent the best source of candidate RA autoantigens. A new target protein with a molecular weight of 26 kDa was found to be recognized by autoantibodies in RA sera and was identified using MALDI-TOF mass spectrometry and second-dimension electrophoresis as carbonic anhydrase III (CAIII). Three similar protein spots at 26 kDa were recognized by both human sera and monoclonal antibody (mAb) directed against CAIII on immunoblotting using the human recombinant CAIII. Interestingly, CAIII expression within the synovial membrane was not observed in non-RA patients and was differentially expressed among RA patients. The sensitivity of these new autoantibodies for RA, using an immunoenzymatic technique, was 17%. Specificity was high when comparing non-autoimmune diseases (100%), while it was found to be weak (67%) when comparing some other autoimmune diseases, and particularly systemic lupus erythematosus (SLE). In conclusion, this study demonstrates that these new autoantibodies against CAIII are not restricted to RA. However the expression of CAIII in the synovial membrane of RA warrants further investigation of the pathophysiological relevance of this finding.     

A novel antagonist of Toll-like receptors 7, 8 and 9 suppresses lupus disease-associated parameters in NZBW/F1 mice

Abstract

Systemic Lupus Erythematosus is an autoimmune disease characterized by production of autoantibodies against nucleic acid-associated antigens. Endogenous DNA and RNA associated with these antigens stimulate inflammatory responses through Toll-like receptors (TLRs) and exacerbate lupus disease pathology. We have evaluated an antagonist of TLR7, 8 and 9 as a therapeutic agent in lupus-prone NZBW/F1 mice. NZBW/F1 mice treated with the antagonist had lower serum levels of autoantibodies targeting DNA, RNP, Smith antigen, SSA and SSB than did untreated mice. Reduction in blood urea nitrogen and proteinuria and improvements in kidney histopathology were observed in antagonist-treated mice. The antagonist treatment also reduced serum IL-12 and IL-1β and increased IL-10 levels. Levels of mRNA for IL-6, iNOS and IL-1β were lower in the kidneys and spleen of antagonist-treated mice than in those of untreated mice. Levels of mRNA for IP-10, TNFRSF9 and FASL were lower and IL-4 mRNA were higher in spleens of antagonist-treated mice than in spleens of untreated mice. mRNA for the inflammasome component NLRP3 was lower and mRNA for the antioxidant enzymes, catalase and glutathione peroxidase 1 was higher in the kidneys of antagonist-treated mice than in those of untreated mice. These results show that the antagonist of TLR7, 8 and 9 effectively inhibits inflammatory pathways involved in the development of lupus in NZBW/F1 mice and constitutes a potential therapeutic approach for the treatment of lupus and other autoimmune diseases.     

Intrinsic hyporesponsiveness of invariant natural killer T cells precedes the onset of lupus

Patients with systemic lupus erythematosus (SLE) display reduced numbers and functions of invariant natural killer T (iNK T) cells, which are restored upon treatment with corticosteroids and rituximab. It is unclear whether the iNK T cell insufficiency is a consequence of disease or is a primary abnormality that precedes the onset of disease. To address this, we analysed iNK T cell function at different stages of disease development using the genetically lupus‐susceptible NZB × NZW F₁ (BWF₁) model. We found that iNK T cell in‐vivo cytokine responses to an iNK T cell ligand α‐galactosylceramide (α‐GalCer) were lower in BWF₁ mice than in non‐autoimmune BALB/c and major histocompatibility complex (MHC)‐matched NZB × N/B10.PL F₁ mice, although iNK T cell numbers in the periphery were unchanged in BWF₁ mice compared to control mice. Such iNK T cell hyporesponsiveness in BWF₁ mice was detected at a young age long before the animals exhibited any sign of autoimmunity. In‐vivo activation of iNK T cells is known to transactivate other immune cells. Such transactivated T and B cell activation markers and/or cytokine responses were also lower in BWF₁ mice than in BALB/c controls. Finally, we show that iNK T cell responses were markedly deficient in the NZB parent but not in NZW parent of BWF₁ mice, suggesting that BWF₁ might inherit the iNK T cell defect from NZB mice. Thus, iNK T cells are functionally insufficient in lupus‐prone BWF₁ mice. Such iNK T cell insufficiency precedes the onset of disease and may play a pathogenic role during early stages of disease development in SLE.