Multi-organ Autoimmune Disease Research Articles

NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells.

We examined the role of NFκB1 in the homeostasis and function of peripheral follicular (Fo) B cells. Aging mice lacking NFκB1 (Nfκb1(-/-)) develop lymphoproliferative and multiorgan autoimmune disease attributed in large part to the deregulated activity of Nfκb1(-/-)Fo B cells that produce excessive levels of the proinflammatory cytokine interleukin 6 (IL-6). Despite enhanced germinal center (GC) B cell differentiation, the formation of GC structures was severely disrupted in the Nfκb1(-/-)mice. Bone marrow chimeric mice revealed that the Fo B cell-intrinsic loss of NFκB1 led to the spontaneous generation of GC B cells. This was primarily the result of an increase in IL-6 levels, which promotes the differentiation of Fo helper CD4(+)T cells and acts in an autocrine manner to reduce antigen receptor and toll-like receptor activation thresholds in a population of proliferating IgM(+)Nfκb1(-/-)Fo B cells. We demonstrate that p50-NFκB1 represses Il-6 transcription in Fo B cells, with the loss of NFκB1 also resulting in the uncontrolled RELA-driven transcription of Il-6.Collectively, our findings identify a previously unrecognized role for NFκB1 in preventing multiorgan autoimmunity through its negative regulation of Il-6 gene expression in Fo B cells.

Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome.

ObjectiveGlycans attached to the Fc portion of IgG are important modulators of IgG effector functions. Interindividual differences in IgG glycome composition are large and they associate strongly with different inflammatory and autoimmune diseases. IKZF1, HLA–DQ2A/B, and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating a potentially causative role of aberrant IgG glycosylation in SLE. We undertook this large multicenter case–control study to determine whether SLE is associated with altered IgG glycosylation.MethodsUsing ultra‐performance liquid chromatography analysis of released glycans, we analyzed the composition of the IgG glycome in 261 SLE patients and 247 matched controls of Latin American Mestizo origin (the discovery cohort) and in 2 independent replication cohorts of different ethnicity (108 SLE patients and 193 controls from Trinidad, and 106 SLE patients and 105 controls from China).ResultsMultiple statistically significant differences in IgG glycome composition were observed between patients and controls. The most significant changes included decreased galactosylation and sialylation of IgG (which regulate proinflammatory and antiinflammatory actions of IgG) as well as decreased core fucose and increased bisecting N‐acetylglucosamine (which affect antibody‐dependent cell‐mediated cytotoxicity).ConclusionThe IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE.

Tracing cellular sources of pathogenic type I-interferon in the TREX1-/- mouse model of lupus like-disease

Loss of function mutations of the intracellular enzyme 3’ repair exonuclease (TREX) 1 cause Aicardi-Goutieres syndrome (AGS). As AGS clinically overlaps with systemic lupus erythematosus (SLE) and, like SLE, features a spontaneous activation of the antiviral type I-interferon (IFN) system as well as production of antinuclear autoantibodies, this condition may be considered a monogenic variant of SLE. TREX1-deficient mice spontaneously develop multiorgan autoimmune disease that is fully dependent on a functional type I-IFN system. This phenotype suggested a new concept of systemic autoimmunity arising from intracellular accumulations of (so far enigmatic) nucleic acid substrates of TREX1, which trigger chronic antiviral IFN responses and thereby autoimmunity. Nonhematopoietic cells were proposed to be the cellular source of the pathogenic IFN. Uncontrolled activity of endogenous retroelements was suspected to induce the chronic antiviral response.

Therapeutic window of interleukin-2 for autoimmune diseases.

An uncontrolled immune system threatens human health as much as a defective one. Autoimmune diseases, such as type 1 diabetes (T1D), result from destruction of healthy tissues by a rogue immune system. Much of the self-policing of the immune system can be attributed to one subset of T cells called regulatory T cells (Tregs) (1). Patients with congenital defects in Tregs develop fatal multiorgan autoimmune diseases early in life (2). Tregs can be identified by the cell surface phenotype of CD4+CD25+CD127lo. CD25 is not merely a marker for Tregs but important for the maintenance and function of these cells as well. It associates with CD122 and CD132 to form the high-affinity receptor for interleukin (IL)-2, a growth factor for T cells. CD25 is constitutively expressed on Tregs, whereas its expression on other T cells is induced only after activation. Therefore, Tregs can better respond to IL-2 than other T cells in the steady state, prompting the consideration of using IL-2 therapeutically to expand Tregs for restoration of immune homeostasis. One challenge to this approach is that other T cells and natural killer (NK) cells constitutively express CD122 and CD132 that can respond to high-dose IL-2, leading to their activation and tissue destruction. In fact, the current U.S. Food and Drug Administration–approved use of IL-2 is for enhancing immunity …

The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases.

Depletion of regulatory T (TReg) cells in otherwise healthy individuals leads to multi-organ autoimmune disease and inflammation. This indicates that in a normal immune system, there are self-specific effector T cells that are ready to attack normal tissue if they are not restrained by TReg cells. The data imply that there is a balance between effector T cells and TReg cells in health and suggest a therapeutic potential of TReg cells in diseases in which this balance is altered. Proof-of-concept clinical trials, now supported by robust mechanistic studies, have shown that low-dose interleukin-2 specifically expands and activates TReg cell populations and thus can control autoimmune diseases and inflammation.

111: Aryl hydrocarbon receptor negatively regulates type I interferon production and the development of murine lupus

Background Systemic lupus erythematosus is a highly heterogenous multi-organ autoimmune disease characterized by the production of diverse autoantibodies and broad spectrum of clinical manifestations. Various studies suggest an important role for type I interferon (IFN) in the pathogenesis of lupus. Type I IFN signaling and subsequent feedback induction of type I IFN production, are critically dependent on the STAT1 transcription factor. However, how type I IFN activity is regulated through inhibition of STAT1 function is poorly understood. In our previous study we demonstrated that the aryl hydrocarbon receptor (AHR) inhibits STAT1 activity through TLR4 signaling. In the current study we investigated a role for AHR in type I IFN signaling through TLR7/9 pathways. Methods and results We showed that type I IFN production and signaling both in plasmacytoid dendritic cells (pDCs), and in vivo , is significantly higher in AHR knockout mice compared to wild-type mice, following stimulation with TLR9 ligands. Type I IFN production was suppressed by AHR agonist and in AHR over-expressing cells. We demonstrated that through TLR9 signaling or by IFN-α stimulation in pDCs, expression of AHR is induced, which in-turn forms an inhibitory interaction with STAT1. This interaction attenuates both type I IFN signaling and in-turn, positive-feedback induction of type I IFN. Interestingly, we also found that AHR also forms an inhibitory interaction with IRF7 (a transcription factor which induces type I IFN production). In pristane-induced murine lupus, we found that expression of IFN-stimulated genes, accumulation of Ly6c high IFN producing cells, production of type I IFN-dependent autoantibody and severity of proteinurea, were significantly higher in AHR knockout mice compared to wild-type mice. Conclusion We firstly report that AHR negatively regulates type I IFN production and signaling through an inhibitory interaction with IRF7 and STAT1 respectively and inhibits interferon-dependent disease in murine lupus.

65: Nuclear Factor-kappa B1 is a critical regulator of mature B cell homeostasis and serves to prevent chronic inflammatory disease

The transcriptional regulator Nuclear Factor-kappa B1 (NF-kB1) plays an essential role in immune function and controls key aspects of cell survival, differentiation and proliferation. Polymorphisms and mutations in the NF-kB1 gene are linked to various human autoimmune diseases and malignancies. Due to its duplicitous roles in the activation and repression of gene transcription, the precise function of NF-kB1 has remained unclear. Through various murine models, we show that NF-kB1 is critical for the normal maintenance of mature follicular B cells. As the loss of NF-kB1 in Fo B cells lowers their activation threshold, and enhances proliferation and survival in vivo . This is largely attributed to the finding that NF-kB1-deficient Fo B cells produce excessive amounts of the proinflammatory cytokine interleukin-6, which promotes the enhanced differentiation of follicular helper CD4 + T cells. In aged mice this culminates in a severe multi-organ autoimmune disease characterized by the spontaneous formation of germinal center B cells, the presence of class-switched antibodies and tissue-specific autoantibodies. Finally, we demonstrate that NF-kB1 is an essential regulator of IL-6 expression in Fo B cells. Collectively, our findings show that NF-kB1 plays a crucial role in maintaining the normal homeostasis of mature B cells and prevents the development of chronic diseases, such as autoimmunity and cancer, through its regulation of the IL-6 gene.

Compromised central tolerance of ICA69 induces multiple organ autoimmunity

For reasons not fully understood, patients with an organ-specific autoimmune disease have increased risks of developing autoimmune responses against other organs/tissues. We identified ICA69, a known β-cell autoantigen in Type 1 diabetes, as a potential common target in multi-organ autoimmunity. NOD mice immunized with ICA69 polypeptides exhibited exacerbated inflammation not only in the islets, but also in the salivary glands. To further investigate ICA69 autoimmunity, two genetically modified mouse lines were generated to modulate thymic ICA69 expression: the heterozygous ICA69del/wt line and the thymic medullary epithelial cell-specific deletion Aire-ΔICA69 line. Suboptimal central negative selection of ICA69-reactive T-cells was observed in both lines. Aire-ΔICA69 mice spontaneously developed coincident autoimmune responses to the pancreas, the salivary glands, the thyroid, and the stomach. Our findings establish a direct link between compromised thymic ICA69 expression and autoimmunity against multiple ICA69-expressing organs, and identify a potential novel mechanism for the development of multi-organ autoimmune diseases.

IgG4 antibodies in autoimmune polyglandular disease and IgG4-related endocrinopathies: pathophysiology and clinical characteristics.

This review discusses the IgG4-related disease spectrum (IgG4-RD), the autoimmune polyglandular syndromes (APS), the association of IgG4 with APS, and possible pathobiology. IgG4-RD is a multiorgan autoimmune disorder characterized by fibrous inflammation, IgG4-positive plasma cell infiltration in affected tissues, and elevated serum concentrations of IgG4. IgG4-RD can affect any organ and has a heterogeneous presentation. Consensus criteria for diagnosis in specific organs have been established. The recognition and diagnosis of IgG4-RD are crucial because the disease responds favorably to immunosuppression (e.g., glucocorticoids, rituximab). The precise mechanisms leading to disease are unknown, but IgG4 antibodies may undergo a half antibody exchange, which renders them incapable of activating the complement pathway. Despite significant advances in disease recognition and treatment strategies, the disorder remains poorly understood. The precise role of IgG4, whether it is protective or pathogenic, is still being debated.

Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.

Monogenic causes of autoimmunity give key insights to the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in 5 individuals with a spectrum of early-onset autoimmune disease including type 1 diabetes. These findings emphasise the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in Hyper IgE syndrome.

FRI0410 The Impact of Pregnancy on Lupus Flares in Korean Patients with Systemic Lupus Erythematosus: 15-Year Experience, Single-Center Study

BackgroundSystemic lupus erytematosus (SLE) is a multi-organ autoimmune disease that affects women of childbearing age. SLE and lupus nephritis have more maternal and fetal complications than the general population. However,...

AB0176 Association between Polymorphisms in Beta-Adducin and Sodium/Calcium Exchanger 1 and SLE with and without Nephritis

BackgroundGenes involved in cytoskeletal assembly and water/electrolyte balance have been previously linked to hypertension, but recent evidences suggest a role also in the development of inflammation and autoimmunity [1-2]. Systemic...

AB0187 Estrogen-Induction of STAT1 and STAT4 Expression by Estrogen Receptor Alpha Suggests a Novel IFN-Alpha-Independent Mechanism of Sex-Bias in Systemic Lupus Erythematosus Pathogenesis

BackgroundSystemic Lupus Erythematosus (SLE) is a devastating multi-organ autoimmune disease displaying an overwhelming female predilection. Estrogen (E2) influences gene expression by binding to estrogen receptors (ERα and ERβ) and has...

Aryl hydrocarbon receptor negatively regulates type I interferon production and the development of murine lupus (CCR1P.245)

Abstract Systemic lupus erythematosus is a highly heterogenous multi-organ autoimmune disease characterized by the production of diverse autoantibodies and a broad spectrum of clinical manifestations. The etiology and pathogenesis of lupus remain unclear. Our current understanding highlights an important role for autoantibodies and numerous studies in both animals and humans now suggest an important role for type I interferon (IFN) in the pathogenesis of lupus. Type I IFN signaling and subsequent feedback induction of type I IFN production, are critically dependent on the STAT1 transcription factor. How type I IFN activity is regulated through inhibition of STAT1 function is poorly understood. Here, we show that type I IFN production and signaling both in cultured plasmatoid dendritic cells, and in vivo, is significantly higher in Aryl hydrocarbon receptor (AHR) knockout mice compared to wild-type mice, following stimulation with TLR7/9 agonists. We demonstrate that through TLR7/9 signaling or by IFN-α, expression of AHR is induced, which in-turn forms an inhibitory interaction with STAT1. This interaction attenuates both type I IFN signaling and in-turn, positive-feedback induction of type I IFN. Furthermore, in pristane-induced murine lupus, we found that production of type I IFN and expression of IFN-stimulated genes in AHR knockout mice is higher than in wild-type mice. In conclusion, AHR negatively regulates type I IFN signaling and production and the development of murine lupus.

The effects of lupus and antiphospholipid antibody syndrome on foetal outcomes.

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease that primarily affects women of childbearing-age. Antiphospholipid syndrome (APS) is a systemic autoimmune disorder defined by the occurrence of venous and arterial thrombosis, often multiple, and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Recently, the long-term outcome of children born to patients with lupus and APS has become a major topic of interest both to patients and physicians. One of the major problems related to maternal disease is preterm delivery with all the consequences that this condition may bring. Prematurity may also be due to the presence of aPL; however, aPL do not generally display any thrombotic potential on neonates. Another complication may be neonatal lupus (NL), mediated by the presence of maternal antibodies (anti-Ro/SSA and anti-La/SSB). In addition, behaviour and neuropsychological outcomes have also been a matter of interest, but there are currently few data available. Beyond the biological influence of both maternal disease and autoimmune background, it is important to focus on the possible influence of maternal chronic illness on the neuropsychological development of her children. Whether aPL exposure could have a direct effect on brain development is still being debated. In children of mothers with APS, language delays have been noted and learning disabilities were described with a higher rate than the general age-school population. Several studies were performed on children born to lupus mothers: even if maternal lupus does not seem to impair intelligence levels, it may increase the occurrence of learning disabilities and particularly dyslexia in male children. To the best of our knowledge, no studies are available on the long-term outcome of children born to mothers with lupus or APS and particularly regarding the development of autoimmune diseases. Nevertheless, common experience of experts in the field is that these children do not show a significantly increased risk of displaying the same autoimmune disease as their mothers. The purpose of this paper is to answer the frequently asked questions of patients with lupus and APS who desire to become mothers, based on the little information available.

Critical role of DNA methylation in the pathogenesis of systemic lupus erythematosus: new advances and future challenges

Systemic lupus erythematosus (SLE) is a systemic multi-organ autoimmune disease with different immunological characteristics and clinical manifestations characterized by an autoantibody response to nuclear and cytoplasmic antigens; the etiology of this disease remains largely unknown. Most recent genome-wide association studies demonstrate that genetics significantly predispose to SLE onset, but the incomplete disease concordance rates between monozygotic twins indicates a role for other complementary factors in SLE pathogenesis. Recently, much evidence strongly supports other molecular mechanisms involved in the regulation of gene expression ultimately causing autoimmune disease, and several studies, both in clinical settings and experimental models, have demonstrated that epigenetic modifications may hold the key to a better understanding of SLE initiation and development. DNA methylation changes the structure of chromatin, being typically able to modulate the fine interactions between promoter-transcription factors and encoding genes within the transcription machinery. Alteration in DNA methylation has been confirmed as a major epigenetic mechanism that may potentially cause a breakdown of immune tolerance and perpetuation of SLE. Based on recent findings, DNA methylation treatments already being used in oncology may soon prove beneficial to patients with SLE. We herein discuss what we currently know, and what we expect in the future.

Mortality in systemic sclerosis

Systemic sclerosis (SSc) has a case-based mortality that is one of the highest among the rheumatic diseases. This article is an appraisal of current knowledge regarding survival, causes of death and risk factors for reduced life-expectancy in systemic sclerosis (SSc). Recent systematic reviews of cohorts studies published worldwide have revealed a pooled standardized mortality ratio in SSc of 3.5, and reiterated the importance of heart-lung involvement as a major cause of death in this disease. Indeed, the pooled hazard ratio (HR) of mortality in SSc patients with pulmonary arterial hypertension (PAH) compared with those without is 3.5, while the pooled HR for mortality in those with interstitial lung disease is 2.6. The average life expectancy of patients with SSc is 16-34 years less than age-matched and sex-matched population peers. Current research efforts are focused on quantifying early as well as late mortality, and modeling for predictors of death in SSc, with the ultimate goal of attenuating this risk and improving survival, as new therapies emerge. Studies have consistently shown a substantially increased mortality in SSc, predominantly due to cardio-pulmonary complications. A better understanding of risk factors for mortality holds the promise of improving outcomes in this devastating multiorgan autoimmune disease.

AB0063 Gammadelta t cells and their intracellular cytokine profile in peripheral blood of patients with systemic lupus erythematosus

BackgroundGammadelta T cells represent a minor population of human peripheral blood T lymphocytes. As very rapid cytokine-producing cells, gammadelta T cells can regulate other lymphocytes activation and assist their local...

PD-1 controls effectors but not the generation or function of natural or induced regulatory T-cells (P1011)

Abstract During T cell activation, the balance of co-stimulatory and co-inhibitory interactions plays an important role in shaping the resulting T cell response. Co-inhibitory signals help maintain peripheral immune tolerance, and thus animals with defective co-inhibitory molecules, such as PD-1 KO mice, are predisposed to autoimmunity. Unlike PD-1 KO mice, which develop mild autoimmunity, adult Rag KO recipients of PD-1 KO hematopoietic stem cells (HSC) succumb to rapid and severe multi-organ autoimmune disease soon after T cells first emerge from the thymus, implicating PD-1 as a critical factor in the control of T cell self-reactivity during lymphopenia induced homeostatic proliferation (LIP). While we have found no reduction in the absolute number of FoxP3+ regulatory T cells (Treg) in diseased PD-1 KO vs. wild type (WT) HSC recipients, some studies have indirectly suggested that PD-1 deficiency may inhibit the development of induced Treg (iTreg) cells from conventional T cells in the periphery. We therefore investigated whether PD-1 deficiency results in an intrinsic inability of T cells to convert to iTreg in vivo, which could lead to disease in PD-1 KO HSC recipients. Surprisingly, our findings suggest that PD-1 deficiency does not inhibit the development of iTreg nor does it affect Treg suppressive function, and that in the context of LIP, co-inhibitor deficient effector T cells cause disease primarily by expanding beyond the ability of Treg to control them.

T-Cell Reconstitution after Thymus Xenotransplantation Induces Hair Depigmentation and Loss

Here we present a mouse model for T-cell targeting of hair follicles, linking the pathogenesis of alopecia to that of depigmentation disorders. Clinically, thymus transplantation has been successfully used to treat T-cell immunodeficiency in congenital athymia, but is associated with autoimmunity. We established a mouse model of thymus transplantation by subcutaneously implanting human thymus tissue into athymic C57BL/6 nude mice. These xenografts supported mouse T-cell development. Surprisingly, we did not detect multiorgan autoimmune disease. However, in all transplanted mice, we noted a striking depigmentation and loss of hair follicles. Transfer of T cells from transplanted nudes to syngeneic black-coated RAG−/− recipients caused progressive, persistent coat-hair whitening, which preceded patchy hair loss in depigmented areas. Further transfer experiments revealed that these phenomena could be induced by CD4+ T cells alone. Immunofluorescent analysis suggested that Trp2+ melanocyte-lineage cells were decreased in depigmented hair follicles, and pathogenic T cells upregulated activation markers when exposed to C57BL/6 melanocytes in vitro, suggesting that these T cells are not tolerant to self-melanocyte antigens. Our data raise interesting questions about the mechanisms underlying tissue-specific tolerance to skin antigens.