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The etiology of autoimmune diseases is due to a combination of genetic predisposition and environmental factors that alter the expression of immune regulatory genes through various mechanisms including epigenetics. Both humoral and cellular elements of the adaptive immune system play a role in the pathogenesis of autoimmune diseases and the presence of autoantibodies have been detected in most but not all autoimmune diseases before the appearance of clinical symptoms. In some cases, the presence or levels of these autoantibodies portends not only the risk of developing a corresponding autoimmune disease, but occasionally the severity as well. This observation is intriguing because it suggests that we can, to some degree, predict who may or may not develop autoimmune diseases. However, the role of autoantibodies in the pathogenesis of autoimmune diseases, whether they actually affect disease progression or are merely an epiphenomenon is still not completely clear in many autoimmune diseases. Because of these gaps in our knowledge, the ability to accurately predict a future autoimmune disease can only be considered a relative risk factor. Importantly, it raises the critical question of defining other events that may drive a patient from a preclinical to a clinical phase of disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Scleritis is a severe and painful ophthalmic disorder, in which a pathogenic role for collagen-directed autoimmunity was repeatedly suggested. We evaluated the presence of sclera-specific antibodies in a large cohort of patients with non-infectious scleritis. Therefore, we prospectively collected serum samples from 121 patients with non-infectious scleritis in a multicenter cohort study in the Netherlands. In addition, healthy (n = 39) and uveitis controls (n = 48) were included. Serum samples were tested for anti-native human type II collagen antibodies using a validated enzyme-linked immunosorbent assay (ELISA). Further, sclera-specific antibodies were determined using indirect immunofluorescence (IIF) on primate retinal/scleral cryosections. Lastly, human leukocyte antigen (HLA) typing was performed in 111 patients with scleritis. Anti-type II collagen antibodies were found in 13% of scleritis patients, in 10% of healthy controls and in 11% of uveitis controls (p = 0.91). A specific reaction to scleral nerve tissue on IIF was observed in 33% of patients with scleritis, which was higher than in healthy controls (11%; p = 0.01), but similar to uveitis controls (25%; p = 0.36). Reactivity to the scleral nerve tissue was significantly associated with earlier onset of scleritis (48 versus 56 years; p < 0.001), bilateral involvement (65% versus 42%; p = 0.01), and less frequent development of scleral necrosis (5% versus 22%; p = 0.02). HLA-B27 was found to be twice as prevalent in patients with scleritis (15.3%) compared to a healthy population (7.2%). In conclusion, scleral nerve autoantibody reactivity was more common in scleritis and uveitis patients in contrast to healthy controls. Further research is needed to characterize these scleral-nerve directed antibodies and assess their clinical value. [Display omitted] • Scleral nerve autoantibody reactivity is more common in patients with scleritis and uveitis compared to healthy controls. • Type II collagen antibodies were not found to occur more frequently in patients with scleritis compared to healthy controls. • A significant association with HLA-B27 is present in patients with scleritis compared to healthy controls. [ABSTRACT FROM AUTHOR]

Lupus glomerulonephritis (GN) is an autoimmune disease characterized by immune complex-deposition, complement activation and glomerular inflammation. In lupus-prone NZM2328 mice, the occurrence of lupus GN was accompanied by a decrease in Treg cells and an increase in proinflammatory cytokine-producing T cells. Because IL-33 in addition to IL-2 has been shown to be important for Treg cell proliferation and ST2 (IL-33 receptor) positive Treg cells are more potent in suppressor activity, a hybrid cytokine with active domains of IL-2 and IL-33 was generated to target the ST2+ Treg cells as a therapeutic agent to treat lupus GN. Three mouse models were used: spontaneous and Ad-IFNα- accelerated lupus GN in NZM2328 and the lymphoproliferative autoimmune GN in MRL/ lpr mice. Daily injections of IL233 for 5 days prevented Ad-IFNα-induced lupus GN and induced remission of spontaneous lupus GN. The remission was permanent in that no relapses were detected. The remission was accompanied by persistent elevation of Treg cells in the renal lymph nodes. IL233 is more potent than IL-2 and IL-33 either singly or in combination in the treatment of lupus GN. The results of this study support the thesis that IL233 should be considered as a novel agent for treating lupus GN. • Lupus prone NZM2328 mice have a deficit in IL-2, IL-10 and Foxp3+ST2+ Tregs. • IL-2 and IL-33 combination in the form of IL-2 and IL-33 fusion cytokine (IL233) induced a sustained increase in Tregs and suppressed inflammation without affecting autoantibodies. • IL233, as a single agent not only prevented the onset, but also induced persistent remission in ongoing lupus glomerulonephritis (GN) in IFNα-accelerated and spontaneous models in NZM2328 mice and in MRL/ lpr mice. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complex autoimmune disease accompanied by production of autoantibodies directed to a variety of self-proteins and nucleic acids. The genetic basis of SLE is also complex with at least 40 susceptibility loci identified. This complexity suggests that there are a variety of SLE manifestations; nevertheless, SLE is treated as a single disease clinically. One unique SLE target is the Smith antigen (Sm), a nuclear ribonucleoprotein complex. Sm response occurs in 25% of patients with SLE. To simplify analysis of the disease and its associated autoantibody repertoire, we focused on this subset [referred to here as “Sm positive”, Sm+]. We analyzed the memory B cell repertoire and identified a V region, Vκ4-1, which was significantly overrepresented in the Sm+ SLE subset. Antibodies that express Vκ4-1 are enriched in antinuclear (ANA) positive specificities and often associated with speckled ANA pattern that is a characteristic of Sm binding. In healthy individuals Vκ4-1 B cells are enriched in the unswitched memory population. Unswitched memory B cells resemble mouse marginal zone B cells and this population is decreased in all SLE patients. Moreover, we found a similar decrease in healthy African American donors. African Americans have a significantly higher prevalence of SLE compared to Caucasians. Thus, reduced unswitched memory B cell compartment may represent a new susceptibility marker for SLE. [ABSTRACT FROM AUTHOR]

Infections are known to trigger flares of autoimmune diseases in humans and serve as an inciting cause of autoimmunity in animals. Evidence suggests a causative role of infections in triggering antigen-specific autoimmunity, previous thought mainly through antigen mimicry. However, an infection can induce bystander autoreactive T and B cell polyclonal activation, believed to result in non-pathogenic and pathogenic autoimmune responses. Lastly, epitope spreading in autoimmunity is a mechanism of epitope changes of autoreactive cells induced by infection, promoting the targeting of additional self-epitopes. This review highlights recent research findings, emphasizes infection-mediated autoimmune responses, and discusses the possible mechanisms involved. • Pathogenic infection can induce normal immunity and autoimmunity. • Infection mediated autoimmune bystander (non-specific) and antigen specific mechanisms contribute to autoimmunity. • Autoimmunity can contribute to the pathogenesis of infectious diseases without the induction of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ inflammatory damage and wide spectrum of autoantibodies. The autoantibodies, especially anti-dsDNA and anti-Sm autoantibodies are highly specific to SLE, and participate in the immune complex formation and inflammatory damage on multiple end-organs such as kidney, skin, and central nervous system (CNS). However, the underlying mechanisms of autoantibody-induced tissue damage and systemic inflammation are still not fully understood. Single cell analysis of autoreactive B cells and monoclonal antibody screening from patients with active SLE has improved our understanding on the origin of autoreactive B cells and the antigen targets of the pathogenic autoantibodies. B cell depletion therapies have been widely studied in the clinics, but the development of more specific therapies against the pathogenic B cell subset and autoantibodies with improved efficacy and safety still remain a big challenge. A more comprehensive autoantibody profiling combined with functional characterization of autoantibodies in diseases development will shed new insights on the etiology and pathogenesis of SLE and guide a specific treatment to individual SLE patients. • The autoantibody can arise from interplay of multiple mechanisms. • Autoantibodies of SLE is highly heterogenous. • Identification of the pathogenic autoantibodies will improve the specificity of the treatment for SLE. [ABSTRACT FROM AUTHOR]

In areas where helminths infections are common, autoimmune diseases are rare. Treatment with helminths and ova from helminths, improved clinical findings of inflammatory bowel disease, multiple-sclerosis and rheumatoid-arthritis. The immunomodulatory functions of some helminths were attributed to the phosphorylcholine (PC) moiety. We aimed to decipher the tolerogenic potential of Tuftsin-PC (TPC) compound in mice genetically prone to develop lupus. Lupus prone NZBXW/F1 mice received subcutaneously TPC (5 μg/1 ml), 3 times a week starting at 14 weeks age. Autoantibodies were tested by ELISA, T-regulatory-cells by FACS, cytokines profile by RT-PCR and cytokines protein levels by DuoSet ELISA. Glomerulonephritis was addressed by detection of proteinuria, and immunoglobulin complex deposition in the mesangium of the kidneys of the mice by immunofluorescence. Our results show that TPC attenuated the development of glomerulonephritis in lupus prone mice, in particular, it ameliorated proteinuria (p < 0.02), and reduced immunoglobulin deposition in the kidney mesangium. TPC also enhanced the expression of TGFβ and IL-10 (p < 0.001), and inhibited the production of IFNγ and IL-17 (p < 0.03). TPC Significantly enhanced the expansion of CD4+CD25+FOXP3+ T-regulatory cells (Tregs) phenotype in the treated mice. These data indicate that TPC hampered lupus development in genetically lupus prone mice which was exemplified by moderate glomerulonephritis, attenuation of pro-inflammatory cytokines and enhancement of anti-inflammatory cytokines expression, as well as Tregs expansion. Our results propose harnessing novel natural therapy for lupus patients. [ABSTRACT FROM AUTHOR]

Abstract: Recently, a new syndrome, namely the “Autoimmune/inflammatory syndrome induced by adjuvants” (ASIA) has been defined. In this syndrome different conditions characterized by common signs and symptoms and induced by the presence of an adjuvant are included. The adjuvant is a substance capable of boosting the immune response and of acting as a trigger in the development of autoimmune diseases. Post-vaccination autoimmune phenomena represent a major issue of ASIA. Indeed, despite vaccines represent a mainstay in the improvement of human health, several of these have been implicated as a potential trigger for autoimmune diseases. Sjogren's Syndrome (SjS) is a systemic chronic autoimmune inflammatory disease characterized by the presence of an inflammatory involvement of exocrine glands accompanied by systemic manifestations. Own to the straight association between infectious agents exposure (mainly viruses) and sicca syndrome development, the possible link between vaccine and SjS is not surprising. Indeed, a few cases of SjS following vaccine delivery have been reported. At the same extent, the induction of SjS following silicone exposure has been described too. Thus, the aim of this review was to focus on SjS and its possible development following vaccine or silicone exposure in order to define another possible facet of the ASIA syndrome. [Copyright &y& Elsevier]

Abstract: In 2011 a new syndrome termed ‘ASIA Autoimmune/Inflammatory Syndrome Induced by Adjuvants’ was defined pointing to summarize for the first time the spectrum of immune-mediated diseases triggered by an adjuvant stimulus such as chronic exposure to silicone, tetramethylpentadecane, pristane, aluminum and other adjuvants, as well as infectious components, that also may have an adjuvant effect. All these environmental factors have been found to induce autoimmunity by themselves both in animal models and in humans: for instance, silicone was associated with siliconosis, aluminum hydroxide with post-vaccination phenomena and macrophagic myofasciitis syndrome. Several mechanisms have been hypothesized to be involved in the onset of adjuvant-induced autoimmunity; a genetic favorable background plays a key role in the appearance on such vaccine-related diseases and also justifies the rarity of these phenomena. This paper will focus on protean facets which are part of ASIA, focusing on the roles and mechanisms of action of different adjuvants which lead to the autoimmune/inflammatory response. The data herein illustrate the critical role of environmental factors in the induction of autoimmunity. Indeed, it is the interplay of genetic susceptibility and environment that is the major player for the initiation of breach of tolerance. [Copyright &y& Elsevier]

Abstract: Patients with the monogenic disease autoimmune polyendocrine syndrome type I (APSI) develop autoimmunity against multiple endocrine organs and suffer from chronic mucocutaneous candidiasis (CMC), a paradoxical complication with an unknown mechanism. We report here that saliva from APSI patients with CMC is defective in inhibiting growth of Candida albicans in vitro and show reduced levels of a salivary protein identified as cystatin SA1. In contrast, APSI patients without CMC express salivary cystatin SA1 and can inhibit C. albicans to the same extent as healthy controls. We evaluated the anti-fungal activity of cystatin SA1 and found that synthesized full length cystatin SA1 efficiently inhibits growth of C. albicans in vitro. Moreover, APSI patients exhibit salivary IgA autoantibodies recognizing myosin-9, a protein expressed in the salivary glands, thus linking autoimmunity to cystatin SA1 deficiency and CMC. This data suggests an autoimmune mechanism behind CMC in APSI and provides rationale for evaluating cystatin SA1 in antifungal therapy. [Copyright &y& Elsevier]

Abstract: Cytokines are key regulators of physiological inflammatory responses, while aberrant cytokine expression contributes to pathogenesis of autoimmune diseases. We noted increased IL-6 levels in human and murine epidermolysis bullosa acquisita (EBA), a prototypic organ-specific autoimmune bullous dermatoses (AIBD) induced by autoantibodies to type VII collagen (COL7). In contrast to rheumatoid arthritis, blockade of IL-6 led to strikingly enhanced experimental EBA, while treatment with recombinant IL-6 was protective. This was due to classical IL-6 signalling and independent of IL-6 trans-signalling, as treatment of mice with sgp130Fc had no impact on EBA manifestation. Induction of EBA in mice led to increased IL-1ra levels in skin and serum, while blockade of IL-6 completely inhibited IL-1ra expression induced by autoantibodies to COL7. In line, treatment of mice with EBA with recombinant IL-6 induced IL-1ra concentrations exceeding those of untreated animals with EBA, and IL-1ra (anakinra) administration significantly impaired experimental EBA induction. We here identified a novel anti-inflammatory pathway in an organ-specific autoimmune disease. Modulation of this IL-1ra pathway by classical IL-6 signalling demonstrates anti-inflammatory and protective activities of IL-6 in vivo. [Copyright &y& Elsevier]

Abstract: The principal central nervous system (CNS) water channel, aquaporin-4 (AQP4), is confined to astrocytic and ependymal membranes and is the target of a pathogenic autoantibody, neuromyelitis optica (NMO)-IgG. This disease-specific autoantibody unifies a spectrum of relapsing CNS autoimmune inflammatory disorders of which NMO exemplifies the classic phenotype. Multiple sclerosis and other immune-mediated demyelinating disorders of the CNS lack a distinctive biomarker. Two AQP4 isoforms, M1 and M23, exist as homotetrameric and heterotetrameric intramembranous particles (IMPs). Orthogonal arrays of predominantly M23 particles (OAPs) are an ultrastructural characteristic of astrocytic membranes. We used high-titered serum from 32 AQP4-IgG-seropositive patients and 85 controls to investigate the nature and molecular location of AQP4 epitopes that bind NMO-IgG, and the influence of supramolecular structure. NMO-IgG bound to denatured AQP4 monomers (68% of cases), to native tetramers and high order arrays (90% of cases), and to AQP4 in live cell membranes (100% of cases). Disease-specific epitopes reside in extracellular loop C more than in loops A or E. IgG binding to intracellular epitopes lacks disease specificity. These observations predict greater disease sensitivity and specificity for tissue-based and cell-based serological assays employing “native” AQP4 than assays employing denatured AQP4 and fragments. NMO-IgG binds most avidly to plasma membrane surface AQP4 epitopes formed by loop interactions within tetramers and by intermolecular interactions within high order structures. The relative abundance and localization of AQP4 high order arrays in distinct CNS regions may explain the variability in clinical phenotype of NMO spectrum disorders. [Copyright &y& Elsevier]

Abstract: The mechanisms leading to autoimmune diseases remain largely unknown despite numerous lines of experimental inquiry and epidemiological evidence. The growing number of genome-wide association studies and the largely incomplete concordance for autoimmune diseases in monozygotic twins support the role of the environment (including infectious agents and chemicals) in the breakdown of tolerance leading to autoimmunity via numerous mechanisms. The present article reviews the major theories on the mechanisms of the environmental influence on autoimmunity by addressing the different degrees of confidence that characterize our knowledge. The theories discussed herein include (i) the role of innate immunity mediated by toll-like receptors in triggering the autoimmune adaptive response characterizing the observed pathology; (ii) changes in spleen marginal zone B cells in autoantibody production with particular focus on the B10 subpopulation; (iii) Th17 cell differentiation and T regulatory cells in the aryl hydrocarbon receptor model; (iv) self antigen changes induced by chemical and infectious agents which could break tolerance by post-translational modifications and molecular mimicry; and finally (v) epigenetic changes, particularly DNA methylation, that are induced by environmental stimuli and may contribute to autoimmunity initiation. We are convinced that these working hypotheses, in most cases supported by solid evidence, should be viewed in parallel with animal models and epidemiological observations to provide a comprehensive picture of the environmental causes of autoimmune diseases. [Copyright &y& Elsevier]

Abstract: Ro52 is a common target of circulating autoantibodies in autoimmune disease. Data indicate that anti-Ro52 antibodies are associated with distinct clinical manifestations. It is therefore of major interest to understand how it becomes an antigenic target and what cells express this protein under what conditions and what cellular function it has. Ro52 contains a RING and a B-box motif, followed by a coiled-coil domain and a B30.2 (or PRYSPRY) region in the C-terminal end. This molecular structure places Ro52 within the family of tripartite motif proteins (TRIM), and it is also denoted TRIM21. Like several other TRIM proteins, Ro52 has E3 ligase activity and functions in the process of ubiquitination. Ro52 is expressed in the immune system as a predominantly cytoplasmic protein that can be upregulated and translocate to the nucleus in a proinflammatory environment. Reported substrates for Ro52-mediated ubiquitination include IRF3, IRF5, IRF7 and IRF8, and via these transcription factors Ro52 regulates type 1 interferon and cytokine production. Ro52 is upregulated at the site of autoimmune inflammation, such as cutaneous lupus lesions. This implies that Ro52 may have an important role in the pathogenesis of autoimmunity, and this paper will review the available data on the role of Ro52 in immune responses and autoimmune pathogenesis. [Copyright &y& Elsevier]

Abstract: Peptidyl arginine deiminases (PADs) catalyze a post-translational protein modification reaction called citrullination, where arginine is converted to citrulline. This modification has been linked to the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA). More recently, several studies have suggested that Alzheimer''s disease (AD), a devastating neurodegenerative disorder, may have an autoimmune component. In the present study, we have investigated the possibility that expression of PADs and protein citrullination plays a role in the production of brain-reactive autoantibodies that may contribute to Alzheimer''s-related brain pathology. Here, we report the selective expression of the PAD isoforms, PAD2 and PAD4, in astrocytes and neurons, respectively, and the concomitant accumulation of citrullinated proteins within PAD4-expressing cells, including neurons of the hippocampus and cerebral cortex. Expression of PADs and citrullinated proteins is prominent in brain regions engaged in neurodegenerative changes typical for AD pathology. Furthermore, we also demonstrate that the pentatricopeptide repeat domain2 (PTCD2) protein, an antigen target of a prominent AD diagnostic autoantibody, is present in a citrullinated form in AD brains. Our results suggest that disease-associated neuronal loss results in the release of cellular contents, including citrullinated proteins, into the brain interstitium. We propose that these citrullinated proteins and their degradation fragments enter into the blood and lymphatic circulation, and some are capable of eliciting an immune response that results in the production of autoantibodies. The long-term and progressive nature of AD and other neurodegenerative diseases results in chronic exposure of the immune system to these citrullinated products and may drive the continual production of autoantibodies. [Copyright &y& Elsevier]

Abstract: Immunoglobulins (Ig) or antibodies are heavy plasma proteins, with sugar chains added to amino acid residues by N-linked glycosylation and occasionally by O-linked glycosylation. The versatility of antibodies is demonstrated by the various functions that they mediate such as neutralization, agglutination, fixation with activation of complement and activation of effector cells. In addition to this plethora of functions, some antibodies express enzymatic activity. Antibodies endowed with enzymatic properties have been described in human autoimmune manifestations in a variety of disorders such as autoimmune thyroiditis, systemic erythematosus (SLE), scleroderma, rheumatoid arthritis (RA), multiple sclerosis (MS) and acquired hemophilia (AH). Antibodies isolated from these conditions were able to specifically hydrolyze thyroglobulin, DNA, RNA, myelin basic protein (MBP), and factor VIII (FVIII) or factor IX (FIX), respectively. The therapeutic relevance of these findings is discussed. [Copyright &y& Elsevier]

Abstract: The intrahepatic biliary destruction of primary biliary cirrhosis (PBC) appears secondary to a multi-lineage response that includes autoantibodies, biliary apotopes, and cellular responses. Although there has been considerable effort in defining the role and specificity of anti-mitochondrial autoantibodies, a major challenge has been the characterization of T effector pathways. This difficulty is due in part to the limitation of current technologies for directly isolating and characterizing autoreactive T cells from patients. Herein, we successfully demonstrate a novel technology for characterizing the surface phenotype of T cell oligoclonal expansions directly ex vivo. Using PBC as a prototypic disease we were able to detect clonal T cell expansions in 15/15 patients examined. Although the T cell expansions from different patients expressed different TCRVβ gene segments, the surface phenotype of the cells was the same. The clonal T cell expansions in PBC patients are CX3CR1+ Fas+ effector-memory T cells, a finding of particular importance given the known up-regulation of fractalkine on injured biliary epithelial cells (BEC). In contrast to the persistent aberrantly expanded T cells observed in the PBC patients, T cell expansions detected in response to a herpes viral infection were very dynamic and resolved over time. This protocol can be used to characterize T cell expansions in other autoimmune diseases. [Copyright &y& Elsevier]

Abstract: Objective: To determine aggregation of autoimmune diseases in the first degree relatives (FDR) of patients with systemic sclerosis (SSc) and to investigate frequencies of antinuclear antibodies (ANA) and other autoantibodies in the FDRs and spouses of patients with SSc. Methods: Information on FDRs including history of autoimmune disease was obtained from unrelated SSc probands in the Scleroderma Family Registry and DNA Repository. FDRs were contacted to verify any reported autoimmune diseases. The prevalence of autoimmune disease in probands’ families was compared with the corresponding prevalence in controls’ families as reported in the literature. Furthermore, sera from probands’ FDRs and spouses in addition to unrelated controls were investigated for the presence of autoantibodies (ANA). Results: We investigated 4612 FDRs of 1071 SSc probands. SSc probands with anti-centromere antibodies (ACA) and limited disease type were more likely to report familial autoimmunity (p =0.022 and p =0.041, respectively). The four most prevalent autoimmune diseases among SSc probands’ FDRs were hypothyroidism (4%), Rheumatoid arthritis (1.5%), hyperthyroidism (1.3%) and systemic lupus erythematosus-SLE (0.4%). Compared to control families, SLE, hypothyroidism and hyperthyroidism were more common in SSc probands’ families. The most striking increase for familial prevalence was observed in SLE (OR=16.98, 95% CI=1.02–227.82, p =0.004). ANA was present in 14.2% of probands’ FDR''s and 8.6% of spouses and did not differ from the prevalence of ANA among controls (p =0.124 and p =0.477, respectively). Only two FDRs of probands had ACA while none had anti-topoisomerase antibodies. Conclusion: Our study implies varying degrees of risk for familial autoimmunity among subtypes of SSc and provides further support for common genetic and potentially environmental factors leading to SSc and SLE. [Copyright &y& Elsevier]

Abstract: Recent studies indicate that genes located on the X-chromosome play a major and unique role in autoimmunity. The fact that most X-linked primary immune deficiencies carry significant autoimmune manifestations greatly supports this notion. Autoimmunity and immune deficiency have been considered two opposite extremes resulting from immune dysregulation and failure of immune development and/or function, respectively. Growing evidence has been accumulating to indicate that autoimmune phenomena occur in patients suffering from primary immune deficiency (PID), and the molecular and cellular mechanisms that interconnect these conditions are being unraveled. The study of rare single-gene disorders associated with significant autoimmunity may shed light on the pathophysiology of more complex multifactorial and polygenic autoimmune disorders. In this regard, primary immunodeficiencies represent unique “experiments of Nature” that illustrate the critical role played by single-gene products in the development, function and homeostasis of the immune system. In this review we will focus on the clinical features and on the cellular and molecular pathophysiology of the known X-linked PID in which autoimmune manifestations are more common, in the attempt to understand what single-gene defects can teach us on the role that key immune pathways and cellular processes may play to prevent autoimmunity. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate the prevalence of serum antibodies against hepatitis C virus and other infectious agents in a large cohort of well-characterized patients with autoimmune diseases (AID). Methods: We utilized 1322 sera from patients with 18 different AID and 236 sera from healthy controls from the same countries and with similar age and sex distribution. All sera were tested for the presence of serum anti-hepatitis C virus (HCV) antibodies as well as antibodies directed at other infectious agents and autoantibodies. Results: Anti-HCV antibody was detected in 115/1322 (8.7%) of patients with AID and 0.4% of matched healthy controls (P <0.0001). The prevalence of anti-HCV antibody was significantly higher in 7/18 different AID (i.e. cryoglobulinemia, mixed cryoglobulinemia pemphigus vulgaris, vasculitis, secondary anti-phospholipid syndrome, Hashimoto''s thyroiditis, and inflammatory bowel disease) compared to controls. Patients with AID and serum anti-HCV positivity had an increased prevalence of antibodies against hepatitis B virus, Toxoplasma gondii and Cytomegalovirus as opposed to a lower frequency of serum autoantibodies. Conclusions: The enhanced prevalence of anti-HCV serum antibodies in AID may suggest a role for HCV in tolerance to breakdown, similarly to its established role in mixed cryoglobulinemia. This immune mediated effect does not rule out the role of other infectious agents. [Copyright &y& Elsevier]

Abstract: Regulatory T cells (Tregs) play an important role in protection against autoimmune disease and are also known to be potent inhibitors of anti-tumor immune responses. The New Zealand Black (NZB) mouse is a murine model for both autoimmune diseases, since high levels of autoantibodies are present, and human CLL, due to the expansion of malignant B-1 cells. In this study, we examined the functional role of CD4+CD25+ Foxp3+ Tregs in these different manifestations. Flow cytometric analysis showed increased levels of Tregs in NZB mice compared to healthy C57Bl/6 controls. Aged NZB mice that have developed a B-1 cell malignancy identified as IgM+CD5+, have the most pronounced increase in Tregs. Ex vivo treatment of splenocytes from NZB mice with IFN-α resulted in a decrease in the frequency of Tregs and malignant B-1 cells. In vivo treatment of both NZB and C57Bl/6 mice with poly (I:C), a potent inducer of IFN-α, also led to a decrease in the levels of Tregs and malignant B-1 cells (NZB only) while amplifying autoimmune manifestations. These results indicate that while high levels of Tregs found in NZB mice might suppress a more severe autoimmune disease, they may also contribute to the development of the B cell malignancy. [Copyright &y& Elsevier]

As iconic and important diagnostic autoantibodies, anti-Ro60 and anti-Ro52/tri-partite motif-containing 21 (TRIM21) make a common appearance in a number of systemic autoimmune disorders such as systemic lupus erythematosus (SLE). These autoantibodies often co-exist together; yet despite their close relationship, there is no evidence that they are physically linked and probably reflect a convergence of separate processes of failed immunological tolerance. Confusingly, they are sometimes classed together as the "SSA" or "Ro" autoantibody system without clear distinction between the two. In this Short Communication, we discuss the diagnostic merits for separate detection and reporting of these two autoantibodies, and discuss avenues for future research. Indeed, further insight into their fascinating origins and pathogenic roles in autoimmunity will surely shed light on how we can prevent and treat devastating autoimmune disorders. • Anti-Ro60 and anti-Ro52/TRIM21 autoantibodies are common autoantibodies. • They are often classed under the same "SSA/Ro" autoantibody system. • Both autoantibodies have important and distinct diagnostic and predictive potentials. • Laboratories and clinicians need to distinguish between the two autoantibodies. [ABSTRACT FROM AUTHOR]

Abstract: Solute carrier family 11 member a1 (SLC11A1) exerts pleiotropic effects on macrophage function. Expression of SLC11A1 is regulated by a (GT)n microsatellite promoter repeat polymorphism of which nine alleles have been described. Enhanced activation of macrophages, associated with increased expression from allele 3, may be functionally linked to the development of autoimmune and inflammatory diseases. Conversely, low expression, driven by allele 2, may afford resistance. We have performed a meta-analysis to determine the association of SLC11A1 promoter alleles 2 and 3 with autoimmunity and inflammation. A random effects pooled odds ratio (OR) of 1.04 (95% confidence interval [CI]=0.20) for allele 3 suggested a weak association of this allele with an increased risk of disease. Calculation of the OR in the absence of asymmetry yielded a random effects pooled OR of 0.88 (95% CI=0.66), effectively reversing the above association. A fixed effects pooled OR of 0.90 (95% CI=0.24) was obtained for allele 2, suggesting a weak predominance of disease in the absence of this allele. Application of the trim-and-fill method resulted in a fixed effects OR of 0.80 (95% CI=0.22), thus strengthening this association. Associations of allele 3 with autoimmune and inflammatory diseases reported in several association studies may be attributable to some form of bias amongst published results. [Copyright &y& Elsevier]

Abstract: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, which can arise from a combination of genetic and environmental factors. In the past, infections (Epstein Barr virus, parvovirus B-19) have been indicated to play a causative role in the development of autoimmune diseases, such as SLE. On the other hand, with the emergence of the “hygiene hypothesis” infections have also shown to play a protective role in autoimmune diseases. Two case studies are presented which provide clinical evidence of SLE patients with severe, long-term disease, despite immunosuppresive therapy. The course of both diseases changed remarkably after they experienced infections with multiple microbes (bacterial, viral and fungal). Surprisingly, their clinical and laboratory signs of SLE normalized and they are now symptom-free after 5 and 3year follow-ups. The second patient has even had a normal pregnancy, which was a trigger factor for disease flare in the past. The infections presumably changed the host immune systems and the mechanisms of their protective effects are most likely multifactorial. Our cases illustrate that infections could be beneficial in SLE patients and re-directing research toward novel innate-based SLE therapy should be explored. [Copyright &y& Elsevier]

Abstract: We have previously shown that iodotyrosyl formation within thyroglobulin (Tg) generates neoantigenic determinants that are immunopathogenic. In the current study, we have examined iodination effects on three tyrosyl-containing Tg peptides that are immunogenic in their non-iodinated form. We found that iodotyrosyl formation can enhance (p179, a.a. 179–194), suppress (p2540, a.a. 2540–2554), or not alter (p2529, a.a. 2529–2545) the immunogenic profiles of these peptides at the T-cell level. On the other hand, iodination did not alter the MHC-restriction profile of p2529 and p2540 (Ak-binders) or p179 (Ak- and Ek-binder) and did not significantly influence the pathogenicity of these determinants. At the B-cell level, addition of an iodine atom on Y192 in p179 generated a neoantigenic determinant, but analogous effects were not discernible in p2529 or p2540. Our results demonstrate that iodotyrosyl formation can exert variable effects on the immunogenic behavior of Tg epitopes which may not always result in enhanced pathology. These findings also suggest that variations in the iodine content of Tg may significantly alter the hierarchy of antigenic determinants, to which the immune system may or may not be tolerant. [Copyright &y& Elsevier]

Abstract: Central Nervous System involvement in Systemic Lupus Erythematosus (CNS-SLE) is very common and ranges between 25%–70% of the patients. The CNS involvement is listed in the ARA criteria for SLE diagnosis. CNS-SLE is associated with more than 20 different autoantibodies. Yet, remarkable among them are the anti-P-ribosomal antibodies (anti-PR). These autoantibodies directed mainly against the carboxy 22 amino acids of the PO, P1 P2 ribosomal phosphoproteins. They are capable of penetrating lived cells and inducing apoptotic changes as well as leading to inhibition of specific cytokine secretion. The titer of the autoantibodies correlate with disease activity, kidney involvement and hepatitis. In this review, the mechanisms involved in CNS involvement and its relationship with anti-P ribosomal antibodies will be described. [Copyright &y& Elsevier]

Abstract: Pulmonary alveolar proteinosis (PAP) is an autoimmune disorder characterized by neutralizing autoantibodies to granulocyte-macrophage colony stimulating factor (GM-CSF). Surfactant metabolism is severely dysregulated in PAP, resulting in a foam cell appearance of alveolar macrophages. Microarray analysis of RNA from PAP bronchoalveolar lavage (BAL) cells to explore autoimmune-related genes yielded evidence of a deficiency of activin A, a cytokine implicated in regulation of B-cell proliferation and reduction of foam cell formation. Subsequent studies confirmed a severe deficiency of activin A gene expression and protein secretion in PAP BAL cells and marked reduction of activin A protein in PAP BAL fluids compared to healthy controls. PAP cells, however, like those of healthy controls, were capable of elevated activin A production in response to GM-CSF. Treatment with activin A in vitro suppressed proliferation of PAP peripheral blood B-cells in a receptor-dependent manner and also reduced secretion of anti-GM-CSF autoantibody. These studies are the first to suggest that activin A may play a role in autoimmune disease. [Copyright &y& Elsevier]

Experimental autoimmune gastritis (EAG) characterised by mononuclear cell infiltrate, parietal and zymogenic cell destruction and circulating autoantibodies to gastric H+/K+ATPase is an animal model for human autoimmune gastritis, that leads to pernicious anaemia. We have previously shown that Fas has a role in initiating damage to target cells in EAG. Here we used three strategies to examine the role of TNFα in this disease. We administered neutralising anti-TNFα antibody either as a single injection or as twice weekly injections for 8 weeks to mice subjected to neonatal thymectomy-induced EAG. To address the role of apoptotic signals through TNFR1, TNFR1 deficient mice were either neonatally thymectomised or crossed to PC-GMCSF transgenic mice that spontaneously develop EAG. Neonatally thymectomised mice treated with anti-TNFα antibody developed destructive gastritis and autoantibodies to gastric H+/K+ATPase similar to control mice. Following either neonatal thymectomy or crossing to PC-GMCSF transgenic mice, TNFR1 deficient mice developed autoantibody-positive destructive gastritis at similar frequency compared with wild type and heterozygous littermates. Our observations that neutralisation of TNFα and absence of TNFR1 has no discernible effect on development of EAG suggest that TNFα is not required for mucosal cell damage or development of autoimmune gastritis. While blocking TNFα activity has therapeutic benefit in certain autoimmune diseases, this is not the case for EAG. [Copyright &y& Elsevier]

Naturally-occurring autoantibodies to certain components of autophagy processes have been described in a few autoimmune diseases, but their fine specificity, their relationships with clinical phenotypes, and their potential pathogenic functions remain elusive. Here, we explored IgG autoantibodies reacting with a panel of cytoplasmic endosomal/lysosomal antigens and individual heat-shock proteins, all of which share links to autophagy. Sera from autoimmune patients and from MRL/lpr and NZB/W lupus-prone mice reacted with the C-terminal residues of lysosome-associated membrane glycoprotein (LAMP)2A. No cross-reaction was observed with LAMP2B or LAMP2C variants, with dsDNA or mononucleosomes, or with heat-shock protein A8. Moreover, administering chromatography-purified LAMP2A autoantibodies to MRL/lpr mice accelerated mortality. Furthermore, flow cytometry revealed elevated cell-surface expression of LAMP2A on MRL/lpr B cells. These findings reveal the involvement of a new class of autoantibodies targeting the C-terminus of LAMP2A, a receptor for cytosolic proteins targeted for degradation via chaperone-mediated autophagy. These autoantibodies could affect the autophagy process, which is abnormally upregulated in lupus. The data presented support a novel connection between autophagy dysregulation, autoimmune processes and pathophysiology in lupus. • This study describes a new class of autoantibodies that target the C-terminus of lysosomal-associated membrane protein 2A. • Affinity-purified LAMP2A-reacting autoantibodies accelerate disease progression in MRL/lpr mouse. • Certain immune cells express LAMP2A at their surface, possibly providing an entryway for LAMP2A antibodies into these cells. • Blocking cell-surface LAMP2A or LAMP2A antibodies may be of therapeutic interest to control the progression of lupus disease. [ABSTRACT FROM AUTHOR]

Abstract: The 11th International Symposium for Sjogren’s syndrome was held in Athens, Greece in September 2011. This symposia is part of a long series of meetings that have attempted to meet the needs of both scientists and physicians in improving the healthcare of their patients with Sjogren’s syndrome. Sjogren’s syndrome affects almost 0.5% of the general population and is second only to rheumatoid arthritis amongst the systemic autoimmune diseases. More importantly, it has daily implications for the millions of sufferers around the world. The goal of this meeting, which included nearly 200 abstracts and invited lectures, was to address the critical needs in the clinical practice of Sjogren’s syndrome. This volume is a composite of select papers that were presented at this meeting and attempts to provide a critical overview of clinical and basic science. The volume includes a variety of themes and, importantly, raises issues that are still unresolved but which are important in our future diagnostic and therapeutic efforts. [Copyright &y& Elsevier]

Abstract: Several matters concerning the term “Autoimmunity” have arisen the last two decades. Most researchers agree that a degree of natural autoimmunity in the absence of disease is needed for the development of effective immune responses against infectious agents or cancer cells. Individuals, however, with suitable genetic background and after exposure to certain environmental triggers (such as UV radiation, bacteria, viruses, etc) may develop an exaggerated immune response against self leading to the development of several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus etc. In this context, a the meeting on “Autoimmunity: Physiological and Pathophysiological Aspects” was held on May in Athens, Greece aiming to bring together and discuss different points of view of the principal investigators that have contributed in the development of this field during the last years. Several aspects of both natural and pathological autoimmunity as well as the possible links between these two states are presented by leading authorities of the field in this special issue. [Copyright &y& Elsevier]

Patients with membranous nephropathy have autoantibodies against PLA2R (up to 80%), or THSD7A (up to 2%). We previously described the immunodominant epitope within PLA2R but epitopes in THSD7A are still unknown. To find anti-THSD7A sera for this study, we screened 1843 sera from biopsy-proven MN patients by ELISA and identified 22 sera as anti-THSD7A positive representing 1.2% of MN cases. Anti-THSD7A positive sera were further characterized by western blotting and slot blotting on THSD7A protein fragments and peptides. Real time interaction analyses and antibodies off-rate could be reliably determined using bio-layer interferometry. A signature motif in the N-terminal domain of THSD7A (T28mer) with sequence homology to the major PLA2R epitope (P28mer) was identified. B-cell epitope prediction analysis and homology modelling revealed this sequence to be antigenic and surface available suggesting it is accessible for the antibody to bind. All ten selected sera bound to the T28mer confirming this sequence as a dominant epitope in THSD7A. Reactivity to this sequence was lost following kallikrein protease cleavage within the predicted epitope. Importantly, cross-reactivity of both PLA2R and THSD7A autoantibodies was observed at the peptide but not the protein level. We propose that this common motif shared by both autoantigens could be an epitope involved in the initial B-cell triggering event in MN. • Membranous nephropathy (MN) is an autoimmune disease characterized by the presence of autoantibodies to podocyte receptors. • The two main antigens are PLA2R in 80% of patients and THSD7A in approximately 2% of the cases. • A novel epitope sequence in THSD7A has high similarities with the PLA2R dominant epitope. • This shared motif is a potential common initiating epitope of autoimmunity in MN. [ABSTRACT FROM AUTHOR]