Limited heterogeneity of autoantigens and T cells in autoimmune diseases?

For many induced and spontaneous autoimmune diseases, a predominant role for T cells in the organ-specific destruction process has been shown. In one of the induced models of autoimmunity, experimental allergic encephalomyelitis (EAE), a very small heterogeneity of T-cell receptor (TcR) molecules is expressed by the pathogenic T cells in both rats and mice. Contrary to induced autoimmune diseases, little is known about the autoantigens recognized by these autoimmune T cells and the heterogeneity of their TcR in spontaneous autoimmune diseases. The aim of this work was to establish a system which allows characterization of relevant autoantigens in spontaneous insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice. A completely different approach was taken to characterize the gene products of the minor lymphocyte stimulatory (Mls) loci. These gene products are responsible for the clonal elimination or the clonal stimulation of T cells expressing particular TcR V beta genes and therefore could be implicated in induction of autoimmune diseases by oligoclonal T-cell populations. The finding that Mls antigens are encoded by retroviral sequences leads to the hypothesis that viruses could be the inducing agents of autoimmune diseases.

Baicalin reduces the severity of experimental autoimmune encephalomyelitis

Scutellaria baicalensis Georgi is one of the important medicinal herbs widely used for the treatment of various inflammatory diseases in Asia. Baicalin (BA) is a bioactive anti-inflammatory flavone found abundantly in Scutellaria baicalensis Georgi. To explore the therapeutic potential of BA, we examined the effects of systemic administration of the flavone (5 and 10 mg/kg, ip) on relapsing/remitting experimental autoimmune encephalomyelitis (EAE) induced by proteolipid protein 139-151 in SJL/J mice, an experimental model of multiple sclerosis. The mice treated with PBS or BA at day -1 and for 3 consecutive days were observed daily for clinical signs of disease up to 60 days after immunization. In the PBS-EAE group, neurological scores were: incidence (100%), mean day of onset (8.0 ± 0.73), peak clinical score (3.0 ± 0.4), and cumulative disease index (141.8 ± 19.4). In the BA-EAE group (5 or 10 mg kg-1 day-1, respectively), incidence (95 or 90%), mean day of onset (9.0 ± 0.80 or 9.2 ± 0.75; P = 0.000), peak clinical score (2.2 ± 0.3 or 2.0 ± 0.3; P = 0.000), and cumulative disease index (75.9 ± 10.1 or 62.9 ± 8.4; P = 0.000) decreased, accompanied by the histopathological findings (decrease of dense mononuclear infiltration surrounding vascellum) for the spinal cord. Additionally, the in vitro effects of BA (5, 10, and 25 µM) on mononuclear cells collected from popliteal and inguinal lymph nodes of day-10 EAE mice were evaluated using an MTT reduction assay for cell proliferation, and ELISA to measure IFN-g and IL-4 cytokines. Compared with the control group, BA caused an increase in IL-4 (EAE-DMSO: 3.56 ± 0.42 pg/mL vs EAE-BA (5, 10, and 25 µM): 6.03 ± 1.1, 7.83 ± 0.65, 10.54 ± 1.13 pg/mL, respectively; P < 0.001); but inhibited IFN-g (EAE-DMSO: 485.76 ± 25.13 pg/mL vs EAE-BA (5, 10, and 25 µM): 87.08 ± 9.24, 36.27 ± 5.44, 19.18 ± 2.93 pg/mL, respectively; P < 0.001) and the proliferation of mononuclear cells (EAE-DMSO: 0.73 ± 0.021 vs EAE-BA (5, 10, and 25 µM): 0.41 ± 0.015, 0.31 ± 0.018, 0.21 ± 0.11, respectively; P < 0.001) in a concentration-dependent manner. The results suggest that BA might be effective in the treatment of multiple sclerosis.

Autoimmune diseases in the TH17 era

A new subtype of CD4+ T lymphocytes characterized by the production of interleukin 17, i.e., TH17 cells, has been recently described. This novel T cell subset is distinct from type 1 and type 2 T helper cells. The major feature of this subpopulation is to generate significant amounts of pro-inflammatory cytokines, therefore appearing to be critically involved in protection against infection caused by extracellular microorganisms, and in the pathogenesis of autoimmune diseases and allergy. The dynamic balance among subsets of T cells is important for the modulation of several steps of the immune response. Disturbances in this balance may cause a shift from normal immunologic physiology to the development of immune-mediated disorders. In autoimmune diseases, the fine balance between the proportion and degree of activation of the various T lymphocyte subsets can contribute to persistent undesirable inflammatory responses and tissue replacement by fibrosis. This review highlights the importance of TH17 cells in this process by providing an update on the biology of these cells and focusing on their biology and differentiation processes in the context of immune-mediated chronic inflammatory diseases.

Shared HLA Class II in Six Autoimmune Diseases in Latin America: A Meta-Analysis

The prevalence and genetic susceptibility of autoimmune diseases (ADs) may vary depending on latitudinal gradient and ethnicity. The aims of this study were to identify common human leukocyte antigen (HLA) class II alleles that contribute to susceptibility to six ADs in Latin Americans through a meta-analysis and to review additional clinical, immunological, and genetic characteristics of those ADs sharing HLA alleles. DRB1���03:01 (OR: 4.04; 95%CI: 1.41���11.53) was found to be a risk factor for systemic lupus erythematosus (SLE), Sjogren’s syndrome (SS), and type 1 diabetes mellitus (T1D). DRB1 ¨ ∗04:05 (OR: 4.64; 95%CI: 2.14–10.05) influences autoimmune hepatitis (AIH), rheumatoid arthritis (RA), and T1D; DRB1���04:01 (OR: 3.86; 95%CI: 2.32–6.42) is a susceptibility factor for RA and T1D. Opposite associations were found between multiple sclerosis (MS) and T1D. DQB1���06:02 and DRB1���15 alleles were risk factors for MS but protective factors for T1D. Likewise, DQB1���06:03 allele was a risk factor for AIH but a protective one for T1D. Several common autoantibodies and clinical associations as well as additional shared genes have been reported in these ADs, which are reviewed herein. These results indicate that in Latin Americans ADs share major loci and immune characteristics.

How Does Age at Onset Influence the Outcome of Autoimmune Diseases?

The age at onset refers to the time period at which an individual experiences the first symptoms of a disease. In autoimmune diseases (ADs), these symptoms can be subtle but are very relevant for diagnosis. They can appear during childhood, adulthood or late in life and may vary depending on the age at onset. Variables like mortality and morbidity and the role of genes will be reviewed with a focus on the major autoimmune disorders, namely, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes mellitus (T1D), Sjögren's syndrome, and autoimmune thyroiditis (AITD). Early age at onset is a worst prognostic factor for some ADs (i.e., SLE and T1D), while for others it does not have a significant influence on the course of disease (i.e., SS) or no unanimous consensus exists (i.e., RA and MS).

Spondyloarthropathies in autoimmune diseases and vice versa

Polyautoimmunity is one of the major clinical characteristics of autoimmune diseases (ADs). The aim of this study was to investigate the prevalence of ADs in spondyloarthropathies (SpAs) and vice versa. This was a two-phase cross-sectional study. First, we examined the presence of ADs in a cohort of patients with SpAs (). Second, we searched for the presence of SpAs in a well-defined group of patients with ADs () including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS). Among patients with SpAs, ankylosing spondylitis was observed in the majority of them (55.6%). There were two patients presenting with SS in the SpA group (1.4%) and 5 patients with autoimmune thyroiditis (3.5%). The global prevalence of ADs in SpAs was 4.86%. In the ADs group, there were 5 patients with SpAs (0.46%). Our results suggest a lack of association between SpAs and ADs. Accordingly, SpAs might correspond more to autoinflammatory diseases rather than to ADs.

Introducing polyautoimmunity: secondary autoimmune diseases no longer exist

Similar pathophysiological mechanisms within autoimmune diseases have stimulated searches for common genetic roots. Polyautoimmunity is defined as the presence of more than one autoimmune disease in a single patient. When three or more autoimmune diseases coexist, this condition is called multiple autoimmune syndrome (MAS). We analyzed the presence of polyautoimmunity in 1,083 patients belonging to four autoimmune disease cohorts. Polyautoimmunity was observed in 373 patients (34.4%). Autoimmune thyroid disease (AITD) and Sjögren's syndrome (SS) were the most frequent diseases encountered. Factors significantly associated with polyautoimmunity were female gender and familial autoimmunity. Through a systematic literature review, an updated search was done for all MAS cases (January 2006–September 2011). There were 142 articles retrieved corresponding to 226 cases. Next, we performed a clustering analysis in which AITD followed by systemic lupus erythematosus and SS were the most hierarchical diseases encountered. Our results indicate that coexistence of autoimmune diseases is not uncommon and follows a grouping pattern. Polyautoimmunity is the term proposed for this association of disorders, which encompasses the concept of a common origin for these diseases.

Is there a common genetic basis for autoimmune diseases?

Autoimmune diseases (ADs) represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. The commonality between them however, is the damage to tissues and organs that arises from the response to self-antigens. The presence of shared pathophysiological mechanisms within ADs has stimulated searches for common genetic roots to these diseases. Two approaches have been undertaken to sustain the “common genetic origin” theory of ADs. Firstly, a clinical genetic analysis showed that autoimmunity aggregates within families of probands diagnosed with primary Sjögren's (pSS) syndrome or type 1 diabetes mellitus (T1D). A literature review supported the establishment of a familiar cluster of ADs depending upon the proband's disease phenotype. Secondly, in a same and well-defined population, a large genetic association study indicated that a number of polymorphic genes (i.e. HLA-DRB1, TNF and PTPN22) influence the susceptibility for acquiring different ADs. Likewise, association and linkage studies in different populations have revealed that several susceptibility loci overlap in ADs, and clinical studies have shown that frequent clustering of several ADs occurs. Thus, the genetic factors for ADs consist of two types: those which are common to many ADs (acting in epistatic pleitropy) and those that are specific to a given disorder. Their identification and functional characterization will allow us to predict their effect as well as to indicate potential new therapeutic interventions. Both autoimmunity family history and the co-occurrence of ADs in affected probands should be considered when performing genetic association and linkage studies.

Organic solvents as risk factor for autoimmune diseases: a systematic review and meta-analysis

Background: Genetic and epigenetic factors interacting with the environment over time are the main causes of complex diseases such as autoimmune diseases (ADs). Among the environmental factors are organic solvents (OSs), which are chemical compounds used routinely in commercial industries. Since controversy exists over whether ADs are caused by OSs, a systematic review and meta-analysis were performed to assess the association between OSs and ADs. Methods and Findings: The systematic search was done in the PubMed, SCOPUS, SciELO and LILACS databases up to February 2012. Any type of study that used accepted classification criteria for ADs and had information about exposure to OSs was selected. Out of a total of 103 articles retrieved, 33 were finally included in the meta-analysis. The final odds ratios (ORs) and 95% confidence intervals (CIs) were obtained by the random effect model. A sensitivity analysis confirmed results were not sensitive to restrictions on the data included. Publication bias was trivial. Exposure to OSs was associated to systemic sclerosis, primary systemic vasculitis and multiple sclerosis individually and also to all the ADs evaluated and taken together as a single trait (OR: 1.54; 95% CI: 1.25-1.92; p-value, 0.001). Conclusion: Exposure to OSs is a risk factor for developing ADs. As a corollary, individuals with non-modifiable risk factors (i.e., familial autoimmunity or carrying genetic factors) should avoid any exposure to OSs in order to avoid increasing their risk of ADs.

How do autoimmune diseases cluster in families? A systematic review and meta-analysis

Background: A primary characteristic of complex genetic diseases is that affected individuals tend to cluster in families (that is, familial aggregation). Aggregation of the same autoimmune condition, also referred to as familial autoimmune disease, has been extensively evaluated. However, aggregation of diverse autoimmune diseases, also known as familial autoimmunity, has been overlooked. Therefore, a systematic review and meta-analysis were performed aimed at gathering evidence about this topic. Methods: Familial autoimmunity was investigated in five major autoimmune diseases, namely, rheumatoid arthritis, systemic lupus erythematosus, autoimmune thyroid disease, multiple sclerosis and type 1 diabetes mellitus. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. Articles were searched in Pubmed and Embase databases. Results: Out of a total of 61 articles, 44 were selected for final analysis. Familial autoimmunity was found in all the autoimmune diseases investigated. Aggregation of autoimmune thyroid disease, followed by systemic lupus erythematosus and rheumatoid arthritis, was the most encountered. Conclusions: Familial autoimmunity is a frequently seen condition. Further study of familial autoimmunity will help to decipher the common mechanisms of autoimmunity.

Targeting medication non-adherence behavior in selected autoimmune diseases: a systematic approach to digital health program development

Background 29 autoimmune diseases, including Rheumatoid Arthritis, gout, Crohn’s Disease, and Systematic Lupus Erythematosus affect 7.6-9.4% of the population. While effective therapy is available, many patients do not follow treatment or use medications as directed. Digital health and Web 2.0 interventions have demonstrated much promise in increasing medication and treatment adherence, but to date many Internet tools have proven disappointing. In fact, most digital interventions continue to suffer from high attrition in patient populations, are burdensome for healthcare professionals, and have relatively short life spans. Objective Digital health tools have traditionally centered on the transformation of existing interventions (such as diaries, trackers, stage-based or cognitive behavioral therapy programs, coupons, or symptom checklists) to electronic format. Advanced digital interventions have also incorporated attributes of Web 2.0 such as social networking, text messaging, and the use of video. Despite these efforts, there has not been little measurable impact in non-adherence for illnesses that require medical interventions, and research must look to other strategies or development methodologies. As a first step in investigating the feasibility of developing such a tool, the objective of the current study is to systematically rate factors of non-adherence that have been reported in past research studies. Methods Grounded Theory, recognized as a rigorous method that facilitates the emergence of new themes through systematic analysis, data collection and coding, was used to analyze quantitative, qualitative and mixed method studies addressing the following autoimmune diseases: Rheumatoid Arthritis, gout, Crohn’s Disease, Systematic Lupus Erythematosus, and inflammatory bowel disease. Studies were only included if they contained primary data addressing the relationship with non-adherence. Results Out of the 27 studies, four non-modifiable and 11 modifiable risk factors were discovered. Over one third of articles identified the following risk factors as common contributors to medication non-adherence (percent of studies reporting): patients not understanding treatment (44%), side effects (41%), age (37%), dose regimen (33%), and perceived medication ineffectiveness (33%). An unanticipated finding that emerged was the need for risk stratification tools (81%) with patient-centric approaches (67%). Conclusions This study systematically identifies and categorizes medication non-adherence risk factors in select autoimmune diseases. Findings indicate that patients understanding of their disease and the role of medication are paramount. An unexpected finding was that the majority of research articles called for the creation of tailored, patient-centric interventions that dispel personal misconceptions about disease, pharmacotherapy, and how the body responds to treatment. To our knowledge, these interventions do not yet exist in digital format. Rather than adopting a systems level approach, digital health programs should focus on cohorts with heterogeneous needs, and develop tailored interventions based on individual non-adherence patterns.

Deficiency of thrombospondin-1 reduces Th17 differentiation and attenuates experimental autoimmune encephalomyelitis

Transforming growth factor beta (TGF-beta) plays a role both in the induction of Treg and in the differentiation of the IL-17-secreting T cells (Th17) which drive inflammation in experimental autoimmune encephalomyelitis (EAE). We investigated the role that thrombospondin-1 (TSP-1) dependent activation of TGF-beta played in the generation of an encephalitic Th17 response in EAE. Upon immunization with myelin oligodendrocyte glycoprotein peptide (MOG(35-55)), TSP-1 deficient (TSP-1(null)) mice and MOG(35-55) TCR transgenic mice that lack of TSP-1 (2D2.TSP-1(null)) exhibited an attenuated form of EAE, and secreted lower levels of IL-17. Adoptive transfer of in vitro-activated 2D2.TSP-1(null) T cells induced a milder form of EAE, independent of TSP-1 expression in the recipient mice. Furthermore, in vitro studies demonstrated that anti-CD3/anti-CD28 pre-activated CD4+ T cells transiently upregulated latent TGF-beta in a TSP-1 dependent way, and such activation of latent TGF-beta was required for the differentiation of Th17 cells. These results demonstrate that TSP-1 participates in the differentiation of Th17 cells through its ability to activate latent TGF-beta, and enhances the inflammatory response in EAE. (C) 2009 Elsevier Ltd. All rights reserved.

Autolytic Mycobacterium leprae Hsp65 fragments may act as biological markers for autoimmune diseases

Investigating the proteolytic activity of the recombinant Mycobacterium leprae Heat Shock Protein of 65 kDa (rHsp65), chaperonin 2 (cpn2), we observed that it displays high instability. The fragmentation process starts at the C-terminus followed by progressive degradation of the N-terminus, which leads to a stable fragment comprising the middle region of the molecule. Urea was able to prevent autolysis, probably due to its denaturing action, while EDTA increased degradation levels indicating the need for metal ions. Peptides originated from autolysis were purified and analyzed by mass spectrometry, generating a continuous map. Since the bacteria and mammalian Hsp60 are known to be targets of the immune response and have been implicated in autoimmune diseases and chronic inflammation, the in vivo effect of rHsp65 peptides was evaluated in the spontaneous Systemic Lupus Erythematosus (SLE) model developed by the (NZB/NZW)F(1) mouse hybrids, and their individual anti-rHsp65 IgG2a/IgG1 antibody titer ratio was determined. The results showed orientation toward a T(H)1 responsiveness, and the treatment with the rHsp65 peptides diminished the environmental variance of the survival time of treated animals. These results outline the fact that environmental factors may also act through the modified stability expression of Heat Shock Proteins intervening during autoimmune processes. (C) 2011 Elsevier Ltd. All rights reserved.

Anti-aquaporin-4 antibodies in the context of assorted immune-mediated diseases

Background and purposes: Anti-aquaporin 4 antibodies are specific markers for Devics disease. This study aimed to test if this high specificity holds in the context of a large spectrum of systemic autoimmune and non-autoimmune diseases. Methods: Anti-aquaporin-4 antibodies (NMO-IgG) were determined by indirect immunofluorescence (IIF) on mouse cerebellum in 673 samples, as follows: group I (clinically defined Devic's disease, n = 47); group II [ inflammatory/demyelinating central nervous system (CNS) diseases, n = 41]; group III (systemic and organ-specific autoimmune diseases, n = 250); group IV (chronic or acute viral diseases, n = 35); and group V (randomly selected samples from a general clinical laboratory, n = 300). Results: MNO-IgG was present in 40/47 patients with classic Devic's disease (85.1% sensitivity) and in 13/22 (59.1%) patients with disorders related to Devic's disease. The latter 13 positive samples had diagnosis of longitudinally extensive transverse myelitis (n = 10) and isolated idiopathic optic neuritis (n = 3). One patient with multiple sclerosis and none of the remaining 602 samples with autoimmune and miscellaneous diseases presented NMO-IgG (99.8% specificity). The autoimmune disease subset included five systemic lupus erythematosus individuals with isolated or combined optic neuritis and myelitis and four primary Sjogren's syndrome (SS) patients with cranial/peripheral neuropathy. Conclusions: The available data clearly point to the high specificity of anti-aquaporin-4 antibodies for Devic's disease and related syndromes also in the context of miscellaneous non-neurologic autoimmune and non-autoimmune disorders.