Autoimmunity In Individuals Research Articles

Islet autoantibody frequency in relatives of children with type 1 diabetes who have a type 2 diabetes diagnosis.

This study aimed to evaluate characteristics of autoimmunity in individuals who have a type 2 diagnosis and are relatives of children with type 1 diabetes. Pre-diagnosis samples (median 17 months before onset) from relatives who were later diagnosed with type 2 diabetes were measured for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) as well as the type 1 diabetes genetic risk score (GRS2). Associations between islet autoantibodies, insulin treatment and GRS2 were analysed using Fisher's exact and t-tests. Among 226 relatives (64% men; mean age at sampling 41 years; mean age 54 years at diagnosis), 32 (14%) were islet autoantibody-positive for at least one autoantibody more than a decade before diagnosis. Approximately half of these (n = 15) were treated with insulin. GADA-positivity was higher in insulin-treated relatives than in non-insulin-treated relatives (12/18 [67%] vs. 6/18 [33%], p < 0.001). IAA-positivity was observed in 13/32 (41%) of relatives with autoantibodies. GRS2 scores were increased in autoantibody-positive relatives (p = 0.032), but there was no clear evidence for a difference according to treatment (p = 0.072). This study highlights the importance of measuring islet autoantibodies, including IAA, in relatives of people with type 1 diabetes to avoid misdiagnosis.

Brief report: can COVID-19 infection trigger rheumatoid arthritis-associated autoimmunity in individuals at risk for the disease? A nested cohort study.

To investigate the association between severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) infection and subsequent development of autoimmunity or pre-clinical manifestations associated with rheumatoid arthritis (RA) in at risk population. This is a nested study within a prospective cohort of first-degree relatives of RA patients (RA-FDR). Participants are tested for RA-associated autoantibodies (anti-citrullinated peptide antibodies (ACPA)/rheumatoid factor (RF)) and clinical signs and symptoms suggestive of early disease. SARS-CoV-2 infections were self-reported between March 2020 and January 2023. All individuals with a pre-pandemic (sample 1) and a post-pandemic sample (sample 2) were included in the analysis. The exposure of interest was self-reported SARS-CoV-2 infection. The primary outcome was a clinically significant change in RA-associated autoantibody serum titers. Secondary outcomes included: becoming seropositive, becoming symptomatic, developing classifiable RA. Among 168 RA-FDRs, 109 reported a SARS-CoV-2 infection between sample 1 and sample 2. During this period, 2 RA-FDRs (1.2%) became anti-CCP2 seropositive, none became anti-CCP3 IgG positive, 6 (3.6%) became RF IgM seropositive, 1 became (0.6%) RF IgA seropositive, 19 (11.3%) became symptomatic and none developed classifiable RA. SARS-CoV-2 infection was not significantly associated with increases in RA autoantibody titers or with secondary outcomes. We could not detect an association between SARS-CoV-2 infection and subsequent development of RA-associated autoimmunity, nor signs or symptoms of RA in an at risk population. These findings do not support the hypothesis that SARS-CoV-2 infections triggers the immune onset of RA.

Is β-Cell Dysfunction Present in Adult Autoantibody Negative Relatives of Individuals with Type 1 Diabetes Mellitus?

Background/Objective: Individuals with a family history of type 1 diabetes mellitus (T1D) are at increased genetic risk for T1D. Previous studies identified the presence of β-cell dysfunction before clinical onset and diagnosis of T1D. However, it is unclear if β-cell dysfunction predates islet autoimmunity in individuals at high genetic risk. Our objective was to test β-cell function in islet antibody negative adults who have a first-degree relative with T1D. We hypothesized that individuals at genetic risk for T1D would exhibit β-cell dysfunction even without detectable islet autoimmunity.Methods: We used ordinary one-way and Brown-Forsythe ANOVA to compare the repeated mixed meal tolerance test (MMTT) and hyperglycemic clamp glucose-stimulated β-cell response and function measures between three groups of individuals: normoglycemic adults without T1D family history age, sex, and BMI-matched islet antibody negative first-degree relatives of individuals with T1D, and islet antibody positive first-degree relatives of individuals with T1D.Results: Neither the MMTT first-phase insulin secretion measures (c-peptide0-15 minutes, c-peptide0-30 minutes, insulin0-15 minutes, insulin0-30 minutes), nor second-phase measures (c-peptide0-120 minutes, insulin0-120 minutes, and glucose0-120 minutes) showed a statistically significant difference between groups. The clamp acute c-peptide response to glucose, insulin sensitivity, c-peptide steady state, first-phase β-cell function, and second-phase β-cell function were similar between subject groups in both visits. Fasting proinsulin:c-peptide ratios, a biomarker of β-cell stress, were also similar between participant groups.Conclusion and Impact: Our data suggest that genetically at-risk autoantibody negative adult relatives of individuals with T1D do not demonstrate β-cell dysfunction compared to controls. Studies show that β-cell ER dysfunction preceding T1D onset is more striking in younger children. Thus, our findings may reflect the use of an adult study population. Alternatively, β-cell dysfunction in T1D may require initial autoimmune activation. This study will contribute to the growing understanding of risk factors contributing to T1D development.This project was funded, in part, with support from the Research Training Program in Diabetes and Obesity funded, in part by grant 3T32DK064466 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding also provided by JDRF grant 2-SRA-2017-498-M-B.

Autoantibodies against ATP4A are a feature of the abundant autoimmunity that develops in first-degree relatives of patients with type 1 diabetes.

Type 1 diabetes is associated with autoantibodies to different organs that include the gut. The objective of the study was to determine the risk of developing gastric parietal cell autoimmunity in relation to other autoimmunity in individuals with a family history of type 1 diabetes. Autoantibodies to the parietal cell autoantigen, H+ /K+ ATPase subunit A (ATP4A) was measured in 2218 first-degree relatives of patients with type 1 diabetes, who were prospectively followed from birth for a median of 14.5 years. All were also tested regularly for the development of islet autoantibodies, transglutaminase autoantibodies, and thyroid peroxidase autoantibodies. The cumulative risk to develop ATP4A autoantibodies was 8.1% (95% CI, 6.6-9.6) by age 20 years with a maximum incidence observed at age 2 years. Risk was increased in females (HR, 1.9; 95% CI, 1.3-2.8; p=0.0004), relatives with the HLA DR4-DQ8/DR4-DQ8 genotype (HR, 3.4; 95% CI, 1.9-5.9; p < 0.0001) and in participants who also had thyroid peroxidase autoantibodies (HR, 3.7; 95% CI, 2.5-5.5; p < 0.0001). Risk for at least one of ATP4A-, islet-, transglutaminase-, or thyroid peroxidase-autoantibodies was 24.7% (95% CI, 22.6-26.7) by age 20 years and was 47.3% (95% CI, 41.3-53.3) in relatives who had an HLA DR3/DR4-DQ8, DR4-DQ8/DR4-DQ8, or DR3/DR3 genotype (p < 0.0001 vs. other genotypes). Relatives of patients with type 1 diabetes who have risk genotypes are at very high risk for the development of autoimmunity against gastric and other organs.

Increased Autoimmunity in Individuals With Down Syndrome and Moyamoya Disease.

Objective: To determine if elevated rates of autoimmune disease are present in children with both Down syndrome and moyamoya disease given the high rates of autoimmune disease reported in both conditions and unknown etiology of angiopathy in this population.Methods: A multi-center retrospective case-control study of children with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome without cerebrovascular disease was performed. Outcome measures included presence of autoimmune disease, presence of autoantibodies and angiopathy severity data. Comparisons across groups was performed using the Kruskal-Wallis, χ2 and multivariate Poisson regression.Results: The prevalence of autoimmune disease were 57.7, 20.3, and 35.3% in persons with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome only groups, respectively (p < 0.001). The prevalence of autoimmune disease among children with Down syndrome and moyamoya syndrome is 3.2 times (p < 0.001, 95% CI: 1.82–5.58) higher than the idiopathic moyamoya group and 1.5 times (p = 0.002, 95% CI: 1.17–1.99) higher than the Down syndrome only group when adjusting for age and sex. The most common autoimmune diseases were thyroid disorders, type I diabetes and Celiac disease. No individuals with idiopathic moyamoya disease had more than one type of autoimmune disorder while 15.4% of individuals with Down syndrome and moyamoya syndrome and 4.8% of individuals with Down syndrome only had >1 disorder (p = 0.05, 95%CI: 1.08–6.08).Interpretation: This study reports elevated rates of autoimmune disease in persons with Down syndrome and moyamoya syndrome providing a nidus for study of the role of autoimmunity in angiopathy in this population.

A Rare Cause of Diabetes: COVID-19

A Rare Cause of Diabetes: COVID-19 Introduction: Environmental factors like viruses have been described in the mechanism of pancreatic beta cell destruction. Various viruses can trigger autoimmunity in individuals genetically predisposed to diabetes. Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) has been shown to bind to angiotensin-converting enzyme 2 (ACE 2) which is expressed throughout the body, including pancreatic cells, leading to direct injury of the endocrine pancreas. We report a case of coronavirus infection disease 2019 (COVID-19) causing a new onset of diabetes mellitus presentation with hyperglycemia, polyuria, polydipsia and weight loss. Case Presentation: A 53 year-old, previously healthy, male presented with five days of fever, fatigue, dry cough, dyspnea and diarrhea. On admission he was hypoxic, with a body mass index of 25 kg/m2 and no evidence of insulin resistance on physical exam. He was diagnosed with SARS CoV-2 and admitted for high requirements of oxygen without the need of the intensive care unit. He was treated with tocilizumab, atazanavir, hydroxychloroquine, full dose anticoagulation and azithromycin. Dexamethasone 4 mg every 8 hours was given for three days. During this admission, his fasting glucose was 75–108 mg/dL. Once started on steroids his fasting and prandial glucose was 85–96 mg/dL and 140 mg/dL on one occasion. He was eventually discharged with 2 liters of nasal cannula which he required for one week. One and a half months after, he presented to the emergency department due to a 6 kg weight loss, polyuria, polydipsia, malaise and fatigue. On arrival his glucose was 549 mg/dL, without anion gap or ketones. He had no evidence of new infection and SARS CoV-2 test was negative. He was started on insulin glargine at night and insulin Humalog before each meal with corrections. Hemoglobin A1c was 13.4% with a C-peptide 0.36 ng/mL and glucose of 195 mg/dL at the time of C-peptide test. His antibodies, anti-islet cell antibody, zinc transporter 8 and glutamic acid decarboxylase-65, were negative. He was discharged with basal/bolus regimen and followed up outpatient with Endocrinology. During follow-up, his c-peptide normalized and he was tapered off insulin. Discussion: In 2003, atypical pneumonia caused by SARS CoV-2 was reported to be associated with hyperglycemia in patients without prior history of diabetes. At 3 year follow-up, the patients no longer had diabetes. Moreover, patients with mild SARS CoV-2 during the first day of hospitalization had a higher fasting plasma glucose than patients admitted for other causes of pneumonia. It is known that SARS CoV-2 binds to ACE 2 which downregulates the receptor, leading to impairment of insulin secretion and hyperglycemia. SARS CoV-2 also produces a direct injury in beta pancreatic cells. It is imperative to monitor patients post COVID-19 to evaluate for new onset diabetes and likely resolution.

Autoimmunity and Genetic Syndromes: A Focus on Down Syndrome.

Within immune system-related diseases, autoimmunity has always represented a field of great interest, although many aspects remain poorly understood even today. Genetic syndromes associated with immunity disorders are common and represent an interesting model for a better understanding of the underlying mechanism of autoimmunity predisposition. Among these conditions, Down syndrome (DS) certainly deserves special attention as it represents the most common genetic syndrome associated with immune dysregulation, involving both innate and adaptive immunity. Autoimmunity represents a well-known complication of DS: it is estimated that people affected by this disease present a risk four to six times higher than the normal population to develop autoimmune diseases such as celiac disease, type 1 diabetes mellitus, and hypo- or hyperthyroidism. Several factors have been considered as possible etiology, including genetic and epigenetic modifications and immune dysregulation. In times in which the life expectancy of people with DS has been extremely prolonged, thanks to improvements in the diagnosis and treatment of congenital heart disease and infectious complications, knowledge of the mechanisms and proper management of autoimmune diseases within this syndrome has become essential. In this short review, we aim to report the current literature regarding the genetic, immune, and environmental factors that have been proposed as the possible underlying mechanism of autoimmunity in individuals with DS, with the intent to provide insight for a comprehensive understanding of these diseases in genetic syndromes.

Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial.

The pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes. We administered a daily oral dose of 4g sodium butyrate or placebo for 1month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1month in between. Participants were randomly allocated to the 'oral sodium butyrate capsules first' or 'oral placebo capsules first' study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers. All 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work. Oral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes. Netherlands Trial Register: NL4832 (www.trialregister.nl). Raw sequencing data are available in the European Nucleotide Archive repository (https://www.ebi.ac.uk/ena/browse) under study PRJEB30292. The study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.

Viewing Autoimmune Pathogenesis from the Perspective of Antigen Processing and Determinant Hierarchy.

Autoimmunity results from the breakdown of immune tolerance to defined target self antigens. Like any foreign antigen, a self antigen is continuously processed by antigen-presenting cells (APCs) and its epitopes are displayed by the major histocompatibility complex on the cell surface (dominant epitopes). However, this self antigen fails to induce a T cell response as the T cells against its dominant epitopes have been purged in the thymus during negative selection. In contrast, the T cells against poorly processed (cryptic) self epitopes escape tolerance induction in the thymus and make it to the periphery. Such T cells are generally harmless as their cognate epitopes in the periphery are not presented efficiently. But, under conditions of inflammation and immune activation, previously cryptic epitopes can be revealed on the APC surface for activation of ambient T cells. This can initiate autoimmunity in individuals who are susceptible owing to their genetic and environmental constellation. Subsequent waves of enhanced processing of other epitopes on the same or different self antigens then cause "diversification" or "spreading" of the initial T cell response, resulting in propagation of autoimmunity. However, depending on the disease process and the self antigen involved, "epitope spreading" may instead contribute to natural regression of autoimmunity. This landmark conceptual framework developed by Eli Sercarz and his team ties together determinant hierarchy, selection of epitope-specific T cells, and the induction/progression of autoimmunity. I am extremely fortunate to have worked with Eli and to have been a part of this fascinating research endeavor.

Age, HLA, and Sex Define a Marked Risk of Organ-Specific Autoimmunity in First-Degree Relatives of Patients With Type 1 Diabetes.

Autoimmune diseases can be diagnosed early through the detection of autoantibodies. The aim of this study was to determine the risk of organ-specific autoimmunity in individuals with a family history of type 1 diabetes. The study cohort included 2,441 first-degree relatives of patients with type 1 diabetes who were prospectively followed from birth to a maximum of 29.4 years (median 13.2 years). All were tested regularly for the development of autoantibodies associated with type 1 diabetes (islet), celiac disease (transglutaminase), or thyroid autoimmunity (thyroid peroxidase). The outcome was defined as an autoantibody-positive status on two consecutive samples. In total, 394 relatives developed one (n = 353) or more (n = 41) of the three disease-associated autoantibodies during follow-up. The risk by age 20 years was 8.0% (95% CI 6.8-9.2%) for islet autoantibodies, 6.3% (5.1-7.5%) for transglutaminase autoantibodies, 10.7% (8.9-12.5%) for thyroid peroxidase autoantibodies, and 21.5% (19.5-23.5%) for any of these autoantibodies. Each of the three disease-associated autoantibodies was defined by distinct HLA, sex, genetic, and age profiles. The risk of developing any of these autoantibodies was 56.5% (40.8-72.2%) in relatives with HLA DR3/DR3 and 44.4% (36.6-52.2%) in relatives with HLA DR3/DR4-DQ8. Relatives of patients with type 1 diabetes have a very high risk of organ-specific autoimmunity. Appropriate counseling and genetic and autoantibody testing for multiple autoimmune diseases may be warranted for relatives of patients with type 1 diabetes.

CLEC16A regulates splenocyte and NK cell function in part through MEK signaling.

CLEC16A is implicated in multiple autoimmune diseases. We generated Clec16a inducible knockout (KO) mice to examine the functional link between CLEC16A auto-inflammation and autoimmunity. Clec16a KO mice exhibited weight loss and thymic and splenic atrophy. Mitochondrial potential was lowered in KO mice splenocytes resulting in aggregation of unhealthy mitochondria in B, T, and NK cells. In Clec16a KO mice we detected disrupted mitophagy in splenic B and T cells. NK cells from Clec16a KO mice exhibited increased cytotoxicity. Incomplete mitophagy was attenuated with PI3K and/or MEK inhibition in Clec16a KO mice. Our results demonstrate a functional link between CLEC16A and disrupted mitophagy in immune cells and show that incomplete mitophagy predisposes the KO mice to inflammation. Taken together, loss of function variants in CLEC16A that are associated with decreased CLEC16A expression levels may contribute to inflammation in autoimmunity through disrupted mitophagy. Drugs modulating mitophagy reverse the process and may be effective in treating and preventing autoimmunity in individuals with risk associated CLEC16A variants.

HLA and non-HLA genes and familial predisposition to autoimmune diseases in families with a child affected by type 1 diabetes.

Genetic predisposition could be assumed to be causing clustering of autoimmunity in individuals and families. We tested whether HLA and non-HLA loci associate with such clustering of autoimmunity. We included 1,745 children with type 1 diabetes from the Finnish Pediatric Diabetes Register. Data on personal or family history of autoimmune diseases were collected with a structured questionnaire and, for a subset, with a detailed search for celiac disease and autoimmune thyroid disease. Children with multiple autoimmune diseases or with multiple affected first- or second-degree relatives were identified. We analysed type 1 diabetes related HLA class II haplotypes and genotyped 41 single nucleotide polymorphisms (SNPs) outside the HLA region. The HLA-DR4-DQ8 haplotype was associated with having type 1 diabetes only whereas the HLA-DR3-DQ2 haplotype was more common in children with multiple autoimmune diseases. Children with multiple autoimmune diseases showed nominal association with RGS1 (rs2816316), and children coming from an autoimmune family with rs11711054 (CCR3-CCR5). In multivariate analyses, the overall effect of non-HLA SNPs on both phenotypes was evident, associations with RGS1 and CCR3-CCR5 region were confirmed and additional associations were implicated: NRP1, FUT2, and CD69 for children with multiple autoimmune diseases. In conclusion, HLA-DR3-DQ2 haplotype and some non-HLA SNPs contribute to the clustering of autoimmune diseases in children with type 1 diabetes and in their families.

Protection against autoimmune diabetes by viral infection

Type 1 Diabetes (T1D) is an autoimmune disease that results from the selective destruction of insulin‐producing beta cells in the pancreas. While it is generally believed that viral infections are responsible for inducing autoimmunity in individuals at risk, experimental evidence indicates that viruses can efficiently prevent T1D. We have identified two mechanisms by which acute lymphocytic choriomeningitis virus (LCMV) infection hampers autoimmune diabetes development in the mouse.The first mechanism is the direct consequence of the early release of inflammatory mediators following LCMV challenge which rapidly confer leukocytes from infected mice the capacity to diminish T1D. The second mechanism involves longer‐term modification of CD4+CD25+ regulatory T cells which become capable of preventing both spontaneous and virally induced T1D as a consequence of TGF‐beta production. Importantly, hampering of autoimmunity by viral infection does not appear to impair antiviral immunity and viral clearance.These findings provide novel mechanistic insight into the ability of viral infection to abort autoimmune diabetes. Induction of such mechanisms during infection may account for the capacity of viruses to prevent T1D as well as other autoimmune disorders.

Unraveling the Pathogenesis of Type 1 Diabetes with Proteomics: Present And Future Directions

Type 1 diabetes (T1D) is the result of selective destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans. T1D is due to a complex interplay between the beta-cell, the immune system, and the environment in genetically susceptible individuals. The initiating mechanism(s) behind the development of T1D are largely unknown, and no genes or proteins are specific for most T1D cases. Different pro-apoptotic cytokines, IL-1 beta in particular, are present in the islets during beta-cell destruction and are able to modulate beta-cell function and induce beta-cell death. In beta-cells exposed to IL-1 beta, a race between destructive and protective events are initiated and in susceptible individuals the deleterious events prevail. Proteins are involved in most cellular processes, and it is thus expected that their cumulative expression profile reflects the specific activity of cells. Proteomics may be useful in describing the protein expression profile and thus the diabetic phenotype. Relatively few studies using proteomics technologies to investigate the T1D pathogenesis have been published to date despite the defined target organ, the beta-cell. Proteomics has been applied in studies of differentiating beta-cells, cytokine exposed islets, dietary manipulated islets, and in transplanted islets. Although that the studies have revealed a complex and detailed picture of the protein expression profiles many functional implications remain to be answered. In conclusion, a rather detailed picture of protein expression in beta-cell lines, islets, and transplanted islets both in vitro and in vivo have been described. The data indicate that the beta-cell is an active participant in its own destruction during diabetes development. No single protein alone seems to be responsible for the development of diabetes. Rather the cumulative pattern of changes seems to be what favors a transition from dynamic stability in the unperturbed beta-cell to dynamic instability and eventually to beta-cell destruction.

Specificity and Immunochemical Properties of Antibodies to Bacterial DNA

DNA is a structurally heterogeneous molecule that elicits antibody production in both normal and aberrant immunity. In the prototypic autoimmune disease systemic lupus erythematosus, anti-DNA antibodies occur prominently and are serological markers for diagnosis and prognosis. These antibodies target conserved sites on both single-stranded (ss) and double-stranded (ds) DNA from essentially all species. In contrast, sera of normal human subjects (NHS) contain antibodies that selectively bind to DNA from certain bacteria. The NHS antibodies differ from lupus anti-DNA in their exclusive binding to foreign DNA as well as in their isotype, light chain distribution, and mode of DNA interaction. The properties of these antibodies suggest that they arise as a specific response to bacterial DNA introduced during infection or colonization. This conclusion is supported by studies demonstrating that bacterial DNA is a potent immunogen in normal mice and can induce antibodies specific for determinants on bacterial ss and dsDNA. Furthermore, immunization of normal animals with bacterial DNA elicits antibodies that bind mammalian as well as bacterial ssDNA; this immunization can also provoke glomerulonephritis. In addition to its immunogenicity, bacterial DNA is mitogenic, stimulating polyclonal activation of murine B cells; bacterial DNA can also induce cytokine production in the mouse. The range of immunological activities of bacterial DNA suggests an important role of this molecule in stimulating host defense in normal individuals and provoking autoimmunity in individuals predisposed to SLE.

Human heart-infiltrating T-cell clones from rheumatic heart disease patients recognize both streptococcal and cardiac proteins.

beta-Hemolytic streptococcal infection in developing countries still causes thousands of causes of rheumatic heart disease, demanding surgical valve correction. Antigenic mimicry between self and streptococcal components has been proposed as the triggering factor leading to autoimmunity in individuals with genetic susceptibility. Although heart streptococcal-M protein cross-reactive antibodies have been demonstrated, heart tissue damage seems to be T lymphocyte-dependent. We studied the infiltrating T lymphocytes in rheumatic heart lesions with the aim of understanding the role of cellular immune response at the site of the lesions. We obtained 107 T-cell clones from surgical fragments of cardiac tissue from four rheumatic heart disease patients. We tested their capacity to recognize streptococcal M protein-derived synthetic peptides and heart proteins. We found eight infiltrating T-cell clones from all four patients that simultaneously recognize streptococcal M and heart proteins. Among the M-protein sequences tested, only synthetic peptides corresponding to regions 1 through 25, 81 through 103, and 163 through 177 were simultaneously recognized with heart protein fractions. Interestingly, regions 81 through 103 and 163 through 177 have been known to bear heart cross-reactive epitopes at the antibody level. Five of these clones are CD4+, and one is CD8+. The presence of heart-M protein cross-reactive T-cell clones in rheumatic heart lesions suggests their direct involvement in the pathogenesis of this disease. The dissection of protective and pathogenic epitopes of streptococcal M protein is an important step in allowing the development of a safe anti-streptococcal synthetic vaccine.

Virus-Induced Autoimmunity

Viral infections in humans commonly result in the transient appearance of a variety of autoantibodies and, in some patients, the development of autoimmune tissue injury and disease. The capacity to cause or exacerbate an autoimmune process is common to many viruses, affecting mainly organs injured by the replicating virus, as demonstrated by several animal models. Viral "footprints" can often be found in patients with autoimmune diseases and include high titers of specific antiviral antibodies, identification of viral (retroviral) sequences, and the presence of alpha-interferons in the serum. Several mechanisms that are not mutually exclusive can account for the pathogenesis of virus-induced autoimmunity. Viruses may modify or release sequestered cellular proteins or affect the host's immune system by direct polyclonal activation of B cells, effects on immunoregulatory cells, and release of lymphokines. The appearance of antiviral antibodies may also be deleterious to the host through molecular mimicry, the generation of anti-idiotypic antibodies, or the formation of immune complexes. No single microorganism or mechanism can explain the extremely varied phenomena of autoimmunity, but growing evidence suggests that certain viral infections may lead to clinically manifest autoimmunity in individuals having genetic and possibly other predisposing factors.