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PubMed1982

The genetic basis of autoimmune disease.

The genetic predisposition to autoimmune disease in man is largely specific for each disease, indicating that these diseases are based not on a generalized breakdown of a tolerance mechanism, but on highly specific abnormalities of immune responsiveness which are subject to genetic transmission. In the presence of particular antigens encoded in the major histocompatibility complex (MHC) the relative risk of certain autoimmune diseases is increased, or in some cases decreased, and the increased risk has been widely attributed to linkage disequilibrium with unidentified disease-causing genes. Our studies on the inheritance of spontaneous autoimmune diseases in New Zealand mice have revealed that small numbers of dominant genes, some associated with the MHC but the remainder elsewhere in the genome, determine susceptibility to these diseases. That MHC-linked genes are not of paramount importance casts doubt on the linkage disequilibrium hypothesis. An alternative possibility is that major and minor histocompatibility antigens themselves predispose to the development of autoimmune diseases by altering the immune response repertoire through the effect of their clonal deletions on the network of paratope-idiotope clonal interactions. Such alterations could influence the chances of emergence, by somatic mutation, of pathogenic forbidden clones.

Anemia, Hemolytic↗
PubMed2000

Generalized essential telangiectasia in a patient with Graves' disease: should the spectrum of autoimmune diseases associated with generalized telangiectasia be expanded?

Generalized essential telangiectasia (GET), as originally described, is not associated with any underlying disease. Although patients with GET lack the typical periungual telangiectases associated with autoimmune collagen vascular diseases, these patients may have an underlying autoimmune process. We present a patient with a history of Graves' disease and low-titer anti-nuclear antibodies, who developed rapidly progressive generalized telangiectases. The gender and age of the majority of patients with GET fit well within the demographics of most autoimmune diseases. The documented occurrence of an autoimmune disease in several of the limited number of patients previously diagnosed with GET provides additional evidence that GET may be associated with an underlying autoimmune disease.

Adult↗
PubMedDate not supplied

Addison's other disease: primary biliary cirrhosis as a model autoimmune disease.

Thomas Addison described three of the classical autoimmune diseases, so can justifiably be regarded as one of the fathers of the study of autoimmunity. The least well recognised of these conditions, the autoimmune liver disease primary biliary cirrhosis (PBC), is in some ways the most interesting. As a result of the relatively advanced state of knowledge of its immunopathogenesis, it represents a good model for the study of autoimmune disease. The classical pathological lesion of PBC is apoptotic damage to the biliary epithelial cells lining the small intrahepatic bile ducts. The disease is typified by two symptom sets: fatigue and pruritus, which can occur at any stage of the disease process, and the features of advanced liver disease, which occur when secondary liver damage results from bile retention. Although autoantibodies directed at, in particular, pyruvate dehydrogenase complex (PDC) are almost universally present in PBC (and represent an important diagnostic tool), it appears likely that CD8+ cytotoxic T cells reactive with self-PDC derived epitopes are directly responsible for target cell damage. Recent studies in humans and a novel murine disease model have shed light on the mechanism of breakdown of immune tolerance to self-PDC; they provide important insights into the pathogenesis of PBC in particular and of autoimmunity in general.

Animals↗
PubMed1999

A conformation-dependent epitope in Addison's disease and other endocrinological autoimmune diseases maps to a carboxyl-terminal functional domain of human steroid 21-hydroxylase.

Idiopathic Addison's disease develops as a consequence of autoimmune destruction of steroid-producing cells in the adrenal gland. A major autoantigen is 21-hydroxylase (21OH; P450c21), which is involved in the biosynthesis of cortisol and aldosterone in the adrenal cortex. We selected a number of functionally important 21OH amino acid substitutions, found in patients with congenital adrenal hyperplasia, to study their effects on the binding of 21OH autoantibodies (21OHAb) to 21OH. The ability of 21OHAb to bind in vitro transcribed and translated wild-type 21OH and five different 21OH mutant proteins was quantified by liquid-phase assays. Sera from 21OHAb-positive patients with idiopathic Addison's disease (n = 24), Graves' disease (n = 3), and insulin-dependent diabetes mellitus (n = 1) were used. While the P105L, delE196, and G291S mutations had no effect on autoantibody binding, the P453S mutation had a considerable effect, and the R483P mutation almost completely abolished binding. Synthetic peptides corresponding to linear epitopes defined by amino acids 447-461 and 477-491 were unable to compete with wild-type 21OH for binding to autoantibodies. Direct 21OH DNA sequencing could not reveal any specific genetic variation in alleles found in 21OHAb-positive patients. We conclude that the region involving R483 plays a key role in the formation of a three-dimensional epitope in a functionally important C-terminal domain of the enzyme.

Addison Disease↗
PubMed2004

Antigen-based immunointervention in human autoimmune diseases.

Antigen administration can ameliorate autoimmune disease via various mechanisms, including deletion of autoreactive cells, induction of regulatory T cells, and deviation to non-pathogenic or protective responses. All these mechanisms of immunointervention have been successfully used to prevent and sometimes treat experimental models of autoimmune diseases. Based on these results, expectations have been raised for exploiting similar strategies to inhibit pathogenic autoreactive T cells in human autoimmune diseases. Among them, mucosal administration of autoantigen is an attractive mode of immunointervention still awaiting demonstration of clinical efficacy in human autoimmune diseases. A further step in this direction is now provided by the clear-cut immune deviation observed following oral administration of a disease-related peptide to rheumatoid arthritis patients, leading to inhibition of Th1 while enhancing Th2 and possibly Foxp3-positive regulatory T cells.

Administration, Oral↗
PubMed2005

[Therapeutic intensification and autologous stem cell transplantation in autoimmune diseases].

THE PATHOPHYSIOLOGY of most autoimmune diseases is often poorly understood. EXPERIMENTAL CONSIDERATIONS and clinical experience suggest that high doses immunoablation followed by stem cell transplantation is a therapeutic option to consider for certain severe autoimmune disorders. THE CONCEPT OF RESTORING NORMAL IMMUNE REACTIVITY must in part br true since current results of 466 transplants (445 autologous, 21 allogeneic) patients suffering from various autoimmune diseases show a beneficial outcome in approximately 2/3 of the patients. TO IMPROVE THE EFFICACY AND SAFETY OF SUCH AN AGGRESSIVE PROCEDURE in patients with potentially affected vital organs by the underlying autoimmune disease, it is especially important to follow international consensus guidelines and to centrally collect clinical data for in depth analysis in the EBMT International Stem Cell Project for Autoimmune Disease in Basel, Switzerland. PHASE III STUDIES ARE RUNNING FOR SYSTEMIC SCLEROSIS (Astis, Autologous Stem cell Transplantation International Rheumatoid Arthritis Trial) started in 2003. A STUDY PROJECT IS PLANNED FOR MULTIPLE SCLEROSIS (Astims, Autologous Stem cell Transplantation International Multiple Sclerosis).

Adolescent↗
PubMedDate not supplied

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.

Animals↗
PubMed1998

Familial autoimmunity in pedigrees of idiopathic inflammatory myopathy patients suggests common genetic risk factors for many autoimmune diseases.

OBJECTIVE: To test the hypothesis that many autoimmune diseases share common genetic risk factors and to define the frequency and distribution of autoimmune diseases in relatives of patients with very rare disorders, the idiopathic inflammatory myopathies (IIM). METHODS: We evaluated, in a prospective case-control study, consecutive patients with IIM who were referred to our center and ascertained without regard to family history or known risk factors for autoimmunity, and all available family members. We used a standardized assessment to determine the presence and type of autoimmune disease in each subject. A matched comparison group of control subjects without autoimmune disease who were referred to our center and their families were similarly assessed. RESULTS: Autoimmune diseases were significantly increased in prevalence (21.9%) in the 151 first-degree relatives of the 21 IIM probands compared with the prevalence (4.9%) in the 143 relatives of the 21 control probands (odds ratio [OR] by regression analysis 7.9, 95% confidence interval [95% CI] 2.9-21.9, P < 0.001). Women had more autoimmune disease than men (OR by regression analysis 4.6, 95% CI 2.3-9.0) and the odds ratio for autoimmune disease increased 0.02 per year of age. These disorders tended to follow the frequency distribution of autoimmune diseases in the general population. Genetic modeling studies showed that a non-Mendelian polygenic inheritance pattern for autoimmune disease was most consistent with these data. CONCLUSION: Autoimmune diseases are significantly increased in frequency in first-degree relatives of IIM patients, affect more women than men, increase with age, and are distributed in a pattern similar to that in the general population. Many autoimmune disorders share genes that together act as polygenic risk factors for autoimmunity.

Adolescent↗
PubMed1996

Anti-neutrophil cytoplasmic antibodies in generalized autoimmune diseases.

Anti-neutrophil cytoplasmic antibodies (ANCA) are a system of autoantibodies which are strongly associated with the primary systemic vasculitides (PSV). cANCA, as detected by indirect immunofluorescence, are mostly reactive to proteinase 3 (PR3) and bear high sensitivity and specificity for Wegener's granulomatosis. pANCA have varied subspecificities and clinical associations. The most important subspecificity of pANCA is anti-myeloperoxidase (MPO), which is strongly associated with microscopic polyaniitis and pauci-immune crescentic glomerulonephritis. pANCA also occur at low to moderate frequency in other PSV, collagen vascular disease, inflammatory bowel disease and autoimmune liver disease. In systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), pANCA of varied subspecificity have been found, including anti-MPO at low rate and low titer, while cANCA and anti-PR3 were generally absent. Consequently, anti-PR3 (PR3-ANCA) and anti-MPO (MPO-ANCA) at moderate and high titer are distinguishing features of the PSV and, in an appropriate clinical setting, argue strongly against the presence of SLE or RA. Since no significant clinical association has been found for other pANCA subspecificities, cANCA, PR3-ANCA and MPO-ANCA remain the critical elements of ANCA testing in the clinical diagnosis of generalized autoimmune diseases.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2005

Vitamin D: important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers.

Vitamin D is very important for overall health and wellbeing. A major source of vitamin D comes from exposure to sunlight. Measurement of 25-hydroxyvitamin D in the blood and not 1,25-dihydroxyvitamin D is used to determine vitamin D status. A blood level of 25-hydroxyvitamin D of at least 20 ng/mL is considered to be vitamin D sufficient. Vitamin D deficiency increases the risk of many common cancers, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, and type I diabetes.

Autoimmune Diseases↗
PubMed2000

Immuno- and genetic therapy in autoimmune diseases.

Animal models of autoimmune disease have been developed that mimic some aspects of the pathophysiology of human disease. These models have increased our understanding of possible mechanisms of pathogenesis at the molecular and cellular level and have been important in the testing, development and validation of new immunotherapies. The susceptibility to develop disease in the majority of these models is polygenic as is the case in humans. The exceptions to this rule are gene knock outs and transgenic models of particular genes which, in particular genetic backgrounds, have also contributed to the understanding of single gene function and their possible contribution to pathogenesis. Gene therapy approaches that target immune functions are being developed with encouraging results, despite the polygenic nature of these diseases. Basically this novel immuno-genetic therapy harnesses the knowledge of immunology with the myriad of biotechnological breakthroughs in vector design and delivery. Autoimmune disease is the result of genetic dysregulation which could be controlled by gene therapy. Here we summarize the genetic basis of these human diseases as well as some of the best characterized murine models. We discuss the strategies for their treatment using immuno- and gene therapy.

Animals↗
PubMed1984

Is schizophrenia an autoimmune disease? A review.

Autoimmunity has been shown to be the basis of an ever-increasing number of human diseases. Schizophrenia shares a number of genetic features with these autoimmune diseases and therefore could be an autoimmune disease itself. Several lines of evidence suggest that overactivity of dopaminergic pathways in some areas of the brain are involved in schizophrenia, but the apparent absence of an increase in dopamine turnover suggests that this hyperactivity could be mediated by a dopamine agonist rather than by dopamine itself. Schizophrenia is reviewed in the light of precedents from the field of autoimmune diseases in which autoantibodies have been shown to be able to interact with, and sometimes stimulate hormone receptors, thereby causing disease.

Arthritis, Rheumatoid↗
PubMed2006

Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease.

Virus infections and autoimmune disease have long been linked. These infections often precede the occurrence of inflammation in the target organ. Several mechanisms often used to explain the association of autoimmunity and virus infection are molecular mimicry, bystander activation (with or without epitope spreading), and viral persistence. These mechanisms have been used separately or in various combinations to account for the immunopathology observed at the site of infection and/or sites of autoimmune disease, such as the brain, heart, and pancreas. These mechanisms are discussed in the context of multiple sclerosis, myocarditis, and diabetes, three immune-medicated diseases often linked with virus infections.

Animals↗