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PubMed1991

Polyclonal B cell activation by the Eta-1 cytokine and the development of systemic autoimmune disease.

Studies of systemic autoimmune disease have led to the view that initiation and progression of the disease process reflects chronic and sustained B cell activation by unidentified polyclonal activating agents. In earlier studies, we found that T cells from MRL/1 mice, which develop murine lupus, express very high levels of a newly defined T cell cytokine, Eta-1. Inasmuch as chronic and sustained B cell stimulation by T cells is a cardinal feature of MRL/1 disease, we determined the effects of this cytokine on Ig production by B cells. We show that both recombinant and biochemically purified natural Eta-1 stimulate IgM and IgG production by mixtures of B cells and macrophages from the autoimmune MRL/l strain. Additional studies suggest that optimal Ig production by Eta-1 may require macrophages and reflect enhanced Ig production by large B cells. These findings support the view that elevated levels of endogenous Eta-1 may cause chronic and sustained polyclonal B cell activation that leads to autoimmune disease in this murine model.

Animals↗
PubMed1995

Immunotolerance and prevention of ocular autoimmune disease.

Immunotherapeutic approaches to autoimmune disease have a common goal of inducing antigen-specific, long-lasting tolerance to autoantigens, without otherwise compromising the immune response. Here we review some of the most interesting experimental advances in this area. We discuss the use of T cell targeting drugs that have been reported to induce long lasting tolerance to ocular antigens. Strategies involving the targeting of idiotypic and clonotypic determinants associated with ocular autoimmunity, such as idiotypic network manipulation and T cell vaccination, are reviewed. The use of cytokines to promote perturbation of the Th1/Th2 balance with its possible implications for treatment of uveitis, is analysed. Finally, we review tolerogenic strategies based on acquisition of tolerance following presentation of antigen through alternative routes, such as injection of antigen into the anterior chamber, intravenous infusion of antigen, and oral administration of retinal antigens. Special emphasis is placed on the last strategy, since there are ongoing clinical trials using oral tolerance as an immunotherapeutic approach to treat autoimmune diseases, among them uveitis.

Animals↗
PubMed1996

IL-4-induced immune deviation as antigen-specific therapy for inflammatory autoimmune disease.

Organ-specific autoimmune diseases are mediated by interferon gamma (IFN-gamma)-producing T helper 1 (Th1) cells. Here, Martin Röcken and colleagues review the experimental basis for an antigen-specific therapeutic approach to inflammatory autoimmune diseases. This strategy involves selective deviation of harmful Th1 responses towards an anti-inflammatory, interleukin 4 (IL-4)-producing Th2 phenotype.

Animals↗
PubMed1999

Linking environmental agents and autoimmune disease: an agenda for future research.

Autoimmune diseases are influenced by multiple factors including genetics, age, gender, reproductive status, hormones, and potential environmental contaminants. A workshop, "Linking Environmental Agents and Autoimmune Diseases," was convened at the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 1-3 September 1998, to review current knowledge about links between environmental exposures and autoimmune disease, to identify and prioritize research needs, and to develop an integrated, multidisciplinary research agenda. Participants spent the last half-day of the workshop in small group discussions for the purpose of developing consensus on research needs. Research needs identified were a) develop research tools needed to explore links between environmental agents and autoimmune disease; b) establish a disease registry or surveillance system; c) develop and validate strategies for screening chemicals for the potential to induce or exacerbate autoimmune disease; d) develop an emergency response strategy to gain information from accidental exposures; and e) conduct hypothesis-driven research in occupationally exposed groups and/or in experimental animals. There was consensus that meetings like this workshop and projects that facilitate interactions between specialties should be encouraged. A multidisciplinary approach is needed to address this problem.

Animals↗
PubMed2002

Experimental chronic Chagas' disease myocarditis is an autoimmune disease preventable by induction of immunological tolerance to myocardial antigens.

The protozoan Trypanosoma cruzi causes chronic Chagas' disease myocarditis (CCDM) in infected mammals. The pathogenesis of CCDM, however, is still unclear. Indirect evidence for either parasite- or heart-specific immune responses playing a pathogenic role is available. In this work, the participation of autoimmunity in the development of CCDM is demonstrated in mice in which immunological tolerance to heart antigens was induced or strengthened prior to their infection by T. cruzi. Tolerance was induced by heart antigen administration in the presence of complete Freund's adjuvant and anti-CD4 antibodies. Tolerized mice developed less intense CCDM than control non-tolerized animals that had received only anti-CD4 and adjuvant. This result confirms the important notion that tolerance to self, and in particular to heart antigens, may be reinforced/induced in normal animals, and raises the possibility that analogous interventions may prevent the development of CCDM in millions of T. cruzi -infected human beings.

Animals↗
PubMed2006

Coexistence of systemic sclerosis with other autoimmune diseases.

To evaluate the coexistence of additional autoimmune disease in a population of patients suffering from systemic sclerosis. The record-charts of 118 Italian patients affected by systemic sclerosis (12 men, 106 women, mean age of 57.2 years, mean duration of disease 8.7 years) followed by a single centre were reviewed; any other diagnose of autoimmune disease the patient was given was recorded. Thirty-eight scleroderma patients (32.2%) were affected by one or two concomitant autoimmune diseases, for a total of 42 diagnoses. The most represented associated autoimmune diseases were autoimmune thyroiditis (17 cases) and primary Sjögren's syndrome (10 cases). Both pulmonary fibrosis as diagnosed by chest X-ray and the extension of skin involvement evaluated by Rodnan total skin score were not correlated with an increased incidence of an additional autoimmune disorder. Our study shows that approximately one third of patients affected by systemic sclerosis developed one or more additional autoimmune diseases. Therefore patients with systemic sclerosis should be carefully evaluated both at onset and during the follow-up for the possible coexistence of other autoimmune disorders.

Adult↗
PubMed1992

Expression of the ED3 antigen on rat macrophages in relation to experimental autoimmune diseases.

Susceptibility to experimental autoimmune diseases (EAD) is rat strain dependent. Susceptible animals are reported to have a defective glucocorticoid response. Although many EAD are regarded as preferentially T cell-mediated, macrophages (M phi) play an important role in several different stages of these diseases. In this study we have investigated the possible effect of the disturbed hypothalamic-pituitary (HPA) axis on M phi phenotype. Therefore we studied M phi differentiation in several different rat strains, especially with regard to the M phi specific differentiation antigen as recognized by monoclonal antibody (mAb) ED3. This mAb is, in normal healthy rats, reactive with very restricted M phi subpopulations present in the lymphoid organs only. However, in autoimmune diseased tissues many of the infiltrated M phi are also ED3-positive. It appeared that M phi, in vitro derived from monocytes out of susceptible rat strains, showed a high ED3 expression in contrast to monocyte-derived M phi out of resistant rat strains. This difference in ED3 expression appeared to be T cell-mediated. Our results are suggestive for the fact that the impaired HPA-axis in EAD susceptible rat strains affects M phi differentiation. The relevance of the observed differences with respect to disease induction, maintenance, or suppression is discussed and obviously needs further investigation.

Animals↗
PubMed2005

Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo.

Generalized vitiligo is an autoimmune disorder in which acquired white patches of skin and overlying hair result from autoimmune loss of melanocytes from involved areas. Although usually sporadic, family clustering of vitiligo may occur, in a non-Mendelian pattern typical of multifactorial, polygenic inheritance. Sporadic vitiligo is associated with autoimmune thyroid disease, pernicious anemia, Addison's disease, and lupus; these same disorders occur at increased frequency in patients' first-degree relatives. Here, we studied 133 'multiplex' generalized vitiligo families, with multiple affected family members. The age of onset of vitiligo is earlier in these 'multiplex' families than in patients with sporadic vitiligo. Affected members of the multiplex vitiligo families have elevated frequencies of autoimmune thyroid disease, rheumatoid arthritis, psoriasis, adult-onset insulin-dependent diabetes mellitus, pernicious anemia, and Addison's disease. Probands' unaffected siblings have elevated frequencies of most of these same autoimmune diseases, particularly if the proband had non-vitiligo autoimmune disease. Familial generalized vitiligo is thus characterized by earlier disease onset and a broader repertoire of associated autoimmune diseases than sporadic vitiligo. This mostly likely reflects a greater inherited genetic component of autoimmune susceptibility in these families. These findings have important implications for autoimmune disease surveillance in families in which multiple members are affected with vitiligo.

Addison Disease↗
PubMed2002

[Association of HLA molecules with autoimmune diseases].

The etiology of autoimmunity diseases includes an immunological reaction against various autoantigens. The HLA molecules play an important role in the antigen presentation process to the immune system. The HLA genes were found as the most significant genetic predisposition factor. The strongest association described in the literature is the association of HLA-B27 with ankylosing spondylitis. Associations were since usually observed with HLA-DR and DQ genes. We are also focused on Diabetes mellitus 1. type. Diabetes is an organ specific autoimmune disease characterised by destruction of beta-cells of Langerhansen pancreatic islets. The cause of the destruction process is not known yet, but it seems to be triggered by repeated presentation of self-antigen hGAD65 to the immune system. This review presents the most interesting solutions and hypotheses of the unanswered question about HLA association mechanism.

Autoimmune Diseases↗
PubMedDate not supplied

[Detection of autoantibodies against phenylalanyl-, tyrosyl-, and tryptophanyl-tRNA-synthetase and anti-idiotypic antibodies to it in serum from patients with autoimmune diseases].

Sera of patients bearing autoimmune diseases (rheumatoid arthritis and systemic lupus erythematosus) and sera of clinically healthy donors were examined by ELISA for the presence of autoantibodies against tryptophanyl-, tyrosyl- and phenylalanyl-tRNA synthetases. Pure bovine synthetases served as antigens. It was shown that in patients with both autoimmune diseases all three enzyme autoantibodies were revealed at serum dilution 1/1600-1/3200. Moreover, by means of monoclonal antibodies against the same enzymes used for immunoaffinity sorption, antiidiotypic antibodies of IgG type against autoantibodies were detected. A conclusion has been made that autoimmune diseases are characterized by autoimmune response for many aminoacyl-tRNA synthetases irrespectively of their quaternary structure, intracellular location etc both at the level of primary and secondary antibodies.

Antibodies, Anti-Idiotypic↗
PubMed1988

Current concepts of autoimmune disease.

Our concepts of autoimmune disease have evolved with our changing understanding of the immune response. In recent years, clonal deletion theories have gradually given way to more dynamic views of the regulation of anti-self immune reactions. It is now clear that self-reactive B cells and some self-reactive T cells persist in the body, and there is every reason to believe that antigen-presenting cells are fully capable of presenting self-antigens in the same manner as foreign antigens. The critical event in the induction of autoimmune disease, therefore, is the quantitative balance of active suppression v the induction of self-reactive help. This help provided a helper T cell response requires that the self-antigens be presented in the context of self-MHC with sufficient affinity and avidity. The antireaction must be potent enough to overcome the totality of suppressive factors, including specific and non-specific suppressor T cells and anti-idiotypic or anti-T-cell-receptor responses.

Antigen-Presenting Cells↗
PubMed2002

[Assessment methods of autoantibodies in autoimmune diseases].

In most of the autoimmune diseases, a humoral and cellular immune response is characteristically seen, with autoantibodies and cells directed to distinct intracellular antigens. This phenomenon can be shown in systemic diseases like sclerosis, systemic lupus erythematosus, Sjogren's syndrome, mixed connective tissue disease, polymyositis and rheumatoid arthritis. It is also evident that autoantibodies are present in many the autoimmune diseases (called organ-specific) like for example Hashimoto, Graves-Basedow or Addison disease. The presence of autoantibodies is important items to be considered in establishing a diagnosis and because of that autoantibodies are included in the diagnostic criteria of many autoimmune diseases. They are useful prognostic markers in some situations and facilitate clinical and treatment follow-up. Since year 1950 (discovering of the first autoantibody--classical rheumatoid factor IgM class) many new methods like: immunoelectrophoresis, counter-electrophoresis, double and radial immunodiffusion in gels, immunoagglutination and haemolytic methods have been used for autoantibodies assessment. It seems to us the indirect immunofluorescence method (IIF) was a most powerful, sensitive and comprehensive test for screening of autoantibodies, until an immunoenzymatic (EIA) methods (ELISA, Western-blotting) in late 60-s was worked out. The immunoenzymatic tests are very useful because of their simplicity and reliability. But there is one more excellent test hybrid named "Colorzyme" (presented by Immuno-Concept Corporation from USA) worked out by combining of the EIA and IIF tests. Instead of FITC-conjugates (like in IIF) a HRP-conjugates for developing of typical ANA-test based on glass fixed Hep-2 cells have been used. The nuclear type of pattern we get using "Colorzyme" test are very strong, nit and rich in details. The prevalence of the "Colorzyme" test relies on that it can be properly done and interpreted by unexperienced technician. More and more new-founded resources of marker autoantibodies and methods force to introduction into standardization both methods and specimens on which they are marked.

Antibody Specificity↗
PubMed2005

X chromosome monosomy: a common mechanism for autoimmune diseases.

The majority of human autoimmune diseases are characterized by female predominance. Although sex hormone influences have been suggested to explain this phenomenon, the mechanism remains unclear. In contrast to the role of hormones, it has been suggested, based on pilot data in primary biliary cirrhosis, that there is an elevation of monosomy X in autoimmune disease. Using peripheral white blood cells from women with systemic sclerosis (SSc), autoimmune thyroid disease (AITD), or healthy age-matched control women, we studied the presence of monosomy X rates using fluorescence in situ hybridization. We also performed dual-color fluorescence in situ hybridization analysis with a chromosome Y alpha-satellite probe to determine the presence of the Y chromosome in the monosomic cells. In subsets of patients and controls, we determined X monosomy rates in white blood cell subpopulations. The rates of monosomy X increased with age in all three populations. However, the rate of monosomy X was significantly higher in patients with SSc and AITD when compared with healthy women (6.2 +/- 0.3% and 4.3 +/- 0.3%, respectively, vs 2.9 +/- 0.2% in healthy women, p < 0.0001 in both comparisons). Importantly, X monosomy rate was more frequent in peripheral T and B lymphocytes than in the other blood cell populations, and there was no evidence for the presence of male fetal microchimerism. These data highlight the thesis that chromosome instability is common to women with SSc and AITD and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance of autoimmune diseases.

Adult↗
PubMed1985

The study and manipulation of experimental autoimmune disease using T lymphocyte lines.

Autoimmune diseases include entities of varied clinical expression such as juvenile onset diabetes mellitus, rheumatoid arthritis, multiple sclerosis, and thyroiditis. Nevertheless, these autoimmune diseases have a common origin; they are caused by clones of lymphocytes that specially attack the individual's own body components. To study autoimmune processes, we have isolated and grown as long-term cell lines the T lymphocytes that mediate several different experimental autoimmune diseases in rats or mice. These cell lines have increased our understanding of pathogenesis, but perhaps more importantly, it appears that suitably attenuated lines can be used to immunize the individual animal against its own autoimmune cells. Thus, autoimmune cells can be used as vaccines to prevent or treat the autoimmune process.

Animals↗
PubMed2004

NKT cell-stimulating synthetic glycolipids as potential therapeutics for autoimmune disease.

Although T cells were previously believed to recognize only peptide antigen associated with the major histocompatibility complex (MHC), recent studies have shown that there are unique T cells specialized for recognition of lipid or glycolipid antigens bound to the MHC class I-like CD1 molecules (CD1a, b, c or d). Among these lipid-specific T cells, CD1d-restricted T cells, also referred to as natural killer (NK) T cells, are of special interest as a target of drug development, since their role in immunoregulation has been indicated in various physiological or disease conditions including autoimmunity. They are unique in their homogeneous ligand specificity for alpha-glycosylated sphingolipid and secrete large amounts of regulatory cytokines shortly after T cell receptor (TCR) engagement. The first glycolipid identified as an NKT cell ligand was alpha-galactosylceramide (alpha-GalCer) derived from marine sponges. alpha-GalCer exhibits significant immunomodulatory effects by stimulating NKT cells. However, we found that an altered analogue of alpha-GalCer with a shorter sphingosine chain (OCH), is more useful than alpha-GalCer for treatment of autoimmune disease models, because of its ability to selectively induce IL-4, a key cytokine for control of autoimmunity. As such, altered glycolipid ligands (AGL) of alpha-GalCer appear to be promising reagents for treatment of human autoimmune diseases.

Animals↗
PubMedDate not supplied

Hypothesis: the role of interleukins in lymphopoiesis - important in autoimmune disease?

The development of multiorgan autoimmune disease is considered in a framework of human lymphocyte ontogeny and immune regulation. A hypothesis is presented that accommodates many typical features of the clinical course and laboratory abnormalities of autoimmune disease by assuming the presence of underlying defects in lymphocyte differentiation. Altered production of and response to poietin-like mediators such as interleukins may be responsible for many of these abnormalities and represent prime candidates for further research into the pathophysiology of autoimmune diseases.

Aging↗