Initiation of autoimmunity by a reactive metabolite of a lupus-inducing drug in the thymus.
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Drug-induced lupus is a side effect of deliberate ingestion of various medications, but its etiology, underlying mechanisms, and pathogenesis are puzzling. In vivo metabolic transformation of lupus-inducing drugs to reactive products explains how a heterogeneous set of drugs can mediate the same disease syndrome. Evidence has accumulated that drugs are transformed by extracellular oxidation from reactive oxygen species and myeloperoxidase produced when neutrophils are activated, maximizing the in situ accumulation of reactive drug metabolites within lymphoid compartments. The metabolite of procainamide, procainamide hydroxylamine, displays diverse biologic properties, but no apparent autoimmune effect has been observed. However, when procainamide hydroxylamine was introduced into the thymus of young adult normal mice, a delayed but robust autoimmune response developed. Disruption of central T-cell tolerance by intrathymic procainamide hydroxylamine resulted in the production of chromatin-reactive T cells that apparently drove the autoantibody response in the periphery. Drug-induced autoantibodies in this mouse model were remarkably similar to those in patients with procainamide-induced lupus. Therefore, this system has considerable promise to provide insight into the initiating events in drug-induced lupus and may provide a paradigm for how other xenobiotics might induce systemic autoimmunity. (+info)
Cytokine regulation of a rodent model of mercuric chloride-induced autoimmunity.
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Experimental models of chemically induced autoimmunity have contributed to our understanding of the development of autoimmune diseases in humans. Heavy metals such as mercury induce a dramatic activation of the immune system and autoantibody production in genetically susceptible rats and mice. This autoimmune syndrome is dependent on T cells, which are important for B-cell activation and cytokine secretion. Several studies have focused on the roles of T-helper (Th)1 and Th2 cells and their respective cytokines in the pathogenesis of mercury-induced disease. This article reviews recent studies that have examined the patterns of cytokine gene expression and where investigators have manipulated the Th1 and Th2 responses that occur during mercury-induced autoimmunity. Finally, we will discuss some biochemical/molecular mechanisms by which heavy metals may induce cytokine gene expression. (+info)
A defect in interleukin 12-induced activation and interferon gamma secretion of peripheral natural killer T cells in nonobese diabetic mice suggests new pathogenic mechanisms for insulin-dependent diabetes mellitus.
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The function of natural killer T (NKT) cells in the immune system has yet to be determined. There is some evidence that their defect is associated with autoimmunity, but it is still unclear how they play a role in regulating the pathogenesis of T cell-mediated autoimmune diseases. It was originally proposed that NKT cells could control autoimmunity by shifting the cytokine profile of autoimmune T cells toward a protective T helper 2 cell (Th2) type. However, it is now clear that the major function of NKT cells in the immune system is not related to their interleukin (IL)-4 secretion. In fact, NKT cells mainly secrete interferon (IFN)-gamma and, activated in the presence of IL-12, acquire a strong inflammatory phenotype and cytotoxic function. (+info)
Autoimmune intestinal pathology induced by hsp60-specific CD8 T cells.
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Due to their ubiquitous distribution and high degree of structural similarity, heat shock proteins (hsp) are potential target antigens in autoimmune diseases. Here, we describe induction of intestinal inflammation following transfer of hsp60-reactive CD8 T cells into mice. Inflammatory reactions were MHC class I dependent and developed primarily in the small intestine. IFN gamma and TNF alpha, as well as gut-derived hsp60, were elevated at sites of T cell infiltration. Intestinal lesions were drastically reduced in mice lacking receptors for TNF alpha. Pathology also developed in germ-free mice, indicating recognition of host-derived hsp60 by CD8 T cells. This report demonstrates that CD8 T cells with defined antigen specificity cause intestinal inflammation, emphasizing a link between infection and autoimmune disease. (+info)
Effect of 1-year treatment with interferon-beta1b on thyroid function and autoimmunity in patients with multiple sclerosis.
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OBJECTIVE: Interferon-beta (IFN-beta) is a widely used therapy for multiple sclerosis (MS), a demyelinating disease of the central nervous system. This study has evaluated the effect on thyroid function and autoimmunity of a 1-year treatment with IFN-beta1b in patients with MS. PATIENTS: We studied 31 patients (age 34+/-7 years, 21 women) with relapsing-remitting MS during IFN-beta1b treatment of 1 year duration. Systematic thyroid assessment and measurements of serum interleukin-6 (IL-6) levels were performed at baseline and every 3 months during treatment. RESULTS: Sixteen percent of the patients had autoimmune thyroiditis before IFN-beta1b, all positive for anti-peroxidase antibodies. The overall incidence of thyroid dysfunction was 33% over 1 year (10% hyperthyroidism, 23% hypothyroidism). Thyroid autoimmunity developed in 5/26 patients (19%), in one case without dysfunction. In addition to autoantibody positivity at baseline, female gender and the presence of an ultrasound thyroid pattern suggestive of thyroiditis were identified by multiple logistic regression as additional risk predictors for the development of thyroid dysfunction. During IFN-beta1b treatment, serum IL-6 levels rose in a consistent biphasic pattern; there was, however, no difference between patients with or without incident thyroid abnormalities. CONCLUSIONS: We conclude that IFN-beta1b therapy can induce multiple alterations in thyroid function, some of which are unrelated to thyroid autoimmunity. IL-6 measurement is not useful to identify patients prone to develop thyroid abnormalities. Though thyroid dysfunction is generally subclinical and often transient, systematic thyroid assessment should be performed during IFN-beta1b treatment. (+info)
Standardized grey scale ultrasonography in Graves' disease: correlation to autoimmune activity.
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OBJECTIVE: Graves' disease leads to thyroid enlargement and to reduction of tissue echogenicity. Our purpose was to correlate grey scale ultrasonography of the thyroid gland with clinical and laboratory findings in patients with Graves' disease. DESIGN: Fifty-three patients with Graves'disease were included in our study, 100 euthyroid volunteers served as control group. Free thyroxine (FT(4)), TSH and TRAb (TSH receptor antibodies) values were measured and correlated with sonographic echogenicity of the thyroid gland. METHODS: All patients and control persons underwent ultrasonographical histogram analyses under standardized conditions. Mean densities of the thyroid tissues were determined in grey scales (GWE). RESULTS: Compared with controls with homogeneous thyroid lobes of normal size (25.6 +/- 2.0GWE, mean +/- S.D.) echogenicity in patients with Graves' disease was significantly lower (21.3 +/- 3. 3GWE, mean +/- S.D., P < 0.0001). Among the patients with Graves' disease significant differences of thyroid echo levels were revealed for patients with suppressed (20.4 +/- 3.1 GWE, mean +/- S.D., n=34) and normalized TSH values (22.5 +/- 3.6GWE, mean +/- S.D., n=19, P < 0.02). Significantly lower echogenicities were also measured in cases of persistent elevated TRAb levels (19.9 +/- 2.9GWE, mean +/- S.D., n=31) in comparison with normal TRAb levels (22.9 +/- 3.5 GWE, mean +/- S.D., n=22, P < 0.0015). No correlation could be verified between echogenicity and either still elevated or already normalized FT(4) values or the thyroid volume. In coincidence of hyperthyroidism and Graves' ophthalmopathy (19.7 +/- 3.5GWE, mean +/- S.D., n=23) significantly lower echogenicity was measured than in the absence of ophthalmological symptoms (22.3 +/- 3.3GWE, mean +/- S.D., n=30, P < 0.016). Patients needing active antithyroid drug treatment revealed significantly lower thyroid echogenicity (20.3 +/- 3.1 GWE, mean +/- S.D., n=40) than patients in remission (23.7 +/- 3.4 GWE, mean +/- S.D., n=13, P < 0.001). Statistical evaluation was carried out using Student's t-test. CONCLUSIONS: Standardized grey scale histogram analysis allows for supplementary judgements of thyroid function and degree of autoimmune activity in Graves' disease. Whether these values help to estimate the risk of recurrence of hyperthyroidism after withdrawal of antithyroid medication should be evaluated in a prospective study. (+info)
Polarized expression of immunoglobulin, spectrin, and protein kinase C beta II occurs in B cells from normal BALB/c, autoimmune lpr, and anti-ssDNA transgenic, tolerant mice.
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The rapid redistribution of B cell surface immunoglobulin to a cap upon cross-linking treatment is a well-described phenomenon, the physiological significance of which is unknown. We describe the observation that splenic B cells from unimmunized normal, autoimmune, and tolerant mice express naturally occurring capped immunoglobulin in the absence of exogenous stimulation. The percentage of capped B cells increases to 20% of B cells by age 16 weeks in the progressive autoimmune lpr mouse. Transgenic, tolerant mice expressing lpr-derived genes for ssDNA-binding antibody also demonstrate a large percentage (35-75%) of immunoglobulin-capped splenic B cells. In these capped B cells, protein kinase C beta II, the cytoskeletal proteins spectrin and ankyrin, and the lipophilic probe diI are enriched beneath the site of the immunoglobulin cap. These data suggest that polarization of surface receptors, signaling molecules, anionic phospholipid domains, and cytoskeletal proteins may be an important part of the B cell immune response in vivo. (+info)
Dendritic cells: the driving force behind autoimmunity in rheumatoid arthritis?
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Dendritic cells (DC) are likely to play a significant role in immune-mediated diseases such as autoimmunity and allergy. To date there are few treatments capable of inducing permanent remission in rheumatoid arthritis (RA) and elucidation of the role of DC may provide specific strategies for disease intervention. Dendritic cells have proven to be powerful tools for immunotherapy and investigations are under way to determine their clinical efficacy in transplantation and viral and tumour immunotherapy. The present review will focus on the current view of DC and their role in autoimmunity, in particular RA. Two possible roles for DC in the pathogenesis of RA will be proposed, based on recent advances in the field. (+info)