Journal of autoimmunity
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Journal of autoimmunity · Sep 2011
ReviewStiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: protean additions to the autoimmune central neuropathies.
Stiff Person Syndrome (SPS) is a rare autoimmune neurological disease attributable to autoantibodies to glutamic acid decarboxylase (anti-GAD) more usually associated with the islet beta cell destruction of autoimmune type 1 diabetes (T1D). SPS is characterized by interference in neurons with the synthesis/activity of the inhibitory neurotransmitter gamma amino butyric acid (GABA) resulting in the prototypic progressive spasmodic muscular rigidity of SPS, or diverse neurological syndromes, cerebellar ataxia, intractable epilepsy, myoclonus and several others. Remarkably, a single autoantibody, anti-GAD, can be common to widely different disease expressions, i.e. ⋯ One explanation for these data is the differences in epitope engagement between the anti-GAD reactivity in SPS and T1D: in both diseases, anti-GAD antibody reactivity is predominantly to a conformational epitope region in the PLP- and C-terminal domains of the 65 kDa isoform but, additionally in SPS, there is reactivity to conformational epitope(s) on GAD67, and short linear epitopes in the C-terminal region and at the N-terminus of GAD65. Another explanation for disease expressions in SPS includes ready access of anti-GAD to antigen sites due to immune responsiveness within the CNS itself according to intrathecal anti-GAD-specific B cells and autoantibody. Closer study of the mysterious stiff-person syndrome should enhance the understanding of this disease itself, and autoimmunity in general.
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Journal of autoimmunity · Mar 2011
Blockade of the kinin receptor B1 protects from autoimmune CNS disease by reducing leukocyte trafficking.
Disruption of the blood brain barrier (BBB) and transendothelial trafficking of immune cells into the central nervous system (CNS) are pathophysiological hallmarks of Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). Kinins are proinflammatory peptides which are released during tissue injury including EAE. They increase vascular permeability and enhance inflammation by acting on distinct bradykinin receptors, B1R and B2R. ⋯ In vitro analyses revealed that B1R suppression reverses the upregulation of ICAM-I and VCAM-I at the inflamed BBB thereby limiting T cell transmigration. In contrast, blocking B2R had no significant impact on EAE. We conclude that B1R inhibition can reduce BBB damage and cell invasion during autoimmune CNS disease and may offer a novel anti-inflammatory strategy for the treatment of MS.
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It is well-known that septic shock undermines immune homeostasis by inducing an initial intense systemic inflammatory response that is rapidly followed by a negative feedback of anti-inflammatory process. This secondary immunoparalysis state is characterized by decreased phagocytic cells, T cells, natural killer cells and B cells function and proinflammatory cytokine release. ⋯ Consequently, a question emerging from these findings concerns the degree to which the manipulation of T regulatory cells might improve the outcome of patients with sepsis. Preliminary studies in animal models suggest that more work is needed to understand the conditions under which such a therapy may be effective.
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Journal of autoimmunity · Aug 2005
Complete deficiencies of complement C4A and C4B including 2-bp insertion in codon 1213 are genetic risk factors of systemic lupus erythematosus in Thai populations.
The complement component C4 is encoded by two genes: C4A and C4B on human chromosome 6p in the major histocompatibility complex (MHC). Most studies have linked the deficiencies in C4 with systemic lupus erythematosus (SLE) in Angio-Irish, North American, Black American, Mexican American, Australian and Japanese populations. Null alleles at either locus (C4AQ0 or C4BQ0) are relatively common in Americans occurring at the C4A and C4B loci in approximately 10% and 16% of normal individuals, respectively. ⋯ In conclusion, both C4AQ0 and C4BQ0 are the strong predisposing factors for SLE in Thais. It was supported by the absence of either C4A or C4B deletion in healthy control. We suggested that the different racial and genetic backgrounds could alter the thresholds for requirement of C4A or C4B protein levels in immune tolerance and regulation.
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Journal of autoimmunity · Jun 2001
An inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite prevents diabetes development in NOD mice.
Peroxynitrite (ONOO(-)) is a highly reactive oxidant produced by the interaction of the free radicals superoxide (O*-2) and nitric oxide (NO(*)). In a previous study, we found that peroxynitrite is formed in islet beta-cells of nonobese diabetic (NOD) mice. Here, we report that guanidinoethyldisulphide (GED), a selective inhibitor of inducible nitric oxide synthase (iNOS) and scavenger of peroxynitrite prevents diabetes in NOD mice. ⋯ GED did not prevent pancreatic islet infiltration by leukocytes; however, beta-cells that stained positive for nitrotyrosine (a marker of peroxynitrite) were significantly decreased in islets of GED-treated mice (1+/-1%) compared with vehicle-treated mice (30+/-9%). In addition, GED significantly inhibited nitric oxide and nitrotyrosine formation and decreased destruction of beta-cells in NOD mouse islets incubated in vitro with the combination of proinflammatory cytokines interleukin 1-beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). These findings indicate that both superoxide and nitric oxide radicals contribute to islet beta-cell destruction in autoimmune diabetes via peroxynitrite formation in the beta-cells.