Autoimmunity
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Immune senescence is associated with a decline in T- and B-cell immune responses. It is, therefore, perhaps surprising that aging is linked to the appearance of serological and clinical autoimmunity. Here we review the mechanisms that contribute to the increase in inflammatory and autoimmune responses in aging. The bulk of this review will focus on aging-associated changes in epigenetic mechanisms, and in particular DNA methylation, as this has emerged as an attractive mechanistic link between aging and autoimmunity.
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Autoantibody production is an important feature of many autoimmune disorders, signifying a breakdown of immune tolerance to self-antigens. In celiac disease, an autoimmune enteropathy with multiple extra-intestinal manifestations, autoantibody reactivity to transglutaminase 2 (TG2) has been shown to closely correlate with the acute phase of the disease. ⋯ The clinical significance of these antibodies is not known, although some may be associated with specific clinical presentations or extra-intestinal manifestations of celiac disease. This review examines the presence of anti-TG2 and other autoantibodies in celiac disease, discussing their diagnostic value, their potential role in disease pathogenesis and current hypotheses that explain how their release may be triggered.
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Review
The role of CD40-CD154 interactions in autoimmunity and the benefit of disrupting this pathway.
Many tissue injuries and immune mediated pathologies such as graft allo-rejections were found to involve CD40-CD40 ligand (CD40L, CD154) signaling pathway. The disruption of this pathway in many animal models led to the improvement of graft survival in these models. CD40-CD154 interactions were also shown to play a significant role in the maintenance of autoimmunity, and the production of auto-antibodies in systemic lupus erythematosus (SLE). ⋯ An increased serum level of soluble CD154 was also reported in SLE, RA, and Sjogren's disease in correlation with the relevant auto-antibodies and with the clinical disease activity. Anti-CD154 antibody therapy prevents auto-antibody production and renal immune complex deposition in lupus nephritis, indicating that disruption of this pathway could be a beneficial treatment in SLE. However, the etiology of the higher than expected number of thromboembolic events in anti-CD154 treated SLE patients should be investigated and preventive measures should be considered.
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We investigated circulating anti-inflammatory and pro-inflammatory cytokines, and their ex vivo PBMC production in the absence or presence of the neuroantigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) and T cell mitogen (PHA) in MS patients in relapse and remission, patients with other neurological disorders (OND) and normal healthy controls. MS patients in relapse exhibited significantly increased PBMC production of TNF-alpha spontaneously compared with MS remission and healthy controls and with MBP compared with MS remission. Patients in relapse had significantly increased spontaneous, PHA- and MBP-induced PBMC IL-1beta production compared with remission MS, and was increased compared (PHA only) with OND and healthy controls. ⋯ Pro-inflammatory cytokines in corresponding plasma samples were undetectable whilst the concentration of biologically active TGF-beta1 was the reverse of ex vivo PBMC findings. The increase in biologically active TGF-beta1 production ex vivo in OND patients, despite active disease, compared with the low level in the MS relapse may indicate a regulatory defect in MS. We conclude that the balance between biologically active TGF-beta1 and the pro-inflammatory TNF-alpha, IL-1beta and IFN-gamma is dysregulated during MS relapse-remission and that normal counter-regulatory mechanisms during the relapse phase are defective.
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Beta 2-glycoprotein I (beta2-GPI) is an antigenic target recognised by antiphospholipid antibodies found in association with the antiphospholipid syndrome (APS). In this study, the prevalence of Immunoglobulin M (IgM) and IgA anti-beta2-GPI antibodies was examined in APS patients and compared with IgG antibodies. In addition the value of measuring antibody isotypes and IgG subclass was investigated in the laboratory diagnosis of APS. ⋯ The presence of IgM and IgA antibodies to beta2-GPI was much less specific and sensitive for APS than IgG, with raised levels of these isotypes seen in a variety of thrombotic and non-thrombotic disorders. Elevated levels of IgG1, IgG2, IgG3 and IgG4 antibodies to beta2-GPI were detected in APS patients. While all four IgG anti-beta2-GPI antibody subclasses were represented in APS patients there appeared to be a significant overall skewing towards to the IgG2 subclass.