We hypothesized that CD40L may play a key role in the pathogenesis of the elevated serum IgM and analyzed genetic
and epigenetic modifications Fer-1 cost of the gene coding for CD40L in CD4+ and CD8+ T cells isolated from circulating mononuclear cells from PBC patients and healthy controls. We herein demonstrate significantly lower levels of DNA methylation of the CD40L promoter in CD4+ T cells from PBC patients, as compared with controls, and this decreased methylation was inversely correlated with levels of serum IgM in PBC patients.Conclusion: The findings of an absence of genetic modifications of the CD40L gene, in concert with decreased DNA methylation of the CD40L promoter in PBC patients, suggests that environmental factors, rather than genetics, must play a major role in the pathogenesis of elevated serum IgM MK-2206 in vitro in PBC. (HEPATOLOGY 2012) Although mechanisms underlying the loss of self-tolerance in autoimmunity
remain largely unknown, recent data have shown that the cluster of differentiation 40 ligand (CD40L) plays an important role in the pathogenesis of a number of autoimmune diseases.1, 2 Naïve T cells require contact with appropriately activated antigen-presenting cells (APCs) to be primed, and the CD40-CD40L system constitutes one of the fundamental accessory systems in T-cell priming.3 CD40 is expressed on all APCs and is up-regulated upon cell activation secondary to infection or inflammation.4 CD40 binds to its natural ligand CD40L, which is expressed primarily on activated CD4+ T cells. MCE Moreover, CD40 is constitutively expressed by B cells and its interaction with CD40L is critical for immunoglobulin (Ig) class-switch recombination5; mutations of the X-linked CD40L gene lead to a disorder characterized by elevated levels of IgM in the blood, immunodeficiency, and a high incidence of opportunistic infections.6 Finally, CD40-CD40L interactions have also been shown
to be essential for peripheral B-cell tolerance.7 Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver, characterized by the presence of high titers of circulating antimitochondrial antibodies (AMAs) and liver-infiltrating autoreactive T lymphocytes, leading to the progressive destruction of small intrahepatic bile ducts.8 Other characteristics of PBC include high levels of serum IgM and a strong gender bias, with a female:male ratio of 9:1.8 Similarly to most autoimmune diseases, PBC is reasoned to result from the combined effects of genetics and the environment.9, 10 Epigenetic modifications, particularly DNA methylation, are known regulatory mechanism of gene expression and appear as ideal candidates to explain the environmental influence on individual susceptibility to complex diseases, such as PBC.11 However, although abnormal DNA demethylation has been shown in CD4+ T cells in women with lupus,12 the actual involvement of epigenetic mechanisms exemplified by abnormal DNA methylation in PBC has not been studied.