The cross-talk of cluster of differentiation (CD)40/CD40 ligand (CD40L) plays a key role in CD4 1 T-cell priming, B-cell terminal maturation, and immunoglobulin (Ig) class-switch recombination. Genetic defects in the CD40L lead to a disorder characterized by elevated concentrations of serum IgM and immunodeficiency. Patients with primary biliary cirrhosis (PBC) characteristically show circulating antimitochondrial antibodies (AMAs), liver-infiltrating autoreactive T lymphocytes against mitochondrial antigens, and high levels of IgM. We hypothesized that CD40L may play a key role in the pathogenesis of the elevated serum IgM and analyzed genetic and epigenetic modifications of the gene coding for CD40L in CD4 1 and CD8 1 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 1 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 in PBC. (HEPATOLOGY 2012;55:153-160) A lthough 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 NaΔ± Β¨ve 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 ΓΎ T cells. Moreover, CD40 is constitutively expressed by B cells and its interaction with CD40L is critical for immunoglobulin (Ig) class-switch recombination 5 ; 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