title: Immunoglobulin M levels inversely correlate with CD40 ligand promoter methylation in patients with primary biliary cirrhosis.
abstract: The cross-talk of cluster of differentiation (CD)40/CD40 ligand (CD40L) plays a key role in CD4(+) 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(+) 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.
  
  
  CONCLUSIONS
  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.
authors: Center for Autoimmune Liver Diseases, Division of Internal Medicine, IRCCS Istituto Clinico Humanitas, Rozzano, Italy.
authors: Ana
authors: A
authors: Lleo
authors: Jieyue
authors: J
authors: Liao
authors: Pietro
authors: P
authors: Invernizzi
authors: Ming
authors: M
authors: Zhao
authors: Francesca
authors: F
authors: Bernuzzi
authors: Le
authors: L
authors: Ma
authors: Gaetana
authors: G
authors: Lanzi
authors: Aftab A
authors: AA
authors: Ansari
authors: Ross L
authors: RL
authors: Coppel
authors: Peng
authors: P
authors: Zhang
authors: Yijun
authors: Y
authors: Li
authors: Zhiguang
authors: Z
authors: Zhou
authors: Qianjin
authors: Q
authors: Lu
authors: M Eric
authors: ME
authors: Gershwin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology; D023201:CD40 Ligand / Q000235:genetics* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology; D019175:DNA Methylation / Q000502:physiology*; D005260:Female; D005838:Genotype; D060148:HapMap Project; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood* / Q000276:immunology; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000502:physiology; D020239:Receptor Cross-Talk / Q000276:immunology
chemical_list: D007075:Immunoglobulin M; D023201:CD40 Ligand