Lupus autoimmunity altered by cellular methylation metabolism

Autoimmunity. 2013 Feb;46(1):21-31. doi: 10.3109/08916934.2012.732133. Epub 2012 Nov 1.


Modifications of both DNA and protein by methylation are key factors in normal T and B cell immune responses as well as in the development of autoimmune disease. For example, the failure to maintain the methylation status of CpG dinucleotides in DNA triggers T cell autoreactivity. Methylated proteins are known targets of autoimmunity, including the symmetrical dimethylarginine residues of SmD1 and SmD3 in SLE. Herein, we demonstrate that altering the metabolism of S-adenosylmethionine (SAM), the major methyl donor for transmethylation reactions, can suppress T cell immunity. A by-product of SAM metabolism, 5'-deoxy-5'-methylthioadenosine (MTA), and an indirect inhibitor of methyltransferases, inhibits T cell responses including T cell activation markers, Th1/Th2 cytokines and TCR-related signaling events. Moreover, treatment of the lupus-prone MRL/lpr mouse with MTA markedly ameliorates splenomegaly, lymphadenopathy, autoantibody titers as well as IgG deposition and cellular infiltration in the kidney. Incubation of cells with SAM, which increases intracellular MTA levels, inhibits both TCR-mediated T cell proliferation and BCR (anti-IgM)-triggered B cell proliferation in a dose-dependent manner. These studies define the central role of MTA and SAM in immune responses and provide a simple approach to altering lymphocyte transmethylation and T cell mediated autoimmune syndromes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / immunology*
  • B-Lymphocytes / immunology*
  • Cell Proliferation
  • Cytokines / blood
  • Cytokines / immunology
  • Female
  • Humans
  • Lupus Erythematosus, Systemic / immunology*
  • Lymphocyte Activation / immunology*
  • Methylation
  • Mice
  • Mice, Inbred MRL lpr
  • Mice, Transgenic
  • S-Adenosylmethionine / immunology*
  • S-Adenosylmethionine / metabolism
  • T-Lymphocytes / immunology*
  • Th1 Cells / immunology
  • Th2 Cells / immunology


  • Cytokines
  • S-Adenosylmethionine