Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus

Arthritis Rheum. 2002 May;46(5):1282-91. doi: 10.1002/art.10234.


Objective: Inhibition of T cell DNA methylation causes autoreactivity in vitro and a lupus-like disease in vivo, suggesting that T cell DNA hypomethylation may contribute to autoimmunity. The hypomethylation effects are due, in part, to overexpression of lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18). Importantly, T cells from patients with active lupus have hypomethylated DNA and overexpress LFA-1 on an autoreactive subset, suggesting that the same mechanism could contribute to human lupus. The present study investigated the nature of the methylation change that affects LFA-1 expression in vitro and in human lupus.

Methods: Bisulfite sequencing was used to determine the methylation status of the ITGAL promoter and flanking regions in T cells from lupus patients and healthy subjects, and in T cells treated with DNA methylation inhibitors. "Patch" methylation of promoter sequences in reporter constructs was used to determine the functional significance of the methylation changes.

Results: Hypomethylation of specific sequences flanking the ITGAL promoter was seen in T cells from patients with active lupus and in T cells treated with 5-azacytidine and procainamide. Patch methylation of this region suppressed ITGAL promoter function.

Conclusion: DNA methylation changes occur in specific sequences that regulate LFA-1 expression in lupus T cells and in the hypomethylation model, indicating that altered methylation of specific genes may play a role in the pathogenesis of lupus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Autoimmunity / genetics
  • Azacitidine / pharmacology
  • Cells, Cultured
  • DNA Methylation / drug effects*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Expression / immunology
  • Humans
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / metabolism*
  • Lymphocyte Function-Associated Antigen-1 / genetics*
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Male
  • Middle Aged
  • Platelet Aggregation Inhibitors / pharmacology
  • Procainamide / pharmacology
  • Promoter Regions, Genetic / immunology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism


  • Enzyme Inhibitors
  • Lymphocyte Function-Associated Antigen-1
  • Platelet Aggregation Inhibitors
  • Procainamide
  • Azacitidine