Genes, environment and immunity in the development of rheumatoid arthritis

The combined role of genes, environment and immunity in the development of rheumatoid arthritis (RA) has been the subject of recent investigations. New data support a gene–environment interaction between smoking and the MHC class II HLA-DRB1 shared epitope (SE) genes in anti-citrulline antibody (anti-CP+) RA but not in anti-CP− disease. These data from genetic epidemiology, together with information on citrullination in the lungs of smokers, have prompted the formulation of a new etiological hypothesis for anti-CP+ RA, suggesting that smoking in the context of HLA-DR SE might trigger immunity to citrulline-modified proteins and that this immunity, after several years, might cause arthritis.