Background Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by myositis-related autoantibodies plus infiltration of leukocytes into muscles and/or the skin, leading to destruction of blood vessels and muscle fibers, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in pediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown.
Methods We elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1,644 Caucasian patients with IIM, plus 3,526 matched healthy controls using realtime PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion.
Results The large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCN of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equaled to 2.58 (2.28-2.91), p=5.0x10-53 for C4T; and 2.82 (2.48-3.21), p=7.0x10-57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44-84.4). Intra-group analyses of IIM patients for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies.
Conclusions C4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM, and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of PM.