Low copy numbers of complementC4andC4Adeficiency are risk factors for myositis, its subgroups and autoantibodies

Abstract

BackgroundIdiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown.MethodsWe elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion.ResultsThe large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28–2.91), p=5.0×10−53 for C4T, and 2.82 (2.48–3.21), p=7.0×10−57 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). Intragroup analyses of patients with IIM 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.ConclusionsC4A 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 polymyositis.

Serum proteomic analysis uncovers novel serum biomarkers for depression

“…Luo et al (28) showed that the peripheral plasma concentration of C3 and C3a was significantly higher in the major depressive disorder group than in the healthy controls; Crider et al (29) showed a significant increase in C3 expression in the prefrontal cortex of depressed suicide patients, and C4A is essential for the propagation of the classical complement pathway. Genetic deficiencies of C4A are the monogenic causative factors for the prototypic autoimmune disease systemic lupus erythematosus (30); Zhou et al (31) showed that C4A deficiency is a risk factor for myositis, its subgroups and autoantibodies. To our knowledge, there are no reports on C4A expression in depression.…”

Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

“…For example, low copy numbers of complement C4 and low C4 protein levels were related to the presence of anti-Ro/La, anti-Jo1, and anti-PM/Scl in IIM. 28 , 29 Since these C4 associations are not completely independent from the association with HLA-DRB1∗03 , both types of genetic variations may contribute independently and interactively to the autoantibody-defined IIM subgroups.…”

“…Our results reinforce the idea that rheumatic diseases share similar genetic risk factors (i.e., HLA ) which predispose to certain autoantibody specificities and that there is a reciprocal relationship between specific genetic HLA variations and the presence of particular autoantibodies. 26 , 27 , 28 , 29 …”

Dermatomyositis: Practical Guidance and Unmet Needs

“… 31 Finally, there are reports of complement C4 deficiencies with active myositis, suggesting that evaluating C3 and C4 levels may be beneficial. 32 …”