The Intricate Role of Complement Component C4 in Human Systemic Lupus Erythematosus

Abstract

It was observed about 50 years ago that low serum complement activity or low protein concentrations of complement C4 concurred with disease activities of systemic lupus erythematosus (SLE). Complete deficiencies of complement components C4A and C4B, albeit rare in human populations, are among the strongest genetic risk factors for SLE or lupus-like disease, across HLA haplotypes and racial backgrounds. However, whether heterozygous or partial deficiency of C4A (C4AQ0) or C4B (C4BQ0) is a predisposing factor for SLE has been a highly controversial topic. In this review we critically analyzed past epidemiologic studies on deficiency of C4A or C4B in human SLE. Cumulative results from more than 35 different studies revealed that heterozygous and homozygous deficiencies of C4A were present in 40-60% of SLE patients from almost all ethnic groups or races investigated, which included northern and central Europeans, Anglo-Saxons, Caucasians in the US, African Americans, Asian Chinese, Koreans and Japanese. In addition, French SLE and control populations had relatively low frequencies of C4AQ0, but the difference between the patient and control groups was statistically significant. The relative risk of C4AQ0 in SLE varied between 2.3 and 5.3 among different ethnic groups. In Caucasian and African SLE patients, the two major causes for C4AQ0 are (1) the presence of a mono-S RCCX (RP-C4-CYP21-TNX) module with a single, short C4B gene in the major histocompatibility complex; and (2) a 2-bp insertion into the sequence for codon 1213 at exon 29 of the mutant C4A gene. Both mono-S structures and 2-bp insertion in exon 29 are absent or extremely rare in the C4AQ0 of Oriental SLE patients. The highly significant association of C4AQ0 with SLE across multiple HLA haplotypes and ethnic groups, and the presence of different mechanisms leading to a C4A protein deficiency among SLE patients suggested that deficiency or low expression level of C4A protein is a primary risk factor for SLE disease susceptibility per se. On the other hand, Spanish, Mexican, Australian Aborigine SLE patients had increased frequencies of C4B deficiency instead of C4A deficiency. Such observations underscore the importance of both C4A and C4B proteins in the fine control of autoimmunity. Different racial and genetic backgrounds could change the thresholds for the requirement of C4A or C4B protein levels in immune tolerance and immune regulation. Most past epidemiological studies of C4 in human SLE did not consider the polygenic and gene size variations of C4A and C4B. In addition, many studies were overly dependent on phenotypic observations or methods that did not distinguish differential C4A and C4B protein expression caused by unequal gene number or different gene size from the absence of a functional C4A or C4B gene. For further longitudinal studies on clinical manifestations of SLE, it would be informative to stratify the patients with accurately defined C4A and C4B genotypes. Likewise, elucidation of epistatic genetic factors interacting with C4AQ0 wou...

Reticulocytes bearing C4d as biomarkers of disease activity for systemic lupus erythematosus

“…However, it should be noted that 2 erythrocyte blood group antigens, Rodgers and Chido, have been shown to correspond to the C4d region of C4A and C4B, respectively (16,28), suggesting that both C4A and C4B can bind to and persist on the surface membranes of normal erythrocytes. C4-null alleles or partial deficiency of C4A and/or C4B has been associated with human SLE (36)(37)(38)(39).…”

Complement genetics, deficiencies, and disease associations

“…Sub-epithelial IC deposits are part of the histopathology of SLE. In the case of SLE and IC disorders, C4 is exclusively correlated with the deficiency of the C4A isotype, even at the level of heterozygous deficiency (Yang et al, 2004). On the other hand, C4 deficiency is also associated with a number of autoimmune disorders that are not characterised by abnormalities of IC clearance (e.g.…”

Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes

“…3 C4A primarily takes part in removing immune complexes, whereas C4B takes part in the defense against intruders. 4 Lower levels of C4A confer higher susceptibility to autoimmune disorders, 5 and lower levels of C4B have been associated with increased prevalence of cardiovascular disease. 6 Integration of the HERV-K(C4) sequence presumably confers protection against exogenous retroviral attacks, but also decreases serum C4 concentrations.…”