Human populations are endowed with a sophisticated genetic diversity of complement C4 and its flanking genes RP, CYP21 and TNX in the RCCX modules of the major histocompatibility complex (MHC) class III region. Since the sequence polymorphisms and modular variations of the RCCX, and the polygenic and gene size variations of C4A and C4B are a potential root cause in the susceptibility to autoimmune and MHC-associated diseases, these areas are a topic of debate. Novel or improved techniques to accurately study the complex genetic patterns of the RCCX have been developed. Chromosomes with one- , two- , three- and four C4 genes were characterized in four informative families. Mutations that created polymorphic Bg/II and TaqI sites in RP and C4, respectively, were characterized. PshAI RFLP was developed to detect TNXB-XA recombinants, which causes congenital adrenal hyperplasia (CAH). TaqI and the novel BsaI RFLP's revealed monomodular-L with CYP21A and bimodular structures with CYP21A-CYP21A at frequencies of 20.5% and 22.7% in 22 CAH patients, respectively. The transcript levels of C4A and C4B showed a direct correlation to the respective gene dosages in liver and kidney tissues. Primary cultures of human mesangial cells with equal numbers of C4A and C4B genes demonstrated a constitutively low expression of C4A, but not C4B. The relative level of C4B mRNA increased ~ 2- to 30-fold upon interferon-γ induction. An analysis of 110 Caucasian SLE patients revealed increases of homozygous C4A deficiency (9.1% vs 0.7%, p=0.0008). Although homozygous C4A deficiency was inherently low in the southern Chinese population, partial C4A deficiency was increased in 291 SLE patients (15.5% vs 7.7%, p=0.007). Furthermore, the distribution of C4A gene dosages was lower in the Caucasian (p=0.0005) and Chinese (p=0.008) patient groups when compared to their respective normal controls. Therefore complete or partial deficiency of C4A is a common risk factor for SLE in two different ethnic populations.
In conclusion, the genetic diversity of the RCCX modules and frequent variations in the numbers of C4A and C4B genes in humans may be related to different intrinsic strengths of the immune response and susceptibilities to autoimmune diseases.
|Advisor:||Yu, Chack Yung|
|School:||The Ohio State University|
|Department:||Medical Microbiology and Immunology|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/09(E), Dissertation Abstracts International|
|Keywords:||C4 deficiency, Complement c4, Major histocompatibility complex, Polygenic variation, Polymorphism, Systemic lupus erythematosus|
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