Year: 2004
Type: article
Study design: Observational Study
Abstract: Human complement C4, located in Major Histocompatibility Complex class III region, is an essential component of both the classical and the lectin activation pathways of the complement system.The protein products are categorized into two isotypes: C4A and C4B that may exhibit different biological functions.Both C4A and C4B have unusually frequent variations in the gene number and a wide range of serum protein levels among different individuals and ethnic groups (100 -1000 µg/ml).The number of C4 genes present in an individual varies from 2 to 6.The variation of C4 gene dosage is always concurrent with three other flanking genes, including RP, CYP21 and TNX.The size of C4 genes can be long (21 kb) and short (14.6 kb), which differs in 6.4 kb due to the presence or absence of an endogenous retroviral sequence in intron 9. Complete or partial deficiency of C4A has been observed to be a risk factor for systemic lupus erythematosus (SLE).However, the deeply ingrained "two-locus" model of human C4 genes greatly hindered its epidemiological study in humans.The first objective of my dissertation was to determine the genetic complexity and protein polymorphism of C4 in Caucasians.It was observed that the protein levels of C4, C4A and C4B are determined by the corresponding gene dosages, gene size and body mass index.There were good correlations between the number of long C4 genes with C4A protein levels, and the number of short C4 genes with C4B protein levels.The short iii C4B gene in the second locus of LS RCCX haplotype not only increased the C4B protein level, but also increased the C4A protein level that was expressed by the long C4A gene in the first locus.The second objective of my dissertation was to determine the molecular basis of C4 mutations from complete C4 deficient subjects.Three novel C4 mutations were discovered in eight C4 deficient individuals from US and Austria, which included a single C-deletion in exon 13 of a short C4B gene, a GT-deletion in exon 13 of a long C4A gene, and a G to A mutation at the 5' donor site of intron 28 in two short C4B genes.SS-PCR strategies were created to allow a rapid screening of known C4 mutations in human populations.The third objective of this dissertation was to study variations of C4 gene dosages and protein polymorphisms in Caucasian and Black SLE patients.When compared with case controls, it was shown that deficiencies of total C4 and C4A genes were increased in both Caucasian and Black SLE patients.Intriguingly, protein levels of total C4, C4A and C4B decreased in SLE patients, even within the same gene dosage group.The low protein levels of total C4 and C4A in SLE were caused by deficiencies of C4 and C4A genes, C4A mutations, and low C4 expression or high C4 consumption, which may in turn lead to inefficient clearance of immune complexes (ICs), deposition of ICs in local tissues, and subsequent tissue injury.The study in my dissertation provides valuable information on C4 polygenic variations in humans that may help diagnosis and therapeutic intervention of C4-related diseases, especially SLE.vii
Author: Yan Yang
Institution: The Ohio State University
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2259333430