Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterised by autoantibody production and systemic inflammation especially affecting renal function, with significant prevalence, morbidity and mortality. Recently, it has been postulated that deficient processing and removal of defunct cells by apoptotic machinery predisposes to SLE.
This PhD project investigates laboratory parameters that will facilitate identification of the distinct mechanisms leading to differential SLE pathology outcomes present in specific patients.
The inflammogen “complement component C4” exercises a divergent role in the pathogenesis of SLE; therefore, it is routinely monitored and used as a tool to assess inflammatory flares in these patients and their responses to corticosteroid therapy.
Seventy five percent of individuals with a genetic deficiency in the synthesis of C4 protein develop severe SLE with renal involvement. However, it is also true that renal inflammation in SLE patients is very often associated with consumption of C4 protein by DNA antigen/antibody complexes deposited along the glomerular basement membrane.
This study focuses on the role of C4 protein in SLE and addresses two specific questions: how does the amount of C4 protein synthesised by an individual correspond with the number C4 genes that individuals possess, and, does the number of C4 genes present in SLE patients explain the persistently low serum C4 protein concentrations often observed in these patients?
It is well established that the number of C4 genes in an individual can vary from 0 to 8 copies (i.e 0 to 4 on each copy of chromosome 6). The total number of C4 genes per individual in a Caucasian population from WA investigated during my undergraduate honours year was shown to vary from two to five, with an approximate Gaussian distribution of complement C4 protein concentrations in serum. Analysis of these data show that the serum C4 protein concentration in 194 persons from the Busselton Population Survey was not proportional to the number of C4 genes present in these individuals. Further, in a small cohort of SLE patients, a low C4 gene copy number did not explain persistently low serum C4 protein concentrations.