[Truncated abstract] The pathogenesis of sporadic inclusion body myositis (sIBM), the most common myopathy in individuals over 50 years of age, is still poorly understood. Although sIBM is classified as an inflammatory myopathy, there is a debate whether it is a primary autoimmune disease or a myodegenerative disease with a secondary immune response. This thesis has investigated the influence of human leukocyte antigen (HLA) alleles and haplotypes on sIBM susceptibility and the clinical phenotype, and the role of humoral autoimmunity. Previous studies reported a strong association with the HLA-‐DRB1*03:01 allele in Caucasian sIBM patients and an earlier age of onset in carriers of the HLA-‐ DRB1*03/*01 haplotype. Using high resolution HLA-‐DRB1 genotyping, this study of the largest sIBM cohort confirmed these associations and demonstrated for the first time that the complementary allele at the HLA-‐DRB1 locus is an important risk determinant in HLA-‐DRB1*03:01 carriers and that there is an association between carriage of HLA-‐DRB1*13:01 and more severe quadriceps weakness. Thus, the allelic heterogeneity at the HLA-‐DRB1 locus also has effects on the clinical phenotype. Prior to this study, the influence of the secondary HLA-‐DRB (HLA-‐DRB3, HLA-‐DRB4 and HLA-‐DRB5) on the risk of sIBM was unknown. This is the first study to demonstrate that haplotypic combinations at the HLA-‐DRB1 and secondary DRB loci have important risk-‐modifying effects in sIBM in Caucasians. A strong association was found between sIBM and the HLA-‐DRB3*01:01 allele, which was shown to be due to the strong linkage disequilibrium with the major risk allele, HLA-‐DRB1*03:01. In contrast, HLA-‐DRB4 and to a lesser extent HLA-‐DRB5, were found to be independently protective, with HLA-‐DRB4 abrogating the risk effect of HLA-‐DRB1*03:01 in carriers. Previous studies have reported an increased frequency of autoantibodies in patients with sIBM but have not had a population control group. This thesis has confirmed the higher frequency of myositis-‐associated antibodies in sIBM patients than in an ethnically matched population control group, and showed that the presence of antibodies was not associated with the carriage of HLA-‐DRB1*03:01. This study also demonstrated that, although myositis-‐specific antibodies are rarely found in sIBM, their presence is not sufficient to exclude the diagnosis of sIBM...
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2013|