Innate immune cellular phenotypes and genotypes in autoimmune type 1 diabetes

• Main Author: Fung, E. Y. M. G.
• Published: University of Cambridge 2010
• Subjects: 616.079
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599264

To improve our understanding of the genetics and immunology of T1D, I carried out the following projects: 1) investigated whether disease-associated alleles defined by single nucleotide polymorphisms (SNPs) reported in other autoimmune diseases also confer susceptibility to T1D; 2) established flow cytometry protocols for multiplexed, single-cell analysis of circulating antigen-presenting cell subsets to facilitate correlation of genotypes/haplotypes with immune cellular phenotypes (immunophenotypes); 3) correlated T1D-associated genotypes with immunophenotypes on fresh circulating cells; and 4) correlated autoimmune-associated <i>IL2RA </i>haplotypes with induced CD25 (interleukin-2 receptor alpha chain or IL-2Rα) expression levels on blood monocyte. Results from the genotyping of up to 7,943 cases and 9,696 controls with 19 genes previously associated with autoimmune disease suggested that variants in the chromosome regions of 17q21/<i>STAT3, </i>2q32/<i>STAT4</i> and 6q23/<i>TNFAIP3</i> are associated also with T1D (<i>P </i>= 3.70 x 10^-3 to 3.20 x 10^-5). Following the establishment of protocols for multiparameter flow cytometry, selected immunophenotypes on unsimulated monocytes and B cells from healthy volunteers were correlated with T1D-asscoaited genotypes. In parallel, I correlated four <i>IL2RA</i> haplotypes with the surface density of induced CD25 protein on monocytes using a short-term cytokine simulation regimen, as monocytes do not constitutively express CD25. The major finding was that a non-coding SNP, rs2104286, which defines a protective <i>IL2RA</i> haplotypes, correlated in a gene dosage-dependent manner with lower CD25 expression on stimulated CD14⁺CD16⁺ monocytes (<i>P</i> = 3.4 x 10^-4, n = 151), a proinflammatory cell subset that is expanded during inflammation. These data suggest that rs2104286 or undefined SNPs in linkage disequilibrium with rs2014286, influences the expression of cell-surface CD25 on activated monocytes by altering mRNA transcript levels.