Date of Award

6-23-2006

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Pércio Gulko

Abstract

Rheumatoid arthritis (RA) is a common autoimmune disease associated with significant morbidity and mortality for which therapeutic options are ineffective in inducing sustained remission. Identification of genes influencing disease severity has the potential to reveal alternative approaches to treatment, and positional cloning of quantitative trait loci (QTLs) regulating pristane- and collagen-induced arthritis (PIA and CIA) is a powerful tool to identify candidate genes and pathways for focused association studies in RA. To better characterize loci regulating arthritis severity in the autoimmune loci-rich telomeric portion of rat chromosome 10, a genotype-guided breeding strategy was used to generate QTL-congenic rats, which were tested for PIA and CIA leading to the identification of four QTLs regulating disease severity in PIA (Cia5d ), CIA (Cia29) or both (Cia5a and Cia27). Additional testing of subcongenics and recombinants refined the critical regions of Cia5a to 3.14 Mb and Cia5d to 16.1 Mb. Histological studies, revealed that Cia5a and Cia5d also regulate highly relevant subphenotypes, including synovial hyperplasia, mononuclear infiltrate, angiogenesis, and cartilage and bone erosions. It was demonstrated with qPCR that Cia5a and Cia27 also regulate levels of IL-1β mRNA in the synovium. Furthermore, Cia5a and Cia29 influenced levels of anticollagen autoantibodies as determined by ELISA, which correlate with arthritis severity. Additionally, Cia5a regulated levels of T cells with a regulatory phenotype (CD4+CD45RClo), and Cia5d regulated levels of CD8+CD45RCloCD25+ T cells, also with a regulatory phenotype. Characterization of these subphenotypes has permitted substantial advance in the understanding of how these QTLs may affect arthritis severity, and is expected to be instrumental for prioritization of cells and genes to be studied upon further narrowing of these QTLs. In all, these results indicate that rat chromosome 10 contains at least four genes, each operating via apparently distinct pathways to regulate arthritis severity, in a region  syntenic  to  human  chromosomes  5q31-q34,  17p13  and  17q22-q25.

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