Date of Award

9-13-2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Bradley, David S.

Abstract

We demonstrate evidence supporting two independent hypotheses related to experimental polychondritis: (1) co-expression of a “nonpathogenic” HLA-DQ allele with a “pathogenic” allele results in enhanced susceptibility to disease; and (2) age related immunological changes allow for the spontaneous onset of disease. Relapsing polychondritis (RP), a human autoimmune disease of unknown etiology in which cartilaginous sites are destroyed by cyclic inflammatory episodes, occurs most commonly during middle age. Collagen-induced polychondritis (CIP) develops in heterologous type II collagen (CII) immunized young (6–8 wk old) mice expressing HLA-DQ6α8β transgenes (tg) regardless of gender, and mirrors clinical RP. Although both DQ6αβ8αβ tg and DQ6α8β tg mice develop CIP, DQ6αβ8αβ tg mice are significantly more susceptible. To determine if co-expression of the DQ8αβ tg, previously shown to induce a strong CII-specific response without inducing polychondritis, with the DQ6α8β tg altered susceptibility to polychondritis, we generated mice expressing both the DQ6α8β and DQ8αβ molecules (DQ6α8αβ tg mice). DQ6α8αβ tg mice displayed a susceptibility to CIP similar to DQ6αβ8αβ tg mice supporting our first hypothesis. We also present evidence that DQ6α8β tg expressing mice develop polychondritis spontaneously (spontaneous polychondritis; SP) at 4.5 to 6 months, the mouse equivalent to 40–50 human years, supporting our second hypothesis. Middle aged DQ8αβ tg mice only developed spontaneous polyarthritis. SP displayed a female preponderance, as some have reported in RP. Auricular chondritis in SP, unlike CIP, exhibited a relapsing/remitting phenotype, requiring several inflammatory cycles to destroy the cartilage, as in RP. Total IgG levels were elevated at the onset of disease in SP, as in RP and CIP. However, SP sera lacked CII-specific IgG, more closely mirroring RP in which as few as 5% of RP patients have been reported to have CII-specific IgG. CIP mice displayed a strong CII-specific immune response. Histological analyses of affected tissues in SP demonstrated a large infiltration of inflammatory cells including a significant number of mast cells. SP provides a model to examine the immuno-pathogenesis of polychondritis in the absence of the strong CII-specific immune response and adjuvant-induced immunostimulatory influence in CIP; as well as age-related changes responsible for enhanced susceptibility to autoimmune diseases.

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