Immunologic and genetic studies of rat adjuvant-induced arthritis

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with a multifactorial and largely unknown etiology. It is influenced by both environmental and genetic factors, and understanding of disease mechanisms and identification of disease-causing genes is hampered by the complex and polygenic nature of the disease. Adjuvant-induced arthritides can be used as experimental systems to delineate genetic components and disease mechanisms that might give clues to the etiology of the human disease. These arthritides are induced by non-specific activators of the immune system, adjuvants, which can be of various structures and origins. One such model is oil-induced arthritis (OIA), which develops in the DA rat after one intradermal injection of the mineral oil incomplete Freund's adjuvant. It is a T cell dependent monophasic polyarthritis influenced by genes both within and outside the major histocompatibility complex (MHC). This thesis immunologically and genetically characterises OIA, as well as a new adjuvant-induced arthritis triggered by an adjuvant of self-origin, squalene. In a search for potentially disease-limiting lymphocyte populations we demonstrate that removal of CD8+ T cells or natural killer (NK) cells by in vivo administration of anti-CD8 monoclonal antibodies causes an earlier onset of OIA. However, the OIA susceptible DA rat does not have a lower proportion of CD8+ T cells or NK cells in draining lymph nodes before arthritis onset than the resistant LEW.1AV1 strain. The picture concerning NK receptor expressing T cells is different, since the proportion of T cells expressing NKR-P1 differs between OIA-resistant LEW.1AV1 and -susceptible DA strains before arthritis onset, with LEW.1AV1 having a 2 to 3 times larger proportion of NK T cells. We demonstrate that arthritis induced with the endogenous adjuvant squalene displays clinical similarities with previously described adjuvant-induced arthritides and RA. The disease is T cell dependent, influenced by both MHC and non-MHC genes and displays a chronic course in certain animals. Susceptibility to squalene-induced arthritis (SIA) is influenced by the quantitative trait loci (QTLs) Oia2 and Oia3, thereby displaying both clinical and genetic resemblances to OIA. Besides the linkage analysis of Oia2 and Oia3 to SIA, we have performed two other studies of QTLs associated with adjuvant-induced arthritides. Firstly, we have confirmed that OIA susceptibility is linked to Oia2 in a backcross between DA and PVG. I AVI, thereby mapping OIA susceptibility within the same chromosome region as an aberrant NK reactivity of the DA rat has been reported to map. Secondly, we have identified Oia4, a new QTL on rat chromosome 10 influencing the rate of progression to maximal arthritis severity. This phenotype is not correlated with disease severity, indicating that these phenotypes are distinct and determined by different genes. Understanding why adjuvants, which are non-specific activators of the immune system, induce a T cell dependent joint inflammation in susceptible rat strains can cast light on some aspects of rheumatoid arthritis and other inflammatory joint diseases in man.