Abstract
Rheumatoid Arthritis (RA) is a chronic joint disease for which there is presently no cure, possibly because rational design of therapy is hindered by lack of knowledge of disease mechanisms (pathogenesis), and disease causing genetic and inducing factors (etiology). In this thesis, etiopathogenetic clues were sought in experimental arthritis, induced in different rat strains using both specific and nonspecific triggers of the immune system, i.e. antigens and adjuvants, respectively.
Injection of incomplete Freund's adjuvant oil (IFA) triggered joint inflammation, which was associated with expression of mRNA for the proinflammatory cytokines TNF-a and IFN-y. However, no arthritis developed when an antigen was added to IFA. This inhibition appeared to correlate with activation of antigen-specific T cells, since mRNA for the T cell cytokines IL-2 and IL-4 were expressed. Thus, joint inflammation appears to develop as a consequence of inflammation triggered in the absence of targets for adaptive immune responses. The generality of this disease principle was fortified, since many structurally different adjuvants could induce joint inflammation, including defined microbial triggers of innate defence, such as lipopolysaccharide and ß-glucan. Several hydrocarbons were also arthritogenic, and the pathogenic capacity of linear alkanes could be determined at the level of single atom differences in structure. Interestingly, the endogenous lipid and cholesterol precursor squalene could also induce a T cell-mediated arthritis.
The role of pathogenic T cells remains elusive in adjuvant arthritis. They may be autoaggressive, in which case arthritogenic joint antigens constitute possible targets. Cartilage oligomeric matrix protein (COMP) is presented as one such candidate, since it could induce autoimmune joint inflammation, as can collagen type II in the same rat strain. Both these forms of autoimmune arthritis were associated with a type 1 cytokine profile, while the type 2 cytokine IL-4 was produced in a resistant strain, depending on genes outside the major histocompatibility complex (MHC). Chromosomal non-MHC regions which determine susceptibility were identified in adjuvant arthritis triggered by IFA, i.e. oil-induced arthritis (OIA).
These loci may be of general importance in experimental autoimmunity, since IFA is commonly used in combination with different autoantigens to induce autoimmune conditions, such as arthritis, encephalomyelitis, thyroiditis and uveoretinitis. More importantly, the susceptibility genes within these loci may give leads to putative autoimmune diseases in humans, including RA.
