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 autoagressive, 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.
Key words: arthritis, adjuvants, autoimmunity, MHC, genetics, rat,
cytokines
ISBN 91-628-2840-