Studies of the immunopathogenesis in three arthritis models in rats

Abstract

The immunopathogenesis of three arthritis models has been studied; oil-induced arthritis (OIA), homologous collagen-induced arthritis (CIA) and COMP-induced arthritis. The induction of a monophasic arthritis, OIA, in the DA rat with a single intradermal injection of Freund's incomplete adjuvant (FIA) was reported. The involvement of specific immunity in the disease course was implicated by the failure to reinduce the disease in animals that had once recovered from OIA. No humoral or cellular responses to screened cartilage antigens could be detected.

The potency of FIA in inducing arthritis was demonstrated by the induction of arthritis via percutaneous exposure to FIA. Repeated treatments with FIA on lightly abrased skin was the most effective means of inducing OIA. The involvement of T-cells in the disease was confirmed by the transfer of passive OIA with CD4+ T-cells from rats with active OIA. These findings highlight the role of adjuvants in inducing experimental autoimmune diseases, and indicate the importance of studying adjuvants in the context of human autoimmune diseases. Analysis of the T-cell receptor (TcR) VB gene usage, by PCR, of T-cells infiltrating the SMs in rats with CIA demonstrated a restricted usage early in disease whereas at a later timepoint no restriction was evident. At no timepoint could such a restriction be detected in the draining Iymphnodes.

These results raise the possibility that similar TcR VB may indeed be used by arthritis-associated T-cells in two different species, and it also demonstrates the importance of studying early disease timepoints when analyzing TcR VB expression. Histological characterization, by immunohistochemistry, of the cellular infiltrates in synovial fluid (SF) and synovial membranes (SM) in CIA revealed a different cellular picture in SF as compared to SM. The SF was dominated by polymorphonuclear cells while SM mainly consisted of mononuclear cells. Investigation of adhesion molecules expressed in these compartments suggests that expression of CD49d and CD49f in SM might retain mononuclear cells while polymorphonuclear cells migrate to the SF, possibly due to attraction by immune complexes.

These results indicate different mechanisms behind the inflammation in SF compared to the inflammation in SM. Analysis of antibody (ab) reactivities to CII, hsp 65kD and the presence of rheumatoid factors (RF) revealed equally high levels of investigated ab in both SF and in sera. Interestingly, normal rats of the autoimmune-prone DA strain had high levels of RF, higher than those in the arthritis-resistant F344 rat strain. Finally, the induction of arthritis with the cartilage protein COMP was reported. Bovine COMP mixed with FIA induced a monophasic arthritis in Lew1av1 rats. Cellular and humoral responses to COMP were detected, as was a strong production of TNF-a and IL-2 by Iymphnode cells. No cross-reactivity to CII could be detected.