SUSCEPTIBILITY TO PRISTANE-INDUCED ARTHRITIS IS ALTERED WITH CHANGES IN BOWEL FLORA

Pristane-induced arthritis (PIA) is unique among the animal arthritides in that a non-infectious, non-antigenic oil induces a chronic immune based arthritis with a prolonged delay between exposure to the inciting agent and development of the disease. Mice with pristane-induced arthritis have elevated T cell and humoral responses to the 65 kDa heat shock protein derived from Mycobacterium bovis (hsp65) and in common with several other models of autoimmune diseases the incidence of PIA is markedly suppressed by preimmunisation with hsp65 in Freund's incomplete adjuvant (Thompson et al. (1990) Eur. J. Immunol. 20, 2479). Recent studies have investigated how autoimmune reactions to heat shock proteins are involved in the development of arthritis. Arthritic CBA/Igb mice given pristane alone develop antibodies to both hsp65 and GroE1 (bacterial 60 kDa heat shock proteins) and to hsp58 (the mammalian equivalent). Moreover, the splenic T cells of such mice proliferate vigorously in response to both bacterial and mammalian 60 kDa heat shock proteins. Remarkably, the anti-hsp65 antibody response in normal mice rises rapidly with age, directly correlating with the age related incidence of PIA. In addition, specific pathogen free mice (SPF) maintained in an isolator have negligible anti-hsp65 responses but these convert to positive responses if the animals are exposed to the open part of the animal facility (Thompson et al. (1992) Arthritis Rheum. 35, 139). The present study was aimed at clarifying the role of environmental antigens in the induction of the anti-hsp responses and has accordingly investigated changes in the bowel flora population on the development of PIA. Stool samples obtained from normal SPF mice maintained in an isolator had a very limited range of culturable organisms compared to samples obtained from littermates exposed to the conventional environment for 7 days. One hundred and fifty days after pristane injection the profile of culturable organisms from the SPF mice maintained in the isolator remained limited. This was in contrast to the changes in number and bacterial species isolated from the stools of mice maintained in the conventional environment 150 days post pristane injection. These findings correlate with the observation that SPF mice maintained under sterile conditions are resistant to the development of PIA. The results suggest that contact with microorganisms in the conventional environment primes the mice for cellular anti-hsp65 reactivity and is necessary for the induction of arthritis.