Streptococcal cell wall‐induced polyarthritis in the rat

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Abstract
Streptococcal cell wall (SCW)-induced arthritis is a chronic, erosive polyarthritis that can be induced in euthymic, susceptible Lewis rats by a single i.p. injection of a sterile, aqueous suspension of SCW. Nude Lewis rats and most other rats strains, including histocompatible F344 rats, are resistant to chronic disease. To study the mechanisms of chronicity and susceptibility to bacterium-induced arthritis, we compared immunological parameters in Lewis and F344 rats. A first observation was that Lewis rats mounted T-cell proliferative responses to SCW after immunisation with SCW or arthritis induction, while F344 rats were completely unable to do so. Depletion of OX8′ cells partially restored this defective response in F344 rats; it did not make them susceptible to polyarthritis, however. As SCW are present throughtout the body and the disease manifests itself mainly, and sometimes uniquely as a joint inflammation, a reason for localisation had to be found. One explanation is the crossreactivity of SCW-primed T cells to cartilage components which can be demonstrated in Lewis but not in F344 rats, in vitro and in vivo. We considered this T-cell unresponsiveness in F344 rats as tolerance to threatening antigens or epitopes, so we changed the state of tolerance in both Lewis and F344 rats followed by induction of arthritis. Tolerance to bacteria was prevented in F344 rats by using them as germfree (GF) animals and was induced in Lewis rats by pretreatment with a bacterial common antigen, the 65 kD mycobacterial heat shock protein. The changed state of tolerance coincided with a reversal of the susceptibility to SCW-induced arthritis in both strains. We suggest that in arthritis-prone individuals (Lewis) tolerance to arthritogenic epitopes is defective, while in normal individuals (F344) tolerance and thus arthritis-resistance is induced and/or maintained by exogenous bacteria or gut flora. Another point to be considered is the involvement of T cells in the chronicity of joint inflammation. We demonstrated that a subsiding arthritis can be reactivated by systemic administration of a small amount of bacteria. This so called flare up is dependent on specific T cells and can therefore be induced in Lewis, but not in F344 rats. Of importance is the observation that even unrelated bacteria are able to reactivate and thus to maintain arthritis induced by streptococci. We would suggest the following mechanism underlying chronic, bacterium-induced arthritis: Rats are primed by bacteria ((subclinical) infection) resulting in a systemic, acute inflammation that among other things damages the joint. Bacterium-specific T cells become activated and, if the supply of bacteria is continuous, the arthritis is maintained by exacerbations, while the crossreactive nature of these T cells might direct the inflammation to the joints. Susceptibility to bacterium-induced arthritis might be due to a lack of immunological tolerance to bacteria or certain bacterial epitopes.

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