The cross-talk between the innate and adaptive immune systems in general as well as in rheumatoid arthritis has regained significant attention (Corr and Firestein 2002) with the "one-way" concept of activation of the adaptive by the innate path less likely. In this regard, there is a general perception of three stages in the course of rheumatoid arthritis: disease initiation, perpetuation and a terminal destructive process (Corr and Firestein 2002; Firestein and Zvaifler 2002; Kouskoff et al. 1996; Mangialaio et al. 1999). However, the distinct role of antigen-specific lymphocytes remains a matter of debate. Recent concepts (Mangialaio et al. 1999) repostulated that the initiation of RA may be antigen-independent by involving joint constituents. Secondly, the inflammatory phase appears to be driven by specific antigens—either foreign or native and either integral to the joint or presented in the periphery. In the third stage, however, destruction of the synovium seems to be again antigen-independent. Although it is not clear to which extent B cells are involved in each stage of the disease, their role appears to be significant either as a link to other immune cells, potentially bridging the innate and the adaptive immune systems, or as directing cellular components in inflammation. Nevertheless, B cells can be considered as an "enhancing element" of rheumatoid arthritis severity by taking into account that patients producing autoantibodies usually have a more severe disease course.
Recently, the K/BxN mouse has generated particular interest. In this model, spontaneous arthritis occurs in mice that express both the transgene encoded KRN T cell receptor and the IAg7 MHC class II allele (Kouskoff et al. 1996;
Maccioni et al. 1999; Matsumoto et al. 1999). The transgenic T cells have a specificity for glucose-6-phosphate isomerase (G6PI) and are able to break tolerance in the B cell compartment, resulting in the production of autoan-tibodies to G6PI. Affinity-purified anti-G6PI Ig from these mice can transfer joint-specific inflammation to healthy recipients (Korganow et al. 1999). A mechanism for joint-specific disease arising from autoimmunity to G6PI has been suggested recently. G6PI bound to the surface of cartilage serves as the target for anti-G6PI binding and subsequent complement-mediated damage. In this model, the inciting event is the expression of an autoreactive T cell receptor in the periphery. However, j oint destruction is delegated by the adaptive response to innate immune mechanisms and can be transferred to animals that lack B and T cells (Korganow et al. 1999; Kouskoff et al. 1996). Whereas these animal studies are very compelling, anti-G6PI antibodies do not frequently occur in the serum of RA patients (Kassahn et al. 2002; Schubert et al. 2002).
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