Autoimmune disease is a condition when body's immune system attacks its own tissue. Very little is known how autoimmunity is initiated or maintained. Frequently, we do not even know what are the (self)-antigens that are targeted by self-reactive T cells or auto-antibodies.
The new paper in journal Science describes an one way how to identify the antigens targeted in autoimmunity. This study, led by Shimon Sakagushi at the Institute for Frontier Medical Sciences, Kyoto University, used SKG mice that has natural mutation in a T cell receptor signaling molecule, called ZAP-70. This mutation alters T cell selection in the thymus and allows peripheral release of self-specific T cells.
Original studies on SKG mice showed that they spontaneously develop arthritis mimicking several hallmarks of human rheumatoid arthritis (RA).
Here, initial experiments showed that SKG T cells expressing different Vbeta chains could induce arthritis equally well when transferred into RAG-KO hosts, implying the poly-clonal nature of self-reactive T cells in SKG mice.
The authors focused on one particular TCR family, Valpha2/Vbeta6 that constitute ~ 1% of joint infiltrating T cells. They cloned several Valpha2/Vbeta6 TCR pairs obtained from SKG arthritic joints, transfected them into RAG2-KO/SKG BM cells and transferred these transfected BM cells into RAG2-KO to generate monoclonal, retrogenic mice.
Out of these retrogenic SKG mice, R7-39, but not R1-23, spontaneously developed arthritis and skin inflammation. As expected, 7-39 TCR on wild-type background, W7-39, (without ZAP70 mutation) did not carry arthritogenic potential, probably due to inactivation in the thymus (and neither 7-39 nor 1-23 TCR develop into Foxp3+ T cells).
To examine the specificity of antigen(s) recognized by R7-39 T cells, the authors co-transferred 7-39 TCR transfected RAG2KO-SKG BM cells together with TCRbeta KO BM cells into RAG-KO hosts. In this setting, B cells developed from TCRbeta KO BM cells will secrete antibody specific to antigens recognized by 7-39 TCR, since only this type of help is available to B cells. Indeed, sera obtained from this mice, "R7-39+B", reacted to protein, RPL23A, identified by mass spectrometric analysis as a component of 60S subunit of ribosomes.
As expected, T cells from R7-39 mice, but not from R1-23, produced inflammatory cytokines in response to recombinant RPL23A.
Finally, the authors showed that sera from RA patients too showed reactivity to RPL23A.
In summary, these results shows one way to study mechanisms of autoimmunity.
Two questions come to mind: it is very strange that SKG mice develop only limited set of autoimmune diseases (joint and skin inflammations), since ZAP70 signaling should affect every T cells. Why is that? Also, RPL23A is a widely expressed protein. So why are target tissues limited to joints and skin in SKG mice? Does it mean that level of expression determines clinical signs? or maybe microbiota play a role?