SKG autoimmune arthritis as a model of human RA

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As discussed above, clinical and immunopathological characteristics of SKG arthritis resemble those of RA in humans, making the strain a suitable model for studying human RA. A cardinal feature of this model is that a genetic defect of T-cells, but not the joint, leads to the development of autoimmune arthritis. Another is that in the presence of this genetic abnormality of the T-cell compartment, environmental stimuli are required for triggering arthritis. The ZAP-70 genetic defect affects the thymic generation of arthritogenic CD4+ T-cells and TR cell-mediated suppressive control of their activation in the periphery while environmental agents act to activate them via stimulating innate immunity (Fig. 3). Then, how is this mechanism of SKG autoimmune arthritis relevant to the pathogenesis of RA?

Like RA, SKG disease is a systemic disease including arthritis and extra-articular lesions. The development of RF and anti-CCP autoantibody is not the consequence of arthritis but an effect of the SKG T-cell anomaly (Fig. 3, see above). One may ask then why SKG mice predominantly develop autoimmune arthritis, but not other autoimmune diseases such as type 1 diabetes (T1D). This could be attributed at least in part to unique features of synovial cells as the target of SKG autoimmu-nity and for that matter of RA. For example, unlike pancreatic P-cells as the target of T1D, the synovium, which is composed of macrophage-like type A and fibrob-last-like type B synoviocytes, is intrinsically capable of producing proinflammatory cytokines (such as IL-1, IL-6 and TNF-a) and chemical mediators (such as matrix metalloproteinases) destroying cartilage and bone [1, 2]. It is devoid of basement membrane and tight junctions, allowing easy invasion of proliferating synoviocytes to the surrounding tissue [1]. In addition, they are highly sensitive to various immunological stimuli including cytokines, biological substances, and presumably

mutation Env. Factors \\ ♦

Thymus

CD4+ Te cells —► Synovium

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CD25+4+ Tr cells

Figure 3

Contribution of genetic and environmental factors to the development of arthritis in SKG mice.

self-reactive T-cells, as typically illustrated by the predominant development of arthritis, but not other diseases, as a result of systemic overproduction of proin-flammatory cytokines such as TNF-a or systemic deficiency of IL-1 receptor antagonist [27, 28]. It is therefore likely that a combination of high self-reactivity of SKG T-cells and high susceptibility of the synovium to inflammatory stimuli may lead to easy development of autoimmune arthritis in SKG mice irrespective of their formation of self-reactive T-cells with various other specificities. It remains to be determined whether T-cells responsible for causing interstitial pneumonitis or helping the formation of anti-CCP and other autoantibodies are also produced in SKG mice in parallel with the production of arthritogenic T-cells.

The ZAP-70W163C mutation as the primary cause of SKG arthritis suggests that mutations of other loci of the ZAP-70 gene or the genes encoding other signaling molecules, especially at TCR proximal steps, may well contribute to the development of autoimmune arthritis by affecting a common signaling pathway(s). There is recent evidence that polymorphism of the PTPN22 gene, which encodes a hematopoietic-specific protein tyrosine phosphatase, also contributes to the risk of RA [29] and other autoimmune diseases including T1D, SLE, and Graves' disease [30-32]. The risk allele can alter the threshold of T-cell activation [30]. It remains to be determined whether the PTPN22 encoded by the risk allele affects thymic T-cell selection and/or the function of regulatory T-cells. It is also likely that variants of more then one gene encoding T-cell signaling molecules, including PTPN22, may have additive effects in altering T-cell signal transduction and thereby raising the genetic risk to RA.

It is well documented that MHC polymorphisms contribute to determining the genetic susceptibility to RA [6, 7]. SKG mice could be a good model for investigat ing the role of MHC in RA, especially in relation to the influence of the environment on arthritis development, as discussed above.

There is epidemiological evidence that environmental factors play significant roles in the development of RA [1, 7, 11]. Various environmental stimuli including viral infections can cause synovitis, which is usually self-limiting [11]. Administration of zymosan and P-glucan can indeed elicit in normal mice a transient arthritis, which is not T-cell-mediated, in contrast with zymosan- or P-glucan-triggered chronic T-cell-mediated autoimmune arthritis in SKG mice [26]. These findings when taken together indicate that synovial inflammation per se may not be sufficient to evoke chronic T-cell-mediated autoimmune arthritis unless one harbors arthritogenic T-cells sufficient in number and/or TCR specificity to mediate arthritis. The findings also suggest that one-time 'hit-and-run' exposure to an arthritogenic environmental agent capable of strongly stimulating innate immunity may suffice to trigger chronic arthritis in those who have already produced and harbor arthritogenic autoimmune T-cells due to genetic anomaly or variation.

Further genetic and immunological analyses of SKG arthritis at each step of the pathogenetic pathway from the ZAP-70 mutation, through thymic generation and peripheral activation of autoimmune T-cells, to inflammatory destruction of the joint, will help to elucidate how a specific combination of genetic and environmental factors leads to the development of RA. This will help then to design novel measures of detecting, treating and preventing RA.

Acknowledgements

The authors thank Dr. Zoltan Fehervari for critical reading of the manuscript. This work was supported by grants-in-aid from the Ministry of Education, Science, Sports and Culture, the Ministry of Human Welfare, and the Science and Technology Agency of Japan.

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