Distinct contribution of IL-6, TNF-α,IL-1, and IL-10 to T cell–mediated spontaneous autoimmune arthritis in mice

Speaker: 林怜伶                            Date:6/1/2005 13:00-14:00

Commentator: 王志堯醫師                    Place: 601教室

Abstrate:

     The etiology of autoimmunity in human remains poorly defined, and animal models provide a unique opportunity to study potential autoimmune mechanisms. A novel model of autoimmune inflammatory arthritis , called SKG mice, results from a point mutation in the ζ-associated–protein of 70 kDa (ZAP-70), which causes abnormal thymic T cell selection and survival of autoreactive clones.¹ In this study, the authors observe that cytokines play key roles in spontaneous CD4⁺ T cell–mediated chronic autoimmune arthritis in SKG mice. Genetic deficiency in IL-6 completely suppressed the development of arthritis in SKG mice, irrespective of the persistence of circulating rheumatoid factor. Either IL-1 or TNF-α deficiency retarded the onset of arthritis and substantially reduced its incidence and severity. IL-10 deficiency, on the other hand, exacerbated disease, whereas IL-4 or IFN-γ deficiency did not alter the disease course. Notably, immunohistochemistry revealed that distinct

subsets of synovial cells produced different cytokines in the inflamed synovium: the superficial synovial lining cells mainly produced IL-1 and TNF-α, whereas scattered subsynovial cells produced IL-6. Thus, IL-6, IL-1, TNF-α, and IL-10 play distinct roles in the development of SKG arthritis; arthritogenic CD4+ T cells are not required to skew to either Th1 or Th2; and the appearance of rheumatoid factor is independent of joint inflammation.² The results also indicate that targeting not only each cytokine but also each cell population secreting distinct cytokines could be an effective treatment of rheumatoid arthritis.

References:

1.      Sakaguchi, N., et al. 2003. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature. 426:454–460

2.      Hata, H., et al. 2004. Distinct contribution of IL-6, TNF-α, IL-1, and IL-10 to T

   cell–mediated spontaneous autoimmune arthritis in mice. J. Clin. Invest.114:

   582–588.