Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Healy, A.M. et al.

Healy, Izmailova, Fitzgerald, Walker, Hattersley, Silva, Siebert, Terkelsen, Picarella, Pickard, LeClair, Chandra, Jaffee,

PKC-theta-deficient mice are protected from Th1-dependent antigen-induced arthritis.

T cell effector functions contribute to the pathogenesis of rheumatoid arthritis. PKC-theta transduces the signal from the TCR through activation of transcription factors NF-kappaB, AP-1, and NFAT. We examined the effects of PKC-theta deficiency on two Th1-dependent models of Ag- induced arthritis and found that PKC-theta-deficient mice develop disease, but at a significantly diminished severity compared with wild-type mice. In the methylated BSA model, cellular infiltrates and articular cartilage damage were mild in the PKC-theta-deficient mice as compared with wild-type mice. Quantitation of histopathology reveals 63 and 77% reduction in overall joint destruction in two independent experiments. In the type II collagen-induced arthritis model, we observed a significant reduction in clinical scores (p < 0.01) in three independent experiments and diminished joint pathology (p < 0.005) in PKC-theta-deficient compared with wild-type littermates. Microcomputerized tomographic imaging revealed that PKC-theta deficiency also protects from bone destruction. PKC-theta-deficient CD4(+) T cells show an impaired proliferative response, decreased intracellular levels of the cytokines IFN-gamma, IL-2, and IL-4, and significantly diminished cell surface expression of the activation markers CD25, CD69, and CD134/OX40 on memory T cells. We demonstrate decreased T-bet expression and significantly reduced IgG1 and IgG2a anti-collagen II Ab levels in PKC-theta-deficient mice. Collectively, our results demonstrate that PKC-theta deficiency results in an attenuated response to Ag-induced arthritis, which is likely mediated by the reduced T cell proliferation, Th1/Th2 cell differentiation and T cell activation before and during disease peak.[1]

References

PKC-theta-deficient mice are protected from Th1-dependent antigen-induced arthritis. Healy, A.M., Izmailova, E., Fitzgerald, M., Walker, R., Hattersley, M., Silva, M., Siebert, E., Terkelsen, J., Picarella, D., Pickard, M.D., LeClair, B., Chandra, S., Jaffee, B. J. Immunol. (2006) [Pubmed]

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