Background/Purpose:

The protein tyrosine phosphatase termed Src homology region 2 domain-containing phosphatase-1 (SHP-1) is known to exert negative regulatory effects on immune cell signaling. Mice with mutations in the Shp1 gene display inflammatory skin disease and autoimmune features, but no arthritis.

The objective of this study is to explore the role of SHP-1 in arthritis using cartilage proteoglycan (PG)-induced arthritis (PGIA), an autoimmune model of rheumatoid arthritis (RA). We generated Shp1 transgenic (Shp1-Tg) mice overexpressing this phosphatase to study the impact of SHP-1 overexpression on arthritis susceptibility and adaptive immune responses.

Methods:

Wild-type (WT) and Shp1-Tg mice were immunized with cartilage PG in adjuvant, and arthritis symptoms were monitored. Tyrosine phosphatase activity, T-cell and B-cell proliferation and activation in response to polyclonal stimulation as well as global protein tyrosine phosphorylation (pTyr) levels were measured in spleen cells from WT and Shp1-Tg mice using cell proliferation and enzyme activity assays, flow cytometry, and Western blot. Statistical analysis was carried out employing GraphPad Prism 7.

Results:

Interestingly, while all of the WT mice developed arthritis after PG immunization, none of the Shp1-Tg mice developed disease (n=13-16 mice per genotype). Shp1-Tg spleen cells showed 7-fold higher tyrosine phosphatase activity than WT cells. In response to polyclonal stimulation, T and B cells from Shp1-Tg mice proliferated less well and expressed significantly lower levels of activation markers than those from WT mice. Global pTyr levels were also lower in T and B cells from Shp1-Tg mice than in cells from WT animals.

Conclusion:

Resistance to autoimmune arthritis in Shp1-Tg mice is likely due to impaired T- and B-cell responses to PG immunization. Reduced T- and B-cell activation and resistance to arthritis in the presence of SHP-1 overexpression seem to result from the impairment of tyrosine phosphorylation (deactivation) of key T-cell and B-cell signaling proteins, due to the overwhelming tyrosine phosphatase activity of the enzyme in Shp1-Tg mice. Our study is the first to investigate the role of SHP-1 in autoimmune arthritis. Further experiments with the animal model may identify a therapeutic target for the treatment of human autoimmune arthritis such as RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/modulation-of-autoimmune-arthritis-by-protein-tyrosine-phosphatase-shp-1/