Background/Purpose: Several genome-wide associations studies have in recent years linked polymorphisms in the PTPN2 locus to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 encodes for the tyrosine phosphatase TC-PTP, an important regulator of cytokine signaling in hematopoietic cells. Complete loss of TC-PTP has previously been shown to result in development of spontaneous erosive arthritis in mice. Also, recent work has reported that lack of TC-PTP in T-cells leads to systemic autoimmunity in mice. Disease-associated variants of PTPN2 are believed to result in a partial loss of protein expression. To model the functional genetics of RA-associated PTPN2 variants in mice, we studied the effect of PTPN2 haploinsufficiency in the SKG mouse, a spontaneous CD4⁺T-cell-driven model of autoimmune arthritis.

Methods: Mice homozygous for the SKG Zap-70^W163C mutation develop IL-17 dependent spontaneous arthritis, which is due to reduced TCR signaling resulting in altered thymic selection and emergence of autoreactive CD4⁺ T-cells. Arthritis in SKG mice can also be induced by administration of the fungal cell wall component mannan. Development of both spontaneous and mannan-induced arthritis was assessed in PTPN2^+/+ and PTPN2^+/- SKG mice.  Also, CD4 T-cells isolated from PTPN2^+/+ and PTPN2^+/- SKG mice were transferred to RAG2^-/-mice and development of spontaneus arthritis was monitored. Clinical scoring of arthritis was followed by histological scoring and micro-CT analysis.  Flow cytrometry was used to asses thymic T-cell development and T-cell effector populations in arthritic joints.  

Results: Haploinsufficiency of PTPN2 significantly increased the severity of arthritis in SKG mice. Importantly, transfer of PTPN2^+/- CD4⁺ T-cells to RAG2^-/- mice was sufficent to increase severity of arthritis when compared to transfer of PTPN2^+/+ CD4⁺ T-cells. Further investigation into the effect of PTPN2 haploinsufficiency in T-cell function revealed no alterations in thymocyte development or selection; however, arthritic PTPN2^+/- SKG mice showed an increased accumulation of Th17 cells in arthritic joints.

Conclusion: Haploinsufficiency of PTPN2 enhances CD4⁺ T-cell mediated autoimmune arthritis in mice.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/functional-genetics-of-ptpn2-in-rheumatoid-arthritis-haploinsufficiency-of-ptpn2-promotes-severity-of-cd4-t-cell-mediated-autoimmune-arthritis/