Rheumatoid Arthritis Associated Haploinsufficiency in PTPN2 Enhances Severity of IL-17 Mediated Autoimmune Arthritis

Mattias N. D. Svensson¹, Karen M. Doody², Shen Yang³, Dennis J. Wu⁴, Cristiano Sacchetti⁵, Isabelle Aubry⁶, Piotr Mydel⁷, Mitchell Kronenberg⁸, Michel L. Tremblay⁹ and Nunzio Bottini², ¹Department of Medicine, University of California San Diego, La Jolla, CA, ²Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, ³Medicine, University of California San Diego, La Jolla, CA, ⁴University of California San Diego, San Diego, CA, ⁵Rheumatology, University of California San Diego, La Jolla, CA, ⁶Biochemistry, McGill University, Montreal, QC, Canada, ⁷University of Bergen, Bergen, Norway, ⁸Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, ⁹Biochemistry, McGill University, Montréal, QC, Canada

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Animal models, autoimmunity and rheumatoid arthritis, IL-6R signaling, T-Regulatory Cells

Session Information

Date: Monday, October 22, 2018

Session Title: 4M085 ACR Abstract: RA–Animal Models (1822–1827)

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose:

Genetic polymorphisms at the PTPN2 locus, which encodes the tyrosine phosphatase TC-PTP, cause reduced gene expression and are linked to rheumatoid arthritis (RA). PTPN2 is an important regulator of cytokine signaling, however it remains unknown by which mechanism polymorphisms in PTPN2 promotes RA. We model the effect of PTPN2 haploinsufficiency in the SKG mouse, a spontaneous CD4⁺ T-cell-driven model of autoimmune arthritis.

Methods: Development of spontaneous and/or mannan-induced arthritis was evaluated in SKG mice. CD4⁺ SKG T-cells were transferred to RAG2^-/- mice. Clinical scoring of arthritis was followed by histological assessment. Flow cytometry was used to assess T-cell populations. Mann-Whitney or un-paired T tests were used for statistical differences.

Results: In SKG mice, haploinsufficiency of PTPN2 caused increased severity of both spontaneous (P=0.003) and mannan-induced (P=0.003) arthritis. Furthermore, increased susceptibility to arthritis could be transferred to RAG2^-/- mice by PTPN2^+/-CD4⁺ T-cells (P=0.011 vs PTPN2^+/+ CD4⁺ T-cells). Next we generated a novel C57BL/6 mouse carrying the SKG mutation and the H2^d haplotype (B6.H2^d.SKG), which showed similar arthritis development as BALB/c SKG mice. B6.H2^d.SKG carrying T-cell specific haploinsufficiency of PTPN2 (Lck-Cre⁺.PTPN2^{floxed/wild type}) developed increased severity of arthritis (P=0.002) when compared to WT mice. Further investigation revealed an increased accumulation of Th17 cells in arthritic ankles (P=0.007) of PTPN2^+/-mice. Importantly, neutralization of IL-6 and IL-17 equalized development of arthritis between PTPN2^+/-and PTPN2^+/+ SKG mice, indicating that enhanced arthritis in PTPN2 haploinsufficient mice were mediated through the IL-6/IL-17 pathway. Mechanistically this was supported by an increased sensitivity to IL-6 induced activation of STAT3 in PTPN2^+/-CD4 T-cells.

Conclusion: Haploinsufficiency of human RA-associated PTPN2 mediates autoimmune arthritis in mice by promoting expansion of pathogenic Th17 cells. We also validate our newly generated B6.H2^d.SKG model as a novel powerful tool for mechanistic studies of RA pathogenesis.

Disclosure: M. N. D. Svensson, None; K. M. Doody, None; S. Yang, None; D. J. Wu, None; C. Sacchetti, None; I. Aubry, None; P. Mydel, None; M. Kronenberg, None; M. L. Tremblay, None; N. Bottini, Roche, 2,Eli Lilly and Co., 2,Kyowa Kirin Pharmaceutical Research, Inc., 2.

To cite this abstract in AMA style:

Svensson MND, Doody KM, Yang S, Wu DJ, Sacchetti C, Aubry I, Mydel P, Kronenberg M, Tremblay ML, Bottini N. Rheumatoid Arthritis Associated Haploinsufficiency in PTPN2 Enhances Severity of IL-17 Mediated Autoimmune Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/rheumatoid-arthritis-associated-haploinsufficiency-in-ptpn2-enhances-severity-of-il-17-mediated-autoimmune-arthritis/. Accessed October 28, 2020.

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