Session Title: Plenary Session III: Discovery 2012
Session Type: Plenary Sessions
Background/Purpose: A coding polymorphism (C1858T) in PTPN22 is strongly associated with risk of Rheumatoid Arthritis (RA) and other autoimmune diseases. PTPN22 encodes Lymphoid Phosphatase (Lyp); the Lyp disease variant bears an R620W substitution (“LypW”). The mechanism by which LypW increases disease susceptibility remains unclear. PTPN22-expressing dendritic cells (DC) and macrophages have been implicated in RA pathology. Such myeloid cells produce type 1 interferons (IFN) and proinflammatory cytokines in response to Toll-like receptor (TLR) engagement. We hypothesized that PTPN22might modulate TLR signaling and attendant innate immune responses.
Methods: We studied TLR signaling and type 1 IFN-mediated antiviral responses and immunoregulation in Ptpn22–deficient myeloid cells and mice, in transgenic mice harboring human LypW or LypR (major allele protein product), and in human LypW carrier peripheral blood mononuclear cells (PBMC).
Results: We found markedly decreased induction of type 1 IFN after TLR3/4/7/9 activation in Ptpn22–/– macrophages, DC, and plasmacytoid DC. Interestingly, Ptpn22 was dispensable for induction of proinflammatory cytokines, including TNFα, IL-6, and IL-1β, after TLR2/3/4/7/9 stimulation. The selective TLR signalling defect in Ptpn22–/– cells was associated with impaired type 1 IFN-dependent immunity, manifested by reduced serum type 1 IFN, impaired dendritic cell activation, and diminished T cell responses after lymphocytic choriomeningitis virus (LCMV) infection of Ptpn22–/– mice. In the K/BxN serum transfer model of rheumatoid arthritis, treatment with type 1 IFN-inducing TLR ligands suppresses disease. However, we observed significantly decreased TLR ligand-mediated suppression of inflammatory arthritis in Ptpn22–/–mice. RA-associated LypW carrier human PBMC and myeloid cells derived from LypW transgenic mice displayed defective induction of type 1 IFN after TLR stimulation. LypR directly associated with TNF receptor-associated factor 3 (TRAF3), a key TLR signaling mediator upstream of type 1 IFN induction. LypR, but not LypW promoted TRAF3 K63-linked polyubiquitinylation, which is required for TLR-induced type 1 IFN production.
Conclusion: PTPN22 is a key positive regulator of TLR-driven upregulation of type 1 IFN. LypW, product of the RA-associated PTPN22 allele, exhibits “loss of function” in type 1 IFN dependent processes, including antiviral host defense and amelioration of inflammatory arthritis. Our findings strongly suggest that PTPN22 could regulate severity of joint inflammation in RA through modulation of TLR signaling in innate immune cells.
J. L. Auger,
F. M. Shoyama,
H. H. Balfour Jr.,
A. C. Chan,
B. A. Binstadt,
E. J. Peterson,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/rheumatoid-arthritis-associated-ptpn22-modulates-toll-like-receptor-mediated-type-1-interferon-dependent-innate-immunoregulation/