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Department of Medicine
University of Minnesota, 1990, M.D.
612-625-5634 - office
Leukocyte activation and development
Investigations carried out in Dr. Erik Peterson’s laboratory aim to increase understanding of the molecular mechanisms behind newly identified risk genes associated with autoimmune diseases. The laboratory uses human peripheral blood, genetically-altered mice, and transformed cell lines to approach questions concerning the biochemical, cellular, and immune response-modulating functions of susceptibility alleles.
The PTPN22 gene is among the strongest genetic predisposition factors for major human autoimmune diseases, including type 1 diabetes (T1D), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). PTPN22 encodes lymphoid tyrosine phosphatase (Lyp); a Lyp variant bearing a R620W substitution (“LypW”) is causally associated with disease risk. Lyp is a well-known negative regulator of T cell receptor (TCR) signaling, and most functional genomic work to date has focused on the potential mechanisms of LypW variant action on adaptive immune processes. Despite intensive study, a comprehensive model for LypW mechanism(s) of action in autoimmune disease is lacking.
In collaboration with others at UMN and elsewhere, our group recently demonstrated that PTPN22 plays a critical positive role in regulating pattern recognition receptor (PRR) signaling leading to production of type 1 Interferons (IFN) by myeloid cells. We established that Lyp protein binds and promotes activation of TNF Receptor Associated Factor 3 (TRAF3) during myeloid cell PRR signaling. Lyp also promotes PRR-induced, type 1 IFN-driven anti-viral host defense and suppression of inflammation in the gut and in the joint lining synovium. Importantly, the LypW variant exhibits reduced-function behavior in PRR signaling and in type 1 IFN-governed suppression of inflammation.
Our observations that PTPN22 modulates myeloid cell signaling suggest new potential mechanisms whereby an autoimmunity-associated gene works in concert with suspected environmental stimuli (e.g. viral infections, inflammatory reactions) to result in tissue damage. Our working model holds that PTPN22 potentiates myeloid cell-directed type 1 IFN-dependent anti-microbial host defense andcounter-inflammatory mechanisms. The model also holds that the reduced function LypW variant enhances potential for autoimmunity by increasing host susceptibility to tissue damage by suboptimally-suppressed infections and/or inflammatory reactions. Major questions about the model remain:
1) Is myeloid cell-intrinsic Lyp function sufficient for major host defense and anti-inflammatory PTPN22 actions in vivo?
2) What is the molecular basis for Lyp promotion of TRAF3 signaling?
3) How does LypW function differently in myeloid cell signaling and type 1 IFN-driven processes in vivo?
4) How do Lyp functions in host-defense and inflammation suppression translate into autoimmune disease risk?
By experimentally addressing questions such as these, we seek to identify novel therapeutic targets, high-quality biomarkers, and ultimately, the cure for systemic rheumatic diseases.