TNF receptors have multiple roles in shaping adaptive and innate immune responses, and dysregulation of multiple TNF family members has been shown to be critical in the pathogenesis of many rheumatic diseases. The lab has two main interests: 1) Biology of TNF-family receptors in lymphocytes and mouse models of autoimmunity 2) Understanding the molecular pathogenesis of single-gene autoimmune and autoinflammatory diseases. We are currently studying the biology of three members of the TNF-R superfamily in detail: TNFR1, Fas/CD95, and DR3. For TNFR1 we are concentrating on the pathogenesis of inflammation associated with TNFR1 and the TNFR1-associated periodic syndrome (TRAPS). We have found that TNFR1 mutation causes receptor misfolding and ER retention that may lead to inflammation through novel TNF-independent mechanisms. For the apoptosis-inducing receptor Fas, we are studying cell intrinsic and extrinsic factors that regulate the efficiency of Fas-induced apoptosis in vitro and in vivo. For DR3, we are defining the pattern of expression and function of DR3 and its ligand TL1A in a number of model systems. In a collaborative project supported by a Bench-to-Bedside initiative, we are examining the pathogenesis of autoimmunity in the Wiskott-Aldrich Syndrome.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Arthritis, Musculoskeletal, Skin Dis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Fu, Qingshan; Fu, Tian-Min; Cruz, Anthony C et al. (2016) Structural Basis and Functional Role of Intramembrane Trimerization of the Fas/CD95 Death Receptor. Mol Cell 61:602-613
Ramaswamy, Madhu; Siegel, Richard M (2012) Autoimmunity: twenty years in the Fas lane. J Immunol 189:5097-100
Meylan, F; Song, Y-J; Fuss, I et al. (2011) The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation. Mucosal Immunol 4:172-85
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Viorritto, Irene C B; Nikolov, Nikolay P; Siegel, Richard M (2007) Autoimmunity versus tolerance: can dying cells tip the balance? Clin Immunol 122:125-34
Ramaswamy, Madhu; Dumont, Celine; Cruz, Anthony C et al. (2007) Cutting edge: Rac GTPases sensitize activated T cells to die via Fas. J Immunol 179:6384-8
Kimberley, Fiona C; Lobito, Adrian A; Siegel, Richard M et al. (2007) Falling into TRAPS--receptor misfolding in the TNF receptor 1-associated periodic fever syndrome. Arthritis Res Ther 9:217
Park, Heiyoung; Teja, Kabir; O'Shea, John J et al. (2007) The Yersinia effector protein YpkA induces apoptosis independently of actin depolymerization. J Immunol 178:6426-34
Bi, Lilia L; Pan, George; Atkinson, T Prescott et al. (2007) Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib. BMC Med Genet 8:41
Liu, Eric H; Siegel, Richard M; Harlan, David M et al. (2007) T cell-directed therapies: lessons learned and future prospects. Nat Immunol 8:25-30

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