This project focuses on the identification of specific self-antigens that activate CD4+ T cells in systemic sclerosis. Cytotoxic CD4+T cells may directly contribute to cell death in tissues and secrete cytokines that lead to fibrosis. They likely receive help from activated B cells in tissues that in turn are induced by T follicular helper cells. Our goal is to use an unbiased approach to identify self antigens that activate clonally expanded cytotoxic CD4+T cells and/or T follicular helper cells from patients with diffuse systemic sclerosis who specifically have inherited HLA-DPB1*1301. Single cell cloning of CD4+ T cells will be used to identify matched T cell receptor alpha and beta chains from the most expanded cytotoxic CD4+ T cells and T follicular helper cells. Soluble T cell receptors will be generated. These soluble receptors will be used to screen a library of all human self peptides fused to HLA-DPB1*1301 and expressed in yeast.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI110495-06
Application #
9730771
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
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Alsufyani, Faisal; Mattoo, Hamid; Zhou, Dawang et al. (2018) The Mst1 Kinase Is Required for Follicular B Cell Homing and B-1 B Cell Development. Front Immunol 9:2393
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Maehara, Takashi; Mattoo, Hamid; Mahajan, Vinay S et al. (2018) The expansion in lymphoid organs of IL-4+ BATF+ T follicular helper cells is linked to IgG4 class switching in vivo. Life Sci Alliance 1:
Della-Torre, Emanuel; Bozzalla-Cassione, Emanuele; Sciorati, Clara et al. (2018) A CD8?- Subset of CD4+SLAMF7+ Cytotoxic T Cells Is Expanded in Patients With IgG4-Related Disease and Decreases Following Glucocorticoid Treatment. Arthritis Rheumatol 70:1133-1143
Fraschilla, Isabella; Pillai, Shiv (2017) Viewing Siglecs through the lens of tumor immunology. Immunol Rev 276:178-191
Mattoo, Hamid; Stone, John H; Pillai, Shiv (2017) Clonally expanded cytotoxic CD4+T cells and the pathogenesis of IgG4-related disease. Autoimmunity 50:19-24
Perugino, Cory A; Mattoo, Hamid; Mahajan, Vinay S et al. (2017) Emerging Treatment Models in Rheumatology: IgG4-Related Disease: Insights Into Human Immunology and Targeted Therapies. Arthritis Rheumatol 69:1722-1732
Maehara, Takashi; Mattoo, Hamid; Ohta, Miho et al. (2017) Lesional CD4+ IFN-?+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis. Ann Rheum Dis 76:377-385

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