This project focuses on the underlying basis of two autoimmune fibrotic disorders, IgG4- related disease and systemic sclerosis. We will use multi-color multispectral imaging of disease tissues, cell distance mapping as well as single-cell transcriptomics to interrogate tissues from IgG4-related disease. In particular we wish to identify and quantitate CD4+cytotoxic T cells and activated B cell subsets and better understand whether they directly contribute to cell death in tissues and thus to fibrosis, or if they primarily secrete fibrogenic products. We also want to understand the molecular basis by which CD4+cytotoxic T cells differentiate. We will test two competing but mutually non- exclusive hypotheses - one that CD4+T cells, with the help of activated B cells drive tissue cell death as a prelude to fibrosis, and the other that the cytokines and enzymes secreted by activated T cells and disease-related B cells are causal for fibrosis. We will also examine the interactions between adaptive and innate immune cells in disease and identify antigens that trigger clonally expanded B and T cells in patients. We will also explore the possibility that somatic mutations in hematopoietic stem cells or in CD4+CTL clones contribute to disease pathogenesis. We will also examine whether intestinal microbial gene expression reveals differences between subsets of disease or explains responsiveness to therapy. The possible contribution of microbial metabolites to immune cell differentiation will be examined and microbial antigens that activate host T cells will also be identified.

Public Health Relevance

New discoveries have been made regarding the underlying mechanism for an autoimmune disease that exhibits 'fibrosis' or scarring of tissues. New knowledge about the immune cells that likely drive this disease will allow the development of new treatments for autoimmunity.

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 #
9730766
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Johnson, David R
Project Start
2014-05-01
Project End
2024-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
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
Wallace, Zachary S; Khosroshahi, Arezou; Carruthers, Mollie D et al. (2018) An International Multispecialty Validation Study of the IgG4-Related Disease Responder Index. Arthritis Care Res (Hoboken) 70:1671-1678
Perugino, Cory A; AlSalem, Sultan B; Mattoo, Hamid et al. (2018) Identification of galectin-3 as an autoantigen in patients with IgG4-related disease. J Allergy Clin Immunol :
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
Jubair, Widian K; Hendrickson, Jason D; Severs, Erin L et al. (2018) Modulation of Inflammatory Arthritis in Mice by Gut Microbiota Through Mucosal Inflammation and Autoantibody Generation. Arthritis Rheumatol 70:1220-1233
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
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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