This work is directed towards obtaining a better understanding of how the antigen receptor on B lymphocytes contributes to the development of different peripheral B cell populations and to the function of B lymphocytes in humoral immunity. Molecules that regulate signaling via the antigen receptor may contribute not only to the development and function of B lymphocytes, but may also be players in the genesis of lymphomas and leukemias, and may contribute to the development of certain autoimmune disorders. In these proposed studies, the contributions of a specific sialic acid O-acetylesterase to the strength of B cell antigen receptor signaling, to the development of marginal zone B cells, and to the emergence of a recirculating perisinusoidal bone marrow B cell population will be examined. In the first specific aim studies are proposed to examine whether luminal/lysosomal sialyl O-acetylesterase alters antigen receptor signal strength by acetylating sialic acid containing ligands for CD22, and thereby contributes to a major reduction in marginal zone B cells in mice lacking this enzyme. The regulation of luminal/lysosomal sialyl O-acetylesterase expression and activity during B cell development and B cell activation will be examined. In the second specific aim studies are proposed to examine why the absence of this sialyl-O-acetylesterase results in the loss of recirculating follicular B cells in the bone marrow. The cell intrinsic nature of this defect will be examined and molecular mechanisms involved in retaining mature B cells in the bone marrow will be explored. In this study we will ask how certain immune cells develop and are activated, and the processes by which cells are invited to reside in the bone marrow will also be examined. Insights obtained may be of importance in leukemias and in autoimmune diseases like lupus. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064930-02
Application #
7241559
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Ferguson, Stacy E
Project Start
2006-06-15
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$367,766
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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
Mahajan, Vinay S; Pillai, Shiv (2016) Sialic acids and autoimmune disease. Immunol Rev 269:145-61
Mahajan, Vinay S; Demissie, Ezana; Mattoo, Hamid et al. (2016) Striking Immune Phenotypes in Gene-Targeted Mice Are Driven by a Copy-Number Variant Originating from a Commercially Available C57BL/6 Strain. Cell Rep 15:1901-9
Yuen, Grace J; Demissie, Ezana; Pillai, Shiv (2016) B lymphocytes and cancer: a love-hate relationship. Trends Cancer 2:747-757
Wallace, Zachary S; Mattoo, Hamid; Carruthers, Mollie et al. (2015) Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann Rheum Dis 74:190-5
Della-Torre, Emanuel; Feeney, Eoin; Deshpande, Vikram et al. (2015) B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease. Ann Rheum Dis 74:2236-43
Ahmad, Maimuna; Mahajan, Vinay S; Mattoo, Hamid et al. (2014) Individuals with IgG4-related disease do not have an increased frequency of the K409 variant of IgG4 that compromises Fab-arm exchange. J Rheumatol 41:185-7
Mattoo, Hamid; Mahajan, Vinay S; Della-Torre, Emanuel et al. (2014) De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol 134:679-87
Kai, Xin; Chellappa, Vasant; Donado, Carlos et al. (2014) I?B kinase ? (IKBKB) mutations in lymphomas that constitutively activate canonical nuclear factor ?B (NF?B) signaling. J Biol Chem 289:26960-72

Showing the most recent 10 out of 27 publications