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Intestinal IgA B cell receptor-specific signals integrate germinal center selection with humoral responses to commensals

Award Number: R21AI173903
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract B lymphocytes in the gastrointestinal tract are constantly stimulated by microbial antigens. In order to prevent commensal outgrowth and maintain intestinal homeostasis, B cells need to mount a rapid antibody response against bacterial antigens. To achieve this task, the humoral immune system relies on a complex multistep process of B cell proliferation and selection in the germinal center, which eventually gives rise to either antibody-secreting plasma cells or memory B cells. Intestinal B cells are mainly expressing immunoglobulin A (IgA), but how this specific antigen receptor isotype shapes B cell fate and antibody response in the gut is poorly understood. Moreover, dysregulation of IgA response is associated with increased infection susceptibility and autoinflammation at the mucosal interfaces. Therefore, elucidating the fundamental mechanisms that intrinsically regulate the fate and function of individual B cell clones in the gut remains a central question in immunology with clear translational implications. Several lines of evidence indicate that distinct B cell receptor isotypes act as intrinsic regulators of germinal center B cell response. However, how B cells integrate IgA antigen receptor signaling with germinal center dynamics and antibody response remains undefined to date. In this application we test the hypothesis that surface IgA directly controls germinal center B cell response through its enhanced intracellular signaling and Ca2+ release. This leads to the generation of a lower threshold of B cell activation, therefore allowing B cell specific for poorly immunogenic commensal species to be recruited into the germinal center and to participate to the humoral response. We also hypothesize that IgA signaling prevents counterselection mediated by FAS, allowing survival of low affinity B cells. Accumulating evidence indicates IgA coating of commensals is less dependent on antigen affinity, but the mechanisms underpinning this phenotype have not been investigated so far. Our aims are: 1) to dissect the role of IgA-dependent BCR signaling on cell migration into the intestinal tissue and on the quality of the antibody response; and 2) to define the role of Fas-FasL axis in counter- selecting mucosal IgA+ germinal center B cells for efficient intestinal response. The proposed studies examine a very poorly understood crosstalk between IgA signaling and adaptive immune system activation in the gut. It is our expectation that these studies will increase our understanding of how intestinal antigen recognition shapes B cell responses and adaptive immunity both at steady state and during enteric infections. Furthermore, our studies will provide a foundation for better understanding of the relationship between BCR-intracellular signaling and differentiation of gut-homing B lymphocytes that assure mucosal humoral immunity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $188,438 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	2	10/24/2023	NON-COMPETING CONTINUATION	$188,438
														Subtotal = $188,438

Issue Date FY: 2023 ( Subtotal = $251,250 )
2023	2023	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	1	11/9/2022	NEW	$251,250
														Subtotal = $251,250

Grand Total All Awards = $439,688

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Intestinal IgA B cell receptor-specific signals integrate germinal center selection with humoral responses to commensals

Award Number: R21AI173903

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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