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Role of CD22 in the Germinal Center Reaction

Award Number: R01AI118842
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/25/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Role of CD22 in the Germinal Center Reaction - Cell surface glycosylation is dynamic and often changes in response to cellular differentiation. Changes in glycosylation can impart a function to cells through glycan-binding proteins. Well-documented changes in cellular glycosylation occur in an immune response when B-cells differentiate into germinal center (GC) B cells. Immunologists routinely use these changes in glycosylation to identify the GC, using the antibody GL7, which is a structure within secondary lymphoid organs where antibody affinity maturation takes place. Remarkably, no function has been attributed to these changes in glycosylation. The change in glycosylation detected by GL7 is intriguing because of its relevance to CD22, a glycan-binding protein and member of the Siglec family of immunomodulatory receptors. CD22 is a negative regulator of the B-cell receptor (BCR) through its ability to recruit the phosphatase SHP-1, although its function in GC B-cells has remained largely unexplored. Specifically, GL7 recognizes a glycan that is a low affinity ligand for CD22; hence, GC B-cells loose the high affinity glycan ligand of CD22 found abundantly on naïve B-cells. High affinity glycan ligands of CD22 regulate its spatial organization on the surface of naïve B-cells, maintaining CD22 and BCR in different microdomains. Accordingly, we hypothesize that loss of high affinity CD22 ligands in GC B-cells promotes the association of CD22 with the BCR. This hypothesis is particularly intriguing in light of recent findings demonstrating that BCR signaling is inhibited in GC B-cells through constitutive co-localization of SHP-1 with the BCR. This project aims to test this hypothesis by assessing: (Aim1) the functional consequence of modulating expression of CD22 or its glycan ligands specifically in GC B-cells; (Aim2) whether changes in glycan ligands in GC B-cells drives co-localization of CD22 with the BCR, which is responsible for recruitment SHP-1 and inhibiting BCR signaling; and (3) the consequence of disrupting the function of CD22 in the context of an antibody-mediated autoimmune disease. Key to testing the hypothesis is a transgenic mouse we have established that maintains expression of high affinity glycan ligands for CD22 in GC B-cells. Preliminary results demonstrate that maintaining high affinity CD22 ligands in GC B-cells results in decreased competitiveness for the GC B-cell repertoire in competition with WT GC B-cells; an effect that requires expression of CD22. If preliminary results reflect a truly GC-specific role for CD22, we expect that modulating expression of CD22 or its glycan ligands in a GC-specific manner will likewise impair GC B-cell responses, increase BCR signaling in GC B-cells, and abrogate disease progression in a mouse model of antibody- mediated autoimmune disease. The long-term objective of this project is to establish the role(s) played by CD22 in the GC reaction in both health and disease. This knowledge will provide new insights into how an ongoing immune response can be modulated to treat an antibody-mediated autoimmune disease.


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 = $0 )
2024	2021	THE GOVERNORS OF THE UNIVERSITY OF ALBERTA	114 STREET AND 89 AVENUE	EDMONTON	AB			CAN	Allergy and Infectious Diseases Research	000	5	5/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $270,000 )
2021	2021	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB			CAN	Allergy and Infectious Diseases Research	000	5	8/16/2021	NON-COMPETING CONTINUATION	$270,000
														Subtotal = $270,000

Issue Date FY: 2020 ( Subtotal = $270,000 )
2020	2020	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB	T6G 2R3		CAN	Allergy and Infectious Diseases Research	000	4	8/17/2020	NON-COMPETING CONTINUATION	$270,000
														Subtotal = $270,000

Issue Date FY: 2019 ( Subtotal = $270,000 )
2019	2019	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB	T6G 2R3		CAN	Allergy and Infectious Diseases Research	000	3	8/29/2019	NON-COMPETING CONTINUATION	$270,000
														Subtotal = $270,000

Issue Date FY: 2018 ( Subtotal = $270,000 )
2018	2018	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB	T6G 2R3		CAN	Allergy and Infectious Diseases Research	000	2	8/7/2018	NON-COMPETING CONTINUATION	$270,000
														Subtotal = $270,000

Issue Date FY: 2017 ( Subtotal = $270,000 )
2017	2017	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	8625 112 ST NW SUITE 222	EDMONTON	AB	T6G 1K8		CAN	Allergy and Infectious Diseases Research	000	1	9/25/2017	NEW	$270,000
														Subtotal = $270,000

Grand Total All Awards = $1,350,000

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Role of CD22 in the Germinal Center Reaction

Award Number: R01AI118842

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/25/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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