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Regulation of B cell function in demyelinating disease by N-glycan branching

Award Number: R01AI144403
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: 01/14/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Regulation of B cell function in demyelinating disease by N-glycan branching - Abstract Our published work has revealed that deficiencies in Asn (N)-linked protein glycosylation reduce inflammatory demyelination in mice and are associated with Multiple Sclerosis (MS). Deficiency in the branching of N-glycan's attached to proteins, either induced experimentally in mice or via natural genetic variation in humans, promotes T-cell mediated inflammatory demyelination and neurodegeneration. For example, branching deficiency induces a spontaneous and slowly progressive MS-like disease in PL/J mice, characterized by inflammatory demyelination, axonal damage and neuronal death. Mechanistically, the branching and number of N-glycans per protein molecule cooperate to regulate binding to galectins, a 14- member family of sugar binding proteins. Galectin binding to cell surface glycoproteins, via their attached N- glycans, forms a macro-molecular lattice at the cell surface that controls the distribution, clustering and endocytosis of surface glycoproteins in a coordinated and predictable manner. N-glycan branching markedly inhibits T cell activity in mice and humans by reducing T cell receptor clustering/signaling at the immune synapse, promoting surface retention of the growth inhibitor CTLA-4 and inhibiting differentiation into pro- inflammatory TH1 and TH17 cells while promoting anti-inflammatory iTreg and TH2 cell differentiation. Although these T cell phenotypes are important regulators of inflammatory demyelination, it has become increasing clear that B cells also play a critical role in MS. This is best exemplified by the potent activity of B cell depleting therapies in MS, such as the anti-CD20 monoclonal antibody ocrelizumab. B cells are unique in the immune system by having both innate and adaptive immune activity; the former exemplified by activation via Toll-like receptors (TLR) and antigen-presenting cell (APC) functions that trigger T cell responses. The mechanism of action of ocrelizumab appears to primarily result from reduced innate immune activity rather than altering antibody production, as ocrelizumab reduces T cell number but not antibody or plasma cell levels in the cerebral spinal fluid of treated MS patients. Here we test the hypothesis that N-glycan branching serves as a critical negative regulator of pro-inflammatory innate immune activity in B cells to suppress pro- inflammatory T cell responses and inflammatory demyelination. To evaluate this hypothesis, the following Aims are proposed. Aim 1 examines regulation of TLR4 and TLR2 responses by N-glycan branching in B cells. Aim 2 examines regulation of B cell receptor signaling by N-glycan branching. Aim 3 examines whether N- glycan branching in B cells suppresses inflammatory demyelination. Positive results will identify N-glycan branching as a major contributor to B cell mediated regulation of inflammatory demyelination and has implications for understanding the mechanism of action of B cell depleting therapies in MS.


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: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Allergy and Infectious Diseases Research	000	5	4/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $500,503 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Allergy and Infectious Diseases Research	000	5	12/14/2022	NON-COMPETING CONTINUATION	$500,503
														Subtotal = $500,503

Issue Date FY: 2022 ( Subtotal = $500,503 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Allergy and Infectious Diseases Research	000	4	12/7/2021	NON-COMPETING CONTINUATION	$500,503
														Subtotal = $500,503

Issue Date FY: 2021 ( Subtotal = $500,503 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Allergy and Infectious Diseases Research	000	3	12/3/2020	NON-COMPETING CONTINUATION	$500,503
														Subtotal = $500,503

Issue Date FY: 2020 ( Subtotal = $500,503 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	12/19/2019	NON-COMPETING CONTINUATION	$500,503
														Subtotal = $500,503

Issue Date FY: 2019 ( Subtotal = $500,503 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Allergy and Infectious Diseases Research	000	1	1/14/2019	NEW	$500,503
														Subtotal = $500,503

Grand Total All Awards = $2,502,515

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Regulation of B cell function in demyelinating disease by N-glycan branching

Award Number: R01AI144403

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: 01/14/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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