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Early Pathogenic Steps in Xenobiotic-Induced Autoimmunity

Award Number: R01ES031863
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/24/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Early Pathogenic Steps in Xenobiotic-Induced Autoimmunity - Autoimmunity is thought to result from a combination of genetics, environmental triggers, and stochastic events. A characteristic of systemic autoimmune diseases, like systemic lupus erythematosus (SLE), are autoantibodies against nuclear antigens (ANA), however the events that initiate such autoantibody responses remain poorly understood. This is due largely to an incomplete understanding of when and how autoimmunity begins in humans and animals models of spontaneous autoimmunity. However, certain environmental/xenobiotic exposures have been linked to autoimmunity in humans and reproduced in experimental animal models, thus providing model systems where the initiating event and its exposure site are known. These induced models of autoimmunity provide a unique opportunity for dissecting the immunological response specific to known inciting agents and are significantly more amenable to identifying the early events necessary for autoimmunity that are difficult to study in spontaneous autoimmune diseases. We propose to exploit this feature in order to study the early molecular and cellular events leading to loss of B cell tolerance and autoantibody production. Mercury exposure in humans is linked with pathological outcomes including inflammatory markers, autoantibodies and renal pathology. These observation have been faithfully reproduced in experimental animal models. Importantly, murine mercury-induced autoimmunity (mHgIA) induces an MHC-restricted autoantibody response against the nucleolar protein fibrillarin which is also found in patients with SLE and Scleroderma. We believe that elucidation of the mercury-induced anti-fibrillarin response will provide insight into the early events necessary for the creation and expansion of autoreactive B cells, a cardinal feature of the autoimmune response. We propose three aims that will define different, but related, events in the secondary lymphoid organs that result in loss of tolerance and autoantibody production following mercury exposure. Aim 1 will define the early immunological steps in xenobiotic-induced autoimmunity, and characterize the immunopathologic changes in the draining lymph nodes (LNs), spleen and bone marrow following single and multiple subcutaneous exposures to mercury. In Aim 2 we will determine what factors are critical for the development of activated CD4 T cells, autoimmune GCs, and autoAbs in the early stages of mHgIA. Proposed experiments will determine how the deficiencies of several key genes required for T-dependent immune responses in SLE or mHgIA (Unc93b1, Tlr7, Il6, and Ifng) affect the early and autoimmune secondary lymphoid organ responses to HgCl2. Finally, Aim 3 studies will determine the Hg-induced autoreactive B cell repertoire by characterizing the evolving B cell antigen receptor repertoire induced by mercury exposure in secondary lymphoid organs. When completed these studies will lead to a greater understanding of the early molecular and cellular events leading to development of autoantibody production.


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 = $542,761 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Environmental Health	000	4	11/19/2024	NON-COMPETING CONTINUATION	$542,761
														Subtotal = $542,761

Issue Date FY: 2024 ( Subtotal = $533,912 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Environmental Health	000	3	11/22/2023	NON-COMPETING CONTINUATION	$533,912
														Subtotal = $533,912

Issue Date FY: 2023 ( Subtotal = $523,588 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Environmental Health	000	2	11/25/2022	NON-COMPETING CONTINUATION	$523,588
														Subtotal = $523,588

Issue Date FY: 2022 ( Subtotal = $523,588 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Environmental Health	000	1	2/24/2022	NEW	$523,588
														Subtotal = $523,588

Grand Total All Awards = $2,123,849

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Early Pathogenic Steps in Xenobiotic-Induced Autoimmunity

Award Number: R01ES031863

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/24/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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