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Understanding the connection between exposure to mercury, auto-immunity and tolerance in B cells.

Award Number: R01ES029484
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Mercury (Hg) is a xenobiotic that is widespread in the environment. Mercury is also a potent immunomodulator that has been implicated as a factor contributing to autoimmune disease in animal models and humans. A recent epidemiological study has now convincingly shown that, in otherwise healthy individuals who were only exposed to low levels of Hg through typical environmental sources, there is a correlation between blood Hg levels and the appearance in the blood of antibodies to double-stranded DNA, an autoimmune biomarker. This finding indicates that under the proper circumstances, exposure to environmental Hg promotes autoimmunity, a precursor to autoimmune disease. Since the discovery of B cells, immunologists have appreciated that, in light of the Clonal Selection Theory, during the normal course of B cell development, large numbers of immature B cells must be generated that produce immunoglobulin that is reactive to many self-antigens (auto- antibodies). However, in the course of normal development, the vast majority of immature auto-reactive B cells are prevented from maturing by processes collectively known as tolerance. Autoimmune disease arises when the mechanisms that promote tolerance are disrupted. For B cells, it is firmly established that tolerance depends to a large extent on signals generated by the B cell receptor (BCR) in immature B cells. Our preliminary and recently published studies have shown that Hg interferes with signal generation by the BCR in immature B cells, through mechanisms that likely involve the tyrosine kinase Lyn, the tyrosine phosphatases SHP-1 and CD45 and elements of the cytoskeleton. Our overall hypothesis is that environmental exposure to Hg disrupts BCR signaling in Hg-exposed compared with non-exposed animals, resulting in the disruption of B cell tolerance in exposed animals. This in turn should lead to the appearance of an excess of mature auto- reactive B cells in Hg-exposed animals that have the potential to cause autoimmune disease. We propose to test this hypothesis by generating anti-hen egg lysozyme (HEL)/hen egg lysozyme double transgenic mice which are designed to be normally tolerant to HEL, and them exposing them or not to Hg, in order to break HEL tolerance (Aim 1). We will expand on our preliminary data to further elucidate the molecular mechanisms that enable Hg to interfere with BCR signaling. We will utilize mouse strains with different genetic susceptibilities to Hg intoxication to directly investigate how Hg interferes with the function of the tyrosine kinase Lyn and the tyrosine phosphatases SHP-1 and CD45 during BCR signaling under the influence of different genetic backgrounds (Aim 2). We will use complementary proteomic and multicolor phosphoflow cytometric approaches to determine how Hg interacts with elements of the cytoskeleton, so as to attenuate BCR signaling (Aim 3).


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: 2023 ( Subtotal = $0 )
2023	2022	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	5	7/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $435,474 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	5	8/4/2022	NON-COMPETING CONTINUATION	$435,474
														Subtotal = $435,474

Issue Date FY: 2021 ( Subtotal = $435,474 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	4	7/6/2021	NON-COMPETING CONTINUATION	$435,474
														Subtotal = $435,474

Issue Date FY: 2020 ( Subtotal = $449,575 )
2020	2020	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	3	7/20/2020	NON-COMPETING CONTINUATION	$449,575
														Subtotal = $449,575

Issue Date FY: 2019 ( Subtotal = $456,120 )
2019	2019	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	2	7/17/2019	NON-COMPETING CONTINUATION	$456,120
														Subtotal = $456,120

Issue Date FY: 2018 ( Subtotal = $463,549 )
2018	2018	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	1	8/27/2018	NEW	$463,549
														Subtotal = $463,549

Grand Total All Awards = $2,240,192

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Understanding the connection between exposure to mercury, auto-immunity and tolerance in B cells.

Award Number: R01ES029484

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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