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Title: Low level exposure to inorganic mercury interferes with B cell receptor signaling in transitional type 1 B cells

Abstract

Mercury (Hg) has been implicated as a factor contributing to autoimmune disease in animal models and humans. However the mechanism by which this occurs has remained elusive. Since the discovery of B cells it has been appreciated by immunologists that during the normal course of B cell development, some immature B cells must be generated that produce immunoglobulin reactive to 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 these mechanisms of tolerance are disrupted. In the B cell compartment, it is firmly established that tolerance depends in part upon negative selection of self-reactive immature (transitional type 1) B cells. In these cells negative selection depends upon signals generated by the B Cell Receptor (BCR), in the sense that those T1 B cells who's BCRs most strongly bind to, and so generate the strongest signals to self-antigens are neutralized. In this report we have utilized multicolor phosphoflow cytometry to show that in immature T1 B cells Hg attenuates signal generation by the BCR through mechanisms that may involve Lyn, a key tyrosine kinase in the BCR signal transductionmore » pathway. We suggest that exposure to low, environmentally relevant levels of Hg, disrupts tolerance by interfering with BCR signaling in immature B cells, potentially leading to the appearance of mature auto-reactive B cells which have the ability to contribute to auto-immune disease. - Highlights: • Hg{sup 2+} interferes with BCR-mediated activation of ERK in immature T1 B cells. • Hg{sup 2+} acts upstream of ERK. • BCR mediated activation of Syk and the CD79a ITAM are attenuated in immature T1 B cells by Hg{sup 2+}. • The mechanism whereby which Hg{sup 2+} affects Syk and CD7a activation involves the tyrosine phosphokinase Lyn.« less

Authors:
 [1];  [2];  [1];  [3]
  1. Department of Immunology, Microbiology and Biochemistry, Wayne State University, Detroit, MI (United States)
  2. Department of Environmental Medicine, University of Rochester, Rochester, NY (United States)
  3. (CURES), Wayne State University, Detroit, MI (United States)
Publication Date:
OSTI Identifier:
22722910
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 330; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; DISEASES; MERCURY; RECEPTORS; SIGNALS; TOLERANCE

Citation Formats

Gill, R., McCabe, M. J., Rosenspire, A.J., E-mail: arosenspire@wayne.edu, and Center for Urban Responses to Environmental Stressors. Low level exposure to inorganic mercury interferes with B cell receptor signaling in transitional type 1 B cells. United States: N. p., 2017. Web. doi:10.1016/J.TAAP.2017.06.022.
Gill, R., McCabe, M. J., Rosenspire, A.J., E-mail: arosenspire@wayne.edu, & Center for Urban Responses to Environmental Stressors. Low level exposure to inorganic mercury interferes with B cell receptor signaling in transitional type 1 B cells. United States. doi:10.1016/J.TAAP.2017.06.022.
Gill, R., McCabe, M. J., Rosenspire, A.J., E-mail: arosenspire@wayne.edu, and Center for Urban Responses to Environmental Stressors. Fri . "Low level exposure to inorganic mercury interferes with B cell receptor signaling in transitional type 1 B cells". United States. doi:10.1016/J.TAAP.2017.06.022.
@article{osti_22722910,
title = {Low level exposure to inorganic mercury interferes with B cell receptor signaling in transitional type 1 B cells},
author = {Gill, R. and McCabe, M. J. and Rosenspire, A.J., E-mail: arosenspire@wayne.edu and Center for Urban Responses to Environmental Stressors},
abstractNote = {Mercury (Hg) has been implicated as a factor contributing to autoimmune disease in animal models and humans. However the mechanism by which this occurs has remained elusive. Since the discovery of B cells it has been appreciated by immunologists that during the normal course of B cell development, some immature B cells must be generated that produce immunoglobulin reactive to 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 these mechanisms of tolerance are disrupted. In the B cell compartment, it is firmly established that tolerance depends in part upon negative selection of self-reactive immature (transitional type 1) B cells. In these cells negative selection depends upon signals generated by the B Cell Receptor (BCR), in the sense that those T1 B cells who's BCRs most strongly bind to, and so generate the strongest signals to self-antigens are neutralized. In this report we have utilized multicolor phosphoflow cytometry to show that in immature T1 B cells Hg attenuates signal generation by the BCR through mechanisms that may involve Lyn, a key tyrosine kinase in the BCR signal transduction pathway. We suggest that exposure to low, environmentally relevant levels of Hg, disrupts tolerance by interfering with BCR signaling in immature B cells, potentially leading to the appearance of mature auto-reactive B cells which have the ability to contribute to auto-immune disease. - Highlights: • Hg{sup 2+} interferes with BCR-mediated activation of ERK in immature T1 B cells. • Hg{sup 2+} acts upstream of ERK. • BCR mediated activation of Syk and the CD79a ITAM are attenuated in immature T1 B cells by Hg{sup 2+}. • The mechanism whereby which Hg{sup 2+} affects Syk and CD7a activation involves the tyrosine phosphokinase Lyn.},
doi = {10.1016/J.TAAP.2017.06.022},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 330,
place = {United States},
year = {2017},
month = {9}
}