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

Toxicol Appl Pharmacol. 2017 Sep 1;330:22-29. doi: 10.1016/j.taap.2017.06.022. Epub 2017 Jun 28.

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 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.

Keywords: Autoimmunity; B cell receptor (BCR); Mercury; Transitional type 1 (T1) B cell.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism*
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Female
  • Immunoglobulins / metabolism
  • Immunohistochemistry
  • Lymphocytes / drug effects
  • MAP Kinase Signaling System / drug effects
  • Mercury Compounds / toxicity*
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Antigen, B-Cell / drug effects*
  • Receptors, Antigen, B-Cell / metabolism*
  • Signal Transduction / drug effects*
  • Spleen / cytology

Substances

  • Immunoglobulins
  • Mercury Compounds
  • Receptors, Antigen, B-Cell