Chronic GVH prevents anergy in bone marrow self-reactive B cells: a selective increase in post-endoplasmic reticulum processing and trafficking to the cell surface of autoreactive IgM receptors

Int Immunol. 2003 Aug;15(8):975-85. doi: 10.1093/intimm/dxg097.

Abstract

B cell autoreactivity is a component of chronic graft versus host (GVH) disease in humans and mice. Chronic GVH driven by I-A disparity results in loss of B cell tolerance in Ig/sHEL tolerant mice. In these mice, B cell anergy is characterized by down-modulation of sIgM mediated by intracellular retention in the endoplasmic reticulum (ER) and/or a block in post-ER processing of IgM receptors. Here, we report that GVH induces a selective increase in post-ER processing of the micro chain and trafficking to the cell surface of IgM receptors in B cells that bind HEL self-antigen. The increase in sIgM was detectable as early as 6 days post-GVH, before the appearance of circulating autoantibodies, and was particularly prominent in B cells that up-regulated surface I-A. A further increase in sIgM was found at later time points, along with circulating anti-HEL autoantibodies and a marked decrease in serum-free HEL, but no significant change in the amounts of HEL bound to B cells in vivo. These findings suggest that (i) abrogation of ER retention of IgM receptors in self-reactive B cells is an early event triggered by allogeneic T cells and (ii) at later stages of GVH disease the appearance of autoantibodies reduces the availability of free autoantigen, which may further escalate anergy escape of self-reactive B cells, and lead to exacerbation and perpetuation of autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigen-Antibody Complex / chemistry
  • Antigens, CD / analysis
  • Autoantibodies / blood
  • Autoantibodies / immunology
  • Autoantibodies / metabolism
  • Autoimmunity / immunology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / physiology
  • B7-2 Antigen
  • Blotting, Western
  • Bone Marrow Cells / chemistry
  • Bone Marrow Cells / cytology
  • CD24 Antigen
  • Chronic Disease
  • Clonal Anergy / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Graft vs Host Disease / immunology*
  • Hexosaminidases / metabolism
  • Histocompatibility Antigens Class II / analysis
  • Immunoglobulin D / analysis
  • Immunoglobulin mu-Chains / analysis
  • Immunoglobulin mu-Chains / metabolism
  • Leukocyte Common Antigens / analysis
  • Lymphocyte Activation / immunology
  • Membrane Glycoproteins / analysis
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muramidase / blood
  • Muramidase / immunology
  • Muramidase / metabolism
  • Protein Processing, Post-Translational
  • Protein Transport / immunology
  • Receptors, Antigen, B-Cell / analysis
  • Receptors, Antigen, B-Cell / immunology
  • Receptors, Antigen, B-Cell / metabolism
  • Receptors, Fc / analysis
  • Receptors, Fc / immunology
  • Receptors, Fc / metabolism*
  • Receptors, IgE / analysis
  • Spleen / chemistry
  • Spleen / cytology

Substances

  • Antigen-Antibody Complex
  • Antigens, CD
  • Autoantibodies
  • B7-2 Antigen
  • CD24 Antigen
  • Cd24a protein, mouse
  • Cd86 protein, mouse
  • Histocompatibility Antigens Class II
  • Immunoglobulin D
  • Immunoglobulin mu-Chains
  • Membrane Glycoproteins
  • Receptors, Antigen, B-Cell
  • Receptors, Fc
  • Receptors, IgE
  • immunoglobulin M receptor
  • Leukocyte Common Antigens
  • Hexosaminidases
  • hen egg lysozyme
  • Muramidase