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.
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.
Feuerstein
Nili
N
Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. feuerstein@email.chop.edu
Shivers
Debra
D
Chen
Fangqi
F
Eisenberg
Robert A
RA
Finkel
Terri H
TH
D019264:Adoptive Transfer; D000818:Animals; D000936:Antigen-Antibody Complex / Q000737:chemistry; D015703:Antigens, CD / Q000032:analysis; D001323:Autoantibodies / Q000097:blood / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D051940:B7-2 Antigen; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000737:chemistry / Q000166:cytology; D051927:CD24 Antigen; D002908:Chronic Disease; D017635:Clonal Anergy / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology*; D006596:Hexosaminidases / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007072:Immunoglobulin D / Q000032:analysis; D007148:Immunoglobulin mu-Chains / Q000032:analysis / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009113:Muramidase / Q000097:blood / Q000276:immunology / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D011961:Receptors, Fc / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D017455:Receptors, IgE / Q000032:analysis; D013154:Spleen / Q000737:chemistry / Q000166:cytology
D000936:Antigen-Antibody Complex; D015703:Antigens, CD; D001323:Autoantibodies; D051940:B7-2 Antigen; D051927:CD24 Antigen; C497890:Cd24a protein, mouse; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; D007072:Immunoglobulin D; D007148:Immunoglobulin mu-Chains; D008562:Membrane Glycoproteins; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc; D017455:Receptors, IgE; C035311:immunoglobulin M receptor; D017493:Leukocyte Common Antigens; D006596:Hexosaminidases; C421864:hen egg lysozyme; D009113:Muramidase