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PMID: 19103878 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors.

The Journal of experimental medicine ·Vol. 206 ·No. 1 ·2009-01-16 ·Pages 139-51

Duty JA, Szodoray P, Zheng NY, Koelsch KA, Zhang Q, Swiatkowski M, Mathias M, Garman L, Helms C, Nakken B, Smith K, Farris AD, Wilson PC

Abstract

Self-reactive B cells not controlled by receptor editing or clonal deletion may become anergic. We report that fully mature human B cells negative for surface IgM and retaining only IgD are autoreactive and functionally attenuated (referred to as naive IgD(+)IgM(-) B cells [B(ND)]). These B(ND) cells typically make up 2.5% of B cells in the peripheral blood, have antibody variable region genes in germline (unmutated) configuration, and, by all current measures, are fully mature. Analysis of 95 recombinant antibodies expressed from the variable genes of single B(ND) cells demonstrated that they are predominantly autoreactive, binding to HEp-2 cell antigens and DNA. Upon B cell receptor cross-linkage, B(ND) cells have a reduced capacity to mobilize intracellular calcium or phosphorylate tyrosines, demonstrating that they are anergic. However, intense stimulation causes B(ND) cells to fully respond, suggesting that these cells could be the precursors of autoantibody secreting plasma cells in autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. This is the first identification of a distinct mature human B cell subset that is naturally autoreactive and controlled by the tolerizing mechanism of functional anergy.

MeSH Terms
Antibodies, Anti-Idiotypic/pharmacology Antibodies, Antinuclear/genetics,immunology Antibodies, Monoclonal/genetics,immunology Antigens, CD/analysis,metabolism Autoantigens/immunology Autoimmunity/immunology B-Lymphocyte Subsets/drug effects,immunology,metabolism Calcium Signaling/drug effects,immunology Clonal Anergy/immunology Genes, Immunoglobulin/genetics Humans Immunoglobulin D/analysis,immunology Immunoglobulin M/analysis,immunology Immunophenotyping Ionomycin/pharmacology Kinetics Lymphocyte Activation/drug effects,immunology Mutation/immunology Phosphorylation/drug effects,immunology Receptors, Antigen, B-Cell/immunology Tyrosine/metabolism
Chemicals
Antibodies, Anti-Idiotypic Antibodies, Antinuclear Antibodies, Monoclonal Antigens, CD Autoantigens Immunoglobulin D Immunoglobulin M Receptors, Antigen, B-Cell anti-IgD anti-IgM Tyrosine Ionomycin
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Duty J Andrew
Immunobiology and Cancer, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Szodoray Peter
Zheng Nai-Ying
Koelsch Kristi A
Zhang Qingzhao
Swiatkowski Mike
Mathias Melissa
Garman Lori
Helms Christina
Nakken Britt
Smith Kenneth
Farris A Darise
Wilson Patrick C
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20080611
Published
2009-01-16
Epub
2008-00-22
Pages
139-51
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2626668
Subset
IM
Grants
NCRR NIH HHS · P20 RR018758 · United States
NIAMS NIH HHS · P30 AR053483 · United States
NIAID NIH HHS · T32 AI007633 · United States
NCRR NIH HHS · P20RR018758-01 · United States
External Links
PubMed source DOI: 10.1084/jem.20080611 PMC Full Text View journal details
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