Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors.
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.
Duty
J Andrew
JA
Immunobiology and Cancer, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Szodoray
Peter
P
Zheng
Nai-Ying
NY
Koelsch
Kristi A
KA
Zhang
Qingzhao
Q
Swiatkowski
Mike
M
Mathias
Melissa
M
Garman
Lori
L
Helms
Christina
C
Nakken
Britt
B
Smith
Kenneth
K
Farris
A Darise
AD
Wilson
Patrick C
PC
D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology*; D005803:Genes, Immunoglobulin / Q000235:genetics; D006801:Humans; D007072:Immunoglobulin D / Q000032:analysis / Q000276:immunology; D007075:Immunoglobulin M / Q000032:analysis / Q000276:immunology; D016130:Immunophenotyping; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D009154:Mutation / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism
D000888:Antibodies, Anti-Idiotypic; D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001324:Autoantigens; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; C039951:anti-IgD; C044203:anti-IgM; D014443:Tyrosine; D015759:Ionomycin