Human immunoglobulin selection associated with class switch and possible tolerogenic origins for C delta class-switched B cells.
Current paradigms of peripheral B cell selection suggest that autoreactive B cells are controlled by clonal deletion, anergy, and developmental arrest. We report that changes to the human antibody repertoire likely resulting from these mechanisms both for a well-characterized autoreactivity from antibodies encoded by the V(H)4-34 gene and for other hallmarks of an autoreactive repertoire are apparent mainly for class-switched B cells and not for IgM germinal center, IgM memory, or IgM plasma cells. Other possible indicators of autoreactivity found selected with immunoglobulin class include J(H)6 gene segment usage, increased frequency of B cells with long third hypervariable regions, and distal J(kappa) gene segment bias. Of particular interest is the finding that B cells with these same characteristics are selected into the lineage of B cells that have undergone the unusual class switch from constant region C mu to C delta (C delta-CS). The C delta-CS population also displays an increased frequency of charged amino acids localized to the complementarity-determining regions, further suggesting autoreactivity, and evidence is presented that these B cells had undergone extensive receptor editing. Thus, the C delta-CS lineage may be a "sink" for B cells harboring autoreactive specificities in normal humans. A model for a new tolerizing mechanism that could account for the C delta-CS lineage is presented.
Zheng
Nai-Ying
NY
Molecular Immunogenetics, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
Wilson
Kenneth
K
Wang
Xiaojian
X
Boston
Angela
A
Kolar
Grant
G
Jackson
Stephen M
SM
Liu
Yong-Jun
YJ
Pascual
Virginia
V
Capra
J Donald
JD
Wilson
Patrick C
PC
D000911:Antibodies, Monoclonal / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D019070:Cell Lineage; D022801:Complementarity Determining Regions; D006801:Humans; D007108:Immune Tolerance; D017578:Immunoglobulin Class Switching; D007127:Immunoglobulin Constant Regions / Q000235:genetics*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000096:biosynthesis; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007138:Immunoglobulin delta-Chains / Q000235:genetics*; D016133:Polymerase Chain Reaction
D000911:Antibodies, Monoclonal; D022801:Complementarity Determining Regions; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D007138:Immunoglobulin delta-Chains