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 VH4-34 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 JH6 gene segment usage, increased frequency of B cells with long third hypervariable regions, and distal Jκ 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 Cμ to Cδ (Cδ-CS). The Cδ-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 Cδ-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 Cδ-CS lineage is presented.
Nai-Ying Zheng, Kenneth Wilson, Xiaojian Wang, Angela Boston, Grant Kolar, Stephen M. Jackson, Yong-Jun Liu, Virginia Pascual, J. Donald Capra, Patrick C. Wilson
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