Human immunoglobulin selection associated with class switch and possible tolerogenic origins for Cδ class-switched B cells

Abstract

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 κ κ 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 µ to Cδ δ (Cδ δ-CS). The Cδ δ-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 δ-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 δ-CS lineage is presented. 1188The Conflict of interest:The authors have declared that no conflict of interest exists. A To ensure accuracy, particular sequences were excluded from certain analyses (Methods). B Studies for which indicated populations were analyzed. Asterisks indicate the studies in which the various populations were included. sc, single-cell.

Immunobiology of the Tonsils and Adenoids

“…It is interesting that sIgD + IgM − B cells appear to express predominantly V-gene repertoires that may allow considerable cross-reactivity, including autoimmunity, but understanding the biological significance of this observation requires further studies (Zheng et al, 2004;Chen and Cerutti, 2010).…”

The Mucosal B Cell System

“…It is interesting that sIgD + IgM − B cells generated by nonclassical switching seem to express predominantly V gene repertoires that may allow considerable crossreactivity, including autoimmunity, but understanding the biological significance of this observation requires further studies (Zheng et al, 2004). Although numerous antimicrobial and other IgD antibody activities have been observed in both murine and human serum, the protective or pathogenic role of circulating IgD has only been explored since the late 1990s (Preud'homme et al, 2000;Cerutti, 2010, 2011).…”

Regulation and Function of Mucosal IgA and IgD

“…These molecular footprints suggest that IgD + IgM − B cells undergo oligoclonal expansion after repeatedly entering the germinal center in response to persistent exposure to respiratory antigens (Koelsch et al, 2007;Zheng et al, 2004). Despite their high mutation rate, human IgD + IgM − B cells are highly polyreactive (Koelsch et al, 2007;Zheng et al, 2004), which may enhance their ability to contain microbes in the upper respiratory mucosa.…”