Mature B cells from healthy people which are permanently class switched to the IgD isotype are autoreactive

Abstract Determining the origin and fate of autoreactive B cells is critical to understanding and treating autoimmune diseases. We report that compared to antibodies from naïve and IgG memory B cells those from cells that have class switched to IgD via genetic recombination (Cδ-CS) are highly reactive with self-antigens, despite being derived from healthy people. Half of the antibodies from Cδ-CS B cells bind various autoantigens, and they are frequently polyreactive. Many also bind HEp-2 antigens. Intriguingly, some Cδ-CS B cells have accumulated residues in the variable regions that mediate anti-DNA reactivity via somatic hypermutation and selection, suggesting an immunological origin for anti-DNA antibodies in healthy people, while other Cδ-CS B cells are naturally autoreactive. We interpret these findings to indicate that autoreactive B cells can either be induced to class switch to IgD or autoreactive B cell clones that use IgD as the B cell receptor are not effectively deleted. Determining the mechanism by which the majority of Cδ-CS B cells are autoreactive may be important in understanding peripheral tolerance mechanisms and may provide insight to the enigmatic function of the secreted IgD antibody.