Mature B cells class switched to IgD are autoreactive in healthy individuals

Kristi Koelsch, Nai Ying Zheng, Qingzhao Zhang, Andrew Duty, Christina Helms, Melissa D. Mathias, Mathew Jared, Kenneth Smith, J. Donald Capra, Patrick C. Wilson

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

Determination of the origin and fate of autoreactive B cells is critical to understanding and treating autoimmune diseases. We report that, despite being derived from healthy people, antibodies from B cells that have class switched to IgD via genetic recombination (and thus become class switched to Cδ [Cδ-CS] cells) are highly reactive to self antigens. Over half of the antibodies from Cδ-CS B cells bind autoantigens on human epithelioma cell line 2 (HEp-2) cells or antinuclear antigens, and a quarter bind double-stranded DNA; both groups of antibodies are frequently polyreactive. Intriguingly, some Cδ-CS B cells have accumulated basic residues in the antibody variable regions that mediate anti-DNA reactivity via somatic hypermutation and selection, while other Cδ-CS B cells are naturally autoreactive. Though the total percentage was appreciably less than for Cδ-CS cells, a surprising 31% of IgG memory cell antibodies were somewhat autoreactive, and as expected, about 24% of naive cell antibodies were autoreactive. We interpret these findings to indicate either that autoreactive B cells can be induced to class switch to IgD or that autoreactive B cells that use IgD as the B cell receptor are not effectively deleted. Determination of 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 into the enigmatic function of the IgD antibody.

Original languageEnglish
Pages (from-to)1558-1565
Number of pages8
JournalJournal of Clinical Investigation
Volume117
Issue number6
DOIs
StatePublished - 1 Jun 2007
Externally publishedYes

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