Human immunoglobulin selection associated with class switch and possible tolerogenic origins for Cδ class-switched B cells
Nai-Ying Zheng, … , J. Donald Capra, Patrick C. Wilson
Nai-Ying Zheng, … , J. Donald Capra, Patrick C. Wilson
Published April 15, 2004
Citation Information: J Clin Invest. 2004;113(8):1188-1201. https://doi.org/10.1172/JCI20255.
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Article Immunology

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 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.

Authors

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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Figure 3

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The autoimmune-associated JH6 gene is counterselected from IgG populatio...
The autoimmune-associated JH6 gene is counterselected from IgG populations and selected into the Cδ-CS lineage. (A and B) The JH4 gene segment is normally the dominant JH gene used in human VH gene rearrangements. The JH6 gene is upregulated in receptor-edited and autoimmune B cells, linking it to autoimmune repertoires. Only usage of JH4 versus JH6 gene segments is shown and compared, as all other JH gene segment use is unchanged (other JH representations are in Table 2). JH analysis was based on naive B cells (ten donors), IgM/D+ pre-GC cells (three donors), IgM+ GC cells (eight donors), IgM+ memory cells (ten donors), IgM+ PCs (two donors), IgG+ GC cells (seven donors), IgG+ memory cells (eight donors), IgG+ PCs (two donors), Cδ-CS PCs (one donor), and Cδ-CS GC cells (ten, five, and four donors for VH4, VH1, and VH3 libraries, respectively). Bars indicate means of all donors and error bars, the SD. Student’s t test P values are indicated. *P < 0.0005 vs. all; **P < 0005; #P < 0.01; ##P < 0.0001.