科研之友
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摘要
Characterization of Ag-specific BCR repertoires is essential for understanding disease mechanisms involving humoral immunity. This is optimally done by interrogation of paired H chain V region (V-H) and L chain V region (V-L) sequences of individual and Ag-specific B cells. By applying single-cell high-throughput sequencing on gut lesion plasma cells (PCs), we have analyzed the transglutaminase 2 (TG2)-specific V-H:V-L autoantibody repertoire of celiac disease (CD) patients. Autoantibodies against TG2 are a hallmark of CD, and anti-TG2 IgA-producing gut PCs accumulate in patients upon gluten ingestion. Altogether, we analyzed paired VH and VL sequences of 1482 TG2-specific and 1421 non-TG2-specific gut PCs from 10 CD patients. Among TG2-specific PCs, we observed a striking bias in IGHV and IGKV/IGLV gene usage, as well as pairing preferences with a particular presence of the IGHV5-51: IGKV1-5 pair. Selective and biased V-H:V-L pairing was particularly evident among expanded clones. In general, TG2-specific PCs had lower numbers of mutations both in V-H and V-L genes than in non-TG2-specific PCs. TG2-specific PCs using IGHV5-51 had particularly few mutations. Importantly, V-L segments paired with IGHV5-51 displayed proportionally low mutation numbers, suggesting that the low mutation rate among IGHV5-51 PCs is dictated by the BCR specificity. Finally, we observed selective amino acid changes in V-H and V-L and striking CDR3 length and J segment selection among TG2-specific IGHV5-51: IGKV1-5 pairs. Hence this study reveals features of a disease-and Ag-specific autoantibody repertoire with preferred V-H:V-L usage and pairings, limited mutations, clonal dominance, and selection of particular CDR3 sequences. The Journal of Immunology, 2017, 199: 782-791.
- 出版日期2017-7-15
