Stereotyped B‐cell responses are linked to IgG constant region polymorphisms in multiple sclerosis.

Clonally related B cells infiltrate the brain, meninges, and cerebrospinal fluid of MS patients, but the mechanisms driving the B‐cell response and shaping the immunoglobulin repertoires remain unclear. Here, we used single‐cell full‐length RNA‐seq and BCR reconstruction to simultaneously assess the phenotypes, isotypes, constant region polymorphisms, and the paired heavy‐ and light‐chain repertoires in intrathecal B cells. We detected extensive clonal connections between the memory B cell and antibody‐secreting cell (ASC) compartments and observed clonally related cells of different isotypes including IgM/IgG1, IgG1/IgA1, IgG1/IgG2, and IgM/IgA1. There was a strong dominance of the G1m1 allotype constant region polymorphisms in ASCs, but not in memory B cells. Tightly linked to the G1m1 allotype, we found a preferential pairing of the immunoglobulin heavy‐chain variable (IGHV)4 gene family with the κ variable (IGKV)1 gene family. The IGHV4‐39 gene was most used and showed the highest frequency of pairing with IGKV1‐5 and IGKV1(D)‐33. These results link IgG constant region polymorphisms to stereotyped B‐cell responses in MS and indicate that the intrathecal B‐cell response in these patients could be directed against structurally similar epitopes. [ABSTRACT FROM AUTHOR]