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 (CSF) of multiple sclerosis (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 B-cell receptor reconstruction to simultaneously assess the phenotypes, isotypes, constant region polymorphisms, and the paired heavy- and light-chain repertoires in intrathecal B-lineage 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 IGHV4 gene family with the {kappa} variable (IGKV)1 gene family. These results link IgG constant region polymorphisms to stereotyped B-cell responses in MS, indicating that the intrathecal B-cell response in these patients could be directed against structurally similar epitopes. The data also suggest that the dominance of the G1m1 allotype in ASCs may occur as a result of biased differentiation of intrathecal memory B cells.