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

Abstract

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.

• Authors: Ida Lindeman, Justyna Polak, Shuo-Wang Qiao, Trygve Holmøy, Rune A Høglund, Frode Vartdal, Pål Berg-Hansen, Ludvig M Sollid, Andreas Lossius
• Journal: European journal of immunology (Eur J Immunol) Vol. 52 Issue 4 Pg. 550-565 (04 2022) ISSN: 1521-4141 [Electronic] Germany
• PMID: 35094395 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.

Chemical References

• Immunoglobulin A
• Immunoglobulin G

Topics

• B-Lymphocytes
• Brain
• Humans
• Immunoglobulin A
• Immunoglobulin G
• Multiple Sclerosis (genetics)