We performed a prospective study of the transitional Breg (tBreg) subpopulations with the CD19+CD24highCD38high phenotype from MS patients and healthy donors by (i) measuring their content during two diverging courses of relapsing-remitting MS: benign multiple sclerosis (BMS) and highly active multiple sclerosis (HAMS); (ii) analyzing BCR repertoires of circulating B cells by high-throughput sequencing; and (iii) measuring the percentage of CD27+ cells in tBregs. This evidence concerns the gene BCR and relapsing-remitting multiple sclerosis.