TLR Ligation Triggers Somatic Hypermutation in Transitional B Cells Inducing the Generation of IgM Memory B Cells

Abstract

TLR9 activation by unmethylated CpG provides a homeostatic mechanism to maintain B cell memory in the absence of Ag. In this study, we demonstrate that CpG also triggers the generation of somatically mutated memory B cells from immature transitional B cells. In response to CpG, a fraction of transitional B cells proliferates and introduces somatic hypermutations in the H chain V regions. The nonproliferating pool of transitional B cells mostly maintains germline configurations. Mutations are VH specific: VH5 is the least mutated family, whereas VH1 and VH4/6 are the most mutated families. CpG stimulation also results in upregulation of VH5 transcripts in proliferating cells. Therefore, early recognition of bacterial DNA preferentially expands VH5-expressing B cells while inducing somatic hypermutations in other families. The mutation frequency, range, and type of substitutions observed in vitro are comparable to those found in memory B cells from the peripheral blood of Hyper IgM type 1 patients and the spleen of normal infants. The process triggered by TLRs may represent a first step leading to additional diversification of the germline repertoire and to the generation of memory B cells that will further refine their repertoire and specificity in the germinal centers.

Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

“…Thus, self-antigens able to activate endosomal TLRs and BCRs will induce robust activation in B cells. Some studies suggest that TLR activation of immature B cells can dysregulate central tolerance pathways (64)(65)(66). We hypothesize that TLR ligation might also explain the failure of peripheral tolerance in autoimmune disease.…”

Clonal Characteristics of Circulating B Lymphocyte Repertoire in Primary Biliary Cholangitis

“…A high level of serum IgM in most PBC patients is a unique phenomenon. Studies suggested it might be a consequence of hyperactive innate immunity independent of T cells and mediated by IgM memory B cells either in the bloodstream or in the spleen (1,5,29,30). Elevated serum IgM level has been used as a diagnostic marker for PBC, and the reduction of serum IgM level has been used as a marker of disease alleviation by clinicians (28,31).…”

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

“…4). Granted that this seems counterintuitive, recent publications have unequivocally demonstrated that affinity maturation and class-switching can occur without T cells, albeit the process is more cumbersome (33)(34)(35)(36).…”