Defective Allelic Exclusion by IgD in the Absence of Autoantigen

Abstract

A considerable proportion of peripheral B cells is autoreactive, and it is unclear how the activation of such potentially harmful cells is regulated. In this study, we show that the different activation thresholds or IgM and IgD BCRs adjust B cell activation to the diverse requirements during development. We rely on the autoreactive 3-83 model BCR to generate and analyze mice expressing exclusively autoreactive IgD BCRs on two different backgrounds that determine two stages of autoreactivity, depending on the presence or absence of the cognate Ag. By comparing these models with IgM-expressing control mice, we found that, compared with IgM, IgD has a higher activation threshold in vivo, as it requires autoantigen to enable normal B cell development, including allelic exclusion. Our data indicate that IgM provides the high sensitivity required during early developmental stages to trigger editing of any autoreactive specificities, including those enabling weak interaction with autoantigen. In contrast, IgD has the unique ability to neglect weakly interacting autoantigens while retaining reactivity to higher-affinity Ag. This IgD function enables mature B cells to ignore autoantigens while remaining able to efficiently respond to foreign threats.

B cells expressing IgM B cell receptors of HIV-1 neutralizing antibodies discriminate antigen affinities by sensing binding association rates

“…A second caveat is that while naive B cells express both IgM and IgD BCRs, this study was limited to the investigation of B cells expressing IgM BCRs only. Recent studies indicate that IgD BCR can regulate antibody responses, and its signaling requirement may be distinct (Amendt et al, 2021;Renna et al, 2022). We have on-going studies to address the role of IgD in cell lines expressing BCRs with bnAb specificities described in this work.…”

The Src-family kinase Lyn plays a critical role in establishing and maintaining B cell anergy by suppressing PI3K-dependent signaling

“…Anergic B cells express normal levels of IgD BCR, which has the same self-antigen-specificity as IgM BCR. Studies that used mice that only express one subclass of BCR suggest that self-antigens preferentially engage with IgM BCRs (79, 80), possibly due to structural differences between surface IgM and IgD (81). While expression of IgD attenuates the transcriptional program of anergic B cells (82), it may primarily enable anergic B cells to respond to cross-reacting foreign antigen, a process coined clonal redemption (83).…”

Role of inhibitory signaling in peripheral B cell tolerance*

“…These structural differences have been proposed to make IgD less sensitive to low‐valency antigen, 158 although this has been challenged 35 . Regardless, in systems where immunoglobulin surface expression was restricted to one class, indirect readouts suggest that IgD is less sensitive to self‐antigen 159,160 …”

“…35 Regardless, in systems where immunoglobulin surface expression was restricted to one class, indirect readouts suggest that IgD is less sensitive to self-antigen. 159,160 The availability of normal surface levels of IgD is often used to determine whether an autoreactive B cell with reduced IgM expression is actively suppressed. If cross-linking of equivalent amounts of surface IgD results in dampened calcium mobilization in the autoreactive B cells, when compared to a naive B cell, this suggests that active inhibitory signaling suppresses activation of the autoreactive B cell in concert with reduced availability of surface IgM.…”