Abstract
Several human B cell subpopulations are recognised in the peripheral blood, which play distinct roles in the humoral immune response. These cells undergo developmental and maturational changes involving VDJ recombination, somatic hypermutation and class switch recombination, altogether shaping their immunoglobulin heavy chain (IgH) repertoire. Here, we sequenced the IgH repertoire of naïve, marginal zone, switched and plasma cells from 10 healthy adults along with matched unsorted and in silico separated CD19+ bulk B cells. Using advanced bioinformatic analysis and machine learning, we show that sorted B cell subpopulations are characterised by distinct repertoire characteristics on both the individual sequence and the repertoire level. Sorted subpopulations shared similar repertoire characteristics with their corresponding in silico separated subsets. Furthermore, certain IgH repertoire characteristics correlated with the position of the constant region on the IgH locus. Overall, this study provides unprecedented insight over mechanisms of B cell repertoire control in peripherally circulating B cell subpopulations.
Highlights
We compared immunoglobulin heavy (IgH) repertoire characteristics between the following B cell subpopulations: Bnaive, BMZ, BPC_MD, BPC_AG, and Bswitched and their corresponding subsets that we obtained in silico from Bbulk: Bbulk_naïve, Bbulk_MD, and Bbulk_switched
When combining repertoire characteristics by isotype subclass and cell type for classswitched transcripts resulting from Bbulk_switched, Bswitched and BPC_AG, we found that samples with the same constant region originating from different cell types overlapped. (Figure 3B)
We show differences in the repertoire characteristics at the isotype subclass level unrelated to cell type that correlate with the position of the constant gene on the IgH locus
Summary
B-cell development starts in the bone marrow where immature B cells must assemble and express on their surface a functional but non-self-reactive B cell antigen receptor (BCR). The generation of the heavy and light chain of the BCR is mediated by the random and imprecise process of V(D)J recombination. Further development of B cells occurs in the periphery in response to stimulation with the process of somatic hypermutation (SHM) through which point mutations are introduced in the genes coding for the V(D)J part of the immunoglobulin heavy (IgH) and light chain. Subsequently, B cells with a mutated BCR providing increased antigen affinity are selected and show increased survival and proliferation capacity.4class-switch recombination (CSR) modifies the IgH constant region resulting in the generation of B cells with nine different immunoglobulin isotypes or isotype subclasses, namely IgD, IgM, IgG1-4, IgA1/2 and IgE. This process involves the replacement of the proximal heavy chain constant gene by a more distal gene. Class-switch recombination (CSR) modifies the IgH constant region resulting in the generation of B cells with nine different immunoglobulin isotypes or isotype subclasses, namely IgD, IgM, IgG1-4, IgA1/2 and IgE.. Class-switch recombination (CSR) modifies the IgH constant region resulting in the generation of B cells with nine different immunoglobulin isotypes or isotype subclasses, namely IgD, IgM, IgG1-4, IgA1/2 and IgE.5 This process involves the replacement of the proximal heavy chain constant gene by a more distal gene. Class switching is an essential mechanism during humoral immune responses as the constant region of an antibody determines its effector function.. Class switching is an essential mechanism during humoral immune responses as the constant region of an antibody determines its effector function.6 Both direct switching and sequential switching upon a second round of antigen exposure have been reported. Class switching is an essential mechanism during humoral immune responses as the constant region of an antibody determines its effector function. Both direct switching and sequential switching upon a second round of antigen exposure have been reported.
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