Abstract
Natural antibodies (NAbs) are produced in the absence of exogenous antigenic stimulation and circulate in the blood of normal, healthy individuals. These antibodies have been shown to provide one of the first lines of defense against both bacterial and viral pathogens. Conservation of the NAb repertoire reactivity profile is observed both within and across species. One view holds that this conservation of NAb self-reactivities reflects the use of germline antibody sequence, whereas the opposing view holds that the self-reactivities reflect selection driven by key conserved self-antigens. In mice, B-1a B cells are a major source of NAbs. A significant fraction of the B-1a antibody repertoire is devoid of N nucleotides in H chain complementarity determining region 3 (CDR-H3) and, thus, completely germline encoded. To test the role of germline DH sequence on the self-reactivity profile of the NAb repertoire, we examined the composition and self-antigen specificity of NAbs produced by a panel of DH gene-targeted BALB/c mice, each strain of which expresses a polyclonal, altered CDR-H3 repertoire that differs from the wild-type norm. We found that in most cases the same key self-antigens were recognized by the NAbs created by each DH-altered strain. The differences in reactivity appeared to represent the genetic signature of the NAb repertoire of each mouse strain. These findings suggest that although germline CDR-H3 sequence may facilitate the production of certain NAbs, a core set of self-antigens are likely the main force driving the selection of Nab self-specificities.
Highlights
Previous studies have shown that the reactivity profile of natural antibody (NAb) remains conserved regardless of gut colonization or depletion of B-1 cell compartment [2, 3, 20]; the influence of inherited CDR-H3 antigen-binding sites on the NAb repertoire remains unclear
To test the extent to which germline antibody gene content controls the composition of NAbs and the innate antibody response to self-antigens, we examined the NAb repertoire in a panel of WT and DH gene-targeted BALB/c mice raised under specific pathogen-free conditions
To test whether the reactivity levels correlate with immunoglobulin specificity or with the relative abundance of the proteins, we compared protein staining with immunoreactivity densities in the same membrane
Summary
Previous studies have shown that the reactivity profile of NAbs remains conserved regardless of gut colonization or depletion of B-1 cell compartment [2, 3, 20]; the influence of inherited CDR-H3 antigen-binding sites on the NAb repertoire remains unclear. We had previously used techniques of cre–loxP-based gene targeting to delete 12 of the 13 DH gene segments in the BALB/c DH locus, retaining only the single DFL16.1 segment (ΔD-DFL mice) [22]. We generated the ΔD-iD strain by replacing the center of the single DFL16.1 segment with an inverted DSP2.2 gene segment [23]. DH gene-targeted BALB/c mice express polyclonal, altered CDR-H3 repertoires that differ from the WT norm [reviewed in Ref. To test the extent to which germline antibody gene content controls the composition of NAbs and the innate antibody response to self-antigens, we examined the NAb repertoire in a panel of WT and DH gene-targeted BALB/c mice raised under specific pathogen-free conditions. Our findings suggest that for most self-reactivities the primary force driving the generation of NAbs is exposure to a key set of self-antigens
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