A Mouse Variable Gene Fragment Binds to DNA Independently of the BCR Context: A Possible Role for Immature B-Cell Repertoire Establishment

Abstract

B-cell maturation occurs in several steps and requires constant stimulus for its continuing development. From the emergence of the pre-B-cell receptor, signal transduction stimulates and supports B-cell development. Current viewpoints indicate that both positive selection pressure for autoantigens and tonic signaling constitutively stimulate B-cell maturation. In this work, we tested for the presence of a putative DNA binding site in a variable gene segment in a germline configuration, independently of VDJ recombination. After a survey of the public antibody databases, we chose a single mouse heavy variable gene segment that is highly represented in anti-nucleic acid antibodies and tested it for ssDNA binding. A phage display approach was used to search for intrinsic binding to oligo deoxythymidine. The results revealed that binding to an antigen can be influenced by the use of a specific DNA binding V gene segment. Our data support the idea that some variable genes have intrinsic reactivity towards specific types of endogenous autoantigens, and this property may contribute to the establishment of the immature B-cell repertoire.

Antibody Epitope Specificity for dsDNA Phosphate Backbone Is an Intrinsic Property of the Heavy Chain Variable Germline Gene Segment Used

“…However, they differed in CDR3 regions ( 31 ), and their contribution to F(0.367) expression is insignificant (Table 1 ), whereas IgM 111.185 (MRL-DNA22) anti-DNA antibody ( 31 ) retains V gene segment in germline configuration. The data presented may be in accord with the idea that V germline gene segments prone to bind a dsDNA epitope should be less dependent on CDR3 regions ( 48 ).…”

Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome

“…5 C and not depicted). Importantly, previous studies have correlated BCR VH10 and VH14 expression with nucleic acid reactivity ( Brigido et al, 1993 ; Whitcomb et al, 1999 ; Jiang et al, 2011 ; Maranhão et al, 2013 ). Thus, our findings suggest that in the setting of WASp deficiency, MyD88 signals promote the selection of BCRs whose specificity correlates with anti-DNA and/or anti-RNA specificities, leading to the observed expansion of VH10 and VH14 family gene usage.…”

BCR and co-receptor crosstalk facilitate the positive selection of self-reactive transitional B cells

“…Interestingly, in both murine and human models of WASp-deficiency, we observed preferential selection for autoreactive-associated VH families (VH10, VH4-34 in murine and human, respectively) at the late transitional to mature, naïve B cell transition. Notably, VH10 and VH4-34 family antibodies have previously been shown to exhibit increased binding affinity to self-antigens that serve as TLR ligands, including dsDNA [45 • ,46], apoptotic debris [47,48], and carbohydrates [49]. Consistent with these predicted specificities, enhanced transitional B cell cycling and altered repertoire selection were antigen-specific and MyD88-dependent-supporting a model in which heightened BCR and TLR signals function coordinately to promote the positive selection of self-reactive specificities into the naïve repertoire.…”