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

Andrea Queiroz Maranhão,Leonardo Guedes,Tainá Raiol,Maria Beatriz Walter Costa,Pedro Manoel Moraes-Vieira,Marcelo Macedo Brigido,Colette Kanellopoulos-Langevin

doi:10.1371/journal.pone.0072625

Andrea Queiroz Maranhão, Leonardo Guedes + Show 5 more

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https://doi.org/10.1371/journal.pone.0072625

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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.

Highlights

The adaptive immune system has evolved to become a highly efficient surveillance system
VDJ recombination was first introduced in the jawed animal lineage and is a major source of antigen receptor variability, allowing a multitude of B cell receptor (BCR) specificities in a polyclonal population that is constantly renewed from a pool of lymphocytes progenitors [1]
BCR signaling is fundamental for survival, strong signaling that is associated with self-antigen stimulation induces V gene edition or cell death, a quality control mechanism that prevents or reduces the chance of producing high affinity autoantibodies [8,9,10]

Summary

Introduction

The adaptive immune system has evolved to become a highly efficient surveillance system. BCR-specific clonal expansion from a naive repertoire is an ancient and fundamental activity of adaptive immunity. B cells are generated in the bone marrow and rely on the constant signaling of the bone marrow BCR [2]. This signaling may occur through antigenic stimulation from the nearby milieu [3,4,5] or antigenic-independent tonic signals [6,7]. BCR signaling is fundamental for survival, strong signaling that is associated with self-antigen stimulation induces V gene edition or cell death, a quality control mechanism that prevents or reduces the chance of producing high affinity autoantibodies [8,9,10]. The resulting B-cells that leave the bone marrow produce the immature naive repertoire, which is further maturated in the periphery, yielding the circulating antibodies that protect and maintain homeostasis in the animal

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