Maturation of the Human Immunoglobulin Heavy Chain Repertoire With Age.

Marie Ghraichy,Enkelejda Miho,Jana Pachlopnik Schmid,Mike Recher,Charlotte M Deane,Dominic F Kelly,Aleksandr Kovaltsuk,Jacob D Galson,Annaïse J Jauch,Johannes Trück,Valentin Von Niederhäusern

doi:10.3389/fimmu.2020.01734

Abstract

B cells play a central role in adaptive immune processes, mainly through the production of antibodies. The maturation of the B cell system with age is poorly studied. We extensively investigated age-related alterations of naïve and antigen-experienced immunoglobulin heavy chain (IgH) repertoires. The most significant changes were observed in the first 10 years of life, and were characterized by altered immunoglobulin gene usage and an increased frequency of mutated antibodies structurally diverging from their germline precursors. Older age was associated with an increased usage of downstream IgH constant region genes and fewer antibodies with self-reactive properties. As mutations accumulated with age, the frequency of germline-encoded self-reactive antibodies decreased, indicating a possible beneficial role of self-reactive B cells in the developing immune system. Our results suggest a continuous process of change through childhood across a broad range of parameters characterizing IgH repertoires and stress the importance of using well-selected, age-appropriate controls in IgH studies.

Highlights

B cells play a central role in physiological adaptive immune processes and exert their main effector function through production of antibodies [1]
Immunoglobulin heavy (IgH) and light chains of a B cell receptor (BCR) are further diversified through rounds of somatic hypermutation (SHM) leading to affinity maturation whereby B cells with improved antigen-binding properties are selected in the germinal center
We found an extensive maturation of B cell responses in the first 10 years of life consistent with what would be expected with cumulative antigen exposure and a generally more developed and stable B cell compartment in older individuals

Summary

Introduction

B cells play a central role in physiological adaptive immune processes and exert their main effector function through production of antibodies [1]. The heavy and light chains of the B cell receptor (BCR) are generated in the bone marrow by recombining individual variable (V), diversity (D), and joining (J) genes through a process called VDJ recombination. Immunoglobulin heavy (IgH) and light chains of a BCR are further diversified through rounds of somatic hypermutation (SHM) leading to affinity maturation whereby B cells with improved antigen-binding properties are selected in the germinal center. Class switch recombination (CSR) is initiated following antigen encounter, causing a change in the IgH constant region of the BCR and in its effector function

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