Autoantibody selection and production in early human life

Abstract

Natural antibodies are autoreactive/polyreactive antibodies believed to be secreted in the absence of xenoantigens. The origin and functional role of this limited and selective autoimmunity are not clear, nor is the specificity and range of autoantigens that drive the development of B cells producing natural antibodies. In this issue of the JCI, Merbl et al. report that in utero, humans generate natural IgM and IgA antibodies that recognize a uniform set of autoantigens (see the related article beginning on page 712), some of which are associated with autoimmune diseases. The authors postulate that this "autoimmunity" at birth favors the emergence of autoimmune diseases in later life. We present a molecular basis for the limited and common repertoire of antibodies produced by fetal B cells, which may be distinct from the abnormalities in B cell development described in patients with autoimmune diseases.

Figure 1. Restricted IgH gene segment recombination during fetal B cell development.

Typical V(D)J recombination events in fetal liver (A) and adult bone marrow (B) are depicted. Fetal liver B cells preferentially rearrange variable V_H6–1 and diversity D7–27 segments located at the 3′ end of their respectable loci, often combined with the J_H3 gene segment as shown. The limited nontemplate nucleotide additions between V_H-D and D-J_H joining regions (red boxes) result in the generation of short IgH CDR3s in early life. Restricted V(D)J recombination during fetal life may result in the production of common natural antibodies recognizing the uniform set of autoantigens identified by Merbl et al. in different individuals (6). In contrast, B cell precursors in adults rarely use V_H6–1 and D7–27 segments, but rather use other Ig gene segments such as V_H3–23 and D3–3, potentially associated with J_H6 as shown. The extensive nontemplate nucleotide additions (red boxes) may result in the generation of long IgH CDR3s, which — together with diverse V, D, and J segment usage — encode a broader antibody repertoire.