IgA Response in Preterm Neonates Shows Little Evidence of Antigen-Driven Selection

Abstract

After birth, contact to environmental antigens induces the production of IgA, which represents a first line of defense for the neonate. We sought to characterize the maturation of the repertoire of IgA H chain transcripts in circulating blood B cells during human ontogeny. We found that IgA H chain transcripts were present in cord blood as early as 27 weeks of gestation and that the restrictions of the primary antibody repertoire (IgM) persisted in the IgA repertoire. Thus, B cells harboring more “mature” VH regions were not preferred for class switch to IgA. Preterm and term neonates expressed a unique IgA repertoire, which was characterized by short CDR-H3 regions, preference of the JH proximal DH7-27 gene segment, and very few somatic mutations. During the first postnatal months, these restrictions were slowly released. Preterm birth did not measurably accelerate the maturation of the IgA repertoire. At a postconceptional age of 60 weeks, somatic mutation frequency of IgA H chain transcripts reached 25% of the adult values but still showed little evidence of antigen-driven selection. These results indicate that similar to IgG, the IgA repertoire expands in a controlled manner after birth. Thus, the IgA repertoire of the newborn has distinctive characteristics that differ from the adult IgA repertoire. These observations might explain the lower affinity and specificity of neonatal IgA antibodies, which could contribute to a higher susceptibility to infections and altered responses to vaccinations, but might also prevent the development of autoimmune and allergic diseases.

The Regulation of IgA Production

“…However, selective IgA deficiency has a mild phenotype in humans and experimental animals; thus it can be reasonably compensated by mucosal IgM and other innate and adaptive responses. The IgA repertoire is progressively affinity matured during aging (Rogosch et al, 2012;Lindner et al, 2012), probably mainly as a direct response to antigenic stimulation from the intestinal lumen (Barone et al, 2011;Benckert et al, 2011). This supports the idea that conventional GC reactions in PP are generating much of the IgA repertoire.…”

“…Although most plasma cells in adult mice and humans are SHM-IgAs (Barone et al, 2011;Benckert et al, 2011), likely largely generated in PP GCs, neonatal humans and mice have a relatively undiversified IgA repertoire (Bergqvist et al, 2010;Rogosch et al, 2012). Moreover, mice lacking PPs and/or GCs contain almost normal numbers of IgA plasma cells in their gut LP (Renshaw et al, 1994;Bergqvist et al, 2006;Tsuji et al, 2008;Yamamoto et al, 2000;Bergqvist et al, 2010).…”

IgG4 and IgE Transcripts in Childhood Allergic Asthma Reflect Divergent Antigen-Driven Selection

“…As evidence of Ag-driven selection, both IgG4 and IgE transcripts exhibited a similar degree of clonal restriction, which was also in the range of IgA transcripts (58). However, IgG4 transcripts harbored more somatic mutations than IgE transcripts.…”

The Mucosal B Cell System

“…This feature is a characteristic of the IgA repertoire of human neonates (Rogosch et al, 2012), as also reflected in neonatal secretions such as saliva (Nogueira et al, 2012). This situation is followed postnatally by a slow immune maturation with an SHM frequency of IgA V H gene transcripts up to 25% of the adult level at around 5 months of age (Rogosch et al, 2012).…”

“…This situation is followed postnatally by a slow immune maturation with an SHM frequency of IgA V H gene transcripts up to 25% of the adult level at around 5 months of age (Rogosch et al, 2012). Both the duodenal and the parotid PC frequency of IgA V H mutations of adults is much higher than that in adult human spleen, apparently because of the constant antigenic pressure on MALT (Dunn-Walters et al, 2000).…”