Antibody repertoire development in fetal and neonatal piglets

• Published in: Molecular immunology 2011-12, Vol.49 (3), p.483-494
• Main Authors: Butler, John E., Sun, Xuizhu, Wertz, Nancy, Lager, Kelly M., Chaloner, Kathryn, Urban, Joseph, Francis, David L., Nara, Peter L., Tobin, Gregory J.
• Format: Article
• Language: English
• Subjects: Antigen independent; Developmental immunology; Piglet model; VH gene usage
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2011.09.018

► Vertical studies of VH gene usage span 80% of fetal life and extend to 5 months postpartum. ► Seven VH genes account for >90% of the pre-immune repertoire and usage is unrelated to location in the genome ► Proportional usage of the majority of VH genes remains constant during fetal and postnatal life. ► Repertoire diversification after birth is by SHM of the same VH genes that comprise the pre-immune repertoire. ► Changes in proportional VH gene usage are age not antigen dependent. Usage of variable region gene segments during development of the antibody repertoire in mammals is unresolved in part because of the complexity of the locus in mice and humans and the difficulty of distinguishing intrinsic from extrinsic influences in these species. We present the first vertical studies on VH usage that spans the fetal and neonatal period using the piglet model. We tracked VH usage in DNA rearrangements and in VDJ transcripts throughout 75 days of gestation (DG) in outbred fetuses, thereafter in outbred germfree and colonized isolator piglets, isolator piglets infected with swine influenza and in conventionally reared nematode-infected adults. Seven VH genes account for >90% of the pre-immune repertoire which is the same among tissues and in both transcripts and DNA rearrangements. Statistical modeling supports the view that proportional usage of the major genes remains constant during fetal life and that postnatal usage ranking is similar to that during fetal life. Changes in usage ranking are developmental not antigen dependent. In this species exposure to environmental antigens results in diversification of the repertoire by somatic hypermutation of the same small number of VH genes that comprise the pre-immune repertoire, not by using other VH gene available in the germline. Therefore in swine a small number of VH genes shape the antibody repertoire throughout life questioning the need for extensive VH polygeny.