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Title: Antibody repertoire development in fetal and neonatal piglets. XXI. VH usage remains constant during development in fetal piglets and postnatally in piglets exposed to environmental antigen

item BUTLER, JOHN - University Of Iowa
item SUN, X - University Of Iowa
item WERTZ, NANCY - University Of Iowa
item Lager, Kelly
item CHALONER, L - University Of Iowa
item Urban, Joseph
item NARA, P - Biological Mimetics, Inc
item TOBIN, G - Biological Mimetics, Inc

Submitted to: Molecular Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/24/2011
Publication Date: 12/1/2011
Citation: Butler, J.E., Sun, X., Wertz, N., Lager, K.M., Chaloner, L., Urban Jr., J., Francis, D.L., Nara, P.L., Tobin, G.J. 2011. Antibody repertoire development in fetal and neonatal piglets XXI. Usage of most VH genes remains constant during fetal and postnatal development. Molecular Immunology. 49(3):483-494.

Interpretive Summary: The development of the mammalian immune system is a complicated process that begins in the first stages of fetal development. After birth, the process continues to a greater or lesser degree for life. The immune system can be divided into two categories; one is the part that develops antibodies, and the second involves specific cells that circulate in the blood. Ideally, these two components work together to provide a balanced protective immune response against disease. This paper characterizes the development of the antibody producing part of the pig's immune system from the first few weeks of fetal development through the first few months of life. Based on mouse and human fetal studies, the early stages of antibody development in the pig is similar. However, the mechanism for the adaptation of the antibody response after birth appears to be different in the pig when compared to mice and humans. This report contributes to the basic understanding of the development of the immune system in mammals. Moreover, this knowledge can provide insight into how certain pathogens might negatively affect the pig's immune system.

Technical Abstract: 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 have addressed this using a highly controlled animal model with a manageable number of VH genes, two functional DH genes and one JH. We tracked VH usage in DNA rearrangements and in VDJ transcripts throughout 75 days of gestation (DG), thereafter in isolator piglets reared germfree, colonized and virus-infected and in conventional adults. We show that the pattern of using five VH genes to form >70% of the pre-immune repertoire persists postnatally in all treatment groups. The repertoire diversification index (RDI) after birth parallels the increased frequency of somatic hypermutation (SHM) in the same small constellation of major VH genes that formed the pre-immune repertoire. This was also paralleled by an increase in serum Ig levels. The frequency of SHM in germfree isolators piglets was the same as in fetal animals. We conclude that: (a) an intrinsic program controls VH gene usage that is independent of age and environmental antigens and (b) repertoire diversification is by SHM of the major genes of the pre-immune repertoire not by the use of other VH genes in the genome. These findings leave unexplained why: (a) the genomic repertoire of eutherian mammals contains so many seldom-used VH genes and (b) certain VH genes are the chosen few.