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J Immunol. 2017 May 15;198(10):3963-3977. doi: 10.4049/jimmunol.1700133. Epub 2017 Apr 24.

Mechanisms That Shape Human Antibody Repertoire Development in Mice Transgenic for Human Ig H and L Chain Loci.

Author information

1
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
2
Pediatric Immunology and Allergology, Department of Pediatrics, Philipps-University Marburg, D-35033 Marburg, Germany.
3
Klinik für Kinder-und Jugendmedizin, Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg, D-35033 Marburg, Germany.
4
Department of General Pediatrics and Neonatology, Saarland University Medical School, D-66421 Homburg, Germany.
5
INSERM & Université Paris Diderot, Sorbonne Paris Cité Centre Viggo Petersen, Hôpital Lariboisière, 75475 Paris, France; and.
6
AMPEL BioSolutions, Charlottesville, VA 22911 peterlipsky@comcast.net.

Abstract

To determine the impact of the milieu on the development of the human B cell repertoire, we carried out a comprehensive analysis of productive and nonproductive Ig gene rearrangements from transgenic mice engineered to express single copies of the unrearranged human H chain and L chain Ig gene loci. By examining the nonproductive repertoire as an indication of the immediate product of the rearrangement machinery without an impact of selection, we discovered that the distribution of human rearrangements arising in the mouse was generally comparable to that seen in humans. However, differences between the distribution of nonproductive and productive rearrangements that reflect the impact of selection suggested species-specific selection played a role in shaping the respective repertoires. Although expression of some VH genes was similar in mouse and human (IGHV3-23, IGHV3-30, and IGHV4-59), other genes behaved differently (IGHV3-33, IGHV3-48, IGHV4-31, IGHV4-34, and IGHV1-18). Gene selection differences were also noted in L chains. Notably, nonproductive human VH rearrangements in the transgenic mice expressed shorter CDRH3 with less N addition. Even the CDRH3s in the productive rearrangements were shorter in length than those of the normal human productive repertoire. Amino acids in the CDRH3s in both species showed positive selection of tyrosines and glycines, and negative selection of leucines. The data indicate that the environment in which B cells develop can affect the expressed Ig repertoire by exerting influences on the distribution of expressed VH and VL genes and by influencing the amino acid composition of the Ag binding site.

PMID:
28438896
DOI:
10.4049/jimmunol.1700133
[Indexed for MEDLINE]
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