Antibodies in a heavy chain knock-in mouse exhibit characteristics of early heavy chain rearrangement.
Studies in autoantibody transgenic mice have demonstrated receptor editing rearrangements at Ab H and L chain loci. However, the physiologic role of H chain editing (V(H) replacement and rearrangement on the second allele) has been called into question. It is unclear if additional rounds of H chain rearrangement are driven by BCR specificity. In this study, we analyze the manner in which B cells undergo additional H chain rearrangements in an anti-DNA H chain knock-in mouse, B6.56R. We find that rearrangements in 56R(+) B cells tend to involve the D gene locus on both alleles and the most J(H)-proximal V(H) gene segments on the endogenous allele. As a result, some B cells exhibit V(D)J rearrangements on both H chain alleles, yet allelic exclusion is tightly maintained in mature 56R B cells. As B cells mature, a higher proportion expresses the nontransgenic H chain allele. Rearrangements on both H chain alleles exhibit junctional diversity consistent with TdT-mediated N-addition, and TdT RNA is expressed exclusively at the pro-B cell stage in B6.56R. Collectively, these findings favor a single, early window of H chain rearrangement in B6.56R that precedes the expression of a functional BCR. B cells that happen to successfully rearrange another H chain may be favored in the periphery.
Yunk
Lenka
L
Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
Meng
Wenzhao
W
Cohen
Philip L
PL
Eisenberg
Robert A
RA
Luning Prak
Eline T
ET
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D055879:Gene Knock-In Techniques / Q000379:methods; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics*; D007072:Immunoglobulin D / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics*; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D000974:Antibodies, Antinuclear; D007072:Immunoglobulin D; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell