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Positive selection of natural poly-reactive B cells in the periphery occurs independent of heavy chain allelic inclusion.

ABSTRACT: Natural autoreactive B cells are important mediators of autoimmune diseases. Receptor editing is known to play an important role in both central and peripheral B cell tolerance. However, the role of allelic inclusion in the development of natural autoreactive B cells is not clear. Previously, we generated ? chain (TgV(H)3B4I) and ?/? chains (TgV(H/L)3B4) transgenic mice using transgene derived from the 3B4 hybridoma, which produce poly-reactive natural autoantibodies. In this study, we demonstrate that a considerable population of B cells edited their B cells receptors (BCRs) via light chain or heavy chain allelic inclusion during their development in TgV(H)3B4I mice. Additionally, allelic inclusion occurred more frequently in the periphery and promoted the differentiation of B cells into marginal zone or B-1a cells in TgV(H)3B4I mice. B cells from TgV(H/L)3B4 mice expressing the intact transgenic 3B4 BCR without receptor editing secreted poly-reactive 3B4 antibody. Interestingly, however, B cell that underwent allelic inclusion in TgV(H)3B4I mice also produced poly-reactive autoantibodies in vivo and in vitro. Our findings suggest that receptor editing plays a minor role in the positive selection of B cells expressing natural poly-reactive BCRs, which can be positively selected through heavy chain allelic inclusion to retain their poly-reactivity in the periphery.

SUBMITTER: Xing Y

PROVIDER: S-EPMC4437983 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Positive selection of natural poly-reactive B cells in the periphery occurs independent of heavy chain allelic inclusion.

Xing Ying Y Ji Qiuhe Q Lin Ying Y Fu Meng M Gao Jixin J Zhang Ping P Hu Xingbin X Feng Lei L Liu Yufeng Y Han Hua H Li Wei W

PloS one 20150519 5

Natural autoreactive B cells are important mediators of autoimmune diseases. Receptor editing is known to play an important role in both central and peripheral B cell tolerance. However, the role of allelic inclusion in the development of natural autoreactive B cells is not clear. Previously, we generated μ chain (TgV(H)3B4I) and μ/κ chains (TgV(H/L)3B4) transgenic mice using transgene derived from the 3B4 hybridoma, which produce poly-reactive natural autoantibodies. In this study, we demonstra ...[more]

PMID: 25993514

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Project description:The study of genomic regions that contain gene copies and structural variation is a major challenge in modern genomics. Unlike variation involving single nucleotide changes, data on the variation of copy number is difficult to collect and few tools exist for analyzing the variation between individuals. The immunoglobulin heavy variable (IGHV) locus, which plays an integral role in the adaptive immune response, is an example of a complex genomic region that varies in gene copy number. Lack of standard methods to genotype this region prevents it from being included in association studies and is holding back the growing field of antibody repertoire analysis. Here we develop a method that takes short reads from high-throughput sequencing and outputs a genetic profile of the IGHV locus with the read coverage depth and a putative nucleotide sequence for each operationally defined gene cluster. Our operationally defined gene clusters aim to address a major challenge in studying the IGHV locus: the high sequence similarity between gene segments in different genomic locations. Tests on simulated data demonstrate that our approach can accurately determine the presence or absence of a gene cluster from reads as short as 70 bp. More detailed resolution on the copy number of gene clusters can be obtained from read coverage depth using longer reads (e.g., ≥ 100 bp). Detail at the nucleotide resolution of single copy genes (genes present in one copy per haplotype) can be determined with 250 bp reads. For IGHV genes with more than one copy, accurate nucleotide-resolution reconstruction is currently beyond the means of our approach. When applied to a family of European ancestry, our pipeline outputs genotypes that are consistent with the family pedigree, confirms existing multigene variants and suggests new copy number variants. This study paves the way for analyzing population-level patterns of variation in IGHV gene clusters in larger diverse datasets and for quantitatively handling regions of copy number variation in other structurally varying and complex loci.

Dataset Information

Positive selection of natural poly-reactive B cells in the periphery occurs independent of heavy chain allelic inclusion.

Publications

Positive selection of natural poly-reactive B cells in the periphery occurs independent of heavy chain allelic inclusion.

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