Class switch from μ to δ is mediated by homologous recombination between σ<sub>μ</sub> and σ<sub>μ</sub> sequences in human immunoglobulin gene loci

Yasui, Hisashi; Akahori, Yasushi; Hirano, Masami; Yamada, Kazumasa; Kurosawa, Yoshikazu

doi:10.1002/eji.1830190808

Cited by 43 publications

(28 citation statements)

References 33 publications

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“…Of particular interest to this study is a lineage of B cells that we refer to as "Cδ-CS" for "Cδ class-switched." Unlike normal Cµ-versus-Cδ usage involving differential splicing of a single VDJ-Cµ-Cδ transcript, Cδ-CS B cells actually undergo class switch from Cµ to Cδ at the genetic level using cryptic switch regions between the Cµ and Cδ exons (5,6). Cδ-CS GC cells can differentiate into IgDsecreting PCs (7) and memory cells (8) and have the unusual characteristics that they use more than 90% λ light chains (7) and accumulate more somatic mutations than any other B cell population (9), and we have shown this population has the highest frequency of receptor-edited heavy chain V regions (10).…”

Section: Introductionmentioning

confidence: 99%

Human immunoglobulin selection associated with class switch and possible tolerogenic origins for Cδ class-switched B cells

Zheng¹,

Wilson²,

Wang³

et al. 2004

J. Clin. Invest.

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Current paradigms of peripheral B cell selection suggest that autoreactive B cells are controlled by clonal deletion, anergy, and developmental arrest. We report that changes to the human antibody repertoire likely resulting from these mechanisms both for a well-characterized autoreactivity from antibodies encoded by the V H 4-34 gene and for other hallmarks of an autoreactive repertoire are apparent mainly for class-switched B cells and not for IgM germinal center, IgM memory, or IgM plasma cells. Other possible indicators of autoreactivity found selected with immunoglobulin class include J H 6 gene segment usage, increased frequency of B cells with long third hypervariable regions, and distal J κ κ gene segment bias. Of particular interest is the finding that B cells with these same characteristics are selected into the lineage of B cells that have undergone the unusual class switch from constant region Cµ µ to Cδ δ (Cδ δ-CS). The Cδ δ-CS population also displays an increased frequency of charged amino acids localized to the complementarity-determining regions, further suggesting autoreactivity, and evidence is presented that these B cells had undergone extensive receptor editing. Thus, the Cδ δ-CS lineage may be a "sink" for B cells harboring autoreactive specificities in normal humans. A model for a new tolerizing mechanism that could account for the Cδ δ-CS lineage is presented. 1188The Conflict of interest:The authors have declared that no conflict of interest exists. A To ensure accuracy, particular sequences were excluded from certain analyses (Methods). B Studies for which indicated populations were analyzed. Asterisks indicate the studies in which the various populations were included. sc, single-cell.

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Section: Introductionmentioning

confidence: 99%

Human immunoglobulin selection associated with class switch and possible tolerogenic origins for Cδ class-switched B cells

Zheng¹,

Wilson²,

Wang³

et al. 2004

J. Clin. Invest.

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“…Gene conversion is important in generating Ab diversity in birds and rabbits (10,11), and may also play a role in the diversification of some mammalian Ab responses (12)(13)(14)(15)(16)(17)(18)(19)(20). Both gene conversion and crossing over occur between Ig H chain constant segments within regions of shared homology (21)(22)(23)(24). The process of mammalian somatic hypermutation is thought to involve strand invasion, homologous pairing, and copying of sequences from the sister chromatid, similar to the process of gene conversion (25).…”

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confidence: 99%

Evidence for the Murine IgH μ Locus Acting as a Hot Spot for Intrachromosomal Homologous Recombination

Raynard

Read

Baker

2002

The Journal of Immunology

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Homologous recombination accomplishes the exchange of genetic information between two similar or identical DNA duplexes. It can occur either by gene conversion, a process of unidirectional genetic exchange, or by reciprocal crossing over. Homologous recombination is well known for its role in generating genetic diversity in meiosis and, in mitosis, as a DNA repair mechanism. In the immune system, the evidence suggests a role for homologous recombination in Ig gene evolution and in the diversification of Ab function. Previously, we reported the occurrence of homologous recombination between repeated, donor and recipient alleles of the Ig H chain μ gene C (Cμ) region residing at the Ig μ locus in mouse hybridoma cells. In this study, we constructed mouse hybridoma cell lines bearing Cμ region heteroalleles to learn more about the intrachromosomal homologous recombination process. A high frequency of homologous recombination (gene conversion) was observed for markers spanning the entire recipient Cμ region, suggesting that recombination might initiate at random sites within the Cμ region. The Cμ region heteroalleles were equally proficient as either conversion donors or recipients. Remarkably, when the same Cμ heteroalleles were tested for recombination in ectopic genomic positions, the mean frequency of gene conversion was reduced by at least 65-fold. These results are consistent with the murine IgH μ locus behaving as a hot spot for intrachromosomal homologous recombination.

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“…It remains unclear as to why it has evolved for humans but not for mice. ADDENDUM Yasui et al (63) have also observed 442/443-bp-repeatmediated recombination in two IgD myelomas from bone marrow. This significantly enhances the generality of the observation reported here.…”

Section: Discussionmentioning

confidence: 93%

Immunoglobulin D switching can occur through homologous recombination in human B cells.

White¹,

Word²,

Humphries³

et al. 1990

Mol. Cell. Biol.

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Prototypical class switching in mouse and human immunoglobulin heavy chains occurs through recombination of tandem blocks of short repeats located 5' to each heavy chain constant region (CH) except C8. Deletion of C, in immunoglobulin D (IgD)-secreting murine plasmacytomas occurs illegitimately. We demonstrate here that in human IgD-secreting myeloma cells freshly isolated from patient bone marrow and in normal peripheral blood B lymphocytes, an IgD switch can occur through homologous recombination of a direct repeat consisting of a 442-bp sequence 1.5 kbp 3' of the JH complex and a 443-bp sequence that is duplicated almost perfectly (96% similarity) 1.7 kbp 5' of the Cc, gene (442/443-base-pair [bp] repeat). This homologous recombination mechanism is not exclusive for IgD switching, since C^deletion endpoints in two established IgD-secreting myeloma cell lines fall outside the 442/443-bp repeat. The 442/443-bp mediated recombination shows cell type specificity, and we propose that it represents a unique mode for increased levels of IgD secretion in humans.The immunoglobulin heavy chain locus is located on chromosome 14 in humans. A heavy chain variable region (VH) gene is composed of one member from each of three gene families designated variable (V), diversity (D), and joining (J). The heavy chain constant region (CH) genes are located downstream of these VH genes in the order C t-CS-Cy3-cyl-C+£-Cal-CyC-y2-cy4-Ce,C.2 (3,12,25). In the primary immune response, the VH gene is transcribed along with the nearest downstream constant region gene, C, , to form a ,u heavy chain mRNA (50). During further B-cell differentiation, however, a given B cell and its progeny may shift from the production of immunoglobulin M (IgM) to one of the other heavy chain isotypes by the expression of downstream CH genes (reviewed in references 28 and 53). Studies primarily with myelomas have indicated that the switch phenomenon is most often the result of an intrachromosomal rearrangement between switch site (S) sequences located upstream of the heavy chain genes. Upon switching, the assembled VDJ gene is brought adjacent to the heavy chain gene to be expressed, resulting in the deletion of the intervening CH genes. Studies, at the DNA sequence level, of mice and humans have demonstrated that these S regions consist of 2 to 10 kilobases (kb) of tandem arrays of repeated sequences (8, 12, 20, 34-36, 41, 42, 48, 56-58). This description of the heavy chain class switch applies to all antibody classes except IgD. To date, the only biological function attributed to IgD with any certainty is serving as an antigen receptor along with IgM on the surface of virgin B cells (22,26,27,33 within the JH-C,, intron some 1.5 kbp 5' of S,, (30).To determine whether either of these sequences is implicated in the secretion of IgD, we have examined primary IgD-secreting myelomas from bone marrow, two established IgD-secreting myeloma cell lines, and normal B lymphocytes from peripheral blood. We found evidence for homologous recombination of the repeat co...

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Class switch from μ to δ is mediated by homologous recombination between σ_μ and σ_μ sequences in human immunoglobulin gene loci

Cited by 43 publications

References 33 publications

Human immunoglobulin selection associated with class switch and possible tolerogenic origins for Cδ class-switched B cells

Human immunoglobulin selection associated with class switch and possible tolerogenic origins for Cδ class-switched B cells

Evidence for the Murine IgH μ Locus Acting as a Hot Spot for Intrachromosomal Homologous Recombination

Immunoglobulin D switching can occur through homologous recombination in human B cells.

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Class switch from μ to δ is mediated by homologous recombination between σμ and σμ sequences in human immunoglobulin gene loci

Cited by 43 publications

References 33 publications

Human immunoglobulin selection associated with class switch and possible tolerogenic origins for Cδ class-switched B cells

Human immunoglobulin selection associated with class switch and possible tolerogenic origins for Cδ class-switched B cells

Evidence for the Murine IgH μ Locus Acting as a Hot Spot for Intrachromosomal Homologous Recombination

Immunoglobulin D switching can occur through homologous recombination in human B cells.

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Class switch from μ to δ is mediated by homologous recombination between σ_μ and σ_μ sequences in human immunoglobulin gene loci