Biased usage of two restricted V<sub>H</sub> gene segments in V<sub>h</sub> replacement

Komori, Toshihisa; Minami, Y; Sakato, Nobuo; Sugiyama, Haruo

doi:10.1002/eji.1830230233

Cited by 9 publications

(9 citation statements)

References 37 publications

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“…This suggests that certain V H genes may be favored in the replacement process. This is consistent with the findings that discrete V H genes were nonstochastically involved in spontaneous 71 and induced 61 V H replacement events in murine B cell lines.…”

Section: Discussionsupporting

confidence: 92%

Immunoglobulin Heavy Chain Variable Region Gene Replacement as a Mechanism for Receptor Revision in Rheumatoid Arthritis Synovial Tissue B Lymphocytes

Itoh

Meffre

Albesiano

et al. 2000

The Journal of Experimental Medicine

120

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Mature B cells can alter their antibody repertoires by several mechanisms, including immunoglobulin heavy chain variable region (VH) replacement. This process changes the antigen combining site by replacing a portion of the original VH/diversity/heavy chain joining region (VHDJH) rearrangement with a corresponding portion of a new VH segment. This exchange can involve cryptic heptamer-like sequences embedded in the coding regions of VH genes.While studying the B lymphocytes that expand in the synovial tissues of patients with rheumatoid arthritis (RA), clones with VHDJH variants that were apparently generated by VH replacement were identified with surprising frequency (∼8%). Examples of multiple independent VH replacement events occurring in distinct progeny clones were also identified. These secondary VH rearrangements were documented at both the cDNA and genomic DNA levels and involved several heptamer-like sequences at four distinct locations within VH (three sites in framework region 3 and one in complementarity determining region 2). The identification of blunt-ended double-stranded DNA breaks at the embedded heptamers and the demonstration of recombinase activating gene (RAG) expression suggested that these rearrangements could occur in the synovial tissues, presumably in pseudo-germinal centers, and that they could be mediated by RAG in a recognition signal sequence–specific manner. The presence of VH mutations in the clones that had undergone replacement indicated that these B cells were immunocompetent and could receive and respond to diversification signals. A relationship between these secondary VH gene rearrangements and the autoimmunity characteristic of RA should be considered.

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Section: Discussionsupporting

confidence: 92%

Immunoglobulin Heavy Chain Variable Region Gene Replacement as a Mechanism for Receptor Revision in Rheumatoid Arthritis Synovial Tissue B Lymphocytes

Itoh

Meffre

Albesiano

et al. 2000

The Journal of Experimental Medicine

120

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“…Two principle mechanisms have been implicated in the occurrence of multiple IGH gene rearrangements in ALL: (1) the persistent activity of the recombinase machinery in the immature B cells in ALL; [28][29][30] and (2) duplication of chromosome 14 (involving the chromosome band 14q32, the locus harboring the IGH) 13 although the link between these two events has not been fully explored to date. The former results in VH replacement to VNDNJ pre-existing rearrangements 31,32 or in an 'open-and-shut' VDJ modification as previously described in ALL patients. 15,[33][34][35][36] V gene replacements can be distinguished into two main groups: (1) ongoing VH to DH-JH joining, when the part of a D segment and the D-J junction is shared by two or more rearrangements, but novel N nucleotides are inserted at the V-D junction; and (2) true VH replacements, with N-D-N-J junction preserved.…”

Section: Introductionmentioning

confidence: 78%

Heterogeneity of VH–JH gene rearrangement patterns: an insight into the biology of B cell precursor ALL

et al. 2001

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Oligoclonal B cell proliferation, as defined by the presence of more than one leukemic clone, has been detected in approximately 20% to 30% of patients with acute lymphoblastic leukemia (ALL) using PCR or Southern blotting. An accurate assessment of these populations is required to avoid false negative measurements of minimal residual disease (MRD) in follow-up bone marrow (BM) samples of ALL patients. In this study, we analysed 29 ALL patients with two or more immunoglobulin heavy (IGH) chain gene rearrangements in the presentation samples using IGH fingerprinting PCR and sequence analysis. Thirty-nine (51%) of 76 sequences (from 15 patients), shared no VNDNJ homology (ie different CDR3 regions). In the remaining 14 patients, at least two related VH sequences were identified in each patient (identical DNJ sequences). Numerical abnormalities of chromosome 14 was detected in 10 patients. Eight patients were analysed at presentation and relapse. In four of them, expansion of a minor presentation-clone was detected at relapse while the major presentation clone disappeared, confirming 'subclonal evolution'. Finally, in our cohort of patients, the presence of related or unrelated IGH clones did not influence overall survival. Leukemia (2001) 15, 1527-1536.

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“…Gene replacement . While the exact Ins/Del mechanism involving palindromes remains unknown, the high incidence of the embedded RSS at V H H ‐FR3 abutting the Del/Ins region 74 ± 1 [Figure 7D and Ins at position 75A of two llama V H H s (Vu et al ., 1997)] supports the gene replacement mechanism (Reth et al ., 1986) involving recombination‐activating gene (RAG) proteins as observed in human and mouse (Kleinfield et al ., 1986; Komori et al ., 1993). The involvement of a RAG‐like activity to initiate the gene replacement predicts a DNA cleavage two bases upstream of the heptamer sequence (Ramsden et al ., 1996).…”

Section: Discussionmentioning

confidence: 99%

“…We noted that some V H and Somatic diversification results from different mechanisms V H H cDNAs employ this D element (Figure 4). In addition, including gene conversion, and somatic hypermutation our cDNA database also contains V H s and V H Hs that make (Wagner and Neuberger, 1996;. use of the same J H element.…”

Section: Identical D and J H Segments In V H And V H H Cdnas A Germli...mentioning

confidence: 99%

“…

and are conserved during evolution (Kabat et al, 1991). The CDR3 of the V H H is longer on average than that of The antigen-binding site of the camel heavy-chain a V H domain (Vu et al, 1997), and is often constrained antibodies devoid of light chain consists of a single by an interloop disulfide bond (Davies and Riechmann, variable domain (V H H) that obviously lacks the V H Desmyter et al, 1996). V L combinatorial diversity.

…”

mentioning

confidence: 99%

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Camel heavy-chain antibodies: diverse germline VHH and specific mechanisms enlarge the antigen-binding repertoire

Nguyen

Hamers

Wyns

et al. 2000

EMBO J

250

200

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and are conserved during evolution (Kabat et al., 1991). The CDR3 of the V H H is longer on average than that of The antigen-binding site of the camel heavy-chain a V H domain (Vu et al., 1997) et al., 1998). This is surprising, sequences were identified, encoded by 42 and 50 since the active site of enzymes has a low antigenicity for different genes, respectively. Sequence comparison conventional Abs (Novotny, 1991). Thus, the HCAbs indicates that the V H Hs evolved within the V H subgroup recognize a broad range of epitopes, some of which differ III. Nevertheless, the V H H germline segments are from those for conventional Abs. highly diverse, leading to a broad structural repertoire Previously, we identified germline V H and V H H segments of the antigen-binding loops. Seven V H H subfamilies indicating that the variable domain of the HCAbs is were recognized, of which five were confirmed to be encoded by a distinct set of V genes (Nguyen et al., expressed in vivo. Comparison of germline and cDNA 1998). In this study, we investigate the potential V H H sequences demonstrates that the rearranged V H Hs are germline repertoire to gain insight into the ways by which extensively diversified by somatic mutation processes, the dromedary HCAbs acquire a complex repertoire of leading to an additional hypervariable region and a Ag-binding sites. In conventional Abs, the diversity of high incidence of nucleotide insertions or deletions.the Ag-binding site is generated at multiple levels. The These diversification processes are driven by hyper-V H is generated by assembling variable (V), diversity (D) mutation and recombination hotspots embedded in and joining (J) elements (Tonegawa, 1983), in which the the V H H germline genes at the regions affecting the V-gene segment encodes the CDR1 and CDR2; the CDR3 structure of the antigen-binding loops.is generated by the V-D-J joining. In this joining process, Keywords: antigen-binding repertoire/camel heavy-chain great sequence variation is introduced by non-template antibody/gene replacement/germline V H /hypermutation addition of nucleotides at the V-D and D-J junctions hotspots (junctional diversity). Random association of a V H and a V L (combinatorial diversity) generates an immensely diverse Ag-binding repertoire. Additional diversification

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Biased usage of two restricted V_H gene segments in V_h replacement

Cited by 9 publications

References 37 publications

Immunoglobulin Heavy Chain Variable Region Gene Replacement as a Mechanism for Receptor Revision in Rheumatoid Arthritis Synovial Tissue B Lymphocytes

Immunoglobulin Heavy Chain Variable Region Gene Replacement as a Mechanism for Receptor Revision in Rheumatoid Arthritis Synovial Tissue B Lymphocytes

Heterogeneity of VH–JH gene rearrangement patterns: an insight into the biology of B cell precursor ALL

Camel heavy-chain antibodies: diverse germline VHH and specific mechanisms enlarge the antigen-binding repertoire

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Biased usage of two restricted VH gene segments in Vh replacement

Cited by 9 publications

References 37 publications

Immunoglobulin Heavy Chain Variable Region Gene Replacement as a Mechanism for Receptor Revision in Rheumatoid Arthritis Synovial Tissue B Lymphocytes

Immunoglobulin Heavy Chain Variable Region Gene Replacement as a Mechanism for Receptor Revision in Rheumatoid Arthritis Synovial Tissue B Lymphocytes

Heterogeneity of VH–JH gene rearrangement patterns: an insight into the biology of B cell precursor ALL

Camel heavy-chain antibodies: diverse germline VHH and specific mechanisms enlarge the antigen-binding repertoire

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Biased usage of two restricted V_H gene segments in V_h replacement