Antibodies to shared idiotypes as agents for analysis and therapy for human B cell tumors

Stevenson, F K; Wrightham, M; Glennie, M J; Jones, D. B.; Cattan, AR; Feizi, Ten; Hamblin, T.J.; Stevenson, G T

doi:10.1182/blood.v68.2.430.430

Cited by 95 publications

(38 citation statements)

References 17 publications

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“…In support of this idea, Stevenson et a1 have shown that the antiidiotypic reagent which specifically recognizes the VH4-21 gene segment inhibits binding to the I/i antigens, implying that the bulk of the cold agglutinidred blood cell interaction is contributed by the V, gene segment itself (45). The 2 possibilities mentioned above are not mutually exclusive: The VH4-21 gene could be preferentially expressed for "mechanistic" and "functional" reasons.…”

Section: Implications For Autoimmunitymentioning

confidence: 98%

V_H4—21, A Human V_H Gene Segment Overrepresented in the Autoimmune Repertoire

Pascual

Capra

1992

Arthritis & Rheumatism

132

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In humans, the immunoglobulin heavy chain locus is located in chromosome band 14q32.33 (1,2). Three different elements, V,, D, and JH, encoded by gene segments which in germline configuration are separated by thousands of basepairs, are brought together by a recombination machinery in order to generate a functional variable region. The existence of many different VH, D, and JH gene segments provides the first substrate for diversifying the repertoire of B cells. Diversity is enhanced by several orders of magnitude by the combinatorial association of these 3 elements and the generation of new amino acids at the V, D and D-JH junctions during the process of rearrangement. Further expansion of the repertoire is accomplished by the mechanism of somatic mutation, which, by acting upon the rearranged gene segments, leads to a practically unlimited spectrum of B cell specificities (for review, see ref. 3).Current knowledge about the human V, complex indicates that the repertoire of available functional VH genes is diverse. Restriction fragment length polymorphism analyses suggest that the total number of germline V, gene segments is -100-200,2040% of

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Section: Implications For Autoimmunitymentioning

confidence: 98%

V_H4—21, A Human V_H Gene Segment Overrepresented in the Autoimmune Repertoire

Pascual

Capra

1992

Arthritis & Rheumatism

132

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“…The fact that V 4-34 is used early in development, and continues to be expressed by 6% of normal adult B cells [12,13], suggests that the encoded immunoglobulin represents an important component of the repertoire. However, levels of V 4-34 -encoded immunoglobulin are surprisingly low in normal serum IgM or IgG [1], suggesting that the circulating B cells may be anergic. If that is the case, anergy can be easily broken by infection with Epstein-Barr virus (EBV) or Mycoplasma pneumoniae, where serum levels can increase dramatically [2].…”

Section: Introductionmentioning

confidence: 98%

“…The V (V H 4-21) gene segment, a member of the V H 4 family, has been widely studied. One of the reasons for this has been the availablility of our MoAb, 9G4, which has been found to be highly specific for immunoglobulins encoded by V [1][2][3]. Using this reagent, we were able to show that the gene is active early in development, and that a significant percentage of B cells in normal lymphoid tissue expresses immunoglobulins encoded by V [1].…”

Section: Introductionmentioning

confidence: 99%

“…One of the reasons for this has been the availablility of our MoAb, 9G4, which has been found to be highly specific for immunoglobulins encoded by V [1][2][3]. Using this reagent, we were able to show that the gene is active early in development, and that a significant percentage of B cells in normal lymphoid tissue expresses immunoglobulins encoded by V [1]. A further interesting aspect, confirmed by sequencing the involved V H genes, is that the gene is mandatory for the pathological antierythrocyte antibodies of I/i specificity [4,5].…”

Section: Introductionmentioning

confidence: 99%

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Tracking of the V4–34 (VH4–21) gene in human tonsil reveals clonal isotype switch events and a highly variable degree of somatic hypermutation

Chapman

Mockridge

Hamblin

et al. 1996

Clinical and Experimental Immunology

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SUMMARYThe V 4-34 (V H 4-21) gene has been found to encode certain IgM autoantibodies, and is mandatory for pathological IgM anti-erythrocyte antibodies of I/i specificity. The gene is also commonly used by normal IgM-positive B lymphocytes, but its involvement in B cells which have undergone class switching to IgG or IgA is less clear. In order to track V 4-34 gene usage and class switching events during a normal immune response, we have probed RNA in a limited area of human tonsil. Results indicate that the V 4-34 gene undergoes class switching to IgG or IgA, with the progeny either remaining unmutated or containing large numbers of somatic mutations. Mutational patterns indicate possible 'hot spots', and some mutations appear deleterious. At the level of individual B cells, we have tracked a clonal isotype switch event from IgM to IgA, with each retaining close to germ-line configuration. In addition, we have followed a clonal switch from a mutated IgM to IgG, with no further accumulation of somatic mutations. These data indicate that the V 4-34 gene is involved in a maturing immune response, and that the routes to production of IgG or IgA antibodies are various.

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“…Starting from the initial studies by Williams et al in 1968, many attempts have been made to localize and characterize a public idiotope in antibodies exerting cold agglutinin activity [15][16][17][18][19]. In a previous work the sequence of Fab fragment from a CA exerting anti-I activity (protein KAU, an IgMIIIb monoclonal) has been reported, and its homology determined with gene V H 4-21 [3].…”

Section: Discussionmentioning

confidence: 99%

The frequent mutation Gly/Asp in CDR1H may determine a cross-reactive idiotope in anti-I cold agglutinins

Abatangelo

Plotkin

Mathov

et al. 1996

Clinical and Experimental Immunology

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Variable domains (VH) of all known anti i/I cold agglutinin (CA) heavy chains are codified by the VH4–21 gene. While anti‐i CAs are the expression of gene rearrangement without mutations represented by amino acid changes, anti‐I CAs present, among others, a frequent somatic mutation of Gly by Asp at position 31. The hydropathy profile calculated for the CDR1H (position 30 to position 35), as well as some adjacent positions of the heavy chain belonging to anti‐i and anti‐I antibodies, showed the conformational changes accompanying the replacement of Gly by Asp. A MoAb (LP91), which had been obtained in BALB/c mice immunized with a Fabμ fragment from a monoclonal IgMκIIIb anti‐I CA (protein KAU), proved capable of inhibiting human adult erythrocyte cryoagglutination by anti‐I CAs but not that of fetal erythrocytes by anti‐i CAs. Western blot analysis disclosed that such MoAbs recognized a sequential epitope located in the Fd fragment of all anti‐I CAs employed in this study. With the purpose of checking whether Asp31 was involved in the epitope recognized by the MoAb, two peptides, D and G, were synthesized which mimicked the CDR1H structure of anti‐I and anti‐i, respectively; the MoAb only reacted with peptide D by ELISA. Subsequent experimental results indicate that the Gly/Asp mutation could be associated with the diverse specificity presented by these autoantibodies, a change determining a characteristic epitope/idiotope, recognized by LP91 in the CDR1H.

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Antibodies to shared idiotypes as agents for analysis and therapy for human B cell tumors

Cited by 95 publications

References 17 publications

V_H4—21, A Human V_H Gene Segment Overrepresented in the Autoimmune Repertoire

V_H4—21, A Human V_H Gene Segment Overrepresented in the Autoimmune Repertoire

Tracking of the V4–34 (VH4–21) gene in human tonsil reveals clonal isotype switch events and a highly variable degree of somatic hypermutation

The frequent mutation Gly/Asp in CDR1H may determine a cross-reactive idiotope in anti-I cold agglutinins

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Antibodies to shared idiotypes as agents for analysis and therapy for human B cell tumors

Cited by 95 publications

References 17 publications

VH4—21, A Human VH Gene Segment Overrepresented in the Autoimmune Repertoire

VH4—21, A Human VH Gene Segment Overrepresented in the Autoimmune Repertoire

Tracking of the V4–34 (VH4–21) gene in human tonsil reveals clonal isotype switch events and a highly variable degree of somatic hypermutation

The frequent mutation Gly/Asp in CDR1H may determine a cross-reactive idiotope in anti-I cold agglutinins

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Product

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About

V_H4—21, A Human V_H Gene Segment Overrepresented in the Autoimmune Repertoire

V_H4—21, A Human V_H Gene Segment Overrepresented in the Autoimmune Repertoire