Immunoglobulin‐specific T‐B cell interaction III. B cell activation by immunoglobulinrecognizing T cell clones

Mazel, Svetlana; Rudensky, Alexander Y.; Yurin, V. L.

doi:10.1002/eji.1830200418

Cited by 13 publications

(7 citation statements)

References 40 publications

(9 reference statements)

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“…However, our result suggests that administering an IgG1 therapeutic antibody carrying the G1m1 allotype might provoke a CD4+ T-cell response in nG1m1 subjects, similar to responses to allotypes observed in mice and rats. 19, 25, 26, 27 A T helper response directed at the constant region could be akin to the ‘carrier protein' situation, where B cells with specificity for the idiotype of the therapeutic could receive immunological help for the Fc-specific CD4+ T cell.…”

Section: Discussionmentioning

confidence: 99%

“…19, 20, 21, 22, 23 Productive, cognate interactions between immunoglobulin allotype-specific helper T cells and B cells in rodents have been demonstrated in vitro . 24, 25, 26, 27 Therefore, a CD4+ T helper cell epitope in the constant region of an exogenously administered antibody could potentially support the development of antibody responses to other novel regions of the protein, as exemplified by the complementarity determining regions, in humans. In such an example, antibodies specific for the G1m1 sequence may be undetectable but a specific CD4+ helper T-cell response could be present.…”

Section: Introductionmentioning

confidence: 99%

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The human G1m1 allotype associates with CD4+ T-cell responsiveness to a highly conserved IgG1 constant region peptide and confers an asparaginyl endopeptidase cleavage site

et al. 2011

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The human G1m1 allotype comprises two amino acids, D12 and L14, in the CH3 domain of IGHG1. Although the G1m1 allotype is prevalent in human populations, ∼40% of Caucasiods are homozygous for the nG1m1 allotype corresponding to E12 and M14. Peptides derived from the G1m1 region were tested for their ability to induce CD4+ T-cell proliferative responses in vitro. A peptide immediately downstream from the G1m1 sequence was recognized by CD4+ T cells in a large percentage of donors (peptide CH315−29). CD4+ T-cell proliferative responses to CH315−29 were found at an increased frequency in nG1m1 homozygous donors. Homozygous nG1m1 donors possessing the HLA-DRB1*07 allele displayed the highest magnitudes of proliferation. CD4+ T cells from donors homozygous for nG1m1 proliferated to G1m1-carrying Fc-fragment proteins, whereas CD4+ T cells from G1m1 homozygous donors did not. The G1m1 sequence creates an enzymatic cleavage site for asparaginyl endopeptidase in vitro. Proteolytic activity at D12 may allow the presentation of the CH315−29 peptide, which in turn may result in the establishment of tolerance to this peptide in G1m1-positive donors. Homozygous nG1m1 patients may be more likely to develop CD4+ T-cell-mediated immune responses to therapeutic antibodies carrying the G1m1 allotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The human G1m1 allotype associates with CD4+ T-cell responsiveness to a highly conserved IgG1 constant region peptide and confers an asparaginyl endopeptidase cleavage site

et al. 2011

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“…Recent analyses of peptides eluted from class II molecules have provided further confirmation of very efficient natural B cell processing and presentation of endogenous Ig by class II molecules (28)(29)(30). It has been suggested that processing and presentation of self-Ig V region peptides leading to induction of Th or T regulatory cells may be important in regulation of immune responses and repertoire (25,31,32) and may also play a role in the induction and maintenance of autoimmune processes. To explore this possibility, we searched for autoreactive T cells capable of recognizing peptides derived from autoAb to DNA in autoimmune BWF1 mice.…”

Section: Discussionmentioning

confidence: 99%

T cell determinants from autoantibodies to DNA can upregulate autoimmunity in murine systemic lupus erythematosus.

Singh

Kumar

Ebling

et al. 1995

The Journal of Experimental Medicine

142

130

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Summary(NZB x NZW) F1 (BWF1) mice develop spontaneous T cell autoimmunity to VH region determinants of syngeneic anti-DNA before the onset of clinical disease. In this study, we characterized the immunogenicity, MHC binding, and lymphokine secretion patterns induced by T cell determinants from the VH region of one such anti-DNA mAb (A6.1) and examined their role in the regulation of autoimmunity. Determinants were identified by proliferation of syngeneic splenic T cells from young, unprimed BWF1 mice in response to overlapping 12-mer peptides representing the entire Vu region sequence. Immunization of young BWF1 mice with any of three determinants (A6H 34-45 [p34], A6H 58-69 [p58], and A6H 84-95 [p84]) elicited proliferative responses upon in vitro recall. Upon immunization with the whole A6.1 molecule, however, proliferative responses could be recalled only to the p58 peptide, defining this as immunodominant. The other two peptides (p34 and p84) elicited minimal or no proliferation and could be termed cryptic. Proliferative responses elicited by the cryptic determinants were restricted by a single class II (I-E d for p34 and I-A u for p84), whereas the immunodominant p58 determinant was restricted by both bE d and I-E u. The cryptic p34 and p84 bound strongly to I-E a and I-A u, respectively, whereas the immunodominant p58 peptide bound poorly to I-E a. A6H p84 elicited T cells that secreted lymphokines in a pattern consistent with a Thl-like phenotype, whereas p58 induced a Th2-1ike cytokine pattern. Immunization with p34 or p84, or adoptive transfer of a p84-reactive T cell line to young BWF1 mice significantly increased IgG anti-DNA levels, accelerated nephritis, and decreased survival. In conclusion, in BWF1 mice, autoreactive T cells recognizing both cryptic and dominant self-determinants on anti-DNA autoantibodies escape deletion or anergy induction. Furthermore, since these cells are spontaneously activated before the onset of clinical disease, they may be involved in the development of the autoimmune process.

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“…It has been hypothesized that Ig V region (idio)peptide-specific Th regulate B lymphocytes [3,4] and represent a line of defense against B cell neoplasms, on which the clonotypic Ig represents a tumor-specific Ag [5]. In support of these contentions, it has been demonstrated that B cells present peptides derived from their intrinsic Ig in complex with MHC class I1 molecules , and thus participate in stimulatory [12] and suppressive [9] cognate Th/B interactions across TcWIg peptide/MHC class I1 bridges. The number and efficiency of Th clones recruited depend on the repertoire of Ig peptides presented and the copy number of each determinant on the B cell surface.…”

Section: Introductionmentioning

confidence: 99%

Engagement of the B lymphocyte antigen receptor induces presentation of intrinsic immunoglobulin peptides on major histocompatibility complex class II molecules

Bartnes

Hannestad

1997

Eur J Immunol

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By means of the clonotypic variable region, the immunoglobulin (Ig) is a tumor-specific antigen on B cell neoplasms. We report that engagement of the B cell antigen receptor (BcR) promotes presentation of peptides derived from the B cell's intrinsic Ig to major histocompatibility complex (MHC) class II-restricted T cells. Thus, anti-Ig endowed normal, ex vivo B lymphocytes from H-2d, Ig constant heavy chain allotype b (IgCHb) mice with the capacity to stimulate an I-Ad-restricted T cell clone which recognizes the gamma 2ab 435-451 allopeptide. The corresponding self gamma 2aa peptide is cryptic and 6000-fold less antigenic than the gamma 2ab allopeptide. Even so, the syngeneic B cell lymphoma A20 which expresses surface(s) IgG2aa, was also recognized by the T cells after BcR ligation. Thus, anti-Ig triggered the disclosure of a cryptic tumor antigen determinant. We propose that autoantigens, by engaging the BcR of self-reactive B cells, induce presentation of intrinsic Ig peptides to which the T helper cell (Th) repertoire is not tolerant. In this way, B cells with anti-self potential may be activated without Th recognition of nominal autoantigen.

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Immunoglobulin‐specific T‐B cell interaction III. B cell activation by immunoglobulinrecognizing T cell clones

Cited by 13 publications

References 40 publications

The human G1m1 allotype associates with CD4+ T-cell responsiveness to a highly conserved IgG1 constant region peptide and confers an asparaginyl endopeptidase cleavage site

The human G1m1 allotype associates with CD4+ T-cell responsiveness to a highly conserved IgG1 constant region peptide and confers an asparaginyl endopeptidase cleavage site

T cell determinants from autoantibodies to DNA can upregulate autoimmunity in murine systemic lupus erythematosus.

Engagement of the B lymphocyte antigen receptor induces presentation of intrinsic immunoglobulin peptides on major histocompatibility complex class II molecules

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