T helper cell recognition of idiotopes on λ2 light chains of M315 and T952: evidence for dependence on somatic mutations in the third hypervariable region

Bogen, Bjarne; Jørgensen, Trond Ø.; Hannestad, Kristian

doi:10.1002/eji.1830150313

Cited by 48 publications

(41 citation statements)

References 26 publications

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“…The diversity arises from both germline sequences and two fundamentally distinct somatic processes that occur at different points in B cell development. Results of previous studies have indicated that normal mice attain a state of tolerance to germline-encoded Ab diversity (25,26,32,33). In this study, we tested whether lupus-prone SNF 1 mice exhibit a global deficiency in such tolerance.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, peptides from the BCR V region may provide an avenue of T cell help to autoreactive B cells. The BCR V region is promising in this regard because of the enormous diversity encompassed by V region peptides and because such peptides can be self-presented in class II MHC by activated B cells, which presumably are dependent upon T cell help (25)(26)(27)(28)(29)(30)(31)(32)(33)(34). We refer to this potential avenue of help to autoreactive B cells as the receptor presentation hypothesis (35).…”

Section: T Cell Tolerance To Germline-encoded Antibody Sequences In Amentioning

confidence: 99%

“…More importantly, somatic hypermutation of Ab V regions in mice and humans occurs primarily in the germinal center at a late stage of development in rare Ag-selected B cells (44 -50). Although previous studies have indicated that T cells in normal mice are tolerant with respect to germline-encoded Ab diversity (26,32,33), this issue has not been explicitly addressed in lupus-prone mice. In this report, we provide evidence that lupusprone SNF 1 mice attain tolerance to germline-encoded Ab diversity and that this state is apparently maintained in diseased animals.…”

Section: T Cell Tolerance To Germline-encoded Antibody Sequences In Amentioning

confidence: 99%

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T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse

Guo

Smith

Guth

et al. 2005

The Journal of Immunology

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The BCR V region has been implicated as a potential avenue of T cell help for autoreactive B cells in systemic lupus erythematosus. In principle, either germline-encoded or somatically generated sequences could function as targets of such help. Preceding studies have indicated that class II MHC-restricted T cells in normal mice attain a state tolerance to germline-encoded Ab diversity. In this study, we tested whether this tolerance is intact in systemic lupus erythematosus-prone (New Zealand Black × SWR)F1 mice (SNF1). Using a hybridoma sampling approach, we found that SNF1 T cells were tolerant to germline-encoded Ab sequences. Specifically, they were tolerant to germline-encoded sequences derived from a lupus anti-chromatin Ab that arose spontaneously in this strain. This was true both for diseased and prediseased mice. Thus, there does not appear to be a global defect in T cell tolerance to Ab V regions in this autoimmune-prone strain either before or during autoimmune disease.

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Section: Discussionmentioning

confidence: 99%

Section: T Cell Tolerance To Germline-encoded Antibody Sequences In Amentioning

confidence: 99%

Section: T Cell Tolerance To Germline-encoded Antibody Sequences In Amentioning

confidence: 99%

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T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse

Guo

Smith

Guth

et al. 2005

The Journal of Immunology

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“…Such processed forms of immunoglobulin would associate with class II molecules and the complexes could be recognized on the surface of B cells by MHC-restricted T cells. However, as emphasized earlier (7,8), there are several possible limitations: (i) some immunoglobulins might be resistant to processing (16); (ii) peptides resulting from processing might not associate with class II molecules; and (iii) T cells might be tolerant to peptides derived from germ-line-encoded immunoglobulin (29). If the latter point is correct, T cells may participate only in the regulation of somatically mutated B-cell clones.…”

Section: Discussionmentioning

confidence: 99%

B-lymphoma cells process and present their endogenous immunoglobulin to major histocompatibility complex-restricted T cells.

Weiß

Bogen

1989

Proc. Natl. Acad. Sci. U.S.A.

199

137

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Antigen-presenting B-lymphoma cells were transfected with the gene encoding the immunoglobulin A2 light chain of MOPC315 cells (A2315). The A2 chain is expressed on the cell surface of the transfectants together with the endogenous heavy chain. (4) and that this recognition was under H-2-linked immune response (Ir) gene control (5). The hypothesis has been supported and extended by later work (6-8). Similar ideas have recently been proposed by others (9, 10), and MHC-restricted T cells specific for idiotypes (11,12) and allotypes (13) have been described. However, it is still unclear whether MHC-restricted T cells recognize processed forms of immunoglobulin exclusively and whether B cells can process their own immunoglobulin.To test this directly we have used recently established T-cell clones specific for an idiotope of A2315 in the context of the I-Ed MHC antigen (7,8). These clones, like the T cells studied in vivo before (4, 5), recognize an idiotypic determinant on A2315 around amino acid positions 94, 95, and 96 (7, 8

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“…Evidence is much stronger for CD4 + than for CD8 + Id-specific T cells. As for CD4 + T cells, results obtained in the k2 315 Ig L-chain model [5,34] and in an anti-p-azophenylarsonate model [35,36] cells in vivo [34] and cloned CD4 + T cells in vitro [5,36] exclusively focused on V-region sequences that expressed somatic mutations, while no CD4 + T cell responses to germline sequences were found. Mutations appeared to influence binding of Id-peptides to MHC class II molecules on APC [7,15,36] as well as the recognition by the Id-reactive TCR [37].…”

Section: T-cell Tolerance To Id-peptides: Experimental Evidencementioning

confidence: 99%

Review: To What Extent are T Cells Tolerant to Immunoglobulin Variable Regions?

Bogen

Ruffini

2009

Scand J Immunol

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Id-specific B cells recognize conformational determinants on complete Ig-moleculesImmunoglobulin V-regions are extremely diversified due to V(D)J recombination and somatic hypermutation [1]. Thus, immunoglobulin V-regions probably represent the largest collection of diverse antigenic determinants on self molecules within the body. B cell recognition of such Id determinants depend on association of L-and H-chain V-regions, which enormously increases the number of serological Id determinants expressed on Ig molecules in the body [2]. It has been argued that the immune system cannot be tolerant to all these conformational Id determinants, otherwise, dangerous holes in the B-cell repertoire for external antigens, such as viruses, would be generated. The lack of B-cell tolerance to V-region antigenic determinants is supported by the observation that immunization with monoclonal Ig readily generates anti-Id antibodies in an individual [3], which is the basis for Jerne's Network theory [4]. Id-specific T cells recognize V-region sequence determinants displayed on MHC moleculesSo what about T cell recognition of Id? In the 1980s it became clear that immunoglobulins are processed and presented by antigen-presenting cells (APC) and that V-region-derived Id-peptides are displayed on MHC class II molecules to Id-specific CD4 + T cells [5][6][7][8]. It was further demonstrated that B cells continuously processed their own BCR and constitutively presented Id-peptides on their MHC class II molecules [9][10][11] [12]. Thus, B cells express two types of Id: (1) conformational Id determinants expressed on intact BCR, serologically detected by anti-Id antibodies and (2) short Id-peptides that are presented on MHC class II molecules to Id-specific T cells [9]. Id-peptide ⁄ MHC II presentation to CD4 + T cells represented at that time a novel type of interaction between T and B cells in the absence of external antigen, and it was suggested that such Id-driven T-B collaboration could play a role in immune regulation, autoimmunity and memory [13]. Later, similar ideas were expressed by others [14,15]. Id-specific T cells in immune regulation and diseaseThis hypothesis has gained support from experiments where Id-driven T-B collaboration was made chronic by use of 'paired' Ig and TCR-transgenic mice as sources of Id + B cells and CD4 + T cells respectively. Perpetual Id-driven T-B collaboration was shown to result in We argue that T cells are to a large extent tolerant to germline-encoded V-region sequences but that there is a T-cell repertoire for rare Id-sequences that arise as a consequence of somatic hyper mutation or N-region diversity. Moreover, when otherwise rare Id-sequences increase in concentration, T-cell tolerance is induced (Fig. 1). For these reasons, T cells that recognize rare Id-peptides, arising as a consequence of somatic genetic events unique to each B cell, may play a special importance in Id-driven T-B collaboration, immunosurveillance of B-cell malignancies, and Id-vaccination.

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T helper cell recognition of idiotopes on λ2 light chains of M315 and T952: evidence for dependence on somatic mutations in the third hypervariable region

Cited by 48 publications

References 26 publications

T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse

T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse

B-lymphoma cells process and present their endogenous immunoglobulin to major histocompatibility complex-restricted T cells.

Review: To What Extent are T Cells Tolerant to Immunoglobulin Variable Regions?

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