MHC-Restricted Ig V Region-Driven T-B Lymphocyte Collaboration: B Cell Receptor Ligation Facilitates Switch to IgG Production

Munthe, Ludvig A.; Os, Audun; Zangani, Michael; Bogen, Bjarne

doi:10.4049/jimmunol.172.12.7476

Cited by 37 publications

(79 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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. development of autoimmune disease [16][17][18][19] and even B lymphomas [20]. These findings were corroborated by detection of Id-specific T cells in mouse models of SLE [14,15] and human autoimmune disease like SLE [21,22], rheumatoid arthritis [23] and multiple sclerosis [24].…”

Section: Introductionsupporting

confidence: 59%

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

Bogen

Ruffini

2009

Scand J Immunol

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionsupporting

confidence: 59%

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

Bogen

Ruffini

2009

Scand J Immunol

View full text Add to dashboard Cite

show abstract

“…Our previous studies demonstrated that B cell Ag presentation (of Id) in itself is insufficient for the generation of the germinal center reaction: B cells also require BCR ligands for the response (31). Contingent upon the presence of DNA, naive anti-dsDNA B cells with one or two CDR3 arginines could be helped by the low-frequency Id-specific Th cells in the mice to isotype switch to IgG and accumulate one or two additional CDR3 arginines by somatic hypermutation.…”

Section: Discussionmentioning

confidence: 99%

“…Diluted serum samples were analyzed for the presence of anti-dsDNA Abs or other autoantibodies, as previously described (32,33) Cells were fixed with paraformaldehyde before acquisition. DTG splenocytes or BALB/c controls were cultured with Th2 cells from Id-specific TCR-TG SCID mice, as described (31). BrdU was added on day 3, and cells were stained on day 5 with the BrdU-APC Staining Kit (BD), including surface stains for B220, CD4, and CD19.…”

Section: Autoantibody Analysismentioning

confidence: 99%

“…In this interaction, B cells can undergo the germinal center reaction, provided that ligands bind the BCR (31). Such Id-driven Th cell-B cell collaboration can also cause expansion of autoreactive B cells, secretion of autoantibodies (26,31), and autoimmune disease (32,33). In the latter studies, mice were double transgenic (DTG): B cells expressed a transgenic (TG) l2 L chain (Id + ), and T cells expressed an MHC class II (I-E d ), Id peptide-restricted TCR transgene.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Idiotype-Specific Th Cells Support Oligoclonal Expansion of Anti-dsDNA B Cells in Mice with Lupus

Aas-Hanssen

Funderud

Thompson

et al. 2014

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is marked by a Th cell–dependent B cell hyperresponsiveness, with frequent germinal center reactions and hypergammaglobulinemia. The specificity of Th cells in lupus remains unclear, but B cell Ids have been suggested. A hallmark is the presence of anti-dsDNA, mutated IgG autoantibodies with a preponderance of arginines in CDR3 of the Ig variable H chain (IgVH). B cells can present V region–derived Id peptides on their MHC class II molecules to Id-specific Th cells. We show that Id-specific Th cells support the proliferation of anti-dsDNA Id+ B cells in mice suffering from systemic autoimmune disease with SLE-like features. Mice developed marked clonal expansions of B cells; half of the IgVH sequences were clonally related. Anti-dsDNA B cells made up 40% of B cells in end-stage disease. The B cells expressed mutated IgVH with multiple arginines in CDR3. Hence, Id-driven T cell–B cell collaboration supported the production of classical anti-dsDNA Abs, recapitulating the characteristics of such Abs in SLE. The results support the concept that Id-specific Th cells may trigger the development of SLE and suggest that manipulation of the Id-specific T cell repertoire could play a role in treatment.

show abstract

“…8 -12 Conversely, Id ϩ B cells can be helped by Id-specific CD4 ϩ T cells and differentiate into antibody 10,13 and autoantibody [13][14][15] secreting B cells. Such findings have paved the way for the concept of Id-driven T-B collaboration, as first suggested by our group.…”

mentioning

confidence: 99%