Tracking Early Autoimmune Disease by Bioluminescent Imaging of NF-κB Activation Reveals Pathology in Multiple Organ Systems

Zangani, Michael; Carlsen, Harald; Kielland, Anders; Os, Audun; Hauglin, H.; Blomhoff, Rune; Munthe, Ludvig A.; Bogen, Bjarne

doi:10.2353/ajpath.2009.080700

Cited by 26 publications

(35 citation statements)

References 43 publications

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“…First, in TCR-transgenic mouse studies, T-cell tolerance induction to Id-sequences is not complete, even in advanced MM disease [49]. Similarly, studies in doubly (Id + Ig x Id-specific TCR) transgenic mice demonstrate an age-dependent leakiness of thymic negative selection of T cells specific for high abundance Id-peptides [18,19]. Second, in studies of patients with B-cell malignancies, it is difficult to test what responsiveness would have been in the absence of disease.…”

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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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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“…We analyzed sera from DTG mice (32,33) and found IgG1 and IgG2a anti-dsDNA autoantibodies from age 6 wk ( Fig. 1A).…”

Section: Anti-dsdna Autoantibodies Are Frequently Expressed In Dtg Micementioning

confidence: 99%

“…Spleens, lymph nodes, kidneys, and blood were collected from euthanized mice, and cell suspensions and serum samples were made as previously described (32,33). Hybridomas were generated by mixing splenocytes with OURI cells (variant of X63-Ag8.653), followed by the drop-wise addition of polyethylene glycol (Roche).…”

Section: Cells and Hybridomasmentioning

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).…”

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.…”

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confidence: 99%

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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

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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.

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