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

Aas-Hanssen, Kristin; Funderud, Ane; Thompson, Keith M.; Bogen, Bjarne; Munthe, Ludvig A.

doi:10.4049/jimmunol.1400640

Cited by 13 publications

(18 citation statements)

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“…We have previously described IgVH sequences from lupus prone mice suffering from Id-driven lupus ( 33 ). Utilizing a data set of 176 sequences with average of 11 IgVH CDR3 aa (Figure 1 A), we compared CDR3 sequences with microbial sequences utilizing Blastp (microbial sequences include non-redundant data from prokaryotic genome sequencing projects, but not viruses or eukaryotic pathogens such as protozoa and fungi), see Materials and Methods .…”

Section: Resultsmentioning

confidence: 99%

“…Another candidate for Th cell antigen is variable regions of antibody, i.e., V region idiotypes, Id. Th cells can have Id:MHC-specific TCR ( 15 – 33 ). It has been demonstrated that anti-dsDNA B cells can present Id:MHC class II to Id-specific Th cells, undergo the germinal center reaction, differentiate, secrete autoantibodies, and cause vasculitis and nephritis ( 28 , 30 , 31 , 33 ).…”

Section: Introductionmentioning

confidence: 99%

“…Th cells can have Id:MHC-specific TCR ( 15 – 33 ). It has been demonstrated that anti-dsDNA B cells can present Id:MHC class II to Id-specific Th cells, undergo the germinal center reaction, differentiate, secrete autoantibodies, and cause vasculitis and nephritis ( 28 , 30 , 31 , 33 ). Moreover, Id-specific Th cell responses increased with disease severity in lupus mice, and disease was aggravated by injection of Id-peptide analogs ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

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Systemic Lupus Erythematosus: Molecular Mimicry between Anti-dsDNA CDR3 Idiotype, Microbial and Self Peptides—As Antigens for Th Cells

et al. 2015

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Systemic lupus erythematosus (SLE) is marked by a T helper (Th) cell-dependent B cell hyperresponsiveness, with frequent germinal center reactions, and gammaglobulinemia. A feature of SLE is the finding of IgG autoantibodies specific for dsDNA. The specificity of the Th cells that drive the expansion of anti-dsDNA B cells is unresolved. However, anti-microbial, anti-histone, and anti-idiotype Th cell responses have been hypothesized to play a role. It has been entirely unclear if these seemingly disparate Th cell responses and hypotheses could be related or unified. Here, we describe that H chain CDR3 idiotypes from IgG+ B cells of lupus mice have sequence similarities with both microbial and self peptides. Matched sequences were more frequent within the mutated CDR3 repertoire and when sequences were derived from lupus mice with expanded anti-dsDNA B cells. Analyses of histone sequences showed that particular histone peptides were similar to VDJ junctions. Moreover, lupus mice had Th cell responses toward histone peptides similar to anti-dsDNA CDR3 sequences. The results suggest that Th cells in lupus may have multiple cross-reactive specificities linked to the IgVH CDR3 Id-peptide sequences as well as similar DNA-associated protein motifs.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Systemic Lupus Erythematosus: Molecular Mimicry between Anti-dsDNA CDR3 Idiotype, Microbial and Self Peptides—As Antigens for Th Cells

et al. 2015

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“…In a recent report, double transgenic mice were created in which the B cells expressed a specific lambda 2 light chain and the T cells expressed a cognate T-cell receptor. These idiotypespecific T cells were found to drive oligoclonal expansion of autoreactive B cells and within a few weeks many of the B cells produced antibodies specific for anti-ds DNA and hypergammaglobulinemia (Aas-Hanssen et al 2014).…”

Section: Mechanisms Of Hypergammaglobulinemiamentioning

confidence: 99%

Immunodeficiencies with hypergammaglobulinemia: a review

Upton

2015

LymphoSign Journal

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Primary immunodeficiencies (PID) can present with recurrent infections, autoimmunity, inflammation, or malignancy and each of these conditions can be associated with elevated immunoglobulin. A high level of immunoglobulin G (IgG) is an uncommon finding, especially in pediatrics, and does not rule out primary immunodeficiency. Deficiencies in varied aspects of immune response have been described with high IgG. Reported PID conditions with elevated IgG include defects in humoral, cellular, and innate immunity. Some of these immunodeficiencies can have fatal outcomes, some require hematopoetic stem cell transplantation, and some require systemic medications. The mechanisms driving elevated IgG are not well understood, but in some cases abnormal cytokine production has been proposed. The evaluation of a patient with high IgG is guided by the patient's history and a physical examination, with special attention to autoimmunity in pediatrics and malignancy and liver disease in adults. In the setting of autoimmunity, chronic gastrointestinal disease, or chronic infections, the measurement of specific antibodies to evaluate the function of the IgG should be considered. An increased appreciation of elevation in IgG reflecting immune dysregulation may lead to earlier PID diagnoses.

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“…Further proof-of-concept studies using cloned B and T cells from the CSF allowed us to demonstrate that MS patients have T cells specific for antigenic determinants within the variable regions of the immunoglobulins (idiotopes), and that these proliferate, secrete cytokines and kill oligodendrocytes upon antigen stimulation (15)(16)(17)(18). Such mechanisms may allow B cells of various specificities to receive help from T cells specific for an unlinked antigen, an idiotope, and has been shown in mouse models to induce immunoglobulin class switching and cause production of auto-antibodies triggering auto-immune disease (12,19,20). An analogous immune response is the generation of anti-drug antibodies to therapeutic monoclonal antibodies (mAbs), where T cell epitopes were mapped to the variable regions (21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

CD4+ T Cells in the Blood of MS Patients Respond to Predicted Epitopes From B cell Receptors Found in Spinal Fluid

et al. 2020

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B cells are important pathogenic players in multiple sclerosis (MS), but their exact role is not known. We have previously demonstrated that B cells from cerebrospinal fluid (CSF) of MS patients can activate T cells that specifically recognize antigenic determinants (idiotopes) from their B cell receptors (BCRs). The aim of this study was to evaluate whether in silico prediction models could identify antigenic idiotopes of immunoglobulin heavy-chain variable (IGHV) transcriptomes in MS patients. We utilized a previously assembled dataset of CSF IGHV repertoires from MS patients. To guide selection of potential antigenic idiotopes, we used in silico predicted HLA-DR affinity, endosomal processing, as well as transcript frequency from nine MS patients. Idiotopes with predicted low affinity and low likelihood of cathepsins cleavage were inert controls. Peripheral blood mononuclear cells from these patients were stimulated with the selected idiotope peptides in presence of anti-CD40 for 12 h. T cells were then labeled for activation status with anti-CD154 antibodies and CD3 + CD4 + T cells phenotyped as memory (CD45RO +) or naïve (CD45RO −), with potential for brain migration (CXCR3 and/or CCR6 expression). Anti-CD14 and-CD8 were utilized to exclude monocytes and CD8 + T cells. Unstimulated cells or insulin peptides were negative controls, and EBNA-1 peptides or CD3/CD28 beads were positive controls. The mean proportion of responding memory CD4 + T cells from all nine MS patients was significantly higher for idiotope peptides with predicted high HLA-DR affinity and high likelihood of cathepsin cleavage, than toward predicted inert peptides. Responses were mainly observed toward peptides affiliated with the CDR3 region. Activated memory CD4 + T cells expressed the chemokine receptor CCR6, affiliated with a Th17 phenotype and allowing passage into the central nervous system (CNS). This in vitro study suggests that that antigenic properties of BCR idiotopes can be identified in silico using HLA affinity and endosomal processing predictions. It further indicates that MS patients have a memory T cell repertoire capable of recognizing frequent BCR idiotopes found in endogenous CSF, and that these T cells express chemokine receptors allowing them to reach the CSF B cells expressing these idiotopes.

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

Cited by 13 publications

References 58 publications

Systemic Lupus Erythematosus: Molecular Mimicry between Anti-dsDNA CDR3 Idiotype, Microbial and Self Peptides—As Antigens for Th Cells

Systemic Lupus Erythematosus: Molecular Mimicry between Anti-dsDNA CDR3 Idiotype, Microbial and Self Peptides—As Antigens for Th Cells

Immunodeficiencies with hypergammaglobulinemia: a review

CD4+ T Cells in the Blood of MS Patients Respond to Predicted Epitopes From B cell Receptors Found in Spinal Fluid

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