The idiotype connection: linking infection and multiple sclerosis

Holmøy, Trygve; Vartdal, Frode; Hestvik, Anne Lise Karlsgot; Munthe, Ludvig A.; Bogen, Bjarne

doi:10.1016/j.it.2009.11.001

Cited by 7 publications

(14 citation statements)

References 69 publications

(103 reference statements)

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“…There were more idiotope-responses among memory-than naïve T cells. For responding CD4 + memory T cells, 21 of 26 idiotope peptides generating responses were associated with the CDR3, consistent with our previous suggestions that this region may be most likely to induce such responses due to the combined events of VDJ-recombination, nucleotide insertions and deletions, and somatic hypermutation (8,9), but does not exclude possibility of idiotopes generating responses elsewhere in the heavy or light chain variable regions. The presence of idiotope-specific memory T cells indicate previous exposure to idiotopes as antigens, and these cells may gain entry into CSF due to expression of CCR6 (45).…”

Section: Discussionsupporting

confidence: 85%

“…We have suggested that the inflammation observed in MS can be initiated and/or maintained by idiotope-specific T cells driving an unlinked T-B collaboration within the CNS (8,18), and that neural network prediction models can identify idiotopes with the requirements needed to be presented to idiotope-specific T cells (9). Here, we demonstrate in vitro that MS patients actually have a repertoire of CD4 + T cells that recognize highly transcribed idiotopes from endogenous CSF B cells, as predicted in silico.…”

Section: Discussionmentioning

confidence: 99%

“…We and others have previously proposed that memory B cells, due to VDJ recombination, nucleotide insertions or deletions, and somatic mutations within the immunoglobulin variable regions, may have B cell receptors (BCRs) that themselves could contain T cell antigens capable of triggering autoimmune diseases (8)(9)(10)(11)(12). We have chosen MS as a model disease to study this concept, as the immune response in MS is characterized by compartmentalized and persisting clonal expansion of B cells that secrete immunoglobulin G (IgG) with these characteristics (13,14).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…It has been argued that idiotope‐mediated T–B cell interactions can take place without antigenic stimulation and participate in induction of B‐cell lymphomas and certain autoimmune diseases []. In a transgenic experimental system, idiotypic T–B collaboration provoked a switch to IgG autoantibodies of various specificities [].…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin class switching appears to be regulated by B‐cell antigen receptor‐specific T‐cell action

et al. 2012

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Summary Antigen affinity is commonly viewed as the driving force behind the selection for dominant clonotypes that can occur during the T cell-dependent processes of class switch recombination (CSR) and immune maturation. To test this view, we analyzed the variable gene repertoires of natural monoclonal antibodies to the hapten 2-phenyloxazolone (phOx) as well as those generated after phOx protein carrier-induced thymus-dependent or Ficoll-induced thymus independent antigen stimulation. In contrast to expectations, the extent of IgM heterogeneity proved similar and many IgM from these three populations exhibited similar or even greater affinities than the classic Ox1 clonotype that dominates only after CSR among primary and memory IgG. The population of clones that were selected during CSR exhibited a reduced VH/VL repertoire that was enriched for variable domains with shorter and more uniform CDR-H3 lengths and almost completely stripped of variable domains encoded by the large VH1 family. Thus, contrary to the current paradigm, T-cell dependent clonal selection during CSR appeared to select for VH family and CDR-H3 loop content even when the affinity provided by alternative clones exhibited similar to increased affinity for antigen.

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“…Несколько ранее T. Hølmoy и соавт. [14] предложили гипотезу о роли идиотипического взаимодействия В-и Т-клеток в патогенезе РС. В ходе иммунного ответа против вируса В-лимфоциты представляют идиотоп (Id) своего В-клеточного рецептора для антигена (BCR) Id-специфическим CD4 + Т-клеткам, образуя пару взаимодействующих клеток.…”

Section: особенности иммунной реактивности против вирусов при рсunclassified

Gerpes viruses and multiple sclerosis

Gf¹,

et al. 2016

Z. nevrol. psikhiatr. im. S.S. Korsakova

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L-lysine aescinat improves intracranial venous outflow, significantly improves the functioning of microcirculation, while not affecting the normal type of microcirculation or changing it in the direction of improvement of hemodynamic parameters, has a modulating effect on the autonomic response, and can be recommended in the complex treatment of young and middle aged patients with disturbances of cerebral venous blood circulation with the predominance of vagotonia as well as hypersympathicotonia.

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The idiotype connection: linking infection and multiple sclerosis

Cited by 7 publications

References 69 publications

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

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

Immunoglobulin class switching appears to be regulated by B‐cell antigen receptor‐specific T‐cell action

Gerpes viruses and multiple sclerosis

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