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. 2020 Dec 9;10:604685. doi: 10.3389/fonc.2020.604685

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Copyright © 2020 Thurner, Hartmann, Neumann, Hoth, Stilgenbauer, Küppers, Preuss and Bewarder

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Paratarg-7-specific T-helper cells in myeloma/monoclonal gammopathy of undetermined significance (MGUS) patients with a SLP2-specific paraprotein as a new type of epitope spreading. (A) Representative IFN-g ELISPOTs first reported by Neumann et al. showed by in vitro stimulation for SLP2(paratarg-7)-specific TH1 cells in 9/14 patients specific responses to the antigen. 8/9 patients had a significant (p << 0.05.) stronger response against the phosphorylated variant of the SLP2-peptides used for stimulation (red columns) compared to the peptides derived from the non-phosphorylated wild type (blue columns) (209). (B) T-helper cells from 5/12 patients showed a significant stronger TH2 response against the modified peptides compared to the wild type peptides. Again, these are the results of in vitro stimulation of myeloma/MGUS patients’ T-helper cells with a paratarg-7/SLP2-specific paraprotein using overlapping 15 amino acids long peptides covering the first 30 amino acids of the SLP2 sequence. Wild-type peptides and peptides with a phosphorylated Ser17 of the posttranslational modifications (PTM) variant were used. Subsequently, the culture supernatant was analyzed by ELISA for the TH2 cytokine IL-5 (209). (C) T-helper cells with a T-cell receptor (TCR) specific for Ser17-phosphorylated version of SLP2 are primed by antigen-presenting cells, equipped with the corresponding permissive MHC-II molecules offering all necessary costimulatory signals for full maturation. (D) Subsequently, T-helper cells with these properties (phosphospecific SLP2-reactive) can stimulate all B cells presenting a phosphorylated Ser17 epitope. The specificity of the receptor of these B cells for the hyperphosphorylated isoform of the antigen is not important. Thus, B cells are also stimulated whose BCRs bind the unmodified wild type of SLP2. This form of epitope spreading comprises the same amino acid of the antigen, but with the difference of posttranslational modification. Therefore, this type of spreading is vertically oriented. For some other posttranslationally modified antigens, the lymphoma BCRs are specific for modified isoform/variant depending on the PTM, i.e. HSP90-SUMO.