title: CD4⁺ T cells in chronic autoantigenic stimulation in MGUS, multiple myeloma and Waldenström's macroglobulinemia.
abstract: Hyperphosphorylated paratarg-7 (pP-7) carrier state is the strongest and most frequent molecular risk factor for MGUS, multiple myeloma (MM) and Waldenström's macroglobulinemia (WM), inherited autosomal-dominantly and, depending on the ethnic background, found in up to one third of patients with MGUS/MM. Since P-7 is the antigenic target of paraproteins that do not distinguish between wtP-7 and pP-7, we investigated CD4(+) T-cell responses in pP-7(+) patients and controls. Peptides spanning amino acids 1-35 or 4-31 containing phosphorylated or nonphosphorylated serine17 were used for stimulation. CD4(+) cells from 9/14 patients (65%) showed a pP-7 specific HLA-DR restricted response. These results demonstrate that pP-7 specific CD4(+) cells can mediate help for pP-7 specific chronic antigenic stimulation of P-7 specific B cells, which might ultimately result in the clonal evolution of a B cell into MGUS/MM/WM producing a P-7 specific paraprotein. Prerequisites for pP-7 specific stimulation of CD4(+) cells appear to be both a pP-7 carrier state and an HLA-DR subtype able to present and recognize pP-7. Our results serve as an explanation for the exclusive autoimmunogenicity of the hyperphosphorylated variant of P-7 and for the different hazard ratios of pP-7 carriers from different ethnic origins to develop MGUS/MM/WM.
authors: José Carreras Center for Immuno and Gene Therapy, Department of Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
authors: Frank
authors: F
authors: Neumann
authors: José Carreras Center for Immuno and Gene Therapy, Department of Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
authors: Michael
authors: M
authors: Pfreundschuh
authors: José Carreras Center for Immuno and Gene Therapy, Department of Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
authors: Klaus D
authors: KD
authors: Preuss
authors: José Carreras Center for Immuno and Gene Therapy, Department of Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
authors: Claudia
authors: C
authors: Schormann
authors: José Carreras Center for Immuno and Gene Therapy, Department of Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
authors: Carsten
authors: C
authors: Zwick
authors: José Carreras Center for Immuno and Gene Therapy, Department of Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
authors: Niels
authors: N
authors: Murawski
authors: José Carreras Center for Immuno and Gene Therapy, Department of Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
authors: Boris
authors: B
authors: Kubuschok
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000276:immunology* / Q000378:metabolism; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism; D010266:Paraproteins / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D008258:Waldenstrom Macroglobulinemia / Q000276:immunology* / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D006684:HLA-DR Antigens; D008565:Membrane Proteins; C475609:P7 antigen, human; D010266:Paraproteins; D010446:Peptide Fragments
keywords: hyperphosphorylated autoantigens; paratarg-7; phosphospecific T-helper cells; plasma cell dyscrasia