Cd4(+) T Cells In Chronic Autoantigenic Stimulation In Mgus, Multiple Myeloma And Waldenstrom'S Macroglobulinemia

Hyperphosphorylated paratarg-7 (pP-7) carrier state is the strongest and most frequent molecular risk factor for MGUS, multiple myeloma (MM) and Waldenstrom'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.What's new? Chronic autoantigenic stimulation involving hyperphosphorylated paratag-7 (pP-7) is thought to play a role in monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM). However, paraproteins against P-7 bind to both the hyperphosphorylated and wild-type forms. The present study suggests that autoantigenic stimulation may be mediated by autoimmunity involving T-helper cells. T-helper responses specific for pP-7 were detected in 9 out of 14 with MGUS, MM, or WM. The pP-7 carrier state and a pP-7-presenting HLA-DR subtype appeared to be required for the specific T-helper response.