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Interrogating Individual Autoreactive Germinal Centers by Photoactivation in a Mixed Chimeric Model of Autoimmunity
Published on: April 11, 2019
CD4⁺ T cells in chronic autoantigenic stimulation in MGUS, multiple myeloma and Waldenström's macroglobulinemia
Frank Neumann1, Michael Pfreundschuh1, Klaus D Preuss1
1José Carreras Center for Immuno and Gene Therapy, Department of Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
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.
Insights
The hyperphosphorylated paratarg-7 (pP-7) carrier state drives MGUS, multiple myeloma, and Waldenström's macroglobulinemia. Specific CD4(+) T-cell responses to pP-7 explain its autoimmunogenicity and varying risk across ethnic groups.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- The hyperphosphorylated paratarg-7 (pP-7) carrier state is a significant risk factor for monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), and Waldenström's macroglobulinemia (WM).
- This condition is inherited autosomal-dominantly and affects up to one-third of patients with MGUS/MM, with prevalence varying by ethnic background.
- Paraproteins target P-7, without differentiating between the wild-type (wtP-7) and phosphorylated (pP-7) forms.
Purpose of the Study:
- To investigate CD4(+) T-cell responses in patients with the pP-7 carrier state compared to controls.
- To elucidate the mechanism behind the autoimmunogenicity of the hyperphosphorylated P-7 variant.
- To understand the varying ethnic risk ratios associated with pP-7 carrier status for developing MGUS/MM/WM.
Main Methods:
- Peptides spanning amino acids 1-35 or 4-31, containing either phosphorylated or nonphosphorylated serine17, were synthesized.
- These peptides were used to stimulate CD4(+) T-cells isolated from pP-7(+) patients and control individuals.
- HLA-DR restriction of T-cell responses was analyzed.
Main Results:
- A pP-7 specific and HLA-DR restricted CD4(+) T-cell response was observed in 65% (9/14) of pP-7(+) patients.
- These findings indicate that pP-7 specific CD4(+) T-cells can provide help for chronic antigenic stimulation of P-7 specific B cells.
- This process may contribute to the clonal evolution of B cells leading to MGUS/MM/WM.
Conclusions:
- The study demonstrates that pP-7 specific CD4(+) T-cell responses are crucial for the autoimmunogenicity of hyperphosphorylated P-7.
- The presence of a pP-7 carrier state and a compatible HLA-DR subtype are prerequisites for pP-7 specific CD4(+) T-cell stimulation.
- These results explain the exclusive autoimmunogenicity of pP-7 and the differential risk of MGUS/MM/WM development among different ethnic groups.
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