PMC9096836_01
Clinical presentation and genetic analysis. (A) Family pedigree, black background used for CD40LG variant. (B, C) Periorbital swelling. (D) Timeline of clinical events and therapy. (E) Tfh in the index patient and a representative control (gated on CD3+CD4+ lymphocytes from whole-blood). (F) Sanger sequencing of CD40LG (NM_000074) c.107T>A p.Met36Lys.
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He had three sisters, and one of them suffered from chronic myalgias ( Figure 1A ). The swelling did not improve with retinoid treatment and transiently responded to low-dose steroid ( Figure 1B ). He had bilateral orbital swelling ( Figure 1C ). A timeline of clinical events is reported in  Figure 1D . Tfh cells ( Figure 1E  and  Supplementary Table 2 ). There was no history of liver and biliary tract disease or neutropenia. The patient was meeting criteria for CVID, even if he did not have a clear history of respiratory tract infections. The variant was confirmed by Sanger sequencing ( Figure 1F ) and was found only in the proband. T CD4+ was also reduced (5.1% with reference value 9.6%-44.8%) ( Figure 2D  and  Supplementary Figure S1 ). T-cell proliferation to PHA and anti-CD3/CD28 was not reduced ( Supplementary Figure S2 ).
Gene model, CD40L expression, and cytokine production. (A) Localization of variants associated to atypical phenotypes and in the transmembrane domain. (B) Crystal structure of CD40L (P25942) from . (C) CD40L expression after polyclonal stimulation (histogram plots show cells gated on CD3+CD4+ T cells from PBMNCs) in the patient and in four different healthy donors (HD). (D) IFN-gamma and IL-17 intracellular staining after polyclonal stimulation in the patient and a representative control (dot plots show cells gated on CD3+CD4+ lymphocytes from PBMNCs).
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Tfh cells ( Figure 1E  and  Supplementary Table 2 ). There was no history of liver and biliary tract disease or neutropenia. The patient was meeting criteria for CVID, even if he did not have a clear history of respiratory tract infections. This variant is localized in the transmembrane domain of the CD40L protein ( Figures 2A, B ). The expression of CD40L on activated T CD4+ cells was confirmed to be significantly reduced (27% with reference value between 40% and 80%) ( Figure 2C ). T CD4+ was also reduced (5.1% with reference value 9.6%-44.8%) ( Figure 2D  and  Supplementary Figure S1 ). T-cell proliferation to PHA and anti-CD3/CD28 was not reduced ( Supplementary Figure S2 ).