APRIL-dependent lifelong plasmacyte maintenance and immunoglobulin production in humans - 04/11/20
, Tomohiro Morio, MD, PhD aAbstract |
Background |
Interactions between the tumor necrosis factor (TNF) ligand superfamily and TNF receptor superfamily play critical roles in B-cell development and maturation. A proliferation-inducing ligand (APRIL), a member of the TNF ligand superfamily, is secreted from myeloid cells and known to induce the differentiation of memory B cells to plasmacytes.
Objective |
We sought to elucidate the role of APRIL in B-cell differentiation and immunoglobulin production through the analysis of complete APRIL deficiency in human.
Methods |
We performed whole exome sequencing in a patient with adult common variable immunodeficiency. His parents were in a consanguineous marriage. TNFSF13 mRNA and protein expression were analyzed in the primary cells and plasma from the patient and in cDNA-transfected cells and supernatants of the cultures in vitro. Immunologic analysis was performed by using flow cytometry and next-generation sequencing. Monocyte-derived dendritic cells differentiated from induced pluripotent stem cells (iPSC-moDCs) were cocultured with memory B cells from healthy controls to examine in vitro plasmacyte differentiation.
Results |
We identified a homozygous frameshift mutation in TNFSF13, the gene encoding APRIL, in the patient. APRIL mRNA and protein were completely absent in the monocytes and iPSC-moDCs of the patient. In contrast to the results of previous animal model studies, the patient showed hypogammaglobulinemia with a markedly reduced level of plasmacytes in peripheral blood and a clearly increased level of circulating marginal zone B cells. Although iPSC-moDC–induced in vitro plasmacyte differentiation was reduced in the patient, recombinant APRIL supplementation corrected this abnormality.
Conclusion |
The first APRIL deficiency in an adult patient with common variable immunodeficiency revealed the role of APRIL in lifelong maintenance of plasmacytes and immunoglobulin production in humans.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : APRIL, BAFF, TACI, BCMA, B cell, plasmacyte, somatic hypermutation, class switch recombination, common variable immunodeficiency
Abbreviations used : APRIL, BAFF, BCR, CFSE, CSR, CVID, DC, HC, iPSC, iPSC-moDC, moDC, MZ, PID, SHM, Tfh, TNF, WT
Plan
| Supported by grants from the Japanese Society for the Promotion of Science Grants-in-Aid for Scientific Research program (grants 15K09640 and 18K07814); the Japan Ministry of Health, Labor, and Welfare; the Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and Development (grants JP16kk0205012 and JP16ek0109179), Japanese Agency for Medical Research and Development; Center for Innovative Medicine (CIMED), the Swedish Cancer Society; the Swedish Research Council; and the Jeffrey Modell Foundation. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 146 - N° 5
P. 1109 - novembre 2020 Retour au numéro
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