Tzu-Wen Yeh1, Tsubasa Okano1, Takuya Naruto2, Motoi Yamashita3, Miko Okamura1, Kay Tanita1, Likun Du4, Qiang Pan-Hammarström4, Noriko Mitsuiki1, Satoshi Okada5, Hirokazu Kanegane3, Kohsuke Imai6, Tomohiro Morio1. 1. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 2. Department of Lifetime Clinical Immunology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 3. Department of Child Health and Development, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 4. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden. 5. Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. 6. Department of Community Pediatrics, Perinatal, and Maternal Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address: kimai.ped@tmd.ac.jp.
Abstract
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.
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.
Authors: Stuart G Tangye; Waleed Al-Herz; Aziz Bousfiha; Charlotte Cunningham-Rundles; Jose Luis Franco; Steven M Holland; Christoph Klein; Tomohiro Morio; Eric Oksenhendler; Capucine Picard; Anne Puel; Jennifer Puck; Mikko R J Seppänen; Raz Somech; Helen C Su; Kathleen E Sullivan; Troy R Torgerson; Isabelle Meyts Journal: J Clin Immunol Date: 2022-06-24 Impact factor: 8.542
Authors: Stuart G Tangye; Waleed Al-Herz; Aziz Bousfiha; Charlotte Cunningham-Rundles; Jose Luis Franco; Steven M Holland; Christoph Klein; Tomohiro Morio; Eric Oksenhendler; Capucine Picard; Anne Puel; Jennifer Puck; Mikko R J Seppänen; Raz Somech; Helen C Su; Kathleen E Sullivan; Troy R Torgerson; Isabelle Meyts Journal: J Clin Immunol Date: 2021-02-18 Impact factor: 8.317