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Home  > Press Release  > APRIL-dependent life-long plasmacyte maintenance and immunoglobulin production in humans

APRIL-dependent life-long plasmacyte maintenance and immunoglobulin production in humans

Abstract

Background
Interactions between 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
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 (WES) in an adult common variable immunodeficiency patient. 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. Immunological analysis was performed using flow cytometry and next generation sequencing. Monocyte-derived dendritic cells differentiated from induced pluripotent stem cells (iPS-moDCs) were co-cultured 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 iPS-moDCs of the patient. In contrast to previous animal model studies, the patient showed hypogammaglobulinemia with markedly reduced plasmacytes in peripheral blood and clearly increased circulating marginal zone B cells. Although iPS-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 common variable immunodeficiency patient revealed the role of APRIL in life-long maintenance of plasmacytes and immunoglobulin production in humans.

Journal Article

JOURNAL:
Journal of Allergy and Clinical Immunology

TITLE:
APRIL-dependent life-long plasmacyte maintenance and immunoglobulin production in humans

DOI:
https://doi.org/10.1016/j.jaci.2020.03.025

Correspondence to

Kohsuke Imai, MD, Ph.D., Associate Professor
Department of Pediatrics, Perinatal and Maternal Medicine,
Tokyo Medical and Dental University(TMDU)
E-mail:kimai.ped (at) tmd.ac.jp

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