Targeting IgE polyadenylation signal with antisense oligonucleotides decreases IgE secretion and plasma cell viability

• DOI: 10.1016/j.jaci.2021.09.039
• Publication Date: 2021-11-02T06:54:32Z
• Authors: Anne Marchalot; Catherine Horiot; Jean-Marie Lambert; Claire Carrion; Christelle Oblet; Justine Pollet; Michel Cogné; Jeanne Moreau; Brice Laffleur; Laurent Delpy
• Keywords: antisense oligonucleotide; Cell Survival; [SDV]Life Sciences [q-bio]; Plasma Cells; 610; Polyadenylation; plasma cells; Mice; 03 medical and health sciences; 0302 clinical medicine; Hypersensitivity; Animals; Humans; polyadenylation; cell viability; B cells; Receptors, IgE; Immunoglobulin E; Oligonucleotides, Antisense; allergy; gene therapy; 3. Good health; [SDV.IMM]Life Sciences [q-bio]/Immunology; Multiple Myeloma

Allergy regroups numerous complex and various diseases classified as IgE-dependent or non-IgE-dependent hypersensitivities. IgEs are expressed as membrane and secreted forms by B cells and plasma cells, respectively. In IgE-mediated hypersensitivity, IgE secretion and binding to the high-affinity IgE receptor FcεRI on effector cells are responsible for the onset of allergic symptoms; in contrast, surface IgE expression as a B-cell receptor is barely detectable.Our aim was to test an innovative antisense approach to reducing IgE secretion.We designed an antisense oligonucleotide (ASO) targeting the polyadenylation signal of human secreted IgE to redirect IgE transcript polyadenylation from the secreted form to the membrane form. ASO treatments were performed on B cells from transgenic mice expressing humanized IgE (InEps mice), as well as on human primary B cells and myeloma cells. In vivo ASO delivery was tested by using an InEps mouse model.We demonstrated that treatment with a morpholino ASO targeting the secreted IgE polyadenylation signal drastically decreased IgE secretion and inversely increased membrane IgE mRNA expression. In addition, ASO treatment induced apoptosis of IgE-expressing U266 myeloma cells, and RNA sequencing revealed attenuation of their plasma cell phenotype. Remarkably, systemic administration of an ASO coupled with Pip6a as an arginine-rich cell-penetrating peptide decreased IgE secretion in vivo.Altogether, this ASO strategy could be an effective way to decrease IgE secretion and allergic symptoms in patients with IgE-dependent allergies, and it could also promote allergen tolerance through apoptosis of IgE+ antibody-secreting cells.