1. Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents
- Author
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Rui Yang, Rubén Martínez-Barricarte, Janet Markle, Franck Rapaport, Stuart G. Tangye, Mathieu Bourgey, David Langlais, Anne Puel, Aziz Belkadi, Masato Ogishi, Simon J. Pelham, Jean-Laurent Casanova, Bertrand Boisson, Cindy S. Ma, Vivien Béziat, Eman Abou Moussa, Jérémie Rosain, Laurent Abel, Tomi Lazarov, Serkan Belkaya, Fatima Ailal, Ibtihal Benhsaien, Coralie Briand, Alessandro Plebani, Romain Lévy, Frederic Geissmann, Caroline Deswarte, Andrea Guennoun, Luis R. Saraiva, Tanwir Habib, Mehdi Emam, Vassilios Lougaris, Philippe Gros, Yu Jerry Zhou, Ahmed Aziz Bousfiha, Geetha Rao, Kathryn Payne, Sylvain Breton, Ai Ing Lim, Kang Liu, Kunihiko Moriya, Danielle T. Avery, Bénédicte Neven, Nico Marr, Jacinta Bustamante, Mélanie Migaud, and James P. Di Santo
- Subjects
Myeloid ,Primary Immunodeficiency Diseases ,Naive B cell ,Adaptive Immunity ,Biology ,Lymphocyte Activation ,Consanguinity ,Immunity ,medicine ,Humans ,Protein Isoforms ,Myeloid Cells ,Lymphocytes ,Child ,B cell ,CD86 ,Host Microbial Interactions ,Homozygote ,Hematopoietic Stem Cell Transplantation ,General Medicine ,Acquired immune system ,Immunity, Innate ,Proto-Oncogene Proteins c-rel ,medicine.anatomical_structure ,Mutation ,Immunology ,Female ,Genes, rel ,REL ,CD8 ,Research Article - Abstract
We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8(+) T cells, memory CD4(+) T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4(+) T cells. In naive CD4(+) T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient’s naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.
- Published
- 2021
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