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Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood

Minji Byun 1, * Cindy S. Ma 2, 3 Arzu Akçay 4 Vincent Pedergnana 5 Umaimainthan Palendira 5, 3 Jinjong Myoung 6 Danielle T. Avery 2 Yifang Liu 7 Avinash Abhyankar 1 Lazaro Lorenzo 5 Monika Schmidt 8 Hye Kyung Lim 1 Olivier Cassart 9 Melanie Migaud 5 Flore Rozenberg 10, 11 Nur Canpolat 12 Gönül Aydoğan 4 Bernhard Fleckenstein 8 Jacinta Bustamante 5, 13 Capucine Picard 5, 13 Antoine Gessain 9 Emmanuelle Jouanguy 5 Ethel Cesarman 7 Martin Olivier 14 Philippe Gros 14 Laurent Abel 1, 5 Michael Croft 15 Stuart G. Tangye 2, 3 Jean-Laurent Casanova 1, 5, 16
* Corresponding author
1 St. Giles Laboratory of Human Genetics of Infectious Diseases
2 Immunology Program
3 St. Vincent’s Clinical School, Faculty of Medicine
4 Pediatric Hematology and Oncology
5 Inserm U980 - Génétique Humaine des Maladies Infectieuses
6 NIBR - Novartis Institutes for BioMedical Research
7 Department of Pathology and Laboratory Medicine
8 Institut für Klinische und Molekulare Virologie
9 EPVO (UMR_3569 / U-Pasteur_3) - Epidémiologie et Physiopathologie des Virus Oncogènes
10 Service de Virologie [CHU Cochin]
11 UPD5 - Université Paris Descartes - Paris 5
12 Department of Pediatric Nephrology
13 CHU Necker - Enfants Malades [AP-HP]
14 McGill University = Université McGill [Montréal, Canada]
15 La Jolla Institute for Immunology [La Jolla, CA, États-Unis]
16 Service d'immuno-hématologie pédiatrique [CHU Necker]
Abstract : Kaposi sarcoma (KS), a human herpes virus 8 (HHV-8; also called KSHV)-induced endothelial tumor, develops only in a small fraction of individuals infected with HHV-8. We hypothesized that inborn errors of immunity to HHV-8 might underlie the exceedingly rare development of classic KS in childhood. We report here autosomal recessive OX40 deficiency in an otherwise healthy adult with childhood-onset classic KS. OX40 is a co-stimulatory receptor expressed on activated T cells. Its ligand, OX40L, is expressed on various cell types, including endothelial cells. We found OX40L was abundantly expressed in KS lesions. The mutant OX40 protein was poorly expressed on the cell surface and failed to bind OX40L, resulting in complete functional OX40 deficiency. The patient had a low proportion of effector memory CD4(+) T cells in the peripheral blood, consistent with impaired CD4(+) T cell responses to recall antigens in vitro. The proportion of effector memory CD8(+) T cells was less diminished. The proportion of circulating memory B cells was low, but the antibody response in vivo was intact, including the response to a vaccine boost. Together, these findings suggest that human OX40 is necessary for robust CD4(+) T cell memory and confers apparently selective protective immunity against HHV-8 infection in endothelial cells.
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Minji Byun, Cindy S. Ma, Arzu Akçay, Vincent Pedergnana, Umaimainthan Palendira, et al.. Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood. Journal of Experimental Medicine, Rockefeller University Press, 2013, 210 (9), pp.1743 - 1759. ⟨10.1084/jem.20130592⟩. ⟨pasteur-01370948⟩

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