title: Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood.
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.
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. miby769@rockefeller.edu
authors.forename: Minji
authors.initials: M
authors.lastname: Byun
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Arzu
authors.initials: A
authors.lastname: Akçay
authors.forename: Vincent
authors.initials: V
authors.lastname: Pedergnana
authors.forename: Umaimainthan
authors.initials: U
authors.lastname: Palendira
authors.forename: Jinjong
authors.initials: J
authors.lastname: Myoung
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.forename: Yifang
authors.initials: Y
authors.lastname: Liu
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Lazaro
authors.initials: L
authors.lastname: Lorenzo
authors.forename: Monika
authors.initials: M
authors.lastname: Schmidt
authors.forename: Hye Kyung
authors.initials: HK
authors.lastname: Lim
authors.forename: Olivier
authors.initials: O
authors.lastname: Cassar
authors.forename: Melanie
authors.initials: M
authors.lastname: Migaud
authors.forename: Flore
authors.initials: F
authors.lastname: Rozenberg
authors.forename: Nur
authors.initials: N
authors.lastname: Canpolat
authors.forename: Gönül
authors.initials: G
authors.lastname: Aydogan
authors.forename: Bernhard
authors.initials: B
authors.lastname: Fleckenstein
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Antoine
authors.initials: A
authors.lastname: Gessain
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.forename: Ethel
authors.initials: E
authors.lastname: Cesarman
authors.forename: Martin
authors.initials: M
authors.lastname: Olivier
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000917:Antibody Formation / Q000276:immunology; D001483:Base Sequence; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D003545:Cysteine / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D040582:Inheritance Patterns / Q000235:genetics*; D042541:Intracellular Space / Q000378:metabolism; D018655:Lymphocyte Count; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D053262:Receptors, OX40 / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D055815:Young Adult
chemical_list: D050505:Mutant Proteins; D053262:Receptors, OX40; D003545:Cysteine
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