Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood

Byun, Minji; Cindy, S.; Akçay, Arzu; Pedergnana, Vincent; Palendira, Umaimainthan; Myoung, Jinjong; Avery, Danielle T.; Liu, Yifang; Abhyankar, Avinash; Lorenzo, Lazaro; Schmidt, Monika; Lim, Hye Kyung; Cassar, Olivier; Migaud, Mélanie; Rozenberg, Flore; Canpolat, Nur; Aydoğan, Gönül; Fleckenstein, Bernhard; Bustamante, Jacinta; Pïcard, Capucine; Gessain, Antoine; Jouanguy, Emmanuelle; Cesarman, Ethel; Olivier, Martin; Gros, Philippe; Abel, Laurent; Croft, Michael; Tangye, Stuart G.; Casanova, Jean‐Laurent

doi:10.1084/jem.20130592

Cited by 118 publications

(115 citation statements)

References 79 publications

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“…The delayed emergence of KS vis-à-vis clinical diseases associated with these other herpesviruses suggests that in addition to KSHV and in addition to immune deficiency, genomic alterations may contribute to KSHV-associated neoplasia. Family linkage studies in classic KS support the notion of susceptibility loci for KS (140)(141)(142). Whereas t(8;14) and related translocations targeting MYC are the defining genomic event in EBV-related Burkitt's lymphoma, MYC translocations are not present in PEL.…”

Section: Genomic Explorations Of Ks and Pelmentioning

confidence: 76%

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

175

152

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Section: Genomic Explorations Of Ks and Pelmentioning

confidence: 76%

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

175

152

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“…We discovered the first (to our knowledge) primary immunodeficiencies underlying Kaposi sarcoma in children with other infectious and tumoral phenotypes. We then determined the genetic basis of rare cases of isolated, classic KS in childhood: mutations of the stromal interaction molecule 1 (STIM1) and OX40 genes (107,108). These studies, which we are currently pursuing, served as a platform for a much more difficult and innovative study, that of herpes simplex virus encephalitis (HSE).…”

Section: Miscellaneous Endeavorsmentioning

confidence: 99%

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

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201

163

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This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

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“…The repertoire of cells that can be induced to express OX40L is broader than for OX40 and reports exist of expression on mast cells [34,35], bronchial smooth muscle [36], malignancies [37], vascular endothelial cells [38] and Langerhans cells [39]. There is constitutive expression on lymphoid tissue inducer cells [40].…”

Section: Expression Of Ox40 Ligandmentioning

confidence: 99%

“…Both mice and humans lacking OX40 have reduced numbers of natural Treg alongside a reduction in other non-naïve T cell subtypes [10,37]. Correspondingly, mice that constitutively express OX40L on T cells have increased numbers of Treg in their spleens alongside autoimmunity (see below; [52]).…”

Section: Ox40 and T Cell Regulationmentioning

confidence: 99%

OX40, OX40L and Autoimmunity: a Comprehensive Review

Webb

Hirschfield

Lane

2015

Clinic Rev Allerg Immunol

204

159

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The tumour necrosis factor receptor OX40 (CD134) is activated by its cognate ligand OX40L (CD134L, CD252) and functions as a T cell co-stimulatory molecule. OX40-OX40L interactions have been proposed as a potential therapeutic target for treating autoimmunity. OX40 is expressed on activated T cells, and in the mouse at rest on regulatory T cells (Treg). OX40L is found on antigen-presenting cells, activated T cells and others including lymphoid tissue inducer cells, some endothelia and mast cells. Expression of both molecules is increased after antigen presentation occurs and also in response to multiple other pro-inflammatory factors including CD28 ligation, CD40L ligation and interferon-gamma signaling. Their interactions promote T cell survival, promote an effector T cell phenotype, promote T cell memory, tend to reduce regulatory function, increase effector cytokine production and enhance cell mobility. In some circumstances, OX40 agonism may be associated with increased tolerance, although timing with respect to antigenic stimulus is important. Further, recent work has suggested that OX40L blockade may be more effective than OX40 blockade in reducing autoimmunity. This article reviews the expression of OX40 and OX40L in health, the effects of their interactions and insights from their under- or over-expression. We then review OX40 and OX40L expression in human autoimmune disease, identified associations of variations in their genes (TNFRSF4 and TNFSF4, respectively) with autoimmunity, and data from animal models of human diseases. A rationale for blocking OX40-OX40L interaction in human autoimmunity is then presented along with commentary on the one trial of OX40L blockade in human disease conducted to date. Finally, we discuss potential problems with clinical use of OX40-OX40L directed pharmacotherapy.

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Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood

Abstract: Human OX40 is necessary for robust CD4+ T cell memory and confers selective protective immunity against HHV-8 infection in endothelial cells.

Cited by 118 publications

References 79 publications

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Severe infectious diseases of childhood as monogenic inborn errors of immunity

OX40, OX40L and Autoimmunity: a Comprehensive Review

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