Immunodeficiency: primary or acquired

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Phenotypic and Functional Defects Underlie Ineffective Control of EBV in Patients with Distinct Primary Immunodeficiencies

Friday, June 16
3:30 PM - 3:45 PM

CD8+ T-cells are largely responsible for controlling infection caused by the common herpes virus EBV. Indeed, due to the efficacy of CD8+ T-cells, primary EBV infection in healthy individuals is often asymptomatic. However, individuals with primary immunodeficiencies characterised by uncontrolled EBV viremia and EBV-induced disease such as fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis and/or lymphoproliferative disorders have been identified. The molecular lesions affecting some of these individuals include heterozygous gain-of-function mutations in PIK3CD, and autosomal recessive biallelic mutations in CD27 or CD70. In order to understand how mutations in these genes contribute to EBV susceptibility, we have utilized polychromatic flow cytometry to enumerate the functional and phenotypic attributes of total and EBV-specific CD8+ T-cells in immunodeficient patients compared to healthy controls. Results show that total and EBV-specific CD8+ T cells are skewed towards TEM/TEMRA phenotype, at the expense of naïve CD8+ T-cells in patientswith mutations in PIK3CD or CD27, with the converse demonstrated in CD70-deficient individuals. In addition, CD8+ T-cells in these patients exhibit altered expression of regulatory molecules including 2B4 and NKG2D, as well as the senescence marker CD57 coupled with aberrant expression of cytolytic molecules granzyme and perforin. Preliminary experiments suggest defective activation and effector function of CD8+ T-cells from affected individuals, and by extension aberrant recognition of EBV-infected targets. Further investigation will give insight into the contribution of these pathways in the generation and function of EBV-specific CD8+ T cells, which will be important in the treatment of EBV-associated diseases and the development of a vaccine against EBV.

Emily S J.. Edwards

Garvan Institute of Medical Research

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Graham Davies

Great Ormond Street Hospital

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Hassan Abolhassani

Karolinska Institutet at Karolinska University Hospital Huddinge

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Theresa Cole

Royal Children's Hospital

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Melanie Wong

Royal Children's Hospital

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Sharon Choo

Royal Children's Hospital

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Asghar Aghamohammadi

Children's Medical Centre

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Nima Rezaei

Children's Medical Centre

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Aydan Ikinciogullari

Ankara University Medical School

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Sule Haskologlu

Ankara University Medical School

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Sevgi Kostel Bal

Ankara University Medical School

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Figen Dogu

Ankara University Medical School

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Nurdan Tacyildiz

Ankara University Medical School

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Matthew Cook

Australian National Univeristy

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Lennart Hammarstrom

Karolinska Institutet at Karolinska University Hospital Huddinge

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Emma Gostick

Cardiff University

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David Price

Cardiff Univrsity

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Kaan Boztug

CeMM Research Center fo Molecular Medicine of the AUstrian Academy of Sciences

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Michael Lenardo

Senior Investigator
NIH

Michael Joseph Lenardo, M.D.
Michael Lenardo was born in Chicago, Illinois on December 1, 1955. He attended the Johns Hopkins University and graduated with a Bachelor of Arts in Natural Sciences in 1977. He attended Washington University St. Louis, Mo. and obtained his Doctor of Medicine (M.D.) in 1981. He carried out clinical and research training at the University of Iowa from 1981-1985. He was then a Research Fellow at the Whitehead Institute for Biomedical Research at Massachusetts Institute of Technology with an adjunct appointment at Harvard Medical School. During this time, he carried out molecular biology research under the mentorship of Nobel laureates David Baltimore and Philip Sharp. He was then appointed Section Chief in the National Institute of Allergy and Infectious Diseases, National Institutes of Health from 1989 to the present, directing research on T-lymphocyte regulation, HIV-1, and genetic diseases of the immune system. Dr. Lenardo has published over 200 scholarly works and holds a number of medical patents. He discovered the propriocidal mechanism of immune regulation and his work has defined several genetic diseases of the immune system including the Autoimmune Lymphoproliferative Syndrome, Caspase-8 deficiency syndrome, and X-linked magnesium deficiency with EBV and neoplasia (XMEN) disease. He is currently the Director of the Clinical Genomics Program and Chief of the Molecular Development Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health. He is a Fellow of the American Association for the Advancement of Science and the American Academy of Arts and Sciences.

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Qiang Pan Hammarstrom

Karolinska Institutet at Karolinska University Hospital Huddinge

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Phenotypic and Functional Defects Underlie Ineffective Control of EBV in Patients with Distinct Primary Immunodeficiencies



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