Loss of early innate immune control leads to severe EBV

Transcription

1 Loss of early innate immune control leads to severe EBV Disease

2 The History of Epstein Barr Virus Glandular Fever (Drusenfieber), Pfeiffer, 1889 Infectious Mononucleosis, Sprunt, 1920

3 The History of Epstein Barr Virus Burkitt s Lymphoma, 1958 Anthony Epstein & Yvonne Barr, and Bert Achong Etiology of IM, Henle & Niederman, 1968

4 Infectious Mononucleosis (Kissing Disease)

5 Other EBV Associated Diseases Burkitt s Lymphoma Post transplant lymphoproliferative disease Other immunosuppressive tumours Hodgkin s dki Lymphoma Nasopharyngeal Carcinoma Multiple Sclerosis

6 Immune Control of EBV nasopharyngeal epithelia B cell CTL NK cell

7 Severe EBV Syndromes Chronic active EBV infection (CAEBV) Hemophagocytic lymphohistiocytosis (HLH) X linked lymphoproliferative disease (XLP) Fulminant infectious mononucleosis Fulminant infectious mononucleosis Hemophagocytosis Massive T cell responses Severe viremia Hepatitis

8 X linked lymphoproliferative disease Rusung Tan, M.D. Ph.D. FRCPC Duncan Disease described by David Purtilo 1975 XLP presents as fulminant infectious mononucleosis, pancytopenia, hepatitis, i hemophagocytosis hypogammaglobulinemia, malignant lymphoma, vasculitis University of British Columbia Mortality > 95%

9 XLP Gene Mutation Rusung Tan, M.D. Ph.D. FRCPC University of British Columbia SLAM associated protein = SAP

10 SLAM associated protein (SAP) X chromosome chromosome, 4 exons, 128 aa, 15 kd SH2 domain containing protein (SH2D1A) binds phosphotyrosines Adaptor protein lacking catalytic domain Rusung Tan, M.D. Ph.D. FRCPC University Associates with of British cytoplasmic Columbia domains of other signalling moelecules (SLAM, 2B4, Ly108 )

11 XLP gene encodes SAP that binds to SLAM and 2B4 Members of the SLAM family (chromosome 1) Homotypic interactions Tyrosine motifs in cytoplasmic domains Co-stimulatory (or inhibitory?) functions CD58 SLAM CD48 CD48 SLAM 2B4 CD2 CD2 CD84 Ly9 SAP SAP SAP SAP

12 Question Why do boys who lack a functional lsap protein develop fulminant EBV infection? Rusung Tan, M.D. Ph.D. FRCPC University of British Columbia

13 SAP Deficient Mice Lack NKT cells Rusung Tan, M.D. Ph.D. FRCPC University of British Columbia

14 XLP Patients Lack NKT cells Rusung Tan, M.D. Ph.D. FRCPC University of British Columbia

15 Natural Killer T (NKT) Cells Rusung Tan, M.D. Ph.D. FRCPC University of British Columbia

16 Hypothesis Natural killer T cells recognize and control early EBV infection and/or transformation.

17 Rationale Humans lacking NKT cells have severe acute EBV infection KSHV and HSV 1 downregulatecd1d on target cells (Sanchez, JCI, 2009 and Yuan, Nat Immunol, 2006) Severe case of disseminated VZV following vaccination in child lacking NKT cells (Levy, JID,2003) Mutations of ITK lead to absence of NKT cells and EBV lymphoproliferation (Huck, JCI, 2009)

18 Does EBV infection downregulate CD1d? ENT Surgeon (Fred Kozak) + EBV transformed B cells (Lymphoblastoid cell lines or LCL) EBV

19 Can NKT cells recognize EBV transformed B cells? Naïve B cells + αgalcer (NKT cell agonist) + LCL (EBV transformed) NKT cell lines (Bm2a.3, J3n.5, M0 from Peter van den Elzen, University of British Columbia)

20 Can NKT cells recognize EBV tranformed B cells? NKT cells recognize naïve but not EBV infected B cells

21 Does EBV infection downregulate CD1d? CD1d is downregulated on B cells following EBV infection. Downregulation is specific for CD1d and not MHC I or II

22 Can CD1d be upregulated on EBV transformed B cells? The retinoic acid pathway agonist AM580 The retinoic acid pathway agonist, AM580 upregulates CD1d on EBV infected B cells

23 Can NKT cells recognize EBV transformed B cells thatexpress CD1d? NKT cells are activated by EBV infected B cells that express CD1d

24 NKT cells recognize EBV transformed B cells even in absence of α GalCer

25 Model

26 Conclusions NKT cells fail to recognize EBV infected and transformed B cells due to downregulation of CD1d CD1d expression on EBV infected B cells restores NKT cells recognition and activation NKT cells recognize CD1d+ EBV transformed B NKT cells recognize CD1d+, EBV transformed B cells in the absence of exogenous antigen

27 Implications To date there are no commercially available or widely effective EBV vaccines Could maintenance of CD1d expression on virus infected B cells or boosting of NKT cells at the time of vaccination result in long term sterilizing immunity?

28 Sidra Medical and Research Center