Immunodeficiencies and Genetic Mutations Affecting NK Cells in Humans Prof. Jordan Orange MD/PhD 1 The screen versions of these slides have full details of copyright and acknowledgements Immunodeficiencies and Genetic Mutations Affecting NK Cells in Humans 1 Prof. Jordan Orange MD/PhD Assistant Professor of Pediatrics University of Pennsylvania School of Medicine Children’s Hospital of Philadelphia NK cells NK cells are lymphocytes important in immune regulation and host defense that are capable of being specifically activated or inhibited after the ligation of germline-encoded receptors LGL • Cytotoxicity 2 J.S. Orange NK K562 – Perforin-mediated Antibody dependent (ADCC) – TRAIL/FAS-L-mediated • Cytokine production (NK1/NK2) – IFN-γ, TNF, IL-5, IL-13 • Costimulation – CD40L (CD154) – OX40L Activation receptor ligand Activation (lysis) receptor NK cell function – inhibition 3 Class I MHC Inhibitory KIR Orange and Ballas Clin. Immunol. 2006 118: 1-10
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Immunodeficiencies and Genetic Mutations Affecting NK Cells in HumansProf. Jordan Orange MD/PhD
1The screen versions of these slides have full details of copyright and acknowledgements
Immunodeficienciesand Genetic Mutations
Affecting NK Cells in Humans
1
Prof. Jordan Orange MD/PhDAssistant Professor of PediatricsUniversity of Pennsylvania School of MedicineChildren’s Hospital of Philadelphia
NK cellsNK cells are lymphocytes important in immune regulation and host defense that are capable of being specifically activated or inhibited after the ligation of germline-encoded receptors
LGL
• Cytotoxicity
2J.S. Orange
NK
K562
y y– Perforin-mediated
Antibody dependent (ADCC)– TRAIL/FAS-L-mediated
• Cytokine production (NK1/NK2)– IFN-γ, TNF, IL-5, IL-13
• Admitted to PICU – given parenteral antibiotics • Developed critical thrombocytopenia and anemia • Blood cultures were negative; Bone marrow aspirate• Developed severe hypotension and respiratory failure • Patient expired after 4 days
24CD163 stain of spleen
Immunodeficiencies and Genetic Mutations Affecting NK Cells in HumansProf. Jordan Orange MD/PhD
9The screen versions of these slides have full details of copyright and acknowledgements
Case presentation – IVNK cell function
Cytotoxicity
15
20
Patient
Control
25
%K
562
lysi
s
Effector to target cell ratio
0
5
10
0 10 20 30 40 50 60
HLH diagnostic guidelines
• Specific molecular diagnosis, or ≥5 of the following
– Fever
– Splenomegally
– Cytopenia affecting ≥2 out of 3 peripheral lineages
26Pediatr Blood Cancer 2007; 48: 124-31
– Hypertriglyceridemia and/or hypofibrinogenemia
– Hematophagocytosis
– No evidence of malignancy
– Elevated ferritin and/or sIL-2R
– Low or absent NK cell cytotoxicity
Management of HLH
• Immunosuppression
• HLH-94/2004 – dexamethasone, VP-16, CsA
27
• HLH-94 – 3-year survival 55%
• HSCT – success ~80%
Immunodeficiencies and Genetic Mutations Affecting NK Cells in HumansProf. Jordan Orange MD/PhD
10The screen versions of these slides have full details of copyright and acknowledgements
Case presentation – Vdiagnosis: perforin deficiency (FEL2)
Control - MFI=91 Patient - MFI=8
Intracellular perforin FACS
28Perforin fluorescence
% o
f max
Critical deficiency of cytolytic synapse: hematophagocytic lymphohistiocytosis
• Example of abnormal antiviral inflammation
• Genetic inability to regulate the antiviral response
• Defect effects both NK cells and CTLs
29
– Timing of response suggests strong role for NK cells
• Abnormal function of the cytolytic immune synapse
• Illustrates the relevance of specific sequence in lytic immunological synapse formation
Model for HLH
Infected monocyte
VirusImmunologic infection
Lymphocyte
IL-12+
TNF+ IFN-γ
IFN-γ
x xx x
x x
x
30
monocyte
NK cell
DC
Monocyte
TNF+
IFN-α
γ
IL-12
TNF
IFN-γ
IL-12+
TNF+
x xx x
xx xx
Immunodeficiencies and Genetic Mutations Affecting NK Cells in HumansProf. Jordan Orange MD/PhD
11The screen versions of these slides have full details of copyright and acknowledgements
Molecular defects leading to HLH
31
Steps in immune-mediated cytolysis
2
1
pSM
AC
AC
F-actin
Actinosome
KinesinCytolytic granule
MTOC
XIAP SAP X
Perforin
3
4 5
6
7 8
X X X XX X
32Target cellNK cell
cSM
ApS
MA
C
Microtubule
Adhesion receptor
Activation/adhesion receptor
Cell membrane
Activation receptor
RAB27aMUNC13-4 Syntaxin-11
123
4 5
6
7 89
XLYSTAP-3
X XX X
Single gene diseases with NK cell defects1978-2002
33J.S. Orange, Microbes and Infection 2002
Immunodeficiencies and Genetic Mutations Affecting NK Cells in HumansProf. Jordan Orange MD/PhD
12The screen versions of these slides have full details of copyright and acknowledgements
Single gene diseases with NK cell defects
2002-2007
34J.S. Orange, Current Opinion in Allergy and Clinical Immunology 2006