Immunodeficiencies and Genetic Mutations Affecting NK Cells in Humans Prof. Jordan Orange MD/PhD
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1 Immunodeficiencies and Genetic Mutations Assistant Professor of Pediatrics University of Pennsylvania School of Medicine Children s Hospital of Philadelphia 1 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 Cytotoicity y Perforin-mediated Antibody dependent (ADCC) TRAIL/FAS-L-mediated Cytokine production (NK1/NK2) IFN-γ, TNF, IL-5, IL-13 Costimulation CD40L (CD154) OX40L J.S. Orange NK K562 2 NK cell function inhibition Activation receptor ligand Activation (lysis) receptor Class I MHC Inhibitory KIR Orange and Ballas Clin. Immunol :
2 NK cell activation missing self Activation receptor ligand Activation (lysis) receptor Granzymes Inhibitory KIR Perforin Orange and Ballas Clin. Immunol : NK cells in defense Important in anti-viral defense Especially herpes viruses Induced by type-i IFN Important in tumor surveillance Function in graft versus tumor in transplant Defective in a number of diseases Single gene immunodeficiencies Polygenic diseases As a result of therapies Rare isolated deficiencies Informative Clinically relevant 5 51 Cr Measuring cytotoicity E Time Measure and compare T T E T E T Eperimental release Detergent T Maimum total release E Media T T Background spontaneous release (Eperimental release - spontaneous release) % lysis = 100 X (Total release - spontaneous release) 6 2
3 The immunological synapse Contact zone between an immune cell and the cell it is recognizing Formation of the supramolecular activation cluster (SMAC) Functions in antigen presentation/recognition Secretion csmac psmac Secretory domain 7 The lytic NK cell immunological synapse J.S. Orange 8 The lytic NK cell immunological synapse J.S. Orange 12,000 50,
4 Learning about NK cells from human single gene deficiencies Insights into function and role in immunity 10 Wiskott-Aldrich syndrome WAS and NK cell-mediated defense 1/3 of patient have severe herpesviral infections 1/3 die from hematopoetic malignancies Historical studies of NK cell function in PBMC are variable 11 NK cell cytotoicity is deficient in WAS NK cells K562 lysi is (%) 12 4
5 WASp function Orange, et al., Cell and Molecluar Life Sciences : Pollard and Borisy, Cell : WASp accumulates with F-actin at the NK cell immunological synapse DIC Actin WASp Perforin Overlay Formation of the cytolytic immunological synapse requires WASp/actin function NK y DIC F-actin CD11a Perforin Merge z WASp - NK* y *same with cytochalasin-d DIC F-actin CD11a Perforin Merge 15 5
6 Surface receptor clustering and polarization of cytolytic granules require WASp/actin function WASp-dependent actin reorganization Surface receptor clustering Lytic granule polarization 16 Polarization of lytic granules to the cytolytic synapse requires microtubules, but SMAC formation does not y DIC F-actin CD11a Perforin Merge NK + Colchicine z 17 Polarization of lytic granules to the cytolytic synapse requires microtubules, but SMAC formation does not WASp-dependent actin reorganization Surface receptor clustering Microtubule-dependent lytic granule polarization 18 6
7 Stages of lytic immunological synapse formation Stage Recognition Effector Termination Step 1, ,15 16,17 18,19 20,21 22,23 NK cell Target cell Approimation Cellular tethering Adhesion Adhesion Activation signaling MTOC polarization MTOC anchoring Actin clearance LG docking LG priming LG fusion LG release Detachment recycling Plasma membrane F-actin corte Lipid raft Accumulated F-actin Lytic granules (LG) Centrosome MTOC Actin reorganization Receptor clustering Raft membrane clustering Activation signaling Minus ended LG movement Plus ended LG movement? Relative inactivity LG transit through corte Downmodulation Tethering receptor and ligand Adhesion receptor and ligand Activation receptor and ligand 19 Steps in lytic immunological synapse formation Stage: Step: NK cell Recognition Plasma membrane F-actin corte Lipid raft Accumulated F-actin Lti Lytic granules (LG) Centrosome MTOC Target cell Tethering receptor Adhesion receptor and ligand and ligand Plus ended LG movement? LG transit through corte Activation receptor and ligand 20 NK EBV-BCL J.S. Orange 21 7
8 Case presentation I history 5 yo male previously very healthy Had congestion and pharyngitis MD diagnosed strep pharyngitis and prescribed antibiotics 1wk later had fever to 40.0 at a family picnic Was taken to ER T=40.8, BP 75/45, HR 148 Had enlarged spleen on eamination 22 Case presentation II laboratory studies WBC=2,100 (2b, 27n, 52L, 3atL, 11m), PLT=80, HgB 7.9 ALT=185 (12-42), AST=317 (20-64), GGT=23 (17-126), LDH 2391, bili=0.1 ( ) Cr=0.3 ( ), BUN=15 (2-19), Fibrinogen=164 ( ) 471), D-dimer= ( ), Ferritin=4280 (10-95), Lipase=70 (10-115), Na=137 ( ), K=4.8 ( ), Cl=112 (96-106), C02 18 (20-26), Glucose=63 (74-127), Ca=7.8 ( ), phos=4.6 ( ), Mg=2.2 ( ), U/A 1+ protein, trace ketones, SG 1034( ) CSF 9WBC, 6425RBC protein 114 (15-40), Glucose 66 (32-82) CSF, blood and urine cultures obtained 23 Case presentation III clinical course 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 epired after 4 days CD163 stain of spleen 24 8
9 Case presentation IV NK cell function Cytotoicity %K562 lysis Control Patient Effector to target cell ratio 25 HLH diagnostic guidelines Specific molecular diagnosis, or 5 of the following Fever Splenomegally Cytopenia affecting 2 out of 3 peripheral lineages Hypertriglyceridemia and/or hypofibrinogenemia Hematophagocytosis No evidence of malignancy Elevated ferritin and/or sil-2r Low or absent NK cell cytotoicity Pediatr Blood Cancer 2007; 48: Management of HLH Immunosuppression HLH-94/2004 deamethasone, VP-16, CsA HLH-94 3-year survival 55% HSCT success ~80% 27 9
10 Case presentation V diagnosis: perforin deficiency (FEL2) Intracellular perforin FACS Control - MFI=91 Patient - MFI=8 % of ma Perforin fluorescence 28 Critical deficiency of cytolytic synapse: hematophagocytic lymphohistiocytosis Eample of abnormal antiviral inflammation Genetic inability to regulate the antiviral response Defect effects both NK cells and CTLs 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 29 Model for HLH Lymphocyte Virus IFN-γ Immunologic infection IL-12+ Infected TNF+ monocyte IFN-α DC IL-12+ NK cell IFN-γ TNF+ Monocyte TNF+ IFN-γγ IL-12 TNF 30 10
11 Molecular defects leading to HLH 31 LYST AP-3 Steps in immune-mediated cytolysis XIAP SAP 4 3 X X NK cell 5 X X psmac X X csma AC psmac Perforin F-actin Actinosome Kinesin Cytolytic granule MTOC 2 1 Target cell RAB27a Syntain-11 MUNC13-4 Microtubule Activation/adhesion receptor Activation receptor Adhesion receptor Cell membrane 32 Single gene diseases with NK cell defects J.S. Orange, Microbes and Infection
12 Single gene diseases with NK cell defects J.S. Orange, Current Opinion in Allergy and Clinical Immunology NK cell population: normal Percent CD3- CD56+ /CD16+ lymphocytes Absolute CD3- CD56+/C CD16+ lymphocytes/ml Adapted from: Comans-Bitter, WM, et al., J Pediatr : Isolated deficiencies of NK cells Do not affect other components of immunity J.S. Orange, Current Opinion in Allergy and Clinical Immunology 2006 Without a diagnosis mechanism is hopeless 36 12
13 ANKD J.S. Orange, Current Opinion in Allergy and Clinical Immunology CNKD J.S. Orange, Current Opinion in Allergy and Clinical Immunology FNKD J.S. Orange, Current Opinion in Allergy and Clinical Immunology
14 What suggests NKD Herpes viral disease Unusually severe Unusually recurrent HPV disease Unusually severe Recalcitrant to therapy Viral susceptibility Rule out other potential eplanations 40 Practical approach to NKD Clinical suspicion of NKD R/O other immunodeficiency NK cell FACS (CD3 - /CD16 + /CD56 + ) Make other D Present Cytotoicity t it testing ti Absent Repeat Still absent (2) Present Impaired (3) R/O secondary cause Cytotoicity testing Consider more advanced testing (phenotype, cytokines) FNKD Present Absent ANKD, or CNKD 41 Comprehensive approach to NKD Etensive phenotypic analysis (FACS) Developmental markers CD16 epitopes E vivo functions Migration, adhesion, synapse formation ADCC Specific receptor functions Cytokine responsiveness In vitro development 42 14
15 Management of NKD Intervention Reported or theoretical benefit Risks Antimicrobials Decrease incidence of disease Adverse drug reactions Microbial resistance IVIG Decrease incidence of disease increase NK cell function? Adverse drug reactions Infections/neurodegeneration Inconvenience IL-2 Increase NK cell function Adverse drug reactions Autoimmunity Stem cell transplantation Correction of defect J.S. Orange, in Up to Date, Rose, B.D. (ed) 2006 v14.1 Defect not corrected Transplant-related mortality or morbidity Orange, J.S., et al., J Clin Invest : Conclusions NK cells serve critical surveillance functions in host defense NK cells are defective in an number of single-gene primary immune deficiencies and are likely of clinical relevance Human genetic immunodeficiency advances the basic mechanistic understanding of NK cell function Isolated deficiencies of NK cells are mechanistically unclear but should be suspected in specific cases
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