医学免疫学课件：NK细胞与HCV

1、2016Natural Killer cells in Hepatitis C Virus infection1. Background2. NK cells in the defense against HCV infection HCV infection NK cells Activation of NK cells - kIR How does NK cell work in HCV infection? NK cells response in every stage of HCV infection Conventional treatment NK cell memory3. T

2、reatment of HCV infection -focus on NK cells4. Problems and Challengesestimated 170million peopleaverage prevalence 3%developed country 2% estimated 15 million peopleprevalence 3.2%higher growth rate than HBVGlobalLYIN CHINAYellow book, Chapter 3, Hepatitis C, Centers for Disease Control and Prevent

3、ion,July 10, 2015Map1. Global epidemiology of Hepatitis C virus infection Structure positive-sense single-stranded RNA protective protein shell， lipid envelope envelope glycoproteins, E1 and E2Hepatitis C virus Bloodborne virus injecting drug use（IDU） the reuse of medical equipment the transfusion o

4、f unscreened bloodsexually and congenitally，low ratePark, Su-Hyung et al. Immune Responses to HCV and Other Hepatitis Viruses. Immunity , 2013, Volume 40 , Issue 1 , 13 - 24A leading cause of end-stage liver diseases throughout the world the most common reason for liver transplantation in Western co

5、untries Hepatitis C virus infectionAcute InfectionChronic Infection liver cirrhosis hepatocellular carcinoma20-30%1- 4%15-45%55-85%55-85%Park, Su-Hyung et al. Immune Responses to HCV and Other Hepatitis Viruses. Immunity , 2013, Volume 40 , Issue 1 , 13 - 24Natural Killer Cell 90% in hepatopathy Thr

6、ee distinct NK cell subsetsCD56brightCD16 - , CD56dimCD16+ ，CD56-CD16+ lack antigen-specific cell surface receptors Cytotoxicity lyse cell by Perforin and granzymes Cytokines IFN-，IL，TNF- .etcLee, Jaewon et al. Epigenetic Modification and Antibody-Dependent Expansion of Memory-like NK Cells in Human

7、 Cytomegalovirus-Infected Individuals. Immunity , 2015,Volume 42 , Issue 3 , 431 - 442NK cells in response to infected cell，Science photo libraryNatural Killer Receptors Natural killer receptor (NKR) is the molecular basis of NK cell function. activation receptorsNKG2C / D、NKp30NKp44、NKp46、Toll-3 .

8、inhibitory receptorsKIR、NKG2A、Ly49s .The integrated effect of various signals determines the state of NK cells.Stephanie Jost and Marcus Altfeld. LControl of Human Viral Infections by Natural Killer Cells. Immunology , 2013.31:163-194NK cells are constitutively inhibited under normal conditions over

9、ride Kayla A. Holder, Rodney S. Russell, and Michael D. Grant, “Natural Killer Cell Function and Dysfunction in Hepatitis C Virus Infection,” BioMed Research International, vol. 2014, 9 pages1. Background2. NK cells in the defense against HCV infection HCV infection NK cells Activation of NK cells -

10、 kIR How does NK cell work? Role of NK cells in every stage of HCV infection Conventional treatment NK cell memory3. Treatment of HCV infection -focus on NK cells4. Problems and ChallengesActivation of NK cells - KIR2DL3/ HLA-C1KIR family of germ line encoded receptors, one of the biggest breakthrou

11、ghclonally in a stochastic manner each NK cell expresses only a portion of the genesKIR receptors recognize conserved epitopes on HLA class I molecules.KIR2DL3/ HLA-C1 - weaker affinity - cell easier to be activited - better resultYellow book, Chapter 3, Hepatitis C, Centers for Disease Control and

12、Prevention,July 10, 2015Conclusion1： KIR2DL3, when present on a homozygous ligand background (HLA-C1/C1), was associated with spontaneous resolution of HCV infection. Conclusion2 : NK cells may make a more effective contribution to the immune response when there is a more limited exposure to virusAc

13、tivation of NK cells - KIR2DL3/ HLA-C1A higher frequency of 2DL3 expressing NK cells has been observed in a cohort of exposed uninfected individuals. Immunological synapse of NK cells，Science photo libraryYellow book, Chapter 3, Hepatitis C, Centers for Disease Control and Prevention,July 10, 2015Ho

14、w does NK cell work in HCV infection？Golden-Mason, L. and Rosen, H. R. Natural killer cells: multifaceted players with key roles in hepatitis C immunity. Immunological Reviews. 2013，255: 6881. Number & subset distribution is altered Direct effector mechanisms Degranulation Receptor mediatied killing

15、 ADCC, TRAIL Cytokine production IFN-Indirect effector mechanisms modulate T cells，DC cellsReceptor mediatied killingKayla A. Holder, Rodney S. Russell, and Michael D. Grant, “Natural Killer Cell Function and Dysfunction in Hepatitis C Virus Infection,” BioMed Research International, vol. 2014, 9 pa

16、gesNatural killer cell antibody-dependent cell-mediated cytotoxicity (ADCC)Falschlehner, C., Schaefer, U. and Walczak, H(2012). Following TRAILs path in the immune system . Immunology, 127: 145154. human tumour necrosis factorrelated apoptosisinducing ligand (TRAIL) apoptosis pathwayCytokine product

17、ion in HCV infection IFN-Shuye Zhang, Banishree Saha1, Karen Kodys1, Gyongyi Szabo1. IFN- production by human natural killer cells in response to HCV-infected hepatoma cells is dependent on accessory cells. Journal of Hepatology, 59:44244, September 2013IFN- was induced by human immune cells in resp

18、onse to HCV infectionNK cells are the major source of IFN- in response to HCV infectionIFN- production in HCV infection depends on accessory cells Shuye Zhang, Banishree Saha1, Karen Kodys1, Gyongyi Szabo1. IFN- production by human natural killer cells in response to HCV-infected hepatoma cells is d

19、ependent on accessory cells. Journal of Hepatology, 59:44244, September 2013HCV-RNA containing exosomesplasmacytoid dendritic cells（pDC）IFN-IFN-IFN- production in HCV infection depends on accessory cells Lazear, Helen M. et al. Interferon-: Immune Functions at Barrier Surfaces and Beyond. Immunity ,

20、 2015 Volume 43 , Issue 1 , 15 - 28HCV and HCV-infected cellcan also inhibit NK cellsNK cell response in every stage of HCV infectionGardiner CM. NK cell function and receptor diversity in the context of HCV infection. Frontiers in Microbiology. 2015;6:1061. Acute infection (Cytotoxicity ) CD56brigh

21、t IFN- NKG2D * NK Cells are Activated in Acute HCV but this does not Appear to Correlate with Outcome.Chronic infection（HCV - Immune escape） CD56bright IFN- CD94-NA2GA 1. Background2. NK cells in the defense against HCV infection HCV infection NK cells Activation of NK cells - kIR How does NK cell w

22、ork? Role of NK cells in every stage of HCV infection Conventional treatment NK cell memory3. Treatment of HCV infection -focus on NK cells4. Problems and Challenges03IFN and RibavirinOnly cure 50% of patientsNot applicable to IDU DAA - WHO 2013Very expensiveIdentification of DAA resistant variants

23、NK cellNK cell memory - HCV vaccine Stage III Stage IStage IITreatment of HCV infectionStage III Stage IStage IIOSullivan, Timothy E. et al. Natural Killer Cell Memory. Immunity , 2015, Volume 43 , Issue 4 , 634 - 645Natural Killer Cell MemoryOSullivan, Timothy E. et al. Natural Killer Cell Memory.

24、Immunity , 2015, Volume 43 , Issue 4 , 634 - 6451. Background2. NK cells in the defense against HCV infection HCV infection NK cells Activation of NK cells - kIR How does NK cell work? Role of NK cells in every stage of HCV infection Conventional treatment NK cell memory3. Treatment of HCV infection

25、 -focus on NK cells4. Problems and ChallengesChallenges and Problems to be solved The lack of small animal models The difficulty in obtaining Specimens The role of NK cells in HCV infection select effective clinical indicators in NK cell that can predict the response of disease-resistant treatment R

26、eferences1. Utzschneider, Daniel T. et al. T Cell Factor 1-Expressing Memory-like CD8+ T Cells Sustain the Immune Response to Chronic Viral Infections. Immunity , Volume 45 , Issue 2 , 415 - 427, 16 August 20162.OSullivan, Timothy E. et al. Natural Killer Cell Memory. Immunity , 2015, Volume 43 , Is

27、sue 4 , 634 - 6453. Su-Hyung et al. Immune Responses to HCV and Other Hepatitis VirusesPark. Immunity, 2014, Volume 40 , Issue 1, 13 - 244.Shuye Zhang, Banishree Saha1, Karen Kodys1, Gyongyi Szabo1. IFN- production by human natural killer cells in response to HCV-infected hepatoma cells is dependent

28、 on accessory cells. Journal of Hepatology,September 2013, 59:44244, 5. Choi YH, Jin N, Kelly F, Sakthivel SK, Yu T (2016) Elevation of Alanine Aminotransferase Activity Occurs after Activation of the Cell-Death Signaling Initiated by Pattern-Recognition Receptors but before Activation of Cytolytic

29、Effectors in NK or CD8+ T Cells in the Liver During Acute HCV Infection. PLOS ONE 11(10): e0165533.6.Yoon JC, Yang CM, Song Y, Lee JM. Natural killer cells in hepatitis C: Current progress. World J Gastroenterol 2016; 22(4): 1449-14607. Yong Q. Cheng,Jun P. Ren. et al. MicroRNA-155 regulates interfe

30、ron-c production in natural killer cells via Tim-3 signalling in chronic hepatitis C virus infection. Immunology, 145, 485497References8. Lucy Golden-Mason Hugo R. Rosen. et al. Natural killer cells: multifaceted players with key roles in hepatitis C immunity. Immunological Reviews , 2013 Vol. 255:

31、68819. Gardiner CM. NK cell function and receptor diversity in the context of HCV infection. Frontiers in Microbiology. 2015;6:1061. 10. Xu, Haifeng C. et al. Type I Interferon Protects Antiviral CD8+ T Cells from NK Cell CytotoxicityImmunity , Volume 40 , Issue 6 , 949 - 96011. Kayla A. Holder, Rodney S. Russell, and Michael D. Grant, “Natural K