慢性乙型肝炎患者NK细胞的特征及其与肝脏病变相关性的研究
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摘要
乙型肝炎病毒(HBV)是一种嗜肝性DNA病毒,病毒本身的复制并不造成肝脏损伤。研究表明,CHB患者肝脏损伤是由于免疫系统不能有效控制病毒复制,却又长期被激活并介导肝细胞破坏而发生的。近十年来,人们逐步开始认识到NK细胞在各类肝脏疾病发生发展过程中发挥了重要作用。然而,HBV慢性感染患者(特别是e抗原阳性的CHB患者)体内NK细胞的功能特点及其临床意义还未被揭示,NK细胞介导的肝损伤机制也未完全阐明。
本研究通过横断面研究,系统观察HBV感染各个时期(包括急性肝炎、慢性HBV感染免疫耐受期和免疫活化期)患者外周血NK细胞的频率、表型和功能特点,并密切结合患者的临床指标(谷丙转氨酶、谷草转氨酶水平和血清HBV载量)进行分析,以期阐明NK细胞变化的临床意义,并在此基础上初步探讨了CHB患者NK细胞免疫活化的可能原因及其介导肝脏免疫损伤的作用机制。
研究发现,与免疫耐受期患者和健康对照者比较,慢性乙肝免疫活化期患者外周血NK细胞亚群发生显著改变,表现为CD56~(dim)CD16~(pos)亚群频率下降而CD56~(bright)CD16~(neg)亚群频率上升。我们还发现尽管急性乙型肝炎病程早期阶段,患者的外周血T细胞和NK细胞表面的活化标志物如HLA-DR、CD38和CD69的表达显著上升,然而慢性乙肝免疫活化期患者的外周血仅NK细胞活化标志显著增加,提示慢乙肝免疫活化期以NK细胞活化为主。进一步的体外功能试验揭示免疫活化期患者NK细胞在IL-12／IL-15刺激后表达更多IFN-γK562刺激后产生更多CD107a,同时杀伤更多的靶细胞K562、HepG2、HepG2.2.15和HuH7.5细胞,更重要的是NK细胞杀伤活性与肝损伤程度密切相关。
本研究通过对乙型肝炎患者NK细胞的表型和功能进行详细分析,发现慢性乙型肝炎免疫活化期患者外周血NK细胞处于高活化状态,进一步支持慢性
乙型肝炎患者NK细胞的高度活化与肝损伤的严重程度密切相关。
Hepatitis B virus (HBV) is a hepadnavirus DNA virus, which does not directly cause liver damage. Therefore, liver damage in CHB patients is believed to be mediated by host immune responses. On one hand, inefficient control of viral replication occurs because specific anti-HBV immune response is inefficiently activated; on the other hand, non specific immune cells are persistently activated in a long period and will eventually mediate liver damages. Over the past decade, NK cells are gradually regarded as a very important player in the immunopathogenesis of various types of liver diseases. However, little is known about their immunological characteristics (including their phenotype and function details, especially during HBeAg-positive hepatic flare) as well as the immune-pathological mechanisms mediated by these cells.
In present study, we conducted a comprehensive cross-sectional analysis of the immunological features (phenotype and functional characteristics) of peripheral NK cells in different phases of HBV-infected patients, including acute hepatitis, chronic HBV infection in immune tolerant phase and in immune activation phase. In order to explain the clinical significance of immunological changes and investigate mechanisms of NK cells activation and immune-mediated liver injury in CHB patients, clinical parameters (ALT, AST and viral load of HBV in serum) were also analyzed and correlated to these immunological features.
We found that immune activated (IA) CHB patients displayed a large redistribution of peripheral NK cell subsets, indicated by decreased CD56~(dim)CD16~(pos) and increased CD56~(bright)CD16~(neg) subsets. More importantly, NK cells expressed significantly high levels of activation markers such as HLA-DR, CD38 and CD69 in IA patients rather than IT patients with chronic HBV infection. Interestingly, these activation molecules are simultaneously up-regulated on both T cells and NK cells in the patients at the early phase of acute resolved hepatitis B, which indicate that only NK cells are preferentially activated in IA patients. Functional analyses revealed that activated NK cells in IA patients secreted more cytokine IFN-y stimulated by IL-12/IL-15 and more CD 107a stimulated by K562 than IT patients and healthy controls. Also activated NK cells in IA patients could kill more target cells, including K562, HepG2, HepG2.2.15 and HuH7.5 cells, In addition, this hyper-activity of NK cells in IA patients was found to closely correlate with the higher level of serum ALT/AST.
Our findings indicate that peripheral NK cells were highly activated in IA patients with CHB rather than IT subjects. Importantly, our data suggest that the over activities of NK cells are closely associated with the severity of liver damage in the CHB patients.
本研究通过横断面研究,系统观察HBV感染各个时期(包括急性肝炎、慢性HBV感染免疫耐受期和免疫活化期)患者外周血NK细胞的频率、表型和功能特点,并密切结合患者的临床指标(谷丙转氨酶、谷草转氨酶水平和血清HBV载量)进行分析,以期阐明NK细胞变化的临床意义,并在此基础上初步探讨了CHB患者NK细胞免疫活化的可能原因及其介导肝脏免疫损伤的作用机制。
研究发现,与免疫耐受期患者和健康对照者比较,慢性乙肝免疫活化期患者外周血NK细胞亚群发生显著改变,表现为CD56~(dim)CD16~(pos)亚群频率下降而CD56~(bright)CD16~(neg)亚群频率上升。我们还发现尽管急性乙型肝炎病程早期阶段,患者的外周血T细胞和NK细胞表面的活化标志物如HLA-DR、CD38和CD69的表达显著上升,然而慢性乙肝免疫活化期患者的外周血仅NK细胞活化标志显著增加,提示慢乙肝免疫活化期以NK细胞活化为主。进一步的体外功能试验揭示免疫活化期患者NK细胞在IL-12／IL-15刺激后表达更多IFN-γK562刺激后产生更多CD107a,同时杀伤更多的靶细胞K562、HepG2、HepG2.2.15和HuH7.5细胞,更重要的是NK细胞杀伤活性与肝损伤程度密切相关。
本研究通过对乙型肝炎患者NK细胞的表型和功能进行详细分析,发现慢性乙型肝炎免疫活化期患者外周血NK细胞处于高活化状态,进一步支持慢性
乙型肝炎患者NK细胞的高度活化与肝损伤的严重程度密切相关。
Hepatitis B virus (HBV) is a hepadnavirus DNA virus, which does not directly cause liver damage. Therefore, liver damage in CHB patients is believed to be mediated by host immune responses. On one hand, inefficient control of viral replication occurs because specific anti-HBV immune response is inefficiently activated; on the other hand, non specific immune cells are persistently activated in a long period and will eventually mediate liver damages. Over the past decade, NK cells are gradually regarded as a very important player in the immunopathogenesis of various types of liver diseases. However, little is known about their immunological characteristics (including their phenotype and function details, especially during HBeAg-positive hepatic flare) as well as the immune-pathological mechanisms mediated by these cells.
In present study, we conducted a comprehensive cross-sectional analysis of the immunological features (phenotype and functional characteristics) of peripheral NK cells in different phases of HBV-infected patients, including acute hepatitis, chronic HBV infection in immune tolerant phase and in immune activation phase. In order to explain the clinical significance of immunological changes and investigate mechanisms of NK cells activation and immune-mediated liver injury in CHB patients, clinical parameters (ALT, AST and viral load of HBV in serum) were also analyzed and correlated to these immunological features.
We found that immune activated (IA) CHB patients displayed a large redistribution of peripheral NK cell subsets, indicated by decreased CD56~(dim)CD16~(pos) and increased CD56~(bright)CD16~(neg) subsets. More importantly, NK cells expressed significantly high levels of activation markers such as HLA-DR, CD38 and CD69 in IA patients rather than IT patients with chronic HBV infection. Interestingly, these activation molecules are simultaneously up-regulated on both T cells and NK cells in the patients at the early phase of acute resolved hepatitis B, which indicate that only NK cells are preferentially activated in IA patients. Functional analyses revealed that activated NK cells in IA patients secreted more cytokine IFN-y stimulated by IL-12/IL-15 and more CD 107a stimulated by K562 than IT patients and healthy controls. Also activated NK cells in IA patients could kill more target cells, including K562, HepG2, HepG2.2.15 and HuH7.5 cells, In addition, this hyper-activity of NK cells in IA patients was found to closely correlate with the higher level of serum ALT/AST.
Our findings indicate that peripheral NK cells were highly activated in IA patients with CHB rather than IT subjects. Importantly, our data suggest that the over activities of NK cells are closely associated with the severity of liver damage in the CHB patients.
引文
1. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005;5:215-29
2. Guidotti LG, Chisari FV. IMMUNOBIOLOGY AND PATHOGENESIS OF VIRAL HEPATITIS. Annual Review of Pathology:Mechanisms of Disease 2006;1:23-61
3. Maini MK, Boni C, Lee CK, et al. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 2000;191:1269-80
4. Sitia G, Isogawa M, Iannacone M, et al. MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs. J Clin Invest 2004;113:1158-67
5. Kakimi K, Lane TE, Wieland S, et al. Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes. J Exp Med 2001;194:1755-66
6. Norris S, Collins C, Doherty DG, et al. Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J Hepatol 1998;28:84-90
7. Lanier LL. Up on the tightrope:natural killer cell activation and inhibition. Nat Immunol 2008;9:495-50
8. Strowig T, Brilot F and Munz C. Noncytotoxic functions of NK cells:direct pathogen restriction and assistance to adaptive immunity. J Immunol 2008;180:7785-91
9. Caligiuri MA. Human natural killer cells. Blood 2008;112:461-9
10. Vivier E, Tomasello E, Baratin M, et al. Functions of natural killer cells. Nat Immunol 2008;9:503-10
11. De Maria A, Fogli M, Costa P, et al. The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44). Eur J Immunol 2003;33:2410-8
12. Mavilio D, Benjamin J, Daucher M, et al. Natural killer cells in HIV-1 infection:dichotomous effects of viremia on inhibitory and activating receptors and their functional correlates. Proc Natl Acad Sci U S A 2003; 100:15011-6
13. De Maria A, Fogli M, Mazza S, et al. Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients. Eur J Immunol 2007;37:445-55
14. Golden-Mason L, Madrigal-Estebas L, McGrath E, et al. Altered natural killer cell subset distributions in resolved and persistent hepatitis C virus infection following single source exposure. Gut 2008;57:1121-8
15. Nattermann J, Feldmann G, Ahlenstiel G, et al. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut 2006;55:869-77
16. Morishima C, Paschal DM, Wang CC, et al. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology 2006;43:573-80
17. Guidotti LG, Rochford R, Chung J, et al. Viral clearance without destruction of infected cells during acute HBV infection. Science 1999;284:825-9
18. Webster GJ, Reignat S, Maini MK, et al. Incubation phase of acute hepatitis B in man:dynamic of cellular immune mechanisms. Hepatology 2000;32:1117-24
19. EASL Clinical Practice Guidelines:Management of chronic hepatitis B. 10.1016/j.jhep.2008.10.001 [doi]
20. Kawarabayashi N, Seki S, Hatsuse K, et al. Decrease of CD56(+)T cells and natural killer cells in cirrhotic livers with hepatitis C may be involved in their susceptibility to hepatocellular carcinoma. Hepatology 2000;32:962-9
21. Cai L, Zhang Z, Zhou L, et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol 2008; 129:428-37
22. Chen Y, Wei H, Gao B, et al. Activation and function of hepatic NK cells in hepatitis B infection:an underinvestigated innate immune response. J Viral Hepat 2005;12:38-45
23. Lin AW, Gonzalez SA, Cunningham-Rundles S, et al. CD56(+dim) and CD56(+bright) cell activation and apoptosis in hepatitis C virus infection. Clin Exp Immunol 2004;137:408-16
24. Poggi A, Massaro AM, Negrini S, et al. Tumor-induced apoptosis of human IL-2-activated NK cells:role of natural cytotoxicity receptors. J Immunol 2005;174:2653-60
25. Radaeva S, Sun R, Jaruga B, et al. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 2006;130:435-52
26. Dunn C, Brunetto M, Reynolds G, et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 2007;204:667-80
27. Das A, Hoare M, Davies N, et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J Exp Med 2008;205:2111-24
28. Zhang Z, Zhang JY, Wherry EJ, et al. Dynamic programmed death 1 expression by virus-specific CD8 T cells correlates with the outcome of acute hepatitis B. Gastroenterology 2008; 134:1938-49,1949 el-3
29. Larkin J, Bost A, Glass JI, et al. Cytokine-activated natural killer cells exert direct killing of hepatoma cells harboring hepatitis C virus replicons. J Interferon Cytokine Res 2006;26:854-65
30. Vilarinho S, Ogasawara K, Nishimura S, et al. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci U S A 2007;104:18187-92
31. Chen Y, Wei H, Sun R, et al. Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells. Hepatology 2007;46:706-15
32. Malhi H, Gores GJ. Cellular and molecular mechanisms of liver injury. Gastroenterology 2008; 134:1641-54
33. Bottino C, Moretta L, Pende D, et al. Learning how to discriminate between friends and enemies, a lesson from Natural Killer cells. Mol Immunol 2004;41 (6-7):569-75
34. Moretta L, Bottino C, Pende D, et al. Different checkpoints in human NK-cell activation. Trends Immunol 2004;25 (12):670-6 35. Nattermann J, Feldmann G, Ahlenstiel G, et al. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut.2006 Jun;55(6):869-77
36. Jinushi M, Takehara T, Tatsumi T, et al. Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol 2004; 173:6072-6081
37. Roberto B, Claudia C, Daniela P, et al. Human natural killer cell receptors and co-receptors. Immunol Rev 2001;181:203-214
38 Jinushi M, Takehara T, Tatsumi T, et al. Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol 2004; 173:6072-6081
39. Alter G, Malenfant JM, Altfeld M. CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods 2004;294 (1-2):15-22
40. Echevarria S, Casafont F, Miera M, et al. Interleukin-2 and natural killer activity in acute type B hepatitis. Hepatogastroenterology 1991;38:307-310
41. Monsalve-De Castillo F, Romero TA, Estevez J, et al. Concentrations of cytokines, soluble interleukin-2 receptor, and soluble CD30 in sera of patients with hepatitis B virus infection during acute and convalescent phases. Clin Diagn Lab Immunol 2002;9:1372-1375
42. Ono K, Yamanaga Y, Yamamoto K, et al. Natural killing activities in chronic liver diseases and hepatocellular carcinoma. J Clin Immunol 1996;16:41-45
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15 Menne S, Roneker CA, Roggendorf M, et al. Deficiencies in the acute-phase cell-mediated immune response to viral antigens are associated with development of chronic woodchuck hepatitis virus infection following neonatal inoculation. J Virol 2002;76:1769-1780
16 Penna A, Artini M, Cavalli A, et al. Longlasting memory T cell responses following self-limited acute hepatitis B. J Clin Invest 1996;98:1185-1194
17 Ciurea A, Hunziker L, Klenerman P, et al. Impairment of CD4+T cell responses during chronic virus infection prevents neutralizing antibody responses against virus escape mutants. J Exp Med 2001; 193:297-305
18 Maini MK, Boni C, Lee CK, et al. The role of virus-specific CD8+cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 2000; 191:1269-1280
19 Wherry EJ, Blattman JN, Murali-Krishna K, et al. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 2003;77:4911-4927
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22 Chen MT, Billaud JN, Sallberg M, et al. A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen. Proc Natl Acad Sci U S A 2004;101:14913-14918
2. Guidotti LG, Chisari FV. IMMUNOBIOLOGY AND PATHOGENESIS OF VIRAL HEPATITIS. Annual Review of Pathology:Mechanisms of Disease 2006;1:23-61
3. Maini MK, Boni C, Lee CK, et al. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 2000;191:1269-80
4. Sitia G, Isogawa M, Iannacone M, et al. MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs. J Clin Invest 2004;113:1158-67
5. Kakimi K, Lane TE, Wieland S, et al. Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes. J Exp Med 2001;194:1755-66
6. Norris S, Collins C, Doherty DG, et al. Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J Hepatol 1998;28:84-90
7. Lanier LL. Up on the tightrope:natural killer cell activation and inhibition. Nat Immunol 2008;9:495-50
8. Strowig T, Brilot F and Munz C. Noncytotoxic functions of NK cells:direct pathogen restriction and assistance to adaptive immunity. J Immunol 2008;180:7785-91
9. Caligiuri MA. Human natural killer cells. Blood 2008;112:461-9
10. Vivier E, Tomasello E, Baratin M, et al. Functions of natural killer cells. Nat Immunol 2008;9:503-10
11. De Maria A, Fogli M, Costa P, et al. The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44). Eur J Immunol 2003;33:2410-8
12. Mavilio D, Benjamin J, Daucher M, et al. Natural killer cells in HIV-1 infection:dichotomous effects of viremia on inhibitory and activating receptors and their functional correlates. Proc Natl Acad Sci U S A 2003; 100:15011-6
13. De Maria A, Fogli M, Mazza S, et al. Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients. Eur J Immunol 2007;37:445-55
14. Golden-Mason L, Madrigal-Estebas L, McGrath E, et al. Altered natural killer cell subset distributions in resolved and persistent hepatitis C virus infection following single source exposure. Gut 2008;57:1121-8
15. Nattermann J, Feldmann G, Ahlenstiel G, et al. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut 2006;55:869-77
16. Morishima C, Paschal DM, Wang CC, et al. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology 2006;43:573-80
17. Guidotti LG, Rochford R, Chung J, et al. Viral clearance without destruction of infected cells during acute HBV infection. Science 1999;284:825-9
18. Webster GJ, Reignat S, Maini MK, et al. Incubation phase of acute hepatitis B in man:dynamic of cellular immune mechanisms. Hepatology 2000;32:1117-24
19. EASL Clinical Practice Guidelines:Management of chronic hepatitis B. 10.1016/j.jhep.2008.10.001 [doi]
20. Kawarabayashi N, Seki S, Hatsuse K, et al. Decrease of CD56(+)T cells and natural killer cells in cirrhotic livers with hepatitis C may be involved in their susceptibility to hepatocellular carcinoma. Hepatology 2000;32:962-9
21. Cai L, Zhang Z, Zhou L, et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol 2008; 129:428-37
22. Chen Y, Wei H, Gao B, et al. Activation and function of hepatic NK cells in hepatitis B infection:an underinvestigated innate immune response. J Viral Hepat 2005;12:38-45
23. Lin AW, Gonzalez SA, Cunningham-Rundles S, et al. CD56(+dim) and CD56(+bright) cell activation and apoptosis in hepatitis C virus infection. Clin Exp Immunol 2004;137:408-16
24. Poggi A, Massaro AM, Negrini S, et al. Tumor-induced apoptosis of human IL-2-activated NK cells:role of natural cytotoxicity receptors. J Immunol 2005;174:2653-60
25. Radaeva S, Sun R, Jaruga B, et al. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 2006;130:435-52
26. Dunn C, Brunetto M, Reynolds G, et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 2007;204:667-80
27. Das A, Hoare M, Davies N, et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J Exp Med 2008;205:2111-24
28. Zhang Z, Zhang JY, Wherry EJ, et al. Dynamic programmed death 1 expression by virus-specific CD8 T cells correlates with the outcome of acute hepatitis B. Gastroenterology 2008; 134:1938-49,1949 el-3
29. Larkin J, Bost A, Glass JI, et al. Cytokine-activated natural killer cells exert direct killing of hepatoma cells harboring hepatitis C virus replicons. J Interferon Cytokine Res 2006;26:854-65
30. Vilarinho S, Ogasawara K, Nishimura S, et al. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci U S A 2007;104:18187-92
31. Chen Y, Wei H, Sun R, et al. Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells. Hepatology 2007;46:706-15
32. Malhi H, Gores GJ. Cellular and molecular mechanisms of liver injury. Gastroenterology 2008; 134:1641-54
33. Bottino C, Moretta L, Pende D, et al. Learning how to discriminate between friends and enemies, a lesson from Natural Killer cells. Mol Immunol 2004;41 (6-7):569-75
34. Moretta L, Bottino C, Pende D, et al. Different checkpoints in human NK-cell activation. Trends Immunol 2004;25 (12):670-6 35. Nattermann J, Feldmann G, Ahlenstiel G, et al. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut.2006 Jun;55(6):869-77
36. Jinushi M, Takehara T, Tatsumi T, et al. Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol 2004; 173:6072-6081
37. Roberto B, Claudia C, Daniela P, et al. Human natural killer cell receptors and co-receptors. Immunol Rev 2001;181:203-214
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