SARS患者感染危险因素及其随访观察研究
|
摘要
2003年严重急性呼吸综合征(severe acute respiratory syndrome, SARS)的流行曾带来世界范围内的灾难,其传染性之强、传播速度之快、流行范围之广、影响之大远超出人们的想象。SARS过后,遗留下的未解之谜还很多,在SARS流行病学方面仍存在众多热点问题值得探讨。
医务人员(healthcare workers, HCW)是SARS感染的高危人群,其感染的危险/保护因素研究较多而结果并不一致。我们采用病例对照研究的方法,选取来自同一医院感染SARS的HCW病例51名,与SARS患者密切接触的HCW对照426名,利用标准调查问卷,对其在诊疗SARS患者时的危险因素及采取的防护措施进行了全面系统的回顾性调查。多因素logistic回归分析表明胸外心脏按压操作(调整OR=4.52,95%CI=1.08–18.81)和接触患者呼吸道分泌物(调整OR=3.27,95% CI=1.41–7.57)是HCW感染SARS的主要危险因素。戴12层棉纱口罩、16层棉纱口罩、多层防护口罩、预防服药、鼻腔清洗和防护知识培训6个因素是SARS发生的保护因素。
近期研究表明SARS发生、发展和预后等与宿主遗传因素有关。本研究选取抗病毒过程中发挥重要作用的基因白介素12受体β1(interleukin-12 receptorβ1, IL12Rβ1)作为候选易感基因,运用病例对照研究设计,采用聚合酶链式反应-限制性片段多态性(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)的方法,探讨IL12Rβ1基因多个SNP位点多态性与SARS的易感性关系。研究结果表明+705A/G、+1158T/C、+1196G/C位点的等位基因以及基因型在病例组和对照组中的分布频率没有显著性差异。+1664C/T(CT)和(TT)基因型在病例组中的分布显著高于对照组(P<0.05),ORs(95%CI)分别为2.09(1.90–7.16)和2.34(1.79–13.37)。单体型分析发现,+705A/G、+1158T/C以及+1196G/C三个位点存在强烈的连锁不平衡(D’=0.90–0.98),+1664C/T与其它三个位点之间存在中等程度的连锁不平衡,ATGC和GCCT单体型是最普遍的单体型,GCCT单体型在病例组中的分布频率显著高于对照组,ORs(95%CI)为2.31(1.72–8.47)。提示IL-12Rβ1基因多态性与中国汉族人群SARS发病存在关联,但与疾病的严重程度无显著性关联。
SARS感染后机体体液免疫状况,包括抗体水平及抗体持续时间是预防再次发生疾病流行的关健因素之一,然而对于抗体动态变化规律的持续时间和影响因素目前未有定论。本研究选取44例临床确诊并且血清抗体阳性的SARS患者进行了4年的追踪随访,用酶联免疫吸附试验(enzyme linked immunosorbent assay, ELISA)方法检测血清SARS-CoV特异性IgG抗体动态变化规律,同时收集流行病学和临床信息等相关资料,估计可能影响抗体水平变化的因素。结果表明,发病后第12、27、40、50个月IgG抗体阳性率分别为85%、80%、62%、32%;IgG抗体滴度的GMTs分别为1:31、1:27、1:13、1:6。生存分析显示不同激素用量、疾病严重程度和抗体转阴时间之间有显著性关联(P=0.033和P=0.024),激素用量越大,抗体水平下降越明显。从上述结果我们认为,4年后抗体滴度降低到保护性水平以下,保护性免疫只能持续有限时间。激素使用、疾病严重程度是影响抗体水平变化的重要因素。
虽然SARS病人的保护性免疫只能持续有限时间,但保护性抗体消失后,患者体内是否存在记忆性淋巴细胞免疫应答反应是决定机体再次接触SARS-CoV后是否患病的关键。本研究进行了SARS康复期患者SARS-CoV特异性T、B细胞淋巴细胞免疫应答反应。结果显示SARS康复期患者在发病6年后,不仅血清IgG抗体消失,而且体内SARS-CoV特异性记忆性B细胞水平也已不能检出,提示自然感染SARS-CoV后体液免疫反应及免疫记忆的持续时间有限。体内记忆性T细胞免疫应答能够维持一定水平,产生的淋巴细胞斑点数显著高于密切接触者和正常健康人群,其对于再次暴发的SARS流行能否提供免疫保护作用的问题仍然需要进一步探索。
本研究结合现场调查、实验室检测,综合应用描述流行病学、分析性流行病学等方法,阐明了SARS感染的环境危险因素及宿主遗传易感因素在SARS发病过程中的作用;通过对SARS队列进行6年的随访观察,阐明了人群免疫水平动态变化规律及其影响因素,通过ELISPOT试验方法,首次提出保护性抗体消失后,SARS康复期患者记忆性B淋巴细胞免疫反应不会长期存在,而记忆性T淋巴细胞免疫应答可在体内长期维持免疫记忆。本研究结果不仅为预防可能再次暴发的SARS提供防控措施和临床治疗的科学依据;同时也可为SARS疫苗开发、新药研制提供可以借鉴的新思路。
Severe acute respiratory syndrome (SARS) is an emerging infectious disease that caused a global epidemic in 2003. The clinical manifestations, laboratory findings, radiologic presentations, and outcomes of SARS for patients have been well described. Much of the epidemiology of the disease is still not fully understood.
Healthcare workers (HCW) were at the highest risk of having the disease. Risk factors for infection in HCWs have been studied extensively, and a review on SARS infection and healthcare workers disclosed a number of risk and protective factors, however with conflicting results from different studies. To evaluate possible risk and protective factors associated with infection of SARS among the HCWs by means of a case control study. Fifty-one infected and 426 uninfected staff members were included. All participants were surveyed about risk behaviours and protective measures when attending to SARS patients. Univariate and multivariate logistic regression analyses were performed to identify the major risk and protective factors. Multivariate analysis confirmed the strong role of performing chest compression (adjusted OR 4.52, 95% confidence interval [CI] 1.08-18.81) and contact with patient secretion (adjusted OR 3.27, 95%CI 1.41-7.57). For the studied protective measures, wearing 16-layer cotton surgical mask, wearing 12-layer cotton surgical mask and wearing multiple layers of mask, taking prophylactic medicine, training activity and nose washing remained protective from SARS infection.
The recent studies displayed the significant role of the genetic host factors in SARS infection. We conducted a case-control study to investigate the association between interleukin (IL)-12receptorβ1 (IL-12Rβ1) gene genetic polymorphisms and SARS in Chinese individuals. The genotypes of 4SNPs on IL-12Rβ1 gene, +705A/G, +1158T/C, +1196G/C and +1664C/T were determined by PCR-RFLP. Comparison between patients and close contacts showed that individuals with the +1664C/T (CT and TT) genotype had a 2.09-fold (95%CI 1.90–7.16) and 2.34-fold (95%CI 1.79–13.37) increased risk of developing SARS, respectively. For any of the other three polymorphisms, however, no significant difference can be detected in allele or genotype frequencies between patients and controls. Pairwise linkage disequilibrium (LD) analysis of the four SNPs showed strong LD among +705A/G, +1158T/C and +1196G/C SNPs (D, = 0.90–0.98) and modest LD value between +1664C/T and one of the other three SNPs (D, = 0.64–0.81), thus revealing two common haplotypes (A-T-G-C (705-1158-1196-1664) and G-C-C-T). The frequency of GCCT haplotype in SARS patients was significantly increased when compared to the control A group (ORs (95% CI) =2.31 (1.72–8.47).
Maintenance of long-term antibody responses is critical for protective immunity against SARS re-infection. However, the duration of humoral immunity has not yet been defined clearly. We performed a longitudinal analysis of antibody titers specific for viral SARS-CoV in 44 subjects for a period of up to 4 years. In addition, possible factors that might influence the dynamic trend of antibodies were assessed. The ELISA results showed positive rates of IgG antibody were 85%, 80%, 63% and 32%, at month 12, 27, 40 and 50, respectively. The geometric mean titers (GMT) of IgG antibody were 1:31, 1:27, 1:13, and 1:6 respectively at four time points after the disease. Survival analysis disclosed a significant association between the antibody duration and steroid use and disease severity, which was further confirmed in survival analysis when using the time of antibody negativation as outcome variable.
However, disappearance of anti-SARS antibodies does not necessarily indicate loss of protection. We then evaluated antigen-specific memory T-cell and B-cell response in 6-yr recovered SARS sample by means of ELISPOT. Possible factors that might influence the dynamic trend of antibodies and the memory cells count were assessed. The results showed with all the individuals observed in the present study had no detectable IgG antibody when 6 years after disease. Then by using ELISPOT method, we demonstrated a moderate SARS Ag-specific immunologic memory in the T cell, but not in the B cell in individuals whose anti-SARS antibody had disappeared. These data indicated that humoral immunological response and memory is short-lived after SARS infection. Humal memory T cell responses specific for SARS-CoV S proten could presist for 6 years in the absence of antigen, immunological response might provide long-term protection, however its ability in providing effective protection in case of SARS-CoV reexposure remained unclear.
医务人员(healthcare workers, HCW)是SARS感染的高危人群,其感染的危险/保护因素研究较多而结果并不一致。我们采用病例对照研究的方法,选取来自同一医院感染SARS的HCW病例51名,与SARS患者密切接触的HCW对照426名,利用标准调查问卷,对其在诊疗SARS患者时的危险因素及采取的防护措施进行了全面系统的回顾性调查。多因素logistic回归分析表明胸外心脏按压操作(调整OR=4.52,95%CI=1.08–18.81)和接触患者呼吸道分泌物(调整OR=3.27,95% CI=1.41–7.57)是HCW感染SARS的主要危险因素。戴12层棉纱口罩、16层棉纱口罩、多层防护口罩、预防服药、鼻腔清洗和防护知识培训6个因素是SARS发生的保护因素。
近期研究表明SARS发生、发展和预后等与宿主遗传因素有关。本研究选取抗病毒过程中发挥重要作用的基因白介素12受体β1(interleukin-12 receptorβ1, IL12Rβ1)作为候选易感基因,运用病例对照研究设计,采用聚合酶链式反应-限制性片段多态性(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)的方法,探讨IL12Rβ1基因多个SNP位点多态性与SARS的易感性关系。研究结果表明+705A/G、+1158T/C、+1196G/C位点的等位基因以及基因型在病例组和对照组中的分布频率没有显著性差异。+1664C/T(CT)和(TT)基因型在病例组中的分布显著高于对照组(P<0.05),ORs(95%CI)分别为2.09(1.90–7.16)和2.34(1.79–13.37)。单体型分析发现,+705A/G、+1158T/C以及+1196G/C三个位点存在强烈的连锁不平衡(D’=0.90–0.98),+1664C/T与其它三个位点之间存在中等程度的连锁不平衡,ATGC和GCCT单体型是最普遍的单体型,GCCT单体型在病例组中的分布频率显著高于对照组,ORs(95%CI)为2.31(1.72–8.47)。提示IL-12Rβ1基因多态性与中国汉族人群SARS发病存在关联,但与疾病的严重程度无显著性关联。
SARS感染后机体体液免疫状况,包括抗体水平及抗体持续时间是预防再次发生疾病流行的关健因素之一,然而对于抗体动态变化规律的持续时间和影响因素目前未有定论。本研究选取44例临床确诊并且血清抗体阳性的SARS患者进行了4年的追踪随访,用酶联免疫吸附试验(enzyme linked immunosorbent assay, ELISA)方法检测血清SARS-CoV特异性IgG抗体动态变化规律,同时收集流行病学和临床信息等相关资料,估计可能影响抗体水平变化的因素。结果表明,发病后第12、27、40、50个月IgG抗体阳性率分别为85%、80%、62%、32%;IgG抗体滴度的GMTs分别为1:31、1:27、1:13、1:6。生存分析显示不同激素用量、疾病严重程度和抗体转阴时间之间有显著性关联(P=0.033和P=0.024),激素用量越大,抗体水平下降越明显。从上述结果我们认为,4年后抗体滴度降低到保护性水平以下,保护性免疫只能持续有限时间。激素使用、疾病严重程度是影响抗体水平变化的重要因素。
虽然SARS病人的保护性免疫只能持续有限时间,但保护性抗体消失后,患者体内是否存在记忆性淋巴细胞免疫应答反应是决定机体再次接触SARS-CoV后是否患病的关键。本研究进行了SARS康复期患者SARS-CoV特异性T、B细胞淋巴细胞免疫应答反应。结果显示SARS康复期患者在发病6年后,不仅血清IgG抗体消失,而且体内SARS-CoV特异性记忆性B细胞水平也已不能检出,提示自然感染SARS-CoV后体液免疫反应及免疫记忆的持续时间有限。体内记忆性T细胞免疫应答能够维持一定水平,产生的淋巴细胞斑点数显著高于密切接触者和正常健康人群,其对于再次暴发的SARS流行能否提供免疫保护作用的问题仍然需要进一步探索。
本研究结合现场调查、实验室检测,综合应用描述流行病学、分析性流行病学等方法,阐明了SARS感染的环境危险因素及宿主遗传易感因素在SARS发病过程中的作用;通过对SARS队列进行6年的随访观察,阐明了人群免疫水平动态变化规律及其影响因素,通过ELISPOT试验方法,首次提出保护性抗体消失后,SARS康复期患者记忆性B淋巴细胞免疫反应不会长期存在,而记忆性T淋巴细胞免疫应答可在体内长期维持免疫记忆。本研究结果不仅为预防可能再次暴发的SARS提供防控措施和临床治疗的科学依据;同时也可为SARS疫苗开发、新药研制提供可以借鉴的新思路。
Severe acute respiratory syndrome (SARS) is an emerging infectious disease that caused a global epidemic in 2003. The clinical manifestations, laboratory findings, radiologic presentations, and outcomes of SARS for patients have been well described. Much of the epidemiology of the disease is still not fully understood.
Healthcare workers (HCW) were at the highest risk of having the disease. Risk factors for infection in HCWs have been studied extensively, and a review on SARS infection and healthcare workers disclosed a number of risk and protective factors, however with conflicting results from different studies. To evaluate possible risk and protective factors associated with infection of SARS among the HCWs by means of a case control study. Fifty-one infected and 426 uninfected staff members were included. All participants were surveyed about risk behaviours and protective measures when attending to SARS patients. Univariate and multivariate logistic regression analyses were performed to identify the major risk and protective factors. Multivariate analysis confirmed the strong role of performing chest compression (adjusted OR 4.52, 95% confidence interval [CI] 1.08-18.81) and contact with patient secretion (adjusted OR 3.27, 95%CI 1.41-7.57). For the studied protective measures, wearing 16-layer cotton surgical mask, wearing 12-layer cotton surgical mask and wearing multiple layers of mask, taking prophylactic medicine, training activity and nose washing remained protective from SARS infection.
The recent studies displayed the significant role of the genetic host factors in SARS infection. We conducted a case-control study to investigate the association between interleukin (IL)-12receptorβ1 (IL-12Rβ1) gene genetic polymorphisms and SARS in Chinese individuals. The genotypes of 4SNPs on IL-12Rβ1 gene, +705A/G, +1158T/C, +1196G/C and +1664C/T were determined by PCR-RFLP. Comparison between patients and close contacts showed that individuals with the +1664C/T (CT and TT) genotype had a 2.09-fold (95%CI 1.90–7.16) and 2.34-fold (95%CI 1.79–13.37) increased risk of developing SARS, respectively. For any of the other three polymorphisms, however, no significant difference can be detected in allele or genotype frequencies between patients and controls. Pairwise linkage disequilibrium (LD) analysis of the four SNPs showed strong LD among +705A/G, +1158T/C and +1196G/C SNPs (D, = 0.90–0.98) and modest LD value between +1664C/T and one of the other three SNPs (D, = 0.64–0.81), thus revealing two common haplotypes (A-T-G-C (705-1158-1196-1664) and G-C-C-T). The frequency of GCCT haplotype in SARS patients was significantly increased when compared to the control A group (ORs (95% CI) =2.31 (1.72–8.47).
Maintenance of long-term antibody responses is critical for protective immunity against SARS re-infection. However, the duration of humoral immunity has not yet been defined clearly. We performed a longitudinal analysis of antibody titers specific for viral SARS-CoV in 44 subjects for a period of up to 4 years. In addition, possible factors that might influence the dynamic trend of antibodies were assessed. The ELISA results showed positive rates of IgG antibody were 85%, 80%, 63% and 32%, at month 12, 27, 40 and 50, respectively. The geometric mean titers (GMT) of IgG antibody were 1:31, 1:27, 1:13, and 1:6 respectively at four time points after the disease. Survival analysis disclosed a significant association between the antibody duration and steroid use and disease severity, which was further confirmed in survival analysis when using the time of antibody negativation as outcome variable.
However, disappearance of anti-SARS antibodies does not necessarily indicate loss of protection. We then evaluated antigen-specific memory T-cell and B-cell response in 6-yr recovered SARS sample by means of ELISPOT. Possible factors that might influence the dynamic trend of antibodies and the memory cells count were assessed. The results showed with all the individuals observed in the present study had no detectable IgG antibody when 6 years after disease. Then by using ELISPOT method, we demonstrated a moderate SARS Ag-specific immunologic memory in the T cell, but not in the B cell in individuals whose anti-SARS antibody had disappeared. These data indicated that humoral immunological response and memory is short-lived after SARS infection. Humal memory T cell responses specific for SARS-CoV S proten could presist for 6 years in the absence of antigen, immunological response might provide long-term protection, however its ability in providing effective protection in case of SARS-CoV reexposure remained unclear.
引文
1. World Health Organization (2003) Cumulative number of reported probable cases of SARS [Online]. WHO. Available from: http://www.who.int/csr/sars/country/2003_07_11/en/index.html (Accessed: 15 October 2007)
2. Feng D, De Vlas SJ, Fang LQ et al. (2009) The SARS epidemic in mainland China: bringing together all epidemiological data. Trop Med Intern Health (in press)
3. Centers for Disease Control and Prevention (2003a) Cluster of severe acute respiratory syndrome cases among protected health-care workers—Toronto, Canada, April 2003. Morbidity and Mortality Weekly Report. 2003; 52: 433–436.
4. Seto WH, Tsang D, Yung RW et al. Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS).Lancet 2003;361:1519–1520.
5. Nishiura H, Kuratsuji T, Quy T & Anderson RM. Rapid awareness and transmission of severe acute respiratory syndrome in Hanoi French Hospital, Vietnam. American Journal of Tropical Medicine and Hygiene.2005; 73:17–25.
6. Chiu RW, Tang NL, Hui DS, Chung GT, Chim SS, et al. ACE2 gene polymorphisms do not affect outcome of severe acute respiratory syndrome. Clin Chem.2004; 50: 1683–1686.
7. Itoyama S, Keicho N, Hijikata M, Quy T, Phi NC, et al. Identification of an alternative 5,-untranslated exon and new polymorphisms of angiotensinconverting enzyme 2 gene: lack of association with SARS in the Vietnamese population. Am J Med Genet A.2005; 136: 52–57.
8. Itoyama S, Keicho N, Quy T, Phi NC, Long HT, et al. ACE1 polymorphism and progression of SARS. Biochem Biophys Res Commun.2004; 323: 1124–1129.
9. Ip WK, Chan KH, Law HK, Tso GH, Kong EK, et al. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. J Infect Dis. 2005; 191: 1697–1704.
10. Zhang H, Zhou G, Zhi L, Yang H, Zhai Y, et al. Association between mannose-binding lectin gene polymorphisms and susceptibility to severe acute respiratory syndrome coronavirus infection. J Infect Dis. 2005; 192:1355–1361.
11. He J, Feng D, de Vlas SJ, Wang H, Fontanet A, et al. Association of SARS susceptibility with single nucleic acid polymorphisms of OAS1 and MxA genes: a case-control study. BMC Infect Dis. 2006; 6:106–112.
12. Chong WP, Ip WK, Tso GH, Ng MW, Wong WH, et al. The interferon gamma gene polymorphism +874 A/T is associated with severe acute respiratory syndrome. BMC Infect Dis. 2006; 6: 82–86.
13. Ng MW, Zhou G, Chong WP, Lee LW, Law HK, et al. The association of RANTES polymorphism with severe acute respiratory syndrome in Hong Kong and Beijing Chinese. BMC Infect Dis.2007; 7: 50.
14. Chan KY, Ching JC, Xu MS, Cheung AN, Yip SP, et al. Association of ICAM3 genetic variant with severe acute respiratory syndrome. J Infect Dis. 2007; 196: 271–280
15. Cao WC, Liu W, Zhang PH, et al. Disappearance of Specific Antibodies to SARS-CoV in Recovered Patients. N Engl J Med. 2007; 357:1162-1163.
16. Liu w, Fontanet A, Zhang PH, et al. Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome. J Infect Dis. 2006; 193:792-795.
17. West D. J, Calandra, G.B. Vaccine induced immunologic memory for hepatitis B surface antigen:implications for policy on booster vaccination. Vaccine.1996; 14: 1019–1027.
18. Tilzey A. J. Hepatitis B vaccine boosting: the debate continues. Lancet.1995. 345: 1000–1001.
19. Margolis H. S. Prevention of acute and chronic liver disease through immunization: hepatitis B and beyond. J. Infect. Dis. 1993; 168: 9–14.
1. Yu IT, Li Y, Wong TW, et al. Evidence of airborne transmission of the severe acute respiratory syndrome virus. N Engl J Med.2004; 350: 1731–1739.
2. Centers for Disease Control and Prevention (2003a) Cluster of severe acute respiratory syndrome cases among protected health-care workers—Toronto, Canada, April 2003. Morbidity and Mortality Weekly Report. 2003; 52: 433–436.
3. Chan-Yeung M & Yu WC.Outbreak of severe acute respiratory syndrome in Hong Kong Special Administrative Region: case report. BMJ. 2003; 326: 850–852.
4. Lau JT, Fung KS, Wong TW. et al.SARS transmission among hospital workers in Hong Kong. Emerg Infect Dis.2004; 10:280–286.
5. Feng D, Vlas SJ, Fang LQ et al. (2009) The SARS epidemic in mainland China: bringing together all epidemiological data. (in press)
6. World Health Organization (2003) Case definitions for surveillance of severe acute respiratory syndrome (SARS). WHO, Geneva. (http://www.who.int/csr/sars/casedefinition/ en ?). Accessed June 2003.
7.马淮健,王宏伟,方立群,等.医务人员SARS感染的危险因素病例对照研究.中华流行病学杂志,2004, 25 (9):741-744.
8. Teleman MD, Boudville IC, Heng BH, Zhu D & Leo YS. Factors associated with transmission of severe acute respiratory syndrome among health-care workers in Singapore. Epidemiology and Infection. 2004; 132:797–803.
9. Ofner M, Lem M, Sarwal S, Vearncombe M & Simor. A Cluster of severe acute respiratory syndrome cases among protected health care workers-Toronto 2003. Canada Communicable Disease Report.2003;29:93–97.
10. Fowler RA, Guest CB, Lapinsky SE, et al. Transmission of severe acute respiratory syndrome during intubation and mechanical ventilation. American Journal of Respiratory and Critical Care Medicine. 2004; 169:1198–1120
11. Centers for Disease Control and Prevention (2003b) Outbreak of severe acute respiratory syndrome—worldwide. Morbidity and Mortality Weekly Report 2003; 52:226–228.
12. Ruan YJ, Wei CL, Ee AL,et al. Comparative full-length genome sequence analysis of 14 SARS coronavirus isolates and common mutations associated with putative origins of infection.Lancet. 2003; 361:1779–1785.
13. Seto WH, Tsang D, Yung RW ,et al. Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS).Lancet; 2003;361:1519–1520.
14. Nishiura H, Kuratsuji T, Quy T & Anderson RM. Rapid awareness and transmission of severe acute respiratory syndrome in Hanoi French Hospital, Vietnam. American Journal of Tropical Medicine and Hygiene.2005; 73:17–25.
15. Varia M, Wilson S, Sarwal S ,et al. Investigation of a nosocomial outbreak of severe acute respiratory syndrome (SARS)in Toronto, Canada. CMAJ. 2003; 169:285–292.
16. Loeb M, McGeer A, Henry B, et al. SARS among critical care nurses, Toronto. Emerg Infect Dis. 2004; 10:251– 255.
1. Peiris JS, Guan Y, Yuen KY. Severe acute respiratory syndrome. Nat Med. 2004;10: S88–97.
2. Lau YL, Peiris JS. Pathogenesis of severe acute respiratory syndrome. Curr Opin Immunol. 2005; 17: 404–410.
3. Booth CM, Matukas LM, Tomlinson GA, Rachlis AR, Rose DB, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA.2003;289: 2801–2809.
4. Chan JW, Ng CK, Chan YH, Mok TY, Lee S, et al. Short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (SARS).Thorax. 2003; 58: 686–689.
5. Chiu RW, Tang NL, Hui DS, Chung GT, Chim SS, et al. ACE2 gene polymorphisms do not affect outcome of severe acute respiratory syndrome. Clin Chem.2004; 50: 1683–1686.
6. Itoyama S, Keicho N, Hijikata M, Quy T, Phi NC, et al. Identification of an alternative
5,-untranslated exon and new polymorphisms of angiotensinconverting enzyme 2 gene: lack of association with SARS in the Vietnamese population. Am J Med Genet A.2005; 136: 52–57.
7. Itoyama S, Keicho N, Quy T, Phi NC, Long HT, et al. ACE1 polymorphism and progression of SARS. Biochem Biophys Res Commun.2004; 323: 1124–1129.
8. Ip WK, Chan KH, Law HK, Tso GH, Kong EK, et al. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. J Infect Dis. 2005; 191: 1697–1704.
9. Zhang H, Zhou G, Zhi L, Yang H, Zhai Y, et al. Association between mannose-binding lectin gene polymorphisms and susceptibility to severe acute respiratory syndrome coronavirus infection. J Infect Dis. 2005; 192:1355–1361.
10. He J, Feng D, de Vlas SJ, Wang H, Fontanet A, et al. Association of SARS susceptibility with single nucleic acid polymorphisms of OAS1 and MxA genes: a case-control study. BMC Infect Dis. 2006; 6:106–112.
11. Chong WP, Ip WK, Tso GH, Ng MW, Wong WH, et al. The interferon gamma gene polymorphism +874 A/T is associated with severe acute respiratory syndrome. BMC Infect Dis. 2006; 6: 82–86.
12. Ng MW, Zhou G, Chong WP, Lee LW, Law HK, et al. The association of RANTES polymorphism with severe acute respiratory syndrome in Hong Kong and Beijing Chinese. BMC Infect Dis.2007; 7: 50.
13. Chan KY, Ching JC, Xu MS, Cheung AN, Yip SP, et al. Association of ICAM3 genetic variantwith severe acute respiratory syndrome. J Infect Dis. 2007; 196: 271–280.
14. Trinchieri G. Proinflammatory and immunoregulatory functions of interleukin-12. Int Rev Immunol.1998; 16: 365–396.
15. Dorman SE, Holland SM. Interferon-gamma and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev. 2000; 11: 321–333.
16. Cameron MJ, Ran L, Xu L, Danesh A, Bermejo-Martin JF, et al. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. J Virol. 2007; 81: 8692–8706.
17. WHO (2003) Case definitions for surveillance of severe acute respiratory syndrome (SARS). Geneva: World Health Organization, (http://www.who.int/ csr/sars/casedefinition/en/). Accessed June 2003.
18. Lee HW, Lee HS, Kim DK, Ko DS, Han SK, et al. Lack of an Association between Interleukin-12Receptor B1 Polymorphisms and Tuberculosis in Koreans. Respiration.2005;72: 365–368.
19. Nyholt DR. A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet. 2004; 74: 765–769.
20. Fieschi C, Dupuis S, Catherinot E, Feinberg J, Bustamante J, et al. Low penetrance, broad resistance, and favorable outcome of Interleukin 12 receptor B1 deficiency: medical and immunological implications. J Exp Med. 2003; 197: 527–535.
21. Caragol I, Raspall M, Fieschi C, Feinberg J, Larrosa MN, et al. Clinical tuberculosis in 2 of 3 siblings with interleukin-12 receptor B1 deficiency. Clin Infect Dis. 2003; 37: 302–306.
22. Staretz-Haham O, Melamed R, Lifshitz M, Porat N, Fieschi C, et al. Interleukin-12 receptor B1 deficiency presenting as recurrent Salmonella infection. Clin Infect Dis. 2003; 37: 137–140.
23. Sakai T, Matsuoka M, Aoki M, Nosaka K, Mitsuya H. Missense mutation of interleukin-12 receptor b1 chain-encoding gene is associated with impaired immunity against Mycobacterium avium complex infection. Blood.2001; 97: 2688–2694.
24. Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol.2004; 136: 95–103.
25. Kennedy MK, Picha KS, Shanebeck KD, Anderson DM, Grabstein KH. Interleukin-12 regulates the proliferation of Th1, but not Th2 or Th0, clones. Eur J Immunol. 1994;24: 2271–2278.
26. Manetti R, Gerosa F, Giudizi MG, Biagiotti R, Parronchi P, et al. Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFNgamma production in established Th2 cell clones. J Exp Med. 1994; 179:1273–1283.
27. Van Reeth K, Van Gucht S, Pensaert M. In vivo studies on cytokine involvement during acute viral respiratory disease of swine: troublesome but rewarding. Vet Immunol Immunopathol.2002; 87: 161–168.
1. Christian MD, SM Poutanen, MR Loutfy, et al. Severe acute respiratory syndrome. Clin Infect Dis 2004; 38:1420–1427.
2. Peiris JS, Yuen KY, Osterhaus AD, et al. The severe acute respiratory syndrome. N Engl J Med. 2003; 349:2431–2441.
3. Wang JT, Chang SC. Severe acute respiratory syndrome. Curr Opin Infect Dis. 2004;17:143–148.
4. Wu LP, Wang NC, Chang YH, et al. Duration of antibody responses after severe acute respiratory syndrome. Emerg Infect Dis. 2007; 13:1562-1564.
5. Cao WC, Liu W, Zhang PH, et al. Disappearance of Specific Antibodies to SARS-CoV in Recovered Patients. N Engl J Med. 2007; 357:1162-1163.
6. Liu w, Fontanet A, Zhang PH, et al. Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome. J Infect Dis. 2006; 193:792-795.
7. Hseuh PR, CH Hsiao, SH Yeh, et al. Microbiologic characteristics, serologic response, and clinical manifestations in severe acute respiratory syndrome, Taiwan. Emerg Infect Dis. 2003; 9:1163–1167.
8. Nie Y, Wang G, Shi X, et al. Neutralizing antibodies in patients with severe acute respiratory syndrome-associated coronavirus infection. J Infect Dis. 2004;190:1119–26.
9. Li G, Chen X, Xu A. Profile of specific antibodies to the SARS associated coronavirus. N Engl J Med. 2003; 349:508–509.
10. Peiris J, Chu CM, Cheng V, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: A prospective study. Lancet. 2003;361:1767–1772.
11. Zhang LQ, Zhang Fw, Yu W, et al. Antibody responses against SARS coronavirus are correlated with disease outcome of infected individuals. J Med Virol.2006; 78:1–8.
12. Liu X, Shi Y, Li P, et al. Profile of antibodies to the nucleocapsid protein of the severe acute respiratory syndrome (SARS)-associated coronavirus in probable SARS patients. Clin Diagn Lab Immunol. 2004; 11:227–228.
13. Chang SC, Wang JT, Huang LM, et al. Longitudinal Analysis of Severe Acute Respiratory Syndrome (SARS) Coronavirus-Specific Antibody in SARS Patients. Clin Diagn Lab Immunol. 2005; 12:1455–1457.
14. Mo H, Zeng G, Ren X, et al. Longitudinal profile of antibodies against SARS-coronavirus in SARS patients and their clinical significance. Respirology. 2006; 11:49–53.
15. Woo PC, Lau SK, Wong BH, et al. Longitudinal profile of immunoglobulin G (IgG), IgM, and IgA antibodies against the severe acute respiratory syndrome (SARS) coronavirus nucleocapsidprotein in patients with pneumonia due to the SARS coronavirus. Clin Diagn Lab Immunol. 2004; 11:665–668.
16. Temperton NJ, Chan PK, Simmons G, et al. Longitudinally profiling neutralizing antibody response to SARS coronavirus with pseudotypes. Emerg Infect Dis.2005; 11:411–416.
17. Lee N, Chan PK, Ip M, et al Anti-SARS-CoV IgG response in relation to disease severity of severe acute respiratory syndrome. J Clin Virol. 2006; 35:179–184.
18. He Z, Dong Q, Zhuang H, Song S, Peng, G. Luo G and Dwyer DE. Kinetics of severe acute respiratory syndrome (SARS) coronavirus specific antibodies in 271 laboratory-confirmed cases of SARS. Clin Diagn Lab Immunol. 2004; 11:792–4.
19. Hsueh, PR, Huang LM, Chen PJ, Kao CL, and Yang PC. Chronological evolution of IgM, IgA, IgG and neutralization antibodies after infection with SARS-associated coronavirus. Clin Microbiol Infect.2004;10:1062–1066.
20. Tso EY, Tsang OT, Lam B, Ng TK, Lim W, Lai TS. Natural course of Severe Acute Respiratory Syndrome–Associated Coronavirus immunoglobulin after infection. J Infect Dis. 2004;190: 1706-1707.
21. Chen W, Xu Z, Mu J, et al. Antibody response and viraemia during the course of severe acute respiratory syndrome (SARS)–associated coronavirus infection. J Med Microbiol. 2004; 53: 435–438.
22. Booth CM, Matukas LM, Tomlinson GA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003;289:2801–2809.
23. Wang SX, Li YM, Chang AH, et al. The Emergence and Containment of Severe acute respiratory syndrome epidemic in a general hospital (Wang SX and Li YM submitted)
24. Wang ShX, Li YM, Sun BC, et al.The SARS outbreak in a general hospital in Tianjin, China -- the case of super-spreader. Epidemiol Infect. 2006; 134:786-791.
25. WHO. Case definitions for surveillance of severe acute respiratorysyndrome (SARS). (2003) http://www.who.int/csr/sars/casedefinition/en/.
26. Woo PCY, Lau SKP, Wong BHL, et al. Detection of specific antibodies to severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein for serodiagnosis of SARS coronavirus pneumonia. J Clin Microbiol. 2004; 42:2306-2309.
27. Nicholls JM, Poon LL, Lee KC, et al. Lung pathology of fatal severe acute respiratory syndrome. Lancet. 2003; 361:1773–1778.
28. Wong KT, Antonio GE, Hui DS, et al. Severe acute respiratory syndrome: Radiographic appearances and pattern of progression in 138 patients. Radiology. 2003; 228:401–406.
29. Slifka MK, Antia R, Whitmire JK, Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity. 1998.8:363-72.
30. Bernasconi NL, Traggiai E, Lanzavecchia A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science. 2002.298:2199-2202.
31. Maruyama M, Lam KP, Rajewsky K. Memory B-cell persistence is independent of persisting immunizing antigen. Nature.2000. 407:636-642.
1. Liu w, Fontanet A, Zhang PH, et al. Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome. J Infect Dis. 2006; 193:792-795.
2. Cao WC, Liu W, Zhang PH, et al. Disappearance of Specific Antibodies to SARS-CoV in Recovered Patients. N Engl J Med. 2007; 357:1162-1163.
3. Wu LP, Wang NC, Chang YH, et al. Duration of antibody responses after severe acute respiratory syndrome. Emerg Infect Dis. 2007; 13:1562-1564.
4. Li G, Chen X, Xu A. Profile of specific antibodies to the SARS associated coronavirus. N Engl J Med. 2003; 349:508–509.
5. Peiris J, Chu CM, Cheng V, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: A prospective study. Lancet. 2003;361:1767–1772.
6. Hseuh PR, CH Hsiao, SH Yeh, et al. Microbiologic characteristics, serologic response, and clinical manifestations in severe acute respiratory syndrome, Taiwan. Emerg Infect Dis 2003; 9:1163–1167.
7. Tso EY, Tsang OT, Lam B, Ng TK, Lim W, Lai TS. Natural course of Severe Acute Respiratory Syndrome–Associated Coronavirus immunoglobulin after infection. J Infect Dis. 2004;190: 1706-1707.
8. Chen W, Xu Z, Mu J, et al. Antibody response and viraemia during the course of severe acute respiratory syndrome (SARS)–associated coronavirus infection. J Med Microbiol. 2004; 53: 435–438.
9. Booth CM, Matukas LM, Tomlinson GA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003;289:281–2809.
10. Crotty S, Kersh EN, Cannons J, Schwartzberg PL and Ahmed R. SAP is required for generating long-term humoral immunity. Nature. 2003;421:282.
11. Manz RA, Arce S, Cassese G, Hauser AE, Hiepe F, and Radbruch A. Humoral immunity and long-lived plasma cells. Curr Opin Immunol. 2002; 14:517.
12. Slifka MK, Antia R, Whitmire JK and Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity 1998; 8:363.
13. Bernasconi NL, Traggiai Eand Lanzavecchia A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science. 2002 ; 298:2199.
14. West DJ, Calandra GB. Vaccine induced immunologic memory for hepatitis B surface antigen:implications for policy on booster vaccination. Vaccine.1996; 14: 1019–1027.
15. Tilzey AJ. Hepatitis B vaccine boosting: the debate continues. Lancet.1995. 345: 1000–1001.
16.Margolis H S. Prevention of acute and chronic liver disease through immunization: hepatitis B and beyond. J. Infect. Dis. 1993; 168: 9–14.
17.杨利桃,朱兆玲,刘惠萍,等.SARS康复者特异性细胞免疫和免疫记忆T细胞功的研究.中华微生物学和免疫学杂志,2005, 25 (3):214-217.
18.杨利桃,朱兆玲,刘惠萍,等.SARS康复者M抗原特异性记忆性T细胞免疫应答的探讨.免疫学杂志,2006, 22 (5):512-218.
19. Yang LT, Peng H, Zhu ZL, et al. Long-lived effector/central memory T-cell responses to severe acute respiratory syndrome coronavirus (SARS-CoV) S antigen in recovered SARS patients. Clin immunol. 2006;120:171-178.
20. Li CK, Wu H, Yang HP, et al. T cell responses to whole SARS coronavirus in humans. J immunol. 2008;181:5490-5500.
21. Li TS , Qiu ZF , Han Y, et al. Rapid loss of both CD4 + and CD8+T lymphocyte subsets during the acute phase of severe acute respiratory syndrome. Chin Med J, 2003, 116: 985-987.
22. Tang XP , Yin ZB , Zhang FC , et al. Measurement of subgroups of peripheral blood T lymphocytes in patients with severe acute respiratory syndrome and its clinical significance. Chin Med J. 2003, 116:827-830.
23.金荣华,张永宏,任翊,等.恢复期SARS患者T淋巴细胞凋亡相关基因蛋白表达.中国免疫学杂志,2004 , 20 (2) : 97-99.
24. Wang Z,Yuan Z,Matsumoto M,et al . Immune responses with DNA vaccines encoded different gene fragments of severe acute respiratory syndrome coronavirus in BablPc mice. Biochem Biophys Res Commun.2005 ; 327(1) :130 - 13521.
25. Yang ZY, Kong WP , Huang Y, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature.2004; 428: 561-564.
26. Huang JL ,Huang J ,Duan ZH ,et al. Th2 predominance and CD8 + memory T cell depletion in patients with severe acute respiratory syndrome[J ] . Microbes Infect, 2005, 7 (3):427-436.
27. Peng H, Yang LT, Wang LY, et al. Long-live memory T lymphocyte responses against SARS coronavirus nucleocapsid protein in SARS-recovered patients. Virology.2006; 351:466-475.
28. Rappuoli R, Miller HI and Falkow S. Medicine: the intangible value of vaccination. Science.2002; 297:937.
29. Crotty S, Felgner P, Davies H, et al. Long term B cell memory in humans after smallpox vaccination. J. Immunol. 2003a; 171: 4969– 4973.
30. Slifka MK, Ahmed R. Limiting dilution analysis of virusspecific memory B cells by an ELISPOT assay. J. Immunol. Methods. 1996; 199:37–46.
31. Hammarlund E, Lewis M.W, Hansen SG, et al. Duration of antiviral immunity after smallpox vaccination. Nat Med.2003; 9: 1131– 1137.
32. Maruyama M, Lam KP, Rajewsky K. Memory B-cell persistence is independent of persistingimmunizing antigen. Nature. 2000; 407:636–642.
33. Amanna IJ, Carlson N , Slifka M K. Duration of Humoral Immunity to Common Viral and Vaccine Antigens. N Engl J Med.2007; 357: 1903–1915.
34.Wang YD , Fion Sin WY, Xu GB , et al . T cell epitopes in severe acute respiratory syndrome (SARS) coronavirus spike protein elicit a specific T cell immune response in patients who recover from SARS. J virol. 2004;78 (11): 561225618.
35. Wang BM, Chen HB , Jiang XD , et al . Identification of an HLA2A *02012restricted CD8 + T cell epitope SSp-1 of SARS-CoV spike protein. Blood.2004; 104 (1): 200-206.
36. Huang JL ,Huang J ,Duan ZH ,et al. Th2 predominance and CD8 + memory T cell depletion in patients with severe acute respiratory syndrome[J ] . Microbes Infect, 2005, 7 (3):427-436.
1. Perlman S, Dandekar AA. Immunopathogenesis of coronavirus infections: implications for SARS. Nat. Rev. Immunol. 2005; 5:917–927.
2. Chen J, Subbarao K. The immunobiology of SARS. Annu Rev Immunol. 2007; 25:443-472.
3.张剑平,冯鑫,刘顺爱,等.SARS患者外周血NK细胞和B淋巴细胞的动态变化及发病机理初探.中国免疫学杂志, 2003,19:378-380.
4.贺莉,丁彦青,王蔚,等.免疫细胞在SARS病变组织中的表达及其作用.第一军医大学学报,2003, 23(8):774-780.
5.国家SARS防治紧急科技行动北京组.传染性非典型肺炎患者外周血自然杀伤细胞数量及其表面杀伤细胞免疫球蛋白样受体变化的研究.中华医学杂志,2004, 84(4):299-300.
6. GlassWG, Subbarao K, Murphy B, Murphy PM. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J. Immunol. 2004; 173:4030–4039
7. Chen JH, Chang YW, Yao CW, Chiueh TS, Huang SC, et al. Plasma proteome of severe acute respiratory syndrome analyzed by two-dimensional gel electrophoresis and mass spectrometry. Proc. Natl. Acad. Sci. USA 2004; 101:17039–44.
8. Cinatl J Jr, Michaelis M, Scholz M, Doerr HW. 2004. Role of interferons in the treatment of severe acute respiratory syndrome. Expert. Opin. Biol. Ther. 4:827–36.
9. Spiegel M, Pichlmair A, Martinez-Sobrido L, Cros J, Garcia-Sastre A, et al. Inhibition of beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor 3. J. Virol. 2005; 79:2079–86.
10. Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, et al. Treatment of SARS with human interferons. Lancet.2003;362:293–294.
11. Haagmans BL, Kuiken T, Martina BE, Fouchier RA, Rimmelzwaan GF, et al. Pegylated interferon-αprotects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat. Med. 2004;10:290-293.
12. Yilla M, Harcourt BH, Hickman CJ, McGrew M, Tamin A, et al. SARS-coronavirus replication in human peripheral monocytes/macrophages. Virus Res. 2005; 107:93–101.
13. Cheung CY, Poon LL, Ng IH, Luk W, Sia SF, et al. Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J. Virol. 2005; 79:7819–7826.
14. Tseng CT, Perrone LA, Zhu H, Makino S, Peters CJ. Severe acute respiratory syndrome and the innate immune responses: modulation of effector cell function without productive infection. J. Immunol. 2005; 174:7977–7985.
15. Poon LL, Guan Y, Nicholls JM, Yuen KY, Peiris JS. The etiology, origins, and diagnosis of severe acute respiratory syndrome. Lancet Infect. Dis. 2004; 4:663–671
16. Cheung CY, Poon LL, Ng IH, Luk W, Sia SF, et al. Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J. Virol. 2005; 79:7819–7826.
17. Law HK, Cheung CY,NgHY, Sia SF, Chan YO, et al. Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells. Blood .2005; 106:2366–2374.
18. Ng LF, Hibberd ML, Ooi EE, Tang KF, Neo SY, et al. A human in vitro model system for investigating genome-wide host responses to SARS coronavirus infection. BMC Infect. Dis. 2004; 4:34.
19. Tang NL, Chan PK,Wong CK, To KF,Wu AK, et al. Early enhanced expression ofinterferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome. Clin. Chem. 2005; 51:2333–2340.
20. Jiang Y, Xu J, Zhou C, Wu Z, Zhong S, et al. Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. Am. J. Respir. Crit. Care Med. 2005; 171:850 857.
21. Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin. Exp. Immunol. 2004; 136:95–103.
22. Huang KJ, Su IJ, Theron M,Wu YC, Lai SK, et al. An interferon-γ-related cytokine storm in SARS patients. J. Med. Virol. 2005 ; 75:185–194.
23. Ng PC, Lam CW, Li AM, Wong CK, Cheng FW, et al. Inflammatory cytokine profile in children with severe acute respiratory syndrome. Pediatrics 2004;113:e7–14.
24. Zhang Y, Li J, Zhan Y,Wu L, Yu X, et al. Analysis of serum cytokines in patients with severe acute respiratory syndrome. Infect. Immun. 2004 ; 72:4410–4415.
25. Lee CH, Chen RF, Liu JW, Yeh WT, Chang JC, et al. Altered p38 mitogenactivated protein kinase expression in different leukocytes with increment of immunosuppressive mediators in patients with severe acute respiratory syndrome. J. Immunol.2004; 172:7841–7847.
26. Cheng VC, Hung IF, Tang BS, Chu CM, Wong MM, et al. Viral replication in the nasopharynx is associated with diarrhea in patients with severe acute respiratory syndrome. Clin. Infect. Dis. 2004; 38:467–475.
27. Peiris JS, Yu WC, Leung CW, Cheung CY, Ng WF, et al. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet. 2004; 363:617–619.
28. Reghunathan R, Jayapal M, Hsu LY, Chng HH, Tai D, et al. Expression profile of immune response genes in patients with severe acute respiratory syndrome. BMC Immunol. 2005;6:2.
29. Cheung CY, Poon LL, Lau AS, LukW, Lau YL, et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 2002;360:1831–1837.
30. Yang ZY, Kong WP , Huang Y, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice.Nature, 2004, 428:561-564.
31. Wang YD , Fion Sin WY, Xu GB , et al . T-cell epitopes in severe acute respiratory syndrome (SARS) coronavirus spike protein elicit a specific T-cell immune response in patients who recover from SARS. J virol, 2004, 78 (11): 5612-5618.
32. Jin H ,Xiao C ,Chen Z, et al. Induction of Th1 type response by DNA vaccinations with N, M and E genes against SARS2 CoV in mice . Biochem Biophys Res Commun, 2005, 328 (4):979 - 986.
33. Wang BM, Chen HB, Jiang XD, et al. Identification of an HLA-A*0201-restricted CD8 + T-cell epitope SSp-1 of SARS-CoV spike protein. Blood, 2004, 104 (1): 200-206.
34. Poccia F, Agrati C, Castilletti C, Bordi L, Gioia C, et al. Anti-severe acute respiratory syndrome coronavirus immune responses: the role played by Vγ9Vδ2 T cells. J. Infect. Dis. 2006; 193:1244–1249
35. Huang JL ,Huang J ,Duan ZH ,et al. Th2 predominance and CD8 + memory T cell depletion in patients with severe acute respiratory syndrome . Microbes Infect, 2005, 7 (3):427-436.
36. Peng H, Yang LT, Wang LY, Li J, Huang J, et al. Long-lived memory T lymphocyte responses against SARS coronavirus nucleocapsid protein in SARS-recovered patients. Virolog. 2006; 351:466–475.
37.杨利桃,朱兆玲,刘惠萍,等.SARS康复者特异性细胞免疫和免疫记忆T细胞功能的研究.中华微生物学和免疫学杂志,2005 , 25 (3) : 214-217.
38.杨利桃,朱兆玲,刘惠萍,等.SARS康复者M抗原特异性T细胞免疫应答的探讨.免疫学杂志,2006 , 5(22): 214-217.
39. Wong RS, Wu A, To KF, Lee N, Lam CW, et al. Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis. BMJ 2003; 326:1358–1362.
40. He Z, Zhao C, Dong Q, Zhuang H, Song S, et al. Effects of severe acute respiratory syndrome (SARS) coronavirus infection on peripheral blood lymphocytes and their subsets. Int. J. Infect. Dis. 2005;9:323–330.
41. Li T, Qiu Z, Han Y, et al. Rapid loss of both CD4 + and CD8 + T lymphocyte subsets during the acute phase of severe acute respiratory syndrome. Chin Med J, 2003, 116 (7): 985-987.
42. Tang XP, Yin ZB, Zhang FC, et al. Measurement of subgroups of peripheral blood Tlymphocytes in patients with severe acute respiratory syndrome and its clinical significance. Chin Med J, 2003, 116 (7): 827-830.
43.杨民,路遥,付琦,等.SARS患者T淋巴细胞亚群的改变及动态观察.中华微生物学和免疫学杂志, 2003,23(12) : 936-938.
44.吴昊,张永宏,陈新月.严重急性呼吸综合征的细胞免疫功能研究.中华传染病学杂志,2003,21(5) : 936-938.
45.张永宏,吴昊,陈新月,等.SARS患者T细胞及其亚群数量变化的动态观察.首都医科大学学报,2003,24(4) : 392-395.
46.李太生,邱志峰,韩扬,等.严重急性呼吸综合征急性期T淋巴细胞亚群异常改变.中华检验医学杂志,2003 ,26 (5) :297-299.
47.王福生,徐东平.SARS冠状病毒的特点和致病机制的研究.传染病信息,2003 ,16(2) ,67-68.
48.赵景明,周光德.传染性非典型肺炎的病理研究近况及进展.传染病信,2003 ,16(2)∶69-70.
49.郎振为,张立洁,张世杰,等.严重呼吸综合征3例尸解病理分析.2003中华医学会系列杂志SARS研究论文集,2003 ,117-120.
50.国家SARS防治紧急科技行动北京组.严重急性呼吸综合征患者外周血B细胞亚群及CD40表达变化的意义.中华结核和呼吸杂志,2003 , 26 (10) : 590-593.
51. Hsueh PR, Huang LM, Chen PJ, Kao CL, Yang PC. 2004. Chronological evolution of IgM, IgA, IgG and neutralization antibodies after infection with SARS-associated coronavirus. Clin. Microbiol. Infect. 10:1062–1066.
52.李刚,陈雪娟,陈文思,等.20例SARS患者特异性抗体变化规律.中国免疫学杂志, 2003,19 (6) :372-375.
53. Cao WC, Liu W, Zhang PH, et al. Disappearance of Specific Antibodies to SARS-CoV in Recovered Patients. N Engl J Med. 2007; 357:1162-1163.
54. Nie Y,Wang G, Shi X, Zhang H, Qiu Y, et al. Neutralizing antibodies in patients with severe acute respiratory syndrome-associated coronavirus infection. J. Infect. Dis. 2004;190:1119–1126.
55. Buchholz UJ, Bukreyev A, Yang L, Lamirande EW, Murphy BR, et al. Contributions of the structural proteins of severe acute respiratory syndrome coronavirus to protective immunity. Proc. Natl. Acad. Sci. USA 2004 ;101:9804–9809.
56. Lu L, Manopo I, Leung BP, Chng HH, Ling AE, et al. Immunological characterization of the spike protein of the severe acute respiratory syndrome coronavirus. J. Clin. Microbiol. 2004; 42:1570–1576.
57. Leung GM, Hedley AJ, Ho LM, Chau P, Wong IO, et al. The epidemiology of severe acute respiratory syndrome in the 2003 Hong Kong epidemic: an analysis of all 1755 patients. Ann. Intern. Med. 2004; 141:662–673.
58. Hon KL, Leung CW, Cheng WT, Chan PK, Chu WC, et al. Clinical presentations and outcome of severe acute respiratory syndrome in children. Lancet 2003; 361:1701–1703.
59.段红梅,申昆玲.儿童SARS特点与免疫关系探讨.中国小儿急救医学,2006,13 (3) :281-282.
60. Vennema H, de Groot RJ, Harbour DA, Dalderup M, Gruffydd-Jones T, et al. Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization. J. Virol. 1990 ;64:1407–1409.
61. Bisht H, Roberts A, Vogel L, Bukreyev A, Collins PL, et al. Severe acute respiratory syndrome coronavirus spike protein expressed by attenuated vaccinia virus protectively immunizes mice. Proc. Natl. Acad. Sci. USA 2004; 101:6641–6646.
62. Stadler K, Roberts A, Becker S, Vogel L, Eickmann M, et al. SARS vaccine protective in mice. Emerg. Infect. Dis. 2005; 11:1312–1314.
63. Yang ZY, Kong WP, Huang Y, Roberts A, Murphy BR, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature.2004; 428:561–564.
64. Greenough TC, Babcock GJ, Roberts A, Hernandez HJ, Thomas WD Jr, et al. Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective immunoprophylaxis in mice. J. Infect. Dis. 2005; 191:507–514.
2. Feng D, De Vlas SJ, Fang LQ et al. (2009) The SARS epidemic in mainland China: bringing together all epidemiological data. Trop Med Intern Health (in press)
3. Centers for Disease Control and Prevention (2003a) Cluster of severe acute respiratory syndrome cases among protected health-care workers—Toronto, Canada, April 2003. Morbidity and Mortality Weekly Report. 2003; 52: 433–436.
4. Seto WH, Tsang D, Yung RW et al. Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS).Lancet 2003;361:1519–1520.
5. Nishiura H, Kuratsuji T, Quy T & Anderson RM. Rapid awareness and transmission of severe acute respiratory syndrome in Hanoi French Hospital, Vietnam. American Journal of Tropical Medicine and Hygiene.2005; 73:17–25.
6. Chiu RW, Tang NL, Hui DS, Chung GT, Chim SS, et al. ACE2 gene polymorphisms do not affect outcome of severe acute respiratory syndrome. Clin Chem.2004; 50: 1683–1686.
7. Itoyama S, Keicho N, Hijikata M, Quy T, Phi NC, et al. Identification of an alternative 5,-untranslated exon and new polymorphisms of angiotensinconverting enzyme 2 gene: lack of association with SARS in the Vietnamese population. Am J Med Genet A.2005; 136: 52–57.
8. Itoyama S, Keicho N, Quy T, Phi NC, Long HT, et al. ACE1 polymorphism and progression of SARS. Biochem Biophys Res Commun.2004; 323: 1124–1129.
9. Ip WK, Chan KH, Law HK, Tso GH, Kong EK, et al. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. J Infect Dis. 2005; 191: 1697–1704.
10. Zhang H, Zhou G, Zhi L, Yang H, Zhai Y, et al. Association between mannose-binding lectin gene polymorphisms and susceptibility to severe acute respiratory syndrome coronavirus infection. J Infect Dis. 2005; 192:1355–1361.
11. He J, Feng D, de Vlas SJ, Wang H, Fontanet A, et al. Association of SARS susceptibility with single nucleic acid polymorphisms of OAS1 and MxA genes: a case-control study. BMC Infect Dis. 2006; 6:106–112.
12. Chong WP, Ip WK, Tso GH, Ng MW, Wong WH, et al. The interferon gamma gene polymorphism +874 A/T is associated with severe acute respiratory syndrome. BMC Infect Dis. 2006; 6: 82–86.
13. Ng MW, Zhou G, Chong WP, Lee LW, Law HK, et al. The association of RANTES polymorphism with severe acute respiratory syndrome in Hong Kong and Beijing Chinese. BMC Infect Dis.2007; 7: 50.
14. Chan KY, Ching JC, Xu MS, Cheung AN, Yip SP, et al. Association of ICAM3 genetic variant with severe acute respiratory syndrome. J Infect Dis. 2007; 196: 271–280
15. Cao WC, Liu W, Zhang PH, et al. Disappearance of Specific Antibodies to SARS-CoV in Recovered Patients. N Engl J Med. 2007; 357:1162-1163.
16. Liu w, Fontanet A, Zhang PH, et al. Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome. J Infect Dis. 2006; 193:792-795.
17. West D. J, Calandra, G.B. Vaccine induced immunologic memory for hepatitis B surface antigen:implications for policy on booster vaccination. Vaccine.1996; 14: 1019–1027.
18. Tilzey A. J. Hepatitis B vaccine boosting: the debate continues. Lancet.1995. 345: 1000–1001.
19. Margolis H. S. Prevention of acute and chronic liver disease through immunization: hepatitis B and beyond. J. Infect. Dis. 1993; 168: 9–14.
1. Yu IT, Li Y, Wong TW, et al. Evidence of airborne transmission of the severe acute respiratory syndrome virus. N Engl J Med.2004; 350: 1731–1739.
2. Centers for Disease Control and Prevention (2003a) Cluster of severe acute respiratory syndrome cases among protected health-care workers—Toronto, Canada, April 2003. Morbidity and Mortality Weekly Report. 2003; 52: 433–436.
3. Chan-Yeung M & Yu WC.Outbreak of severe acute respiratory syndrome in Hong Kong Special Administrative Region: case report. BMJ. 2003; 326: 850–852.
4. Lau JT, Fung KS, Wong TW. et al.SARS transmission among hospital workers in Hong Kong. Emerg Infect Dis.2004; 10:280–286.
5. Feng D, Vlas SJ, Fang LQ et al. (2009) The SARS epidemic in mainland China: bringing together all epidemiological data. (in press)
6. World Health Organization (2003) Case definitions for surveillance of severe acute respiratory syndrome (SARS). WHO, Geneva. (http://www.who.int/csr/sars/casedefinition/ en ?). Accessed June 2003.
7.马淮健,王宏伟,方立群,等.医务人员SARS感染的危险因素病例对照研究.中华流行病学杂志,2004, 25 (9):741-744.
8. Teleman MD, Boudville IC, Heng BH, Zhu D & Leo YS. Factors associated with transmission of severe acute respiratory syndrome among health-care workers in Singapore. Epidemiology and Infection. 2004; 132:797–803.
9. Ofner M, Lem M, Sarwal S, Vearncombe M & Simor. A Cluster of severe acute respiratory syndrome cases among protected health care workers-Toronto 2003. Canada Communicable Disease Report.2003;29:93–97.
10. Fowler RA, Guest CB, Lapinsky SE, et al. Transmission of severe acute respiratory syndrome during intubation and mechanical ventilation. American Journal of Respiratory and Critical Care Medicine. 2004; 169:1198–1120
11. Centers for Disease Control and Prevention (2003b) Outbreak of severe acute respiratory syndrome—worldwide. Morbidity and Mortality Weekly Report 2003; 52:226–228.
12. Ruan YJ, Wei CL, Ee AL,et al. Comparative full-length genome sequence analysis of 14 SARS coronavirus isolates and common mutations associated with putative origins of infection.Lancet. 2003; 361:1779–1785.
13. Seto WH, Tsang D, Yung RW ,et al. Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS).Lancet; 2003;361:1519–1520.
14. Nishiura H, Kuratsuji T, Quy T & Anderson RM. Rapid awareness and transmission of severe acute respiratory syndrome in Hanoi French Hospital, Vietnam. American Journal of Tropical Medicine and Hygiene.2005; 73:17–25.
15. Varia M, Wilson S, Sarwal S ,et al. Investigation of a nosocomial outbreak of severe acute respiratory syndrome (SARS)in Toronto, Canada. CMAJ. 2003; 169:285–292.
16. Loeb M, McGeer A, Henry B, et al. SARS among critical care nurses, Toronto. Emerg Infect Dis. 2004; 10:251– 255.
1. Peiris JS, Guan Y, Yuen KY. Severe acute respiratory syndrome. Nat Med. 2004;10: S88–97.
2. Lau YL, Peiris JS. Pathogenesis of severe acute respiratory syndrome. Curr Opin Immunol. 2005; 17: 404–410.
3. Booth CM, Matukas LM, Tomlinson GA, Rachlis AR, Rose DB, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA.2003;289: 2801–2809.
4. Chan JW, Ng CK, Chan YH, Mok TY, Lee S, et al. Short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (SARS).Thorax. 2003; 58: 686–689.
5. Chiu RW, Tang NL, Hui DS, Chung GT, Chim SS, et al. ACE2 gene polymorphisms do not affect outcome of severe acute respiratory syndrome. Clin Chem.2004; 50: 1683–1686.
6. Itoyama S, Keicho N, Hijikata M, Quy T, Phi NC, et al. Identification of an alternative
5,-untranslated exon and new polymorphisms of angiotensinconverting enzyme 2 gene: lack of association with SARS in the Vietnamese population. Am J Med Genet A.2005; 136: 52–57.
7. Itoyama S, Keicho N, Quy T, Phi NC, Long HT, et al. ACE1 polymorphism and progression of SARS. Biochem Biophys Res Commun.2004; 323: 1124–1129.
8. Ip WK, Chan KH, Law HK, Tso GH, Kong EK, et al. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. J Infect Dis. 2005; 191: 1697–1704.
9. Zhang H, Zhou G, Zhi L, Yang H, Zhai Y, et al. Association between mannose-binding lectin gene polymorphisms and susceptibility to severe acute respiratory syndrome coronavirus infection. J Infect Dis. 2005; 192:1355–1361.
10. He J, Feng D, de Vlas SJ, Wang H, Fontanet A, et al. Association of SARS susceptibility with single nucleic acid polymorphisms of OAS1 and MxA genes: a case-control study. BMC Infect Dis. 2006; 6:106–112.
11. Chong WP, Ip WK, Tso GH, Ng MW, Wong WH, et al. The interferon gamma gene polymorphism +874 A/T is associated with severe acute respiratory syndrome. BMC Infect Dis. 2006; 6: 82–86.
12. Ng MW, Zhou G, Chong WP, Lee LW, Law HK, et al. The association of RANTES polymorphism with severe acute respiratory syndrome in Hong Kong and Beijing Chinese. BMC Infect Dis.2007; 7: 50.
13. Chan KY, Ching JC, Xu MS, Cheung AN, Yip SP, et al. Association of ICAM3 genetic variantwith severe acute respiratory syndrome. J Infect Dis. 2007; 196: 271–280.
14. Trinchieri G. Proinflammatory and immunoregulatory functions of interleukin-12. Int Rev Immunol.1998; 16: 365–396.
15. Dorman SE, Holland SM. Interferon-gamma and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev. 2000; 11: 321–333.
16. Cameron MJ, Ran L, Xu L, Danesh A, Bermejo-Martin JF, et al. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. J Virol. 2007; 81: 8692–8706.
17. WHO (2003) Case definitions for surveillance of severe acute respiratory syndrome (SARS). Geneva: World Health Organization, (http://www.who.int/ csr/sars/casedefinition/en/). Accessed June 2003.
18. Lee HW, Lee HS, Kim DK, Ko DS, Han SK, et al. Lack of an Association between Interleukin-12Receptor B1 Polymorphisms and Tuberculosis in Koreans. Respiration.2005;72: 365–368.
19. Nyholt DR. A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet. 2004; 74: 765–769.
20. Fieschi C, Dupuis S, Catherinot E, Feinberg J, Bustamante J, et al. Low penetrance, broad resistance, and favorable outcome of Interleukin 12 receptor B1 deficiency: medical and immunological implications. J Exp Med. 2003; 197: 527–535.
21. Caragol I, Raspall M, Fieschi C, Feinberg J, Larrosa MN, et al. Clinical tuberculosis in 2 of 3 siblings with interleukin-12 receptor B1 deficiency. Clin Infect Dis. 2003; 37: 302–306.
22. Staretz-Haham O, Melamed R, Lifshitz M, Porat N, Fieschi C, et al. Interleukin-12 receptor B1 deficiency presenting as recurrent Salmonella infection. Clin Infect Dis. 2003; 37: 137–140.
23. Sakai T, Matsuoka M, Aoki M, Nosaka K, Mitsuya H. Missense mutation of interleukin-12 receptor b1 chain-encoding gene is associated with impaired immunity against Mycobacterium avium complex infection. Blood.2001; 97: 2688–2694.
24. Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol.2004; 136: 95–103.
25. Kennedy MK, Picha KS, Shanebeck KD, Anderson DM, Grabstein KH. Interleukin-12 regulates the proliferation of Th1, but not Th2 or Th0, clones. Eur J Immunol. 1994;24: 2271–2278.
26. Manetti R, Gerosa F, Giudizi MG, Biagiotti R, Parronchi P, et al. Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFNgamma production in established Th2 cell clones. J Exp Med. 1994; 179:1273–1283.
27. Van Reeth K, Van Gucht S, Pensaert M. In vivo studies on cytokine involvement during acute viral respiratory disease of swine: troublesome but rewarding. Vet Immunol Immunopathol.2002; 87: 161–168.
1. Christian MD, SM Poutanen, MR Loutfy, et al. Severe acute respiratory syndrome. Clin Infect Dis 2004; 38:1420–1427.
2. Peiris JS, Yuen KY, Osterhaus AD, et al. The severe acute respiratory syndrome. N Engl J Med. 2003; 349:2431–2441.
3. Wang JT, Chang SC. Severe acute respiratory syndrome. Curr Opin Infect Dis. 2004;17:143–148.
4. Wu LP, Wang NC, Chang YH, et al. Duration of antibody responses after severe acute respiratory syndrome. Emerg Infect Dis. 2007; 13:1562-1564.
5. Cao WC, Liu W, Zhang PH, et al. Disappearance of Specific Antibodies to SARS-CoV in Recovered Patients. N Engl J Med. 2007; 357:1162-1163.
6. Liu w, Fontanet A, Zhang PH, et al. Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome. J Infect Dis. 2006; 193:792-795.
7. Hseuh PR, CH Hsiao, SH Yeh, et al. Microbiologic characteristics, serologic response, and clinical manifestations in severe acute respiratory syndrome, Taiwan. Emerg Infect Dis. 2003; 9:1163–1167.
8. Nie Y, Wang G, Shi X, et al. Neutralizing antibodies in patients with severe acute respiratory syndrome-associated coronavirus infection. J Infect Dis. 2004;190:1119–26.
9. Li G, Chen X, Xu A. Profile of specific antibodies to the SARS associated coronavirus. N Engl J Med. 2003; 349:508–509.
10. Peiris J, Chu CM, Cheng V, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: A prospective study. Lancet. 2003;361:1767–1772.
11. Zhang LQ, Zhang Fw, Yu W, et al. Antibody responses against SARS coronavirus are correlated with disease outcome of infected individuals. J Med Virol.2006; 78:1–8.
12. Liu X, Shi Y, Li P, et al. Profile of antibodies to the nucleocapsid protein of the severe acute respiratory syndrome (SARS)-associated coronavirus in probable SARS patients. Clin Diagn Lab Immunol. 2004; 11:227–228.
13. Chang SC, Wang JT, Huang LM, et al. Longitudinal Analysis of Severe Acute Respiratory Syndrome (SARS) Coronavirus-Specific Antibody in SARS Patients. Clin Diagn Lab Immunol. 2005; 12:1455–1457.
14. Mo H, Zeng G, Ren X, et al. Longitudinal profile of antibodies against SARS-coronavirus in SARS patients and their clinical significance. Respirology. 2006; 11:49–53.
15. Woo PC, Lau SK, Wong BH, et al. Longitudinal profile of immunoglobulin G (IgG), IgM, and IgA antibodies against the severe acute respiratory syndrome (SARS) coronavirus nucleocapsidprotein in patients with pneumonia due to the SARS coronavirus. Clin Diagn Lab Immunol. 2004; 11:665–668.
16. Temperton NJ, Chan PK, Simmons G, et al. Longitudinally profiling neutralizing antibody response to SARS coronavirus with pseudotypes. Emerg Infect Dis.2005; 11:411–416.
17. Lee N, Chan PK, Ip M, et al Anti-SARS-CoV IgG response in relation to disease severity of severe acute respiratory syndrome. J Clin Virol. 2006; 35:179–184.
18. He Z, Dong Q, Zhuang H, Song S, Peng, G. Luo G and Dwyer DE. Kinetics of severe acute respiratory syndrome (SARS) coronavirus specific antibodies in 271 laboratory-confirmed cases of SARS. Clin Diagn Lab Immunol. 2004; 11:792–4.
19. Hsueh, PR, Huang LM, Chen PJ, Kao CL, and Yang PC. Chronological evolution of IgM, IgA, IgG and neutralization antibodies after infection with SARS-associated coronavirus. Clin Microbiol Infect.2004;10:1062–1066.
20. Tso EY, Tsang OT, Lam B, Ng TK, Lim W, Lai TS. Natural course of Severe Acute Respiratory Syndrome–Associated Coronavirus immunoglobulin after infection. J Infect Dis. 2004;190: 1706-1707.
21. Chen W, Xu Z, Mu J, et al. Antibody response and viraemia during the course of severe acute respiratory syndrome (SARS)–associated coronavirus infection. J Med Microbiol. 2004; 53: 435–438.
22. Booth CM, Matukas LM, Tomlinson GA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003;289:2801–2809.
23. Wang SX, Li YM, Chang AH, et al. The Emergence and Containment of Severe acute respiratory syndrome epidemic in a general hospital (Wang SX and Li YM submitted)
24. Wang ShX, Li YM, Sun BC, et al.The SARS outbreak in a general hospital in Tianjin, China -- the case of super-spreader. Epidemiol Infect. 2006; 134:786-791.
25. WHO. Case definitions for surveillance of severe acute respiratorysyndrome (SARS). (2003) http://www.who.int/csr/sars/casedefinition/en/.
26. Woo PCY, Lau SKP, Wong BHL, et al. Detection of specific antibodies to severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein for serodiagnosis of SARS coronavirus pneumonia. J Clin Microbiol. 2004; 42:2306-2309.
27. Nicholls JM, Poon LL, Lee KC, et al. Lung pathology of fatal severe acute respiratory syndrome. Lancet. 2003; 361:1773–1778.
28. Wong KT, Antonio GE, Hui DS, et al. Severe acute respiratory syndrome: Radiographic appearances and pattern of progression in 138 patients. Radiology. 2003; 228:401–406.
29. Slifka MK, Antia R, Whitmire JK, Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity. 1998.8:363-72.
30. Bernasconi NL, Traggiai E, Lanzavecchia A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science. 2002.298:2199-2202.
31. Maruyama M, Lam KP, Rajewsky K. Memory B-cell persistence is independent of persisting immunizing antigen. Nature.2000. 407:636-642.
1. Liu w, Fontanet A, Zhang PH, et al. Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome. J Infect Dis. 2006; 193:792-795.
2. Cao WC, Liu W, Zhang PH, et al. Disappearance of Specific Antibodies to SARS-CoV in Recovered Patients. N Engl J Med. 2007; 357:1162-1163.
3. Wu LP, Wang NC, Chang YH, et al. Duration of antibody responses after severe acute respiratory syndrome. Emerg Infect Dis. 2007; 13:1562-1564.
4. Li G, Chen X, Xu A. Profile of specific antibodies to the SARS associated coronavirus. N Engl J Med. 2003; 349:508–509.
5. Peiris J, Chu CM, Cheng V, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: A prospective study. Lancet. 2003;361:1767–1772.
6. Hseuh PR, CH Hsiao, SH Yeh, et al. Microbiologic characteristics, serologic response, and clinical manifestations in severe acute respiratory syndrome, Taiwan. Emerg Infect Dis 2003; 9:1163–1167.
7. Tso EY, Tsang OT, Lam B, Ng TK, Lim W, Lai TS. Natural course of Severe Acute Respiratory Syndrome–Associated Coronavirus immunoglobulin after infection. J Infect Dis. 2004;190: 1706-1707.
8. Chen W, Xu Z, Mu J, et al. Antibody response and viraemia during the course of severe acute respiratory syndrome (SARS)–associated coronavirus infection. J Med Microbiol. 2004; 53: 435–438.
9. Booth CM, Matukas LM, Tomlinson GA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003;289:281–2809.
10. Crotty S, Kersh EN, Cannons J, Schwartzberg PL and Ahmed R. SAP is required for generating long-term humoral immunity. Nature. 2003;421:282.
11. Manz RA, Arce S, Cassese G, Hauser AE, Hiepe F, and Radbruch A. Humoral immunity and long-lived plasma cells. Curr Opin Immunol. 2002; 14:517.
12. Slifka MK, Antia R, Whitmire JK and Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity 1998; 8:363.
13. Bernasconi NL, Traggiai Eand Lanzavecchia A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science. 2002 ; 298:2199.
14. West DJ, Calandra GB. Vaccine induced immunologic memory for hepatitis B surface antigen:implications for policy on booster vaccination. Vaccine.1996; 14: 1019–1027.
15. Tilzey AJ. Hepatitis B vaccine boosting: the debate continues. Lancet.1995. 345: 1000–1001.
16.Margolis H S. Prevention of acute and chronic liver disease through immunization: hepatitis B and beyond. J. Infect. Dis. 1993; 168: 9–14.
17.杨利桃,朱兆玲,刘惠萍,等.SARS康复者特异性细胞免疫和免疫记忆T细胞功的研究.中华微生物学和免疫学杂志,2005, 25 (3):214-217.
18.杨利桃,朱兆玲,刘惠萍,等.SARS康复者M抗原特异性记忆性T细胞免疫应答的探讨.免疫学杂志,2006, 22 (5):512-218.
19. Yang LT, Peng H, Zhu ZL, et al. Long-lived effector/central memory T-cell responses to severe acute respiratory syndrome coronavirus (SARS-CoV) S antigen in recovered SARS patients. Clin immunol. 2006;120:171-178.
20. Li CK, Wu H, Yang HP, et al. T cell responses to whole SARS coronavirus in humans. J immunol. 2008;181:5490-5500.
21. Li TS , Qiu ZF , Han Y, et al. Rapid loss of both CD4 + and CD8+T lymphocyte subsets during the acute phase of severe acute respiratory syndrome. Chin Med J, 2003, 116: 985-987.
22. Tang XP , Yin ZB , Zhang FC , et al. Measurement of subgroups of peripheral blood T lymphocytes in patients with severe acute respiratory syndrome and its clinical significance. Chin Med J. 2003, 116:827-830.
23.金荣华,张永宏,任翊,等.恢复期SARS患者T淋巴细胞凋亡相关基因蛋白表达.中国免疫学杂志,2004 , 20 (2) : 97-99.
24. Wang Z,Yuan Z,Matsumoto M,et al . Immune responses with DNA vaccines encoded different gene fragments of severe acute respiratory syndrome coronavirus in BablPc mice. Biochem Biophys Res Commun.2005 ; 327(1) :130 - 13521.
25. Yang ZY, Kong WP , Huang Y, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature.2004; 428: 561-564.
26. Huang JL ,Huang J ,Duan ZH ,et al. Th2 predominance and CD8 + memory T cell depletion in patients with severe acute respiratory syndrome[J ] . Microbes Infect, 2005, 7 (3):427-436.
27. Peng H, Yang LT, Wang LY, et al. Long-live memory T lymphocyte responses against SARS coronavirus nucleocapsid protein in SARS-recovered patients. Virology.2006; 351:466-475.
28. Rappuoli R, Miller HI and Falkow S. Medicine: the intangible value of vaccination. Science.2002; 297:937.
29. Crotty S, Felgner P, Davies H, et al. Long term B cell memory in humans after smallpox vaccination. J. Immunol. 2003a; 171: 4969– 4973.
30. Slifka MK, Ahmed R. Limiting dilution analysis of virusspecific memory B cells by an ELISPOT assay. J. Immunol. Methods. 1996; 199:37–46.
31. Hammarlund E, Lewis M.W, Hansen SG, et al. Duration of antiviral immunity after smallpox vaccination. Nat Med.2003; 9: 1131– 1137.
32. Maruyama M, Lam KP, Rajewsky K. Memory B-cell persistence is independent of persistingimmunizing antigen. Nature. 2000; 407:636–642.
33. Amanna IJ, Carlson N , Slifka M K. Duration of Humoral Immunity to Common Viral and Vaccine Antigens. N Engl J Med.2007; 357: 1903–1915.
34.Wang YD , Fion Sin WY, Xu GB , et al . T cell epitopes in severe acute respiratory syndrome (SARS) coronavirus spike protein elicit a specific T cell immune response in patients who recover from SARS. J virol. 2004;78 (11): 561225618.
35. Wang BM, Chen HB , Jiang XD , et al . Identification of an HLA2A *02012restricted CD8 + T cell epitope SSp-1 of SARS-CoV spike protein. Blood.2004; 104 (1): 200-206.
36. Huang JL ,Huang J ,Duan ZH ,et al. Th2 predominance and CD8 + memory T cell depletion in patients with severe acute respiratory syndrome[J ] . Microbes Infect, 2005, 7 (3):427-436.
1. Perlman S, Dandekar AA. Immunopathogenesis of coronavirus infections: implications for SARS. Nat. Rev. Immunol. 2005; 5:917–927.
2. Chen J, Subbarao K. The immunobiology of SARS. Annu Rev Immunol. 2007; 25:443-472.
3.张剑平,冯鑫,刘顺爱,等.SARS患者外周血NK细胞和B淋巴细胞的动态变化及发病机理初探.中国免疫学杂志, 2003,19:378-380.
4.贺莉,丁彦青,王蔚,等.免疫细胞在SARS病变组织中的表达及其作用.第一军医大学学报,2003, 23(8):774-780.
5.国家SARS防治紧急科技行动北京组.传染性非典型肺炎患者外周血自然杀伤细胞数量及其表面杀伤细胞免疫球蛋白样受体变化的研究.中华医学杂志,2004, 84(4):299-300.
6. GlassWG, Subbarao K, Murphy B, Murphy PM. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J. Immunol. 2004; 173:4030–4039
7. Chen JH, Chang YW, Yao CW, Chiueh TS, Huang SC, et al. Plasma proteome of severe acute respiratory syndrome analyzed by two-dimensional gel electrophoresis and mass spectrometry. Proc. Natl. Acad. Sci. USA 2004; 101:17039–44.
8. Cinatl J Jr, Michaelis M, Scholz M, Doerr HW. 2004. Role of interferons in the treatment of severe acute respiratory syndrome. Expert. Opin. Biol. Ther. 4:827–36.
9. Spiegel M, Pichlmair A, Martinez-Sobrido L, Cros J, Garcia-Sastre A, et al. Inhibition of beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor 3. J. Virol. 2005; 79:2079–86.
10. Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, et al. Treatment of SARS with human interferons. Lancet.2003;362:293–294.
11. Haagmans BL, Kuiken T, Martina BE, Fouchier RA, Rimmelzwaan GF, et al. Pegylated interferon-αprotects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat. Med. 2004;10:290-293.
12. Yilla M, Harcourt BH, Hickman CJ, McGrew M, Tamin A, et al. SARS-coronavirus replication in human peripheral monocytes/macrophages. Virus Res. 2005; 107:93–101.
13. Cheung CY, Poon LL, Ng IH, Luk W, Sia SF, et al. Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J. Virol. 2005; 79:7819–7826.
14. Tseng CT, Perrone LA, Zhu H, Makino S, Peters CJ. Severe acute respiratory syndrome and the innate immune responses: modulation of effector cell function without productive infection. J. Immunol. 2005; 174:7977–7985.
15. Poon LL, Guan Y, Nicholls JM, Yuen KY, Peiris JS. The etiology, origins, and diagnosis of severe acute respiratory syndrome. Lancet Infect. Dis. 2004; 4:663–671
16. Cheung CY, Poon LL, Ng IH, Luk W, Sia SF, et al. Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J. Virol. 2005; 79:7819–7826.
17. Law HK, Cheung CY,NgHY, Sia SF, Chan YO, et al. Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells. Blood .2005; 106:2366–2374.
18. Ng LF, Hibberd ML, Ooi EE, Tang KF, Neo SY, et al. A human in vitro model system for investigating genome-wide host responses to SARS coronavirus infection. BMC Infect. Dis. 2004; 4:34.
19. Tang NL, Chan PK,Wong CK, To KF,Wu AK, et al. Early enhanced expression ofinterferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome. Clin. Chem. 2005; 51:2333–2340.
20. Jiang Y, Xu J, Zhou C, Wu Z, Zhong S, et al. Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. Am. J. Respir. Crit. Care Med. 2005; 171:850 857.
21. Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin. Exp. Immunol. 2004; 136:95–103.
22. Huang KJ, Su IJ, Theron M,Wu YC, Lai SK, et al. An interferon-γ-related cytokine storm in SARS patients. J. Med. Virol. 2005 ; 75:185–194.
23. Ng PC, Lam CW, Li AM, Wong CK, Cheng FW, et al. Inflammatory cytokine profile in children with severe acute respiratory syndrome. Pediatrics 2004;113:e7–14.
24. Zhang Y, Li J, Zhan Y,Wu L, Yu X, et al. Analysis of serum cytokines in patients with severe acute respiratory syndrome. Infect. Immun. 2004 ; 72:4410–4415.
25. Lee CH, Chen RF, Liu JW, Yeh WT, Chang JC, et al. Altered p38 mitogenactivated protein kinase expression in different leukocytes with increment of immunosuppressive mediators in patients with severe acute respiratory syndrome. J. Immunol.2004; 172:7841–7847.
26. Cheng VC, Hung IF, Tang BS, Chu CM, Wong MM, et al. Viral replication in the nasopharynx is associated with diarrhea in patients with severe acute respiratory syndrome. Clin. Infect. Dis. 2004; 38:467–475.
27. Peiris JS, Yu WC, Leung CW, Cheung CY, Ng WF, et al. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet. 2004; 363:617–619.
28. Reghunathan R, Jayapal M, Hsu LY, Chng HH, Tai D, et al. Expression profile of immune response genes in patients with severe acute respiratory syndrome. BMC Immunol. 2005;6:2.
29. Cheung CY, Poon LL, Lau AS, LukW, Lau YL, et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 2002;360:1831–1837.
30. Yang ZY, Kong WP , Huang Y, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice.Nature, 2004, 428:561-564.
31. Wang YD , Fion Sin WY, Xu GB , et al . T-cell epitopes in severe acute respiratory syndrome (SARS) coronavirus spike protein elicit a specific T-cell immune response in patients who recover from SARS. J virol, 2004, 78 (11): 5612-5618.
32. Jin H ,Xiao C ,Chen Z, et al. Induction of Th1 type response by DNA vaccinations with N, M and E genes against SARS2 CoV in mice . Biochem Biophys Res Commun, 2005, 328 (4):979 - 986.
33. Wang BM, Chen HB, Jiang XD, et al. Identification of an HLA-A*0201-restricted CD8 + T-cell epitope SSp-1 of SARS-CoV spike protein. Blood, 2004, 104 (1): 200-206.
34. Poccia F, Agrati C, Castilletti C, Bordi L, Gioia C, et al. Anti-severe acute respiratory syndrome coronavirus immune responses: the role played by Vγ9Vδ2 T cells. J. Infect. Dis. 2006; 193:1244–1249
35. Huang JL ,Huang J ,Duan ZH ,et al. Th2 predominance and CD8 + memory T cell depletion in patients with severe acute respiratory syndrome . Microbes Infect, 2005, 7 (3):427-436.
36. Peng H, Yang LT, Wang LY, Li J, Huang J, et al. Long-lived memory T lymphocyte responses against SARS coronavirus nucleocapsid protein in SARS-recovered patients. Virolog. 2006; 351:466–475.
37.杨利桃,朱兆玲,刘惠萍,等.SARS康复者特异性细胞免疫和免疫记忆T细胞功能的研究.中华微生物学和免疫学杂志,2005 , 25 (3) : 214-217.
38.杨利桃,朱兆玲,刘惠萍,等.SARS康复者M抗原特异性T细胞免疫应答的探讨.免疫学杂志,2006 , 5(22): 214-217.
39. Wong RS, Wu A, To KF, Lee N, Lam CW, et al. Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis. BMJ 2003; 326:1358–1362.
40. He Z, Zhao C, Dong Q, Zhuang H, Song S, et al. Effects of severe acute respiratory syndrome (SARS) coronavirus infection on peripheral blood lymphocytes and their subsets. Int. J. Infect. Dis. 2005;9:323–330.
41. Li T, Qiu Z, Han Y, et al. Rapid loss of both CD4 + and CD8 + T lymphocyte subsets during the acute phase of severe acute respiratory syndrome. Chin Med J, 2003, 116 (7): 985-987.
42. Tang XP, Yin ZB, Zhang FC, et al. Measurement of subgroups of peripheral blood Tlymphocytes in patients with severe acute respiratory syndrome and its clinical significance. Chin Med J, 2003, 116 (7): 827-830.
43.杨民,路遥,付琦,等.SARS患者T淋巴细胞亚群的改变及动态观察.中华微生物学和免疫学杂志, 2003,23(12) : 936-938.
44.吴昊,张永宏,陈新月.严重急性呼吸综合征的细胞免疫功能研究.中华传染病学杂志,2003,21(5) : 936-938.
45.张永宏,吴昊,陈新月,等.SARS患者T细胞及其亚群数量变化的动态观察.首都医科大学学报,2003,24(4) : 392-395.
46.李太生,邱志峰,韩扬,等.严重急性呼吸综合征急性期T淋巴细胞亚群异常改变.中华检验医学杂志,2003 ,26 (5) :297-299.
47.王福生,徐东平.SARS冠状病毒的特点和致病机制的研究.传染病信息,2003 ,16(2) ,67-68.
48.赵景明,周光德.传染性非典型肺炎的病理研究近况及进展.传染病信,2003 ,16(2)∶69-70.
49.郎振为,张立洁,张世杰,等.严重呼吸综合征3例尸解病理分析.2003中华医学会系列杂志SARS研究论文集,2003 ,117-120.
50.国家SARS防治紧急科技行动北京组.严重急性呼吸综合征患者外周血B细胞亚群及CD40表达变化的意义.中华结核和呼吸杂志,2003 , 26 (10) : 590-593.
51. Hsueh PR, Huang LM, Chen PJ, Kao CL, Yang PC. 2004. Chronological evolution of IgM, IgA, IgG and neutralization antibodies after infection with SARS-associated coronavirus. Clin. Microbiol. Infect. 10:1062–1066.
52.李刚,陈雪娟,陈文思,等.20例SARS患者特异性抗体变化规律.中国免疫学杂志, 2003,19 (6) :372-375.
53. Cao WC, Liu W, Zhang PH, et al. Disappearance of Specific Antibodies to SARS-CoV in Recovered Patients. N Engl J Med. 2007; 357:1162-1163.
54. Nie Y,Wang G, Shi X, Zhang H, Qiu Y, et al. Neutralizing antibodies in patients with severe acute respiratory syndrome-associated coronavirus infection. J. Infect. Dis. 2004;190:1119–1126.
55. Buchholz UJ, Bukreyev A, Yang L, Lamirande EW, Murphy BR, et al. Contributions of the structural proteins of severe acute respiratory syndrome coronavirus to protective immunity. Proc. Natl. Acad. Sci. USA 2004 ;101:9804–9809.
56. Lu L, Manopo I, Leung BP, Chng HH, Ling AE, et al. Immunological characterization of the spike protein of the severe acute respiratory syndrome coronavirus. J. Clin. Microbiol. 2004; 42:1570–1576.
57. Leung GM, Hedley AJ, Ho LM, Chau P, Wong IO, et al. The epidemiology of severe acute respiratory syndrome in the 2003 Hong Kong epidemic: an analysis of all 1755 patients. Ann. Intern. Med. 2004; 141:662–673.
58. Hon KL, Leung CW, Cheng WT, Chan PK, Chu WC, et al. Clinical presentations and outcome of severe acute respiratory syndrome in children. Lancet 2003; 361:1701–1703.
59.段红梅,申昆玲.儿童SARS特点与免疫关系探讨.中国小儿急救医学,2006,13 (3) :281-282.
60. Vennema H, de Groot RJ, Harbour DA, Dalderup M, Gruffydd-Jones T, et al. Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization. J. Virol. 1990 ;64:1407–1409.
61. Bisht H, Roberts A, Vogel L, Bukreyev A, Collins PL, et al. Severe acute respiratory syndrome coronavirus spike protein expressed by attenuated vaccinia virus protectively immunizes mice. Proc. Natl. Acad. Sci. USA 2004; 101:6641–6646.
62. Stadler K, Roberts A, Becker S, Vogel L, Eickmann M, et al. SARS vaccine protective in mice. Emerg. Infect. Dis. 2005; 11:1312–1314.
63. Yang ZY, Kong WP, Huang Y, Roberts A, Murphy BR, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature.2004; 428:561–564.
64. Greenough TC, Babcock GJ, Roberts A, Hernandez HJ, Thomas WD Jr, et al. Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective immunoprophylaxis in mice. J. Infect. Dis. 2005; 191:507–514.