Current understanding of the immune response to tuberculosis in children

Current Opinion in Infectious Diseases

Volumn 25, Issue 3, 2012, Pages 250-257

  Basu Roy, Robindra ^a   Whittaker, Elizabeth ^a   Kampmann, Beate ^a,b  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

^b MEDICAL RESEARCH COUNCIL LABORATORIES   (Gambia)

Author keywords

adaptive immunity; immunity; innate; paediatrics; tuberculosis

Indexed keywords

VITAMIN D;

ADAPTIVE IMMUNITY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CHILDHOOD DISEASE; DIAGNOSTIC TEST; DIFFERENTIAL DIAGNOSIS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNE RESPONSE; INFECTION SENSITIVITY; INNATE IMMUNITY; LATENT TUBERCULOSIS; MYCOBACTERIOSIS; MYCOBACTERIUM TUBERCULOSIS; NEUTROPHIL; PATIENT MONITORING; PREVALENCE; REGULATORY T LYMPHOCYTE; REVIEW; TREATMENT RESPONSE; TUBERCULOSIS;

ADAPTIVE IMMUNITY; CHILD; CHILD, PRESCHOOL; CYTOKINES; HUMANS; IMMUNITY, INNATE; MYCOBACTERIUM TUBERCULOSIS; T-LYMPHOCYTES; TUBERCULOSIS;

EID: 84861094880     PISSN: 09517375     EISSN: 14736527     Source Type: Journal    
DOI: 10.1097/QCO.0b013e3283529af9     Document Type: Review

References (74)

1. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intrathoracic tuberculosis: A critical review of literature from the prechemotherapy era. Int J Tuberc Lung Dis 2004; 8:392-402.
2. Nicol MP, Workman L, Isaacs W, et al. Accuracy of the Xpert MTB/RIF test for the diagnosis of pulmonary tuberculosis in children admitted to hospital in Cape Town, South Africa: A descriptive study. Lancet Infect Dis 2011; 11:819-824. The first paediatric study to evaluate Xpert MTB/RIF which not only demonstrates its superiority to smear microscopy, but also highlights that a microbiological approach cannot be relied upon in paediatric TB.
3. Qu H-Q, Fisher-Hoch SP, McCormick JB. Molecular immunity to mycobacteria: Knowledge from the mutation and phenotype spectrum analysis of Mendelian susceptibility to mycobacterial diseases. Int J Infect Dis 2011; 15:e305-e313.
4. Cottle L. Mendelian susceptibility to mycobacterial disease. Clin Genet 2011; 79:17-22.
5. Bustamante J, Arias AA, Vogt G, et al. Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease. Nat Immunol 2011; 12:213-221. The authors identify a new X-linked member of the MSMD group, implicating macrophage respiratory burst as key in host defence.
6. Sester M, Giehl C, McNerney R, et al. Challenges and perspectives for improved management of HIV/Mycobacterium tuberculosis co-infection. Eur Respir J 2010; 36:1242-1247.
7. Marais BJ, Rabie H, Cotton MF. TB and HIV in children - advances in prevention and management. Paediatr Respir Rev 2011; 12:39-45. An excellent review of challenges of HIV-MTB co-infection in paediatrics.
8. Elenga N, Kouakoussui KA, Bonard D, et al. Diagnosed tuberculosis during the follow-up of a cohort of human immunodeficiency virus-infected children in Abidjan, Cote d'Ivoire: ANRS 1278 study. Pediatr Infect Dis J 2005; 24:1077-1082.
9. Jones CE, Naidoo S, De Beer C, et al. Maternal HIV infection and antibody responses against vaccine-preventable diseases in uninfected infants. JAMA 2011; 305:576-584. This highlighted reduced immunological responses and increased morbidity and mortality even in uninfected HIV-exposed infants.
10. Koyanagi A, Humphrey JH, Ntozini R, et al. Morbidity among human immunodeficiency virus-exposed but uninfected, human immunodeficiency virusinfected, and human immunodeficiency virus-unexposed infants in Zimbabwe before availability of highly active antiretroviral therapy. Pediatr Infect Dis J 2011; 30:45-51. The study highlighted reduced immunological responses and increased morbidity and mortality even in uninfected HIV-exposed infants.
11. Geldmacher C, Ngwenyama N, Schuetz A, et al. Preferential infection and depletion of Mycobacterium tuberculosis-specific CD4 T cells after HIV-1 infection. J Exp Med 2010; 207:2869-2881.
12. Clark S, Page E, Ford T, et al. Reduced TH1/TH17 CD4 T cell numbers are associated with impaired purified protein derivative-specific cytokine responses in patients with HIV-1 infection. J Allergy Clin Immunol 2011; 128:838-846.
13. Kampmann B, Tena-Coki GN, Nicol MP, et al. Reconstitution of antimycobacterial immune responses in HIV-infected children receiving HAART. AIDS 2006; 20:1011-1018.
14. Jones C, Whittaker E, Bamford A, Kampmann B. Immunology and pathogenesis of childhood TB. Paediatr Respir Rev 2011; 12:3-8.
15. Mendez-Samperio P. Role of antimicrobial peptides in host defense against mycobacterial infections. Peptides 2008; 29:1836-1841.
16. Heier I, Malmström K, Pelkonen A, et al. Bronchial response pattern of antigen presenting cells and regulatory T cells in children less than 2 years of age. Thorax 2008; 63:703-709.
17. Khoo A-L, Chai LYA, Koenen HJPM, et al. Vitamin D3 down-regulates proinflammatory cytokine response to Mycobacterium tuberculosis through pattern recognition receptors while inducing protective cathelicidin production. Cytokine 2011; 55:294-300.
18. Martineau AR, Wilkinson KA, Newton SM, et al. IFN-gamma and TNF-alpha independent vitamin D-inducible human suppression of Mycobacteria: The role of cathelicidin LL-37. J Immunol 2007; 178:7190-7198.
19. Fabri M, Stenger S, Shin DM, et al. Vitamin D is required for IFN-gamma mediated antimicrobial activity of human macrophages. Sci Transl Med 2011; 3:104ra2. The authors of this study investigated the antimicrobial mechanisms of TB-infected macrophages and determined that vitamin D is required for TH1 T cell released IFNg-induced activation.
20. Williams B, Williams A, Anderson S. Vitamin D deficiency and insufficiency in children with tuberculosis. Pediatr Infect Dis J 2008; 27:941-942.
21. Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D3 during intensive-phase antimicrobial treatment of pulmonary tuberculosis: A doubleblind randomised controlled trial. Lancet 2011; 377:242-250.
22. Lowe DM, Redford PS, Wilkinson RJ, et al. Neutrophils in tuberculosis: Friend or foe ? Trends Immunol 2012; 33:14-25. This excellent review summarizes the current knowledge of the role of the neutrophil in TB infection and disease.
23. Berry MPR, Graham CM, McNab FW, et al. An interferon-inducible neutrophildriven blood transcriptional signature in human tuberculosis. Nature 2010; 466:973-977.
24. Martineau AR, Newton SM, Wilkinson KA, et al. Neutrophil-mediated innate immune resistance to mycobacteria. J Clin Invest 2007; 117:1988-1994.
25. Filias A, Theodorou GL, Mouzopoulou S, et al. Phagocytic ability of neutrophils and monocytes in neonates. BMC Pediatr 2011; 11:29.
26. Lewinsohn DA, Gennaro ML, Scholvinck L, Lewinsohn DM. Tuberculosis immunology in children: Diagnostic and therapeutic challenges and opportunities. Int J Tuberc Lung Dis 2004; 8:658-674.
27. Sepulveda RL, Arredondo S, Rodriguez E, et al. Effect of human newborn BCG immunization on monocyte viability and function at 3 months of age. Int J Tuberc Lung Dis 1997; 1:122-127.
28. Gold MC, Robinson TL, Cook MS, et al. Human neonatal dendritic cells are competent in MHC class I antigen processing and presentation. PLoS One 2007; 2:e957.
29. Upham JW, Rate A, Rowe J, et al. Dendritic cell immaturity during infancy restricts the capacity to express vaccine-specific T-cell memory. Infect Immun 2006; 74:1106-1112.
30. White GP, Watt PM, Holt BJ, Holt PG. Differential patterns of methylation of the IFN-gamma promoter at CpG and non-CpG sites underlie differences in IFN-gamma gene expression between human neonatal and adult CD45RO- T cells. J Immunol 2002; 168:2820-2827.
31. Marais BJ, Gie RP, Schaaf HS, et al. The clinical epidemiology of childhood pulmonary tuberculosis: A critical review of literature from the prechemotherapy era. Int J Tuberc Lung Dis 2004; 8:278-285.
32. Shey MS, Hughes EJ, de Kock M, et al. Optimization of a whole blood intracellular cytokine assay for measuring innate cell responses to mycobacteria. J Immunol Methods 2012; 376:79-88.
33. Kollmann TR, Crabtree J, Rein-Weston A, et al. Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol 2009; 183:7150-7160.
34. Burl S, Townend J, Njie-Jobe J, et al. Age-dependent maturation of Toll-like receptor-mediated cytokine responses in Gambian infants. PLoS One 2011; 6:e18185. This study increases our understanding of age-related differences in TLR responses and may inform the development of vaccine adjuvant use for infants.
35. Swaminathan S, Gong J, Zhang M, et al. Cytokine production in children with tuberculous infection and disease. Clin Infect Dis 1999; 28:1290-1293.
36. Barber DL, Mayer-Barber KD, Feng CG, et al. CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J Immunol 2011; 186:1598-1607. Surprisingly, knockout of the inhibitory T-cell pathway in mice actually causes more severe disease.
37. Alvarez IB, Pasquinelli V, Jurado JO, et al. Role played by the programmed death-1-programmed death ligand pathway during innate immunity against Mycobacterium tuberculosis. J Infect Dis 2010; 202:524-532.
38. McNab FW, Berry MP, Graham CM, et al. Programmed death ligand 1 is overexpressed by neutrophils in the blood of patients with active tuberculosis. Eur J Immunol 2011; 41:1941-1947.
39. Gallegos AM, van Heijst JWJ, Samstein M, et al. A gamma interferon independent mechanism of CD4 T cell mediated control of M. tuberculosis infection in vivo. PLoS Pathog 2011; 7:e1002052. Again murine experiments highlight the need to challenge assumptions about the mechanism of T-cell function, although they are an imperfect model of disease.
40. Soares AP, Scriba TJ, Joseph S, et al. Bacillus Calmette-Guerin vaccination of human newborns induces T cells with complex cytokine and phenotypic profiles. J Immunol 2008; 180:3569-3577.
41. Commandeur S, Lin MY, van Meijgaarden KE, et al. Double- and monofunctional CD4+ and CD8+ T-cell responses to Mycobacterium tuberculosis DosR antigens and peptides in long-term latently infected individuals. Eur J Immunol 2011; 41:2925-2936.
42. Day CL, Abrahams DA, Lerumo L, et al. Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load. J Immunol 2011; 187:2222-2232. This approach shows potential, although it will be a challenge to translate into a widely used test.
43. Kagina BMN, Abel B, Scriba TJ, et al. Specific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after Bacillus Calmette-Guerin vaccination of newborns. Am J Respir Crit Care Med 2010; 182:1073-1079. It is of vital importance to correlate immunological measures to clinical outcomes in prospective studies such as this.
44. Semple PL, Watkins M, Davids V, et al. Induction of granulysin and perforin cytolytic mediator expression in 10-week-old infants vaccinated with BCG at birth. Clin Dev Immunol 2011; 2011:438463. This article contributes to our understanding of the innate immune response to BCG vaccination in neonates.
45. Quiroga MF, Pasquinelli V, Martínez GJ, et al. Inducible costimulator: A modulator of IFN-gamma production in human tuberculosis. J Immunol 2006; 176:5965-5974.
46. Nouailles G, Day TA, Kuhlmann S, et al. Impact of inducible co-stimulatory molecule (ICOS) on T-cell responses and protection against Mycobacterium tuberculosis infection. Eur J Immunol 2011; 41:981-991.
47. Tena-Coki NG, Scriba TJ, Peteni N, et al. CD4 and CD8 T-cell responses to mycobacterial antigens in African children. Am J Respir Crit Care Med 2010; 182:120-129. This study provides a detailed description of phenotype and function of T-cell subsets in children with TB and HIV.
48. Caccamo N, Guggino G, Meraviglia S, et al. Analysis of Mycobacterium tuberculosis-specific CD8 T-cells in patients with active tuberculosis and in individuals with latent infection. PLoS One 2009; 4:e5528-e15528.
49. Lancioni C, Nyendak M, Kiguli S, et al. CD8+ T cells provide an immunologic signature of tuberculosis in young children. Am J Respir Crit Care Med 2012; 185:206-212. Children under 5 represent the most challenging patient group, therefore the results here are of great importance.
50. Caccamo N, Meraviglia S, La Mendola C, et al. Phenotypical and functional analysis of memory and effector human CD8 T cells specific for mycobacterial antigens. J Immunol 2006; 177:1780-1785.
51. Beetz S, Wesch D, Marischen L, et al. Innate immune functions of human gammadelta T cells. Immunobiology 2008; 213:173-182.
52. Hoft DF, Brown RM, Roodman ST. Bacille Calmette-Guerin vaccination enhances human gammadelta T cell responsiveness to mycobacteria suggestive of a memory-like phenotype. J Immunol 1998; 161:1045-1054.
53. Dieli F, Sireci G, Caccamo N, et al. Selective depression of interferon-gamma and granulysin production with increase of proliferative response by Vgamma9/Vdelta2 T cells in children with tuberculosis. J Infect Dis 2002; 186:1835-1839.
54. Scriba TJ, Kalsdorf B, Abrahams D-a, et al. Distinct, specific IL-17- and IL-22- producing CD4 T cell subsets contribute to the human anti-mycobacterial immune response. J Immunol 2008; 180:1962-1970.
55. Kumar NP, Anuradha R, Suresh R, et al. Suppressed type 1, type 2, and type 17 cytokine responses in active tuberculosis in children. Clin Vaccine Immunol 2011; 18:1856-1864.
56. Scriba TJ, Tameris M, Mansoor N, et al. Modified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cells. Eur J Immunol 2010; 40:279-290.
57. Moretta A, Bottino C, Mingari MC, et al. What is a natural killer cell? Nat Immunol 2002; 3:6-8.
58. Roy S, Barnes PF, Garg A, et al. NK cells lyse T regulatory cells that expand in response to an intracellular pathogen. J Immunol 2008; 180:1729-1736.
59. Vankayalapati R, Barnes PF. Innate and adaptive immune responses to human Mycobacterium tuberculosis infection. Tuberculosis 2009; 89:S77-S80.
60. Di Liberto D, Buccheri S, Caccamo N, et al. Decreased serum granulysin levels in childhood tuberculosis which reverse after therapy. Tuberculosis 2007; 87:322-328.
61. Ulrichs T, Kosmiadi GA, Trusov V, et al. Human tuberculous granulomas induce peripheral lymphoid follicle-like structures to orchestrate local host defence in the lung. J Pathol 2004; 204:217-228.
62. Maglione PJ, Chan J. How B cells shape the immune response against Mycobacterium tuberculosis. Eur J Immunol 2009; 39:676-686.
63. Steingart KR, Flores LL, Dendukuri N, et al. Commercial serological tests for the diagnosis of active pulmonary and extrapulmonary tuberculosis: An updated systematic review and meta-analysis. PLoS Med 2011; 8:e1001062.
64. De Almeida AS, Fiske CT, Sterling TR, Kalams SA. Increased frequency of regulatory T cells and T lymphocyte activation in persons with previously treated extrapulmonary tuberculosis. Clin Vaccine Immunol 2012; 19:45-52.
65. Mandalakas A, Detjen A, Hesseling A, et al. Interferon-gamma release assays and childhood tuberculosis: Systematic review and meta-analysis. Int J Tuberc Lung Dis 2011; 15:1018-1032. See [67 & ].
66. Ling D, Zwerling A, Steingart K, Pai M. Immune-based diagnostics for TB in children: What is the evidence? Paediatr Resp Rev 2011; 12:9-15. See [67 & ].
67. Machingaidze S, Wiysonge CS, Gonzalez-Angulo Y, et al. The utility of an interferon gamma release assay for diagnosis of latent tuberculosis infection and disease in children: A systematic review and meta-analysis. Pediatr Infect Dis J 2011; 30:694-700. The recent paediatric reviews in the study provide a good overview.
68. Diel R, Goletti D, Ferrara G, et al. Interferon gamma release assays for the diagnosis of latent M. tuberculosis infection: A systematic review and metaanalysis. Eur Respir J 2011; 37:88-99.
69. Rangaka MX, Wilkinson KA, Glynn JR, et al. Predictive value of interferongamma release assays for incident active tuberculosis: A systematic review and meta-analysis. Lancet Infect Dis 2012; 12:45-55.
70. Kampmann B, Tena-Coki G, Anderson S. Blood tests for diagnosis of tuberculosis. Lancet 2006; 368:282-283.
71. Bamford AR, Angela CM, Clark J, et al. Comparison of interferon-gamma release assays and tuberculin skin test in predicting active tuberculosis (TB) in children in the UK - A Paediatric TB Network Study. Arch Dis Child 2010; 95:180-186.
72. Yassin MA, Petrucci R, Garie KT, et al. Can interferon-gamma or interferongamma- induced-protein-10 differentiate tuberculosis infection and disease in children of high endemic areas? PLoS One 2011; 6:e23733-e23740.
73. Alsleben N, Ruhwald M, Rüssmann H, et al. Interferon-gamma inducible protein 10 as a biomarker for active tuberculosis and latent tuberculosis infection in children: A case-control study. Scand J Infect Dis 2011. doi:10.3109/00365548.2011.632644). [Epub ahead of print]
74. Whittaker E, Gordon A, Kampmann B. Is IP-10 a better biomarker for active and latent tuberculosis in children than IFN-gamma? PLoS One 2008; 3:e3901.