Skip to main content

Advertisement

SpringerLink
Log in

Endogenously Activated Interleukin-4 Differentiates Disease Progressors and Non-Progressors in Tuberculosis Susceptible Families: A 2-Year Biomarkers Follow-Up Study

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Objective

Dynamic cytokine profiles from endogenously activated T cells in transit from lymph node to the infected sites via the blood compartment after recent exposure to Mycobacterium tuberculosis may differentiate disease progressors from non-disease progressors in a BCG-vaccinated population.

Methods

Household contacts (N = 107) from families with (six families) or without (14 families) secondary cases were assessed for Types 1 and 2 cytokines serially in plasma of whole blood cultures without exogenous stimulation. “ARMS” PCR was carried out for detection of single nucleotide polymorphism T/A in IFN-γ +874.

Results

In the absence of IFN-γ expansion, raised IL-4 at 6 months was associated with disease progression in TB-susceptible families. Resistant families on the other hand showed overrepresentation of IFN-γ +874 A allele and expansion of IFN-γ secreting cells at 6 months followed by contraction at 12 months.

Conclusion

Six months may be an important checkpoint for biomarker assessment in high-risk individuals post-exposure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

CBA:

Cytometric bead array

TB:

Tuberculosis

HC:

Household contacts

PTB-I:

Pulmonary TB index case

AFB:

Acid-fast bacilli

PMN:

Pulmonary minimal disease

PMD:

Pulmonary moderate disease

PAD:

Pulmonary advance disease

DHC:

Disease household contacts

FHC:

Household contacts of family with secondary cases

TST:

Tuberculin skin test

SNP:

Single nucleotide polymorphism

PCR:

Polymerase chain reaction

Tcm:

T central memory

Tem:

T effector memory

References

  1. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR. An Essential role for Interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993;178(6):2249–54.

    Article  PubMed  CAS  Google Scholar 

  2. Jouanguy E, Dupuis S, Pallier A, Doffinger R, Fondaneche M-D, Fieschi C, et al. In a novel form of INF-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ. J Clin Invest. 2000;105(10):1429–36.

    Article  PubMed  CAS  Google Scholar 

  3. Jouanguy E, Altare F, Lamhamedi S, Revy P, Emile JF, Newport M, et al. Interferon gamma receptor deficiency in an infant with fatal Bacille Calmette-Guerin infection. N Engl J Med. 1996;335:1956–61.

    Article  PubMed  CAS  Google Scholar 

  4. Pierre-Audigier C, Jouanguy E, Lamhamedi S, Atlare F, Rauzier J, Vincent V. Fatal disseminated Mycobacterium smegmatis infection in a child with inherited interferon gamma receptor deficiency. Clin Infect Dis. 1997;24:982–4.

    Article  PubMed  CAS  Google Scholar 

  5. Rossouw M, Nel HJ, Cooke GS, van Helden PD, Hoal EG. Association between tuberculosis and a polymorphic NFkappaB binding site in the interferon gamma gene. Lancet. 2003;361:1871–2.

    Article  PubMed  CAS  Google Scholar 

  6. Leandro AC, Rocha MA, Cardoso CS, Bonecini-Almeida MG. Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-gamma genes and its association with susceptibility to tuberculosis. Braz J Med Biol Res. 2009;42(4):312–22.

    Article  PubMed  CAS  Google Scholar 

  7. Mansouri D, Adimi P, Mirsaeidi M, Mansouri N, Khalilzadeh S, Masjedi MR, et al. Inherited disorders of the IL-12-IFN-gamma axis in patients with disseminated BCG infection. Eur J Pediatr. 2005;164(12):753–7.

    Article  PubMed  CAS  Google Scholar 

  8. Chapgier A, Boisson-Dupuis S, Jouanguy E, Vogt G, Feinberg J, Prochnicka-Chalufour A, et al. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease 4. PLoS Genet. 2006;2(8):e131.

    Article  PubMed  Google Scholar 

  9. Cooke GS, Campbell SJ, Sillah J, Gustafson P, Bah B, Sirugo G, et al. Polymorphism within the Interferon-γ/Receptor Complex is associated with Pulmonary Tuberculosis. Am J Respir Crit Care Med. 2006;174:339–43.

    Article  PubMed  CAS  Google Scholar 

  10. Pacheco AG, Cardoso CC, Moraes MO. IFNG +874T/A, IL10–1082G/A and TNF -308G/A polymorphisms in association with tuberculosis susceptibility: a meta-analysis study. Hum Genet. 2008;123(5):477–84.

    Article  PubMed  CAS  Google Scholar 

  11. Nemeth J, Winkler HM, Boeck L, Adegnika AA, Clement E, Mve TM, et al. Specific cytokine patterns of pulmonary tuberculosis in Central Africa. Clin Immunol. 2011;138(1):50–9.

    Article  PubMed  CAS  Google Scholar 

  12. O’Garra A, Vieira PL, Vieira P, Goldfeld AE. IL-10 producing and naturally occurring CD4+ Tregs: limiting collateral damage. J Clin Invest. 2004;114(10):1372–8.

    PubMed  Google Scholar 

  13. Dlugovitzky D, Torres-Morales A, Rateni L, Farroni MA, Largacha C, Molteni O, et al. Circulating profile of Th1 and Th2 cytokines in tuberculosis patients with different degrees of pulmonary involvement. FEMS Immunol Med Microbiol. 1997;18:203–7.

    Article  PubMed  CAS  Google Scholar 

  14. Verbon A, Juffermans N, Deventer SJH, Speelman P, Deutekom HV, Poll TVD. Serum concentrations of cytokines in patients with active tuberculosis (TB) and after treatment. Clin Exp Immunol. 1999;115:110–3.

    Article  PubMed  CAS  Google Scholar 

  15. Hasan Z, Jamil B, Khan J, Ali R, Khan MA, Nasir N, et al. Relationship between circulating levels of IFN-gamma, IL-10, CXCL9 and CCL2 in pulmonary and extrapulmonary tuberculosis is dependent on disease severity. Scand J Immunol. 2009;69(3):259–67.

    Article  PubMed  CAS  Google Scholar 

  16. Dlugovitzky D, Bay ML, Rateni L, Urizar L, Rondelli CF, Largacha C, et al. In vitro synthesis of interferon-gamma, interleukin-4, transforming growth factor-beta and interleukin-1 beta by peripheral blood mononuclear cells from tuberculosis patients: relationship with the severity of pulmonary involvement. Scand J Immunol. 1999;49(2):210–7.

    Article  PubMed  CAS  Google Scholar 

  17. Hussain R, Kaleem A, Shahid F, Dojki M, Jamil B, Mehmood H, et al. Cytokine profiles using whole blood assays can discriminate between tuberculosis patients and healthy endemic controls in BCG-vaccinated population. J Immunol Meth. 2002;264:95–108.

    Article  CAS  Google Scholar 

  18. Barnes PF, Lu S, Abrams JS, Wang E, Yamamura M, Modlin RL. Cytokine production at the site of disease in human tuberculosis. Infect Immun. 1993;61(8):3482–8.

    PubMed  CAS  Google Scholar 

  19. Wilkinson KA, Wilkinson RJ, Pathan A, Ewer K, Prakash M, Klenerman P, et al. Ex Vivo characterization of early secretory antigenic target 6-specific T cells at sites of active disease in pleural tuberculosis. Clin Infect Dis. 2005;40:184–7.

    Article  PubMed  Google Scholar 

  20. Hirsch CS, Toossi Z, Johnson JL, Luzze H, Ntambi L, Peters P, et al. Augmentation of apoptosis and interferon-gamma production at sites of active Mycobacterium tuberculosis infection in human tuberculosis. J Infect Dis. 2001;183(5):779–88.

    Article  PubMed  CAS  Google Scholar 

  21. Vankayalapati R, Wizel B, Weis SE, Klucar P, Shams H, Samten B, et al. Serum cytokine concentrations do not parallel Mycobacterium tuberculosis-induced cytokine production in patients with tuberculosis. Clin Infect Dis. 2003;36:24–8.

    Article  PubMed  CAS  Google Scholar 

  22. Jason J, Archibald LK, Nwanyanwu OC, Byrd MG, Kazembe PN, Dobbie H, et al. Comparison of serum and cell-specific cytokines in humans. Clin Diag Lab Immunol. 2001;8(6):1097–103.

    CAS  Google Scholar 

  23. WHO. Global Tuberculosis Control WHO report 2009: WHO/HTM/TB/2009411. Geneva: WHO; 2009. Report No.: WHO report 2009 Country Profile.

    Google Scholar 

  24. Akhtar S, White F, Hasan R, Rozi S, Younus M, Ahmed F, et al. Hyperendemic pulmonary tuberculosis in peri-urban areas of Karachi, Pakistan. BMC Public Health. 2007;7:70.

    Article  PubMed  Google Scholar 

  25. Tapaninen P, Korhonen A, Pusa L, Seppala I, Tuuminen T. Effector memory T-cells dominate immune responses in tuberculosis treatment: antigen or bacteria persistence? Int J Tuberc Lung Dis. 2010;14(3):347–55.

    PubMed  CAS  Google Scholar 

  26. Talat N, Shahid F, Perry S, Dawood G, Hussain R. Th1/Th2 Cytometric Bead Array can discriminate cytokine secretion from endogenously activated cells in pulmonary disease, recent and remote infection in tuberculosis. Cytokine. 2011;54(2):136–43.

    Article  PubMed  CAS  Google Scholar 

  27. Crofton J. Crofton and Douglas respiratory diseases. Clinical features of tuberculosis. 4th ed. London: Blackwell; 1990. p. 395–421.

    Google Scholar 

  28. Ansari A, Talat N, Jamil B, Hasan Z, Razzaki T, Dawood G, et al. Cytokine gene polymorphisms across tuberculosis clinical spectrum in Pakistani patients. PLoS One. 2009;4(3):e4778.

    Article  PubMed  Google Scholar 

  29. Talat N, Shahid F, Dawood G, Hussain R. Dynamic changes in biomarker profiles associated with clinical and subclinical tuberculosis in a high transmission setting: a four-year follow-up study. Scand J Immunol. 2009;69(6):537–46.

    Article  PubMed  CAS  Google Scholar 

  30. Comstock G. Epidemiology of tuberculosis. Am J Respir Crit Care Med. 1982;125:8–15.

    CAS  Google Scholar 

  31. Rook GA, Hernandez-Pando R, Dheda K, Teng SG. IL-4 in tuberculosis: implications for vaccine design. Trends Immunol. 2004;25(9):483–8.

    Article  PubMed  CAS  Google Scholar 

  32. Moller M, Hoal EG. Current findings, challenges and novel approaches in human genetic susceptibility to tuberculosis. Tuberculosis (Edinb). 2010;90(2):71–83.

    Article  CAS  Google Scholar 

  33. van der Eijk EA, van de Vosse E, Vandenbroucke JP, van Dissel JT. Heredity versus environment in tuberculosis in twins: the 1950s United Kingdom Prophit Survey Simonds and Comstock revisited. Am J Respir Crit Care Med. 2007;176(12):1281–8.

    Article  PubMed  Google Scholar 

  34. Mendez A, Hernandez-Pando R, Contreras S, Aguilar D, Rook GA. CCL2, CCL18 and sIL-4R in renal, meningeal and pulmonary TB; a 2 year study of patients and contacts. Tuberculosis (Edinb). 2011;91(2):140–5.

    Article  CAS  Google Scholar 

  35. Hussain R, Talat N, Shahid F, Dawood G. Longitudinal tracking of cytokines after acute exposure to Tuberculosis: Association of Distinct Cytokine patterns with protection and disease development. Clin Vaccine Immunol. 2007;14(12):1578–86.

    Article  PubMed  CAS  Google Scholar 

  36. Goletti D, Butera O, Bizzoni F, Casetti R, Girardi E, Poccia F. Region of difference 1 antigen-specific CD4+ memory T cells correlate with a favorable outcome of tuberculosis. J Infect Dis. 2006;194:984–92.

    Article  PubMed  CAS  Google Scholar 

  37. Kim SH, Lee CE. Counter-regulation mechanism of IL-4 and IFN-alpha signal transduction through cytosolic retention of the pY-STAT6:pY-STAT2:p48 complex. Eur J Immunol. 2011;41(2):461–72.

    Article  PubMed  CAS  Google Scholar 

  38. Apte SH, Groves P, Olver S, Baz A, Doolan DL, Kelso A, et al. IFN-gamma inhibits IL-4-induced type 2 cytokine expression by CD8 T cells in vivo and modulates the anti-tumor response. J Immunol. 2010;185(2):998–1004.

    Article  PubMed  CAS  Google Scholar 

  39. Bogdan C, Vodovotz Y, Paik J, Xie QW, Nathan C. Mechanism of suppression of nitric oxide synthase expression by interleukin-4 in primary mouse macrophages. J Leukoc Biol. 1994;55(2):227–33.

    PubMed  CAS  Google Scholar 

  40. Krutzik SR, Ochoa MT, Sieling PA, Uematsu S, Ng YW, Legaspi A, et al. Activation and regulation of Toll like receptors 2 and 1 in human leprosy. Nature Med. 2003;9(5):525–32.

    Article  PubMed  CAS  Google Scholar 

  41. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23–35.

    Article  PubMed  CAS  Google Scholar 

  42. Fletcher HA, Owiafe P, Jeffries D, Hill P, Rook GA, Zumla A, et al. Increased expression of mRNA encoding interleukin (IL)-4 and its splice variant IL-4delta2 in cells from contacts of Mycobacterium tuberculosis, in the absence of in vitro stimulation. Immunology. 2004;112(4):669–73.

    Article  PubMed  CAS  Google Scholar 

  43. Demissie A, Abebe M, Aseffa A, Rook G, Fletcher H, Zumla A, et al. Healthy individuals that control a latent infection with Mycobacterium tuberculosis express high levels of Th1 cytokines and the IL-4 antagonist IL-4delta2. J Immunol. 2004;172(11):6938–43.

    PubMed  CAS  Google Scholar 

  44. Luzina IG, Lockatell V, Todd NW, Keegan AD, Hasday JD, Atamas SP. Splice isoforms of human interleukin-4 are functionally active in mice in vivo. Immunology. 2011;132(3):385–93.

    Article  PubMed  CAS  Google Scholar 

  45. Dheda K, Chang JS, Breen RA, Kim LU, Haddock JA, Huggett JF, et al. In vivo and in vitro studies of a novel cytokine, interleukin 4delta2, in pulmonary tuberculosis. Am J Respir Crit Care Med. 2005;172(4):501–8.

    Article  PubMed  Google Scholar 

  46. Doganci A, Eigenbrod T, Krug N, De Sanctis GT, Hausding M, Erpenbeck VJ, et al. The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo. J Clin Invest. 2005;115(2):313–25.

    PubMed  CAS  Google Scholar 

  47. Biselli R, Mariotti S, Sargentini V, Sauzullo I, Lastilla M, Mengoni F, et al. Detection of interleukin-2 in addition to interferon-gamma discriminates active tuberculosis patients, latently infected individuals, and controls. Clin Microbiol Infect. 2010;16(8):1282–4.

    Article  PubMed  CAS  Google Scholar 

  48. Sargentini V, Mariotti S, Carrara S, Gagliardi MC, Teloni R, Goletti D, et al. Cytometric detection of antigen-specific IFN-gamma/IL-2 secreting cells in the diagnosis of tuberculosis. BMC Infect Dis. 2009;9:99.

    Article  PubMed  Google Scholar 

  49. Ribeiro-Rodrigues R. Resende Co T, Rojas R, Toossi Z, Dietze R, Boom WH, et al. A role of CD4+CD25+ T cells in regulation of the immune response during human tuberculosis. Clin Exp Immunol. 2006;144:25–34.

    Article  PubMed  CAS  Google Scholar 

  50. Elliot AM, Hodsdon WS, Kyosiimire J, Quigley MA, Nakiyingi JS, Namujju PB, et al. Cytokine responses and progression to active tuberculosis in HIV-1-infected Ugandans: a prospective study. Trans Roy SocTrop Med & Hyg. 2004;98:660–70.

    Article  Google Scholar 

Download references

Acknowledgements

We acknowledge the Higher Education Commission (HEC), Government of Pakistan for providing financial support for this project through Grant No. 20-796/R&D/07. We also thank Mr. Mohammed Anwar for blood collection and Ms Muniba Islam for technical support.

Author information

Authors and Affiliations

  1. Department of Pathology and Microbiology, Aga Khan University, Stadium Road, P.O. Box 3500, Karachi, 74800, Pakistan

    Rabia Hussain, Najeeha Talat, Ambreen Ansari, Firdaus Shahid & Zahra Hasan

  2. Masoomeen General Hospital, Kharadar Karachi, Pakistan

    Ghaffar Dawood

Authors
  1. Rabia Hussain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Najeeha Talat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ambreen Ansari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Firdaus Shahid
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zahra Hasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ghaffar Dawood
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rabia Hussain.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Figure S1

Cumulative frequency of disease progression in household contacts (HC = 110) of 20 families. Disease progression occurred over a period of 6–60 months. Diagnosis was based on signs and symptoms, hematology (N = 10), radiology (N = 10), microscopy (N = 3), and response to ATT treatment. Pulmonary disease was diagnosed in 9/10 DHC (4 = minimal, three moderate and two advanced lung involvement) and abdominal in 1/10 DHC. ATT was started immediately at diagnosis. All patients showed complete clinical recovery after ATT. (JPEG 56 kb)

High resolution image. (TIFF 121 kb)

Figure S2

IL-4 and IFN-γ responses in tuberculosis disease susceptible and resistant groups at 6 months post-exposure. Groups were assessed at 6 months (HC = 55, FHC = 30, DHC = 10); results are shown as mean responses (picograms per milliliter). All other details are the same as Fig. 1. (JPEG 38 kb)

High resolution image. (TIFF 111 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hussain, R., Talat, N., Ansari, A. et al. Endogenously Activated Interleukin-4 Differentiates Disease Progressors and Non-Progressors in Tuberculosis Susceptible Families: A 2-Year Biomarkers Follow-Up Study. J Clin Immunol 31, 913–923 (2011). https://doi.org/10.1007/s10875-011-9566-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-011-9566-y

Keywords

Search

Navigation