Abnormal Immune Responses in Persons with Previous Extrapulmonary Tuberculosis in an In Vitro Model That Simulates In Vivo Infection with Mycobacterium tuberculosis

ABSTRACT Persons with previous extrapulmonary tuberculosis have reduced peripheral blood mononuclear cell cytokine production and CD4+ lymphocytes compared to persons with previous pulmonary tuberculosis or latent tuberculosis infection, but specific defects related to Mycobacterium tuberculosis infection of macrophages have not been characterized. The objective of this study was to further characterize the in vitro immune responses to M. tuberculosis infection in HIV-seronegative persons with previous extrapulmonary tuberculosis. Peripheral blood mononuclear cells were isolated from HIV-seronegative persons with previous extrapulmonary tuberculosis (n = 11), previous pulmonary tuberculosis (n = 21), latent M. tuberculosis infection (n = 19), and uninfected tuberculosis contacts (n = 20). Experimental conditions included M. tuberculosis-infected macrophages cultured with and without monocyte-depleted peripheral blood mononuclear cells. Concentrations of interleukin 1β (IL-1β), IL-4, IL-6, CXCL8 (IL-8), IL-10, IL-12p70, IL-17, CCL2 (monocyte chemoattractant protein 1), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) were measured by multiplex cytokine array. When M. tuberculosis-infected macrophages were cocultured with monocyte-depleted peripheral blood mononuclear cells, IFN-γ (P = 0.01), TNF-α (P = 0.04), IL-10 (P < 0.001), and IL-6 (P = 0.03) exhibited similar continua of responses, with uninfected persons producing the lowest levels, followed by extrapulmonary tuberculosis cases, pulmonary tuberculosis controls, and persons with latent M. tuberculosis infection. A similar pattern was observed with CXCL8 (P = 0.04), IL-10 (P = 0.02), and CCL2 (P = 0.03) when monocyte-depleted peripheral blood mononuclear cells from the four groups were cultured alone. Persons with previous extrapulmonary tuberculosis had decreased production of several cytokines, both at rest and after stimulation with M. tuberculosis. Our results suggest that persons who develop extrapulmonary tuberculosis have a subtle global immune defect that affects their response to M. tuberculosis infection.

[1]  L. Valdés,et al.  Tuberculous pleural effusion , 2014, Radiopaedia.org.

[2]  Andrea De Maria,et al.  Immunology of Tuberculosis , 2014, Mediterranean journal of hematology and infectious diseases.

[3]  E. Hershfield,et al.  Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection , 2013, Pediatric Clinical Practice Guidelines & Policies.

[4]  M. Rottenberg,et al.  Mycobacterium tuberculosis Sonicate–Induced IFNγ, CXCL10 and IL10 can Differentiate Severity in Tuberculosis , 2012, Scandinavian journal of immunology.

[5]  S. Kalams,et al.  Increased Frequency of Regulatory T Cells and T Lymphocyte Activation in Persons with Previously Treated Extrapulmonary Tuberculosis , 2011, Clinical and Vaccine Immunology.

[6]  B. Samten,et al.  Exposure to Cigarette Smoke Inhibits the Pulmonary T-Cell Response to Influenza Virus and Mycobacterium tuberculosis , 2010, Infection and Immunity.

[7]  M. Rojas,et al.  Regulatory T cell frequency and modulation of IFN-gamma and IL-17 in active and latent tuberculosis. , 2010, Tuberculosis.

[8]  S. Kalams,et al.  Abnormal Immune Responses In Persons With Previous Extrapulmonary Tuberculosis In An In Vitro Macrophage Model That Simulates In Vivo Infection With M. Tuberculosis , 2010, ATS 2010.

[9]  S. Nakae,et al.  Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung , 2010, The Journal of Immunology.

[10]  T. Sterling,et al.  Black race, sex, and extrapulmonary tuberculosis risk: an observational study , 2010, BMC infectious diseases.

[11]  J. Samet,et al.  Smoking and risk of tuberculosis incidence, mortality, and recurrence in South Korean men and women. , 2009, American journal of epidemiology.

[12]  A. Diacon,et al.  Differential cytokine/chemokines and KL-6 profiles in patients with different forms of tuberculosis. , 2009, Cytokine.

[13]  Z. Hasan,et al.  ESAT6-Induced IFNγ and CXCL9 Can Differentiate Severity of Tuberculosis , 2009, PloS one.

[14]  M. A. Khan,et al.  Relationship between Circulating Levels of IFN‐γ, IL‐10, CXCL9 and CCL2 in Pulmonary and Extrapulmonary Tuberculosis is Dependent on Disease Severity , 2009, Scandinavian journal of immunology.

[15]  V. Valluri,et al.  In Vitro Levels of Interleukin 10 (IL-10) and IL-12 in Response to a Recombinant 32-Kilodalton Antigen of Mycobacterium bovis BCG after Treatment for Tuberculosis , 2008, Clinical and Vaccine Immunology.

[16]  C. Hamilton,et al.  Alcohol use and clinical manifestations of tuberculosis. , 2008, The Journal of infection.

[17]  S. Holland,et al.  Immune Function in Young Children With Previous Pulmonary or Miliary/Meningeal Tuberculosis and Impact of BCG Vaccination , 2007, Pediatrics.

[18]  Z. Hasan,et al.  Interferonγ/IL10 ratio defines the disease severity in pulmonary and extra pulmonary tuberculosis , 2007 .

[19]  F. Poccia,et al.  Region of difference 1 antigen-specific CD4+ memory T cells correlate with a favorable outcome of tuberculosis. , 2006, The Journal of infectious diseases.

[20]  J. Pedrosa,et al.  Cutting Edge: IFN-γ Regulates the Induction and Expansion of IL-17-Producing CD4 T Cells during Mycobacterial Infection1 , 2006, The Journal of Immunology.

[21]  J. Hackman,et al.  Decreased CD4+ lymphocytes and innate immune responses in adults with previous extrapulmonary tuberculosis. , 2006, The Journal of allergy and clinical immunology.

[22]  M. Selman,et al.  A functional promoter polymorphism in monocyte chemoattractant protein–1 is associated with increased susceptibility to pulmonary tuberculosis , 2005, The Journal of experimental medicine.

[23]  I. Zaidi,et al.  Elevated ex vivo monocyte chemotactic protein-1 (CCL2) in pulmonary as compared with extra-pulmonary tuberculosis , 2005, BMC Immunology.

[24]  R. Horsburgh,et al.  Priorities for the treatment of latent tuberculosis infection in the United States. , 2004, The New England journal of medicine.

[25]  M. Gennaro,et al.  Tuberculosis immunology in children: diagnostic and therapeutic challenges and opportunities. , 2004, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[26]  H. Dockrell,et al.  Dynamics of cytokine generation in patients with active pulmonary tuberculosis , 2003, Current opinion in infectious diseases.

[27]  R. Pandey,et al.  Cytokine Polarization in Miliary and Pleural Tuberculosis , 2002, Journal of Clinical Immunology.

[28]  H. Dockrell,et al.  Cytokine profiles using whole-blood assays can discriminate between tuberculosis patients and healthy endemic controls in a BCG-vaccinated population. , 2002, Journal of immunological methods.

[29]  K. Edwards,et al.  Iron-cofactored superoxide dismutase inhibits host responses to Mycobacterium tuberculosis. , 2001, American journal of respiratory and critical care medicine.

[30]  J. Hackman,et al.  Human immunodeficiency virus-seronegative adults with extrapulmonary tuberculosis have abnormal innate immune responses. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[31]  Lim,et al.  Dysregulated Production of Interferon‐γ, Interleukin‐4 and Interleukin‐6 in Early Tuberculosis Patients in Response to Antigen 85B of Mycobacterium tuberculosis , 2000, Scandinavian journal of immunology.

[32]  M. Iseman.  A Clinician's Guide to Tuberculosis , 2000 .

[33]  Z. Toossi,et al.  Depressed T-cell interferon-gamma responses in pulmonary tuberculosis: analysis of underlying mechanisms and modulation with therapy. , 1999, The Journal of infectious diseases.

[34]  A. Wells,et al.  Human in vitro immune responses to Mycobacterium tuberculosis. , 1999, Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[35]  N. Juffermans,et al.  Serum concentrations of cytokines in patients with active tuberculosis (TB) and after treatment , 1999, Clinical and experimental immunology.

[36]  R. Wilkinson,et al.  Peptide-specific T cell response to Mycobacterium tuberculosis: clinical spectrum, compartmentalization, and effect of chemotherapy. , 1998, The Journal of infectious diseases.

[37]  P. Barnes,et al.  Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. , 1993, The American review of respiratory disease.

[38]  J. Abrams,et al.  Cytokine production at the site of disease in human tuberculosis , 1993, Infection and immunity.

[39]  L. Diehl,et al.  Leukopenia, neutropenia, and reduced hemoglobin levels in healthy American blacks. , 1991, Archives of internal medicine.

[40]  A. J. Crowle,et al.  Relative permissiveness of macrophages from black and white people for virulent tubercle bacilli , 1990, Infection and immunity.

[41]  M. Rojas,et al.  Mycobacterium tuberculosis alters the differentiation of monocytes into macrophages in vitro. , 2011, Cellular immunology.

[42]  Z. Hasan,et al.  Interferon gamma/IL10 ratio defines the disease severity in pulmonary and extra pulmonary tuberculosis. , 2007, Tuberculosis.

[43]  DAVID M. SOULELES,et al.  Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC. , 2005, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.