Abnormal Immune Responses in Persons with Previous Extrapulmonary Tuberculosis in anIn VitroModel That SimulatesIn VivoInfection with Mycobacterium tuberculosis

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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 toMycobacterium tuberculosisinfection of macrophages have not been characterized. The objective of this study was to further characterize thein vitroimmune responses toM. tuberculosisinfection 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), latentM. tuberculosisinfection (n= 19), and uninfected tuberculosis contacts (n= 20). Experimental conditions includedM. 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. WhenM. 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 latentM. tuberculosisinfection. 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 withM. tuberculosis. Our results suggest that persons who develop extrapulmonary tuberculosis have a subtle global immune defect that affects their response toM. tuberculosisinfection.

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