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

Persons with previous extrapulmonary tuberculosis have reduced peripheral bloodmononuclear cell cytokine production and CD4 lymphocytes compared to persons with previous pulmonary tuberculosis or latent tuberculosis infection, but specific de-fects related toMycobacterium tuberculosis infection of macrophages have not been characterized. The objective of this study was to further characterize the in vitro immune responses toM. tuberculosis infection in HIV-seronegative persons with previ-ous extrapulmonary tuberculosis. Peripheral bloodmononuclear cells were isolated fromHIV-seronegative persons with previ-ous extrapulmonary tuberculosis (n 11), previous pulmonary tuberculosis (n 21), latentM. tuberculosis infection (n 19), and uninfected tuberculosis contacts (n 20). Experimental conditions includedM. tuberculosis-infected macrophages cultured with and without monocyte-depleted peripheral bloodmononuclear cells. Concentrations of interleukin 1 (IL-1), IL-4, IL-6, CXCL8 (IL-8), IL-10, IL-12p70, IL-17, CCL2 (monocyte chemoattractant protein 1), tumor necrosis factor alpha (TNF-), and gamma interferon (IFN-) were measured by multiplex cytokine array. WhenM. tuberculosis-infected macrophages were cocul-tured with monocyte-depleted peripheral bloodmononuclear cells, IFN- (P 0.01), TNF- (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 ex-trapulmonary tuberculosis cases, pulmonary tuberculosis controls, and persons with latentM. tuberculosis infection. A similar pattern was observed with CXCL8 (P 0.04), IL-10 (P 0.02), and CCL2 (P 0.03) whenmonocyte-depleted peripheral blood mononuclear cells from the four groups were cultured alone. Persons with previous extrapulmonary tuberculosis had decrease