Suppressed Type 1, Type 2, and Type 17 Cytokine Responses in Active Tuberculosis in Children

Type 1 cytokine responses are known to play an important role in immunity to tuberculosis (TB) in children, although little is known about other factors that might be important. In addition, children are more prone to developing extrapulmonary manifestations of TB than adults. To identify the immune responses important both in control of infection and in extrapulmonary dissemination, we examined mycobacterium-specific cytokine responses of children with pulmonary TB (PTB) and extrapulmonary TB (ETB) and compared them with those of healthy control children (HC). No significant differences were found in the cytokine responses either with no stimulation or following mycobacterial-antigen (Ag) stimulation between children with PTB and ETB. On the other hand, children with active TB compared with HC showed markedly diminished production of type 1 (gamma interferon [IFN-gamma] and tumor necrosis factor alpha [TNF-alpha]), 2 (interleukin 4 [IL-4] and IL-13), and 17 (IL-17A, IL-21, and IL-23)-associated cytokines with no stimulation and in response to mycobacterial antigens. This was not associated with significantly altered production of IL-10 or transforming growth factor beta (TGF-beta). Among children with ETB, those with neurologic involvement exhibited more significantly diminished Ag-driven IFN-gamma and IL-17 production. Pediatric TB is characterized by diminished type 1, 2, and 17 cytokine responses, with the most profound diminution favoring development of neurologic TB, suggesting a crucial role for these cytokines in protection against pediatric tuberculosis.