Mycobacterial antigen driven activation of CD14⁺⁺CD16^-monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome.

Andrade, B.B .; Singh, A .; Narendran, G .; Schechter, M.E .; Nayak, K .; Subramanian, S .; Anbalagan, S .; Jensen, S.M .; Porter, B.O.; Antonelli, L.R .; Wilkinson, K.A .; Wilkinson, R.J .; Meintjes, G .; van der Plas, H .; Follmann, D .; Barber, D.L .; Swaminathan, S .; Sher, A .; Sereti, I .

PLoS Pathogens; 2014; 10; e1004433.

Abstract: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa . Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14 ++ CD16 ¯ monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment.

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