4.4 Article

Modulation of the complement system in monocytes contributes to tuberculosis-associated immune reconstitution inflammatory syndrome

Journal

AIDS
Volume 27, Issue 11, Pages 1725-1734

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0b013e328361648b

Keywords

combined antiretroviral therapy; complement system; HIV-tuberculosis co-infection; immune reconstitution inflammatory syndrome; monocytes

Funding

  1. EC FP6 Specific Targeted Research Project (STREP) [LSHP-CT-2007-037659-TBIRIS]
  2. Netherlands Organization for Scientific Research - WOTRO Science for Global Development [NACCAP W 07.05.20100]

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Objective:Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a common complication in HIV-TB co-infected patients receiving combined antiretroviral therapy (cART). This study investigated a putative contribution of monocytes to the development of TB-IRIS.Design:A prospective study was designed to compare gene expression between patients who developed TB-IRIS with matched non-TB-IRIS controls.Methods:We performed a hypothesis-generating transcriptome analysis on monocytes of HIV-TB co-infected patients. Identified pathways were subsequently analysed in patients' monocytes before and shortly after cART initiation, in a technically independent set-up (nCounter). Additionally, protein expression and enzymatic activities of specific factors were assessed at the systemic level.Results:Pathway analysis of microarray datasets and focused gene expression study revealed that, even before initiation of cART, the complement system is dysregulated in HIV-TB co-infected patients who are predisposed to developing TB-IRIS. Detailed analysis revealed differences between TB-IRIS patients and matched non-TB-IRIS cases, at the level of the balance between the effector C1Q and the inhibitor C1-INH, both before and 2 weeks after cART initiation. These differences were mirrored by increases in the downstream pro-inflammatory complement factor C5 over the course of 2 weeks of cART. Our results suggest that inappropriate control of complement activation could be associated with the flaring up' of inflammation observed during TB-IRIS.Conclusion:The current study reveals a contribution of monocytes and the complement system to TB-IRIS development. An intriguing possibility is that the development of TB-IRIS may depend partially on the relative balance between C1Q and C1-INH.

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