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doi: 10.1097/QAD.0b013e328361648b
Basic Science

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

Tran, Huyen T.T.a,b,*; Van den Bergh, Rafaela,b,*; Loembé, Marguerite M.c; Worodria, Williamd; Mayanja-Kizza, Harrietd; Colebunders, Roberte,f; Mascart, Françoiseg; Stordeur, Patrickh; Kestens, Lucc,i; De Baetselier, Patricka,b; Raes, Geerta,b; for the TB-IRIS study group

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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.

© 2013 Lippincott Williams & Wilkins, Inc.


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