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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,bfor the TB-IRIS study group

doi: 10.1097/QAD.0b013e328361648b
Basic Science

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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aCellular and Molecular Immunology Unit, Vrije Universiteit Brussel

bMyeloid Cell Immunology Laboratory, VIB, Brussels

cLaboratory of Immunology, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium

dDepartment of Medicine, Mulago Hospital, College of Health Sciences, Makerere University, Kampala, Uganda

eDepartment of Clinical Sciences, Institute of Tropical Medicine

fEpidemiology and Social Medicine, University of Antwerp, Antwerp

gLaboratory of Vaccinology and Mucosal Immunity, Université Libre de Bruxelles

hImmunobiology Clinic, Erasme Hospital, Université Libre de Bruxelles, Brussels

iDepartment of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.

*Huyen T.T. Tran and Rafael Van den Bergh contributed equally to this study.

Correspondence to Geert Raes, Cellular and Molecular Immunology Unit, Vrije Universiteit Brussel, Pleinlaan 2, Building E, 8th Floor, B-1050 Brussels, Belgium. Tel: +32 2 629 1978; fax: +32 2 629 1981; e-mail:

Received 2 December, 2012

Revised 6 March, 2013

Accepted 18 March, 2013

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© 2013 Lippincott Williams & Wilkins, Inc.