TLR2-induced cytokine responses may characterize HIV-infected patients experiencing mycobacterial immune restoration disease

Tan , D.B.; Lim , A.; Yong , Y.K.; Ponnampalavanar , S.; Omar , S.; Kamarulzaman , A.; French , M.A; Price , P. (2011) TLR2-induced cytokine responses may characterize HIV-infected patients experiencing mycobacterial immune restoration disease. AIDS, 25 (12). 1455-1515 . ISSN 02699370

Abstract

OBJECTIVES: Most HIV patients who experience Mycobacterium tuberculosis-associated immune restoration disease (TB IRD) display elevated interferon-gamma (IFNγ) responses against mycobacterial antigens, but these can occur without an IRD. Recognition of mycobacteria-associated molecular patterns through toll-like receptors (TLRs) on dendritic cells and monocytes induces cytokine production. Here, we investigate TLR-induced responses in IRD. DESIGN: Peripheral blood mononuclear cells (PBMCs) were collected at approximately weeks 0, 6, 12, 24 and 48 after antiretroviral therapy from five patients experiencing TB IRD, nine matched non-IRD patients and 15 healthy controls. METHODS: IFNγ production by PBMC stimulated with protein purified derivative (PPD) was assessed by ELISpot. TLR2 expression on myeloid dendritic cells (mDCs) and monocytes was assessed by flow cytometry. TNFα, IL-12p40 and IL-10 were measured by ELISA in 24-h cultures of PBMC with lipomannan (mycobacteria-derived TLR2 agonist). RESULTS: TLR2 expression on mDC and monocytes was higher in patients than controls at baseline (P < 0.005). TLR2 expression decreased to normal levels on mDC by week 12, but remained higher on monocytes at week 24 (P = 0.02). At week 24, IRD patients showed higher IFNγ responses to PPD (P = 0.02), TLR2 expression on monocytes (P = 0.006) and lipomannan-induced TNFα production (P = 0.016) than non-IRD patients. Lipomannan-induced TNFα and IL-12p40 responses paralleled TB IRD in the patients with high TLR2 expression. IL-10 levels did not associate with IRD. CONCLUSION: TLR2-induced pro-inflammatory cytokines by dendritic cells or monocytes may contribute to the pathogenesis of mycobacterial IRD.

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