Mycobacterial Antigen Driven Activation of CD14++CD16− Monocytes Is a Predictor of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

PLoS Pathogens

Alan Sher¹  Soumya Swaminathan²  Katalin A. Wilkinson²  Dean Follmann²  Robert J. Wilkinson²  Stig M. R. Jensen³  Brian O. Porter³  Amrit Singh³  Melissa E. Schechter³  Graeme Meintjes⁴  Daniel L. Barber⁴  Bruno B. Andrade⁵  Lis R. Antonelli⁶  Helen van der Plas⁷  Kaustuv Nayak⁸  Selvaraj Anbalagan⁸  Gopalan Narendran⁸  Sudha Subramanian⁸  Irini Sereti⁹ 

[1] Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America;Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa;Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America;Department of Medicine, Imperial College London, London, United Kingdom;Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America;Laboratório de Imunopatologia, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil;MRC National Institute for Medical Research, London, United Kingdom;National Institute for Research in Tuberculosis, Chennai, India;T-Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: Monocytes;    Cytokines;    Biomarkers;    Inflammation;    Mycobacterium tuberculosis;    Blood plasma;    HIV;    T cells;   

DOI  :  10.1371/journal.ppat.1004433

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY