title: Mycobacterial antigen driven activation of CD14++CD16- monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome.
abstract: 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.
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Bruno B
authors.initials: BB
authors.lastname: Andrade
authors.affiliation: 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.
authors.forename: Amrit
authors.initials: A
authors.lastname: Singh
authors.affiliation: National Institute for Research in Tuberculosis, Chennai, India.
authors.forename: Gopalan
authors.initials: G
authors.lastname: Narendran
authors.affiliation: 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.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Schechter
authors.affiliation: National Institute for Research in Tuberculosis, Chennai, India.
authors.forename: Kaustuv
authors.initials: K
authors.lastname: Nayak
authors.affiliation: National Institute for Research in Tuberculosis, Chennai, India.
authors.forename: Sudha
authors.initials: S
authors.lastname: Subramanian
authors.affiliation: National Institute for Research in Tuberculosis, Chennai, India.
authors.forename: Selvaraj
authors.initials: S
authors.lastname: Anbalagan
authors.affiliation: 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.
authors.forename: Stig M R
authors.initials: SM
authors.lastname: Jensen
authors.affiliation: 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.
authors.forename: Brian O
authors.initials: BO
authors.lastname: Porter
authors.affiliation: Laboratório de Imunopatologia, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Lis R
authors.initials: LR
authors.lastname: Antonelli
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Wilkinson
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa; Department of Medicine, Imperial College London, London, United Kingdom; MRC National Institute for Medical Research, London, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa; Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Helen
authors.initials: H
authors.lastname: van der Plas
authors.affiliation: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Dean
authors.initials: D
authors.lastname: Follmann
authors.affiliation: 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.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Barber
authors.affiliation: National Institute for Research in Tuberculosis, Chennai, India.
authors.forename: Soumya
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
authors.affiliation: 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.
authors.forename: Irini
authors.initials: I
authors.lastname: Sereti
mesh_terms: D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000235:genetics / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D008297:Male; D009000:Monocytes / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology*; D014376:Tuberculosis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D015415:Biomarkers; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D018950:Lipopolysaccharide Receptors; D017452:Receptors, IgG