title: Lesion-Specific Immune Response in Granulomas of Patients with Pulmonary Tuberculosis: A Pilot Study.
abstract: The formation and maintenance of granulomas is central to the host response to Mycobacterium tuberculosis (Mtb) infection. It is widely accepted that the lungs of patients with tuberculosis (TB) usually contain multiple infection foci, and that the granulomas evolve and differentiate independently, resulting in considerable heterogeneity. Although gene expression profiles of human blood cells have been proposed as biomarkers of Mtb infection and/or active disease, the immune profiles of discrete lesion types has not been studied extensively. Using histology, immunopathology and genome-wide transcriptome analysis, we explored the immunological profile of human lung TB granulomas. We show that although the different granulomas share core similarities in their immunological/inflammatory characteristics, they also exhibit significant divergence. Despite similar numbers of CD68+ macrophages in the different lesions, the extent of immune reactivity, as determined by the density of CD3+ T cells in the macrophage rich areas, and the extent of fibrosis, shows considerable variation. Both quantitative and qualitative differences among significantly differentially expressed genes (SDEG) were noted in each of the lesion types studied. Further, network/pathway analysis of SDEG revealed differential regulation of inflammatory response, immune cell trafficking, and cell mediated immune response in the different lesions. Our data highlight the formidable challenges facing ongoing efforts to identify peripheral blood biomarkers due to the diversity of lesion types and complexity of local immune responses in the lung.
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute (PHRI), Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Subbian
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute (PHRI), Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America; Department of Biological Sciences, NYC College of Technology, Brooklyn, New York, United States of America.
authors.forename: Liana
authors.initials: L
authors.lastname: Tsenova
authors.affiliation: Department of Immunobiology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Division of Anatomical Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Wainwright
authors.affiliation: Division of Anatomical Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Annalie
authors.initials: A
authors.lastname: Visser
authors.affiliation: Department of Biomedical Engineering, High-Throughput Biology Center and Institute of Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Nirmalya
authors.initials: N
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Biomedical Engineering, High-Throughput Biology Center and Institute of Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Bader
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine and Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Petros C
authors.initials: PC
authors.lastname: Karakousis
authors.affiliation: Department of General and Thoracic Surgery, Medisch Centrum Leeuwarden, Leeuwarden, The Netherlands.
authors.forename: Gabriele B
authors.initials: GB
authors.lastname: Murrmann
authors.affiliation: The Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Linda-Gail
authors.initials: LG
authors.lastname: Bekker
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
authors.forename: David G
authors.initials: DG
authors.lastname: Russell
authors.affiliation: Bill and Melinda Gates Foundation, Seattle, Washington, United States of America.
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
mesh_terms: D060833:Cellular Microenvironment; D005355:Fibrosis; D020869:Gene Expression Profiling; D015769:Granuloma, Respiratory Tract / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007249:Inflammation; D015851:Interleukin-7 / Q000502:physiology; D008168:Lung / Q000473:pathology*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D009336:Necrosis; D010865:Pilot Projects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D018167:Receptors, Calcitriol / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D059467:Transcriptome; D018088:Tuberculosis, Multidrug-Resistant / Q000235:genetics / Q000276:immunology / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology / Q000473:pathology*
chemical_list: C508605:IL7 protein, human; D015851:Interleukin-7; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C579457:VDR protein, human