title: Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis.
abstract: The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-γ as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell damage.
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, United States of America; Division of Infectious Diseases, Department of Medicine, F. Hebert School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, United States of America.
authors.forename: Anil A
authors.initials: AA
authors.lastname: Panackal
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Simone C
authors.initials: SC
authors.lastname: Wuest
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Yen-Chih
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Tianxia
authors.initials: T
authors.lastname: Wu
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Kosa
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Mika
authors.initials: M
authors.lastname: Komori
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Blake
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Browne
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Lindsey B
authors.initials: LB
authors.lastname: Rosen
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
authors.forename: Ferry
authors.initials: F
authors.lastname: Hagen
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands; Department of Medical Microbiology, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Jacques
authors.initials: J
authors.lastname: Meis
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Levitz
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.affiliation: Center for Infectious Disease Imaging, Radiology and Imaging Sciences, National Institutes of Health/Clinical Center, Bethesda, Maryland, United States of America.
authors.forename: Dima
authors.initials: D
authors.lastname: Hammoud
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: John E
authors.initials: JE
authors.lastname: Bennett
authors.affiliation: Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Bibi
authors.initials: B
authors.lastname: Bielekova
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Williamson
mesh_terms: D000328:Adult; D001344:Autopsy; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D015331:Cohort Studies; D003455:Cryptococcus neoformans / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology* / Q000382:microbiology; D008213:Lymphocyte Activation; D008297:Male; D016919:Meningitis, Cryptococcal / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000382:microbiology; D008875:Middle Aged; D018417:Th1 Cells / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines