title: The immunopathogenesis of cryptococcal immune reconstitution inflammatory syndrome: understanding a conundrum.
abstract: OBJECTIVE
  Cryptococcal meningitis causes significant mortality among HIV-infected patients, despite antifungal therapy and use of antiretroviral therapy (ART). In patients with cryptococcal meningitis, ART is often complicated by immune reconstitution inflammatory syndrome (IRIS), manifesting as unmasking of previously unrecognized subclinical infection (unmasking CM-IRIS) or paradoxical worsening of symptoms in the central nervous system after prior improvement with antifungal therapy (paradoxical CM-IRIS). We review our current understanding of the pathogenesis of this phenomenon, focusing on unifying innate and adaptive immune mechanisms leading to the development of this often fatal syndrome.
  
  
  RESULTS
  We propose that HIV-associated CD4 T-cell depletion, chemokine-driven trafficking of monocytes into cerebrospinal fluid in response to cryptococcal meningitis, and poor localized innate cytokine responses lead to inadequate cryptococcal killing and clearance of the fungus. Subsequent ART-associated recovery of T-cell signaling and restored cytokine responses, characterized by IFN-γ production, triggers an inflammatory response. The inflammatory response triggered by ART is dysregulated because of impaired homeostatic and regulatory mechanisms, culminating in the development of CM-IRIS.
  
  
  CONCLUSIONS
  Despite our incomplete understanding of the immunopathogenesis of CM-IRIS, emerging data exploring innate and adaptive immune responses could be exploited to predict, prevent and manage CM-IRIS and associated morbid consequences.
authors.affiliation: aInfectious Disease Institute, Makerere University, Kampala, Uganda bDepartment of Medicine, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota, Minneapolis, Minnesota, USA cSchool of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda dDivision of Infectious Diseases, Department of Medicine, Johns Hopkins University, Baltimore, Maryland eMucosal and Vaccine Research Program Colorado (MAVRC), University of Colorado Denver fDenver Veterans Affairs Medical Center, Denver, Colorado, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Meya
authors.forename: Yukari C
authors.initials: YC
authors.lastname: Manabe
authors.forename: David R
authors.initials: DR
authors.lastname: Boulware
authors.forename: Edward N
authors.initials: EN
authors.lastname: Janoff
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D056704:Adaptive Immunity; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D007113:Immunity, Innate; D016919:Meningitis, Cryptococcal / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D012307:Risk Factors
chemical_list: D019380:Anti-HIV Agents; D000935:Antifungal Agents