title: Disseminated Cryptococcosis Due to Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in the Absence of Pulmonary Alveolar Proteinosis.
abstract: BACKGROUND
  Autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) can cause acquired pulmonary alveolar proteinosis (PAP). Cases of acquired PAP susceptible to typical respiratory pathogens and opportunistic infections have been reported. Anti-GM-CSF autoantibodies have been reported in a few patients with cryptococcal meningitis. This study evaluated the presence of neutralizing anti-GM-CSF autoantibodies in patients without known congenital or acquired immunodeficiency with severe pulmonary or extrapulmonary cryptococcal infection but without PAP.
  
  
  METHODS
  We took a clinical history and performed an immunologic evaluation and screening of anti-cytokine autoantibodies in patients with cryptococcal meningitis. The impact of autoantibodies to GM-CSF on immune function was assessed by intracellular staining of GM-CSF-induced STAT5 phosphorylation and MIP-1α production in normal peripheral blood mononuclear cells incubated with plasma from patients or normal control subjects.
  
  
  RESULTS
  Neutralizing anti-GM-CSF autoantibodies were identified in four patients with disseminated cryptococcosis, none of whom exhibited PAP. Plasma from patients blocked GM-CSF signaling and inhibited STAT5 phosphorylation and production of MIP-1α. One patient died of disseminated cryptococcosis involving the central nervous system, which was associated with defective GM-CSF activity.
  
  
  CONCLUSIONS
  Anti-GM-CSF autoantibodies increase susceptibility to cryptococcal infection in adults without PAP. Cryptococcal central nervous system infection associated with anti-GM-CSF autoantibodies could result in neurological sequelae or be life-threatening. Therefore, timely detection of neutralizing anti-GM-CSF autoantibodies and development of an effective therapy are necessary to prevent deterioration of cryptococcal infection in these patients.
authors.affiliation: Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|Division of Infectious Diseases, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chen-Yen
authors.initials: CY
authors.lastname: Kuo
authors.affiliation: Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|Department of Trauma and Emergency Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Shang-Yu
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Han-Po
authors.initials: HP
authors.lastname: Shih
authors.affiliation: Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|Department of Nephrology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Kun-Hua
authors.initials: KH
authors.lastname: Tu
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Ding
authors.affiliation: Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chia-Hao
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|Division of Infectious Diseases, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chun-Fu
authors.initials: CF
authors.lastname: Yeh
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.|Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Mao-Wang
authors.initials: MW
authors.lastname: Ho
authors.affiliation: Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shi-Chuan
authors.initials: SC
authors.lastname: Chang
authors.affiliation: Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chi-Ying
authors.initials: CY
authors.lastname: He
authors.affiliation: Laboratory of Translational Medicine, Development Center for Biotechnology, New Taipei City, Taiwan.
authors.forename: Hung-Kai
authors.initials: HK
authors.lastname: Chen
authors.affiliation: Laboratory of Translational Medicine, Development Center for Biotechnology, New Taipei City, Taiwan.
authors.forename: Chen-Hsuan
authors.initials: CH
authors.lastname: Ho
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Chen-Hsiang
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.|School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.|Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chih-Yu
authors.initials: CY
authors.lastname: Chi
authors.affiliation: Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan. clku@mail.cgu.edu.tw.|Division of Infectious Diseases, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan. clku@mail.cgu.edu.tw.|Graduate Institute of Clinical Medical Sciences, China Medical University, 259 Wen-Hwa 1st Road, Kwei-Shan, Taoyuan City, 333, Taiwan. clku@mail.cgu.edu.tw.|Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan. clku@mail.cgu.edu.tw.
authors.forename: Cheng-Lung
authors.identifier: http://orcid.org/0000-0002-0643-2256
authors.initials: CL
authors.lastname: Ku
mesh_terms: D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D000935:Antifungal Agents / Q000627:therapeutic use; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D015415:Biomarkers; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D054405:Chemokine CCL3 / Q000096:biosynthesis; D003453:Cryptococcosis / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology* / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D016130:Immunophenotyping; D007958:Leukocyte Count; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections / Q000175:diagnosis / Q000209:etiology / Q000382:microbiology; D010766:Phosphorylation; D011649:Pulmonary Alveolar Proteinosis / Q000209:etiology; D013902:Radiography, Thoracic; D050799:STAT5 Transcription Factor / Q000378:metabolism; D014057:Tomography, X-Ray Computed
chemical_list: D057134:Antibodies, Neutralizing; D000935:Antifungal Agents; D001323:Autoantibodies; D015415:Biomarkers; D054405:Chemokine CCL3; D007074:Immunoglobulin G; D050799:STAT5 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Granulocyte-macrophage colony-stimulating factor; anti-cytokine autoantibodies; cryptococcal infection; opportunistic infection