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Disseminated Cryptococcosis Due to Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in the Absence of Pulmonary Alveolar Proteinosis

Authors
  • Kuo, Chen-Yen1, 2
  • Wang, Shang-Yu1, 3
  • Shih, Han-Po1
  • Tu, Kun-Hua1, 4
  • Huang, Wen-Chi5
  • Ding, Jing-Ya1
  • Lin, Chia-Hao1
  • Yeh, Chun-Fu1, 6
  • Ho, Mao-Wang7, 8
  • Chang, Shi-Chuan9
  • He, Chi-Ying1, 10
  • Chen, Hung-Kai11
  • Ho, Chen-Hsuan11
  • Lee, Chen-Hsiang5
  • Chi, Chih-Yu1, 7, 8
  • Ku, Cheng-Lung1, 6, 12, 13
  • 1 Chang Gung University, Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Taoyuan, Taiwan , Taoyuan (Taiwan)
  • 2 Linkou Chang Gung Memorial Hospital, Division of Infectious Diseases, Department of Pediatrics, Taoyuan, Taiwan , Taoyuan (Taiwan)
  • 3 Linkou Chang Gung Memorial Hospital, Department of Trauma and Emergency Surgery, Taoyuan, Taiwan , Taoyuan (Taiwan)
  • 4 Linkou Chang Gung Memorial Hospital, Department of Nephrology, Taoyuan, Taiwan , Taoyuan (Taiwan)
  • 5 Kaohsiung Chang Gung Memorial Hospital, Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung, Taiwan , Kaohsiung (Taiwan)
  • 6 Linkou Chang Gung Memorial Hospital, Division of Infectious Diseases, Department of Internal Medicine, Taoyuan, Taiwan , Taoyuan (Taiwan)
  • 7 China Medical University, School of Medicine, College of Medicine, Taichung, Taiwan , Taichung (Taiwan)
  • 8 China Medical University Hospital, Division of Infectious Diseases, Department of Internal Medicine, Taichung, Taiwan , Taichung (Taiwan)
  • 9 Taipei Veterans General Hospital, Department of Chest Medicine, Taipei, Taiwan , Taipei (Taiwan)
  • 10 Chang Gung University, Department of Biomedical Sciences, Taoyuan, Taiwan , Taoyuan (Taiwan)
  • 11 Development Center for Biotechnology, Laboratory of Translational Medicine, New Taipei City, Taiwan , New Taipei City (Taiwan)
  • 12 China Medical University, Graduate Institute of Clinical Medical Sciences, 259 Wen-Hwa 1st Road, Kwei-Shan, Taoyuan City, 333, Taiwan , Taoyuan City (Taiwan)
  • 13 Chang Gung Memorial Hospital and Chang Gung University, Chang Gung Immunology Consortium, Taoyuan, Taiwan , Taoyuan (Taiwan)
Type
Published Article
Journal
Journal of Clinical Immunology
Publisher
Springer-Verlag
Publication Date
Dec 24, 2016
Volume
37
Issue
2
Pages
143–152
Identifiers
DOI: 10.1007/s10875-016-0364-4
Source
Springer Nature
Keywords
License
Yellow

Abstract

IntroductionAutoantibodies 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.MethodsWe 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.ResultsNeutralizing 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.ConclusionsAnti-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.

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