title: Elderly-onset hereditary pulmonary alveolar proteinosis and its cytokine profile.
abstract: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by surfactant accumulation, and is caused by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. Abnormalities in CSF2 receptor alpha (CSF2RA) were reported to cause pediatric hereditary PAP. We report here the first case of CSF2RA-mutated, elderly-onset hereditary (h) PAP.
  
  
  
  The patient developed dyspnea on exertion, and was diagnosed with PAP at the age of 77 years, based on findings from chest computed tomography scan and bronchoalveolar lavage. She tested negative for GM-CSF autoantibodies, with no underlying disease. Her serum GM-CSF level was elevated (91.3 pg/mL), indicating GM-CSF signaling impairment and genetic defects in the GM-CSF receptor. GM-CSF-stimulated phosphorylation in signal transducer and activator of transcription 5 (STAT5) was not observed, and GM-CSF-Rα expression was defective in her blood cells. Genetic screening revealed a homozygous, single-base C > T mutation at nt 508-a nonsense mutation that yields a stop codon (Q170X)-in exon 7 of CSF2RA. High-resolution analysis of single nucleotide polymorphism array confirmed a 22.8-Mb loss of heterozygosity region in Xp22.33p22.11, encompassing the CSF2RA gene. She was successfully treated with whole lung lavage (WLL), which reduced the serum levels of interleukin (IL)-2, IL-5, and IL-17, although IL-3 and M-CSF levels remained high.
  
  
  
  This is the first known report of elderly-onset hPAP associated with a CSF2RA mutation, which caused defective GM-CSF-Rα expression and impaired signaling. The analyses of serum cytokine levels during WLL suggested that GM-CSF signaling might be compensated by other signaling pathways, leading to elderly-onset PAP.
authors.affiliation: Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata, 951-8520, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakagome
authors.affiliation: Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Ohta
authors.affiliation: Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata, 951-8520, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Akasaka
authors.affiliation: Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata, 951-8520, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Shiono
authors.affiliation: Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata, 951-8520, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Takada
authors.affiliation: Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nagata
authors.affiliation: National Hospital Organization Nishi-Niigata Chuo Hospital, Niigata, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Tohyama
authors.affiliation: Department of Respiratory Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hagiwara
authors.affiliation: Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Kanazawa
authors.affiliation: Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata, 951-8520, Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Nakata
authors.affiliation: Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata, 951-8520, Japan. ryushi@med.niigata-u.ac.jp.
authors.forename: Ryushi
authors.identifier: 0000-0002-4580-004X
authors.initials: R
authors.lastname: Tazawa
mesh_terms: D017668:Age of Onset; D000368:Aged; D001323:Autoantibodies / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood*; D006801:Humans; D007378:Interleukins / Q000097:blood; D016676:Macrophages, Alveolar / Q000276:immunology; D009154:Mutation; D011649:Pulmonary Alveolar Proteinosis / Q000000981:diagnostic imaging / Q000235:genetics*; D013902:Radiography, Thoracic; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed
chemical_list: D001323:Autoantibodies; C521678:CSF2RA protein, human; D007378:Interleukins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Cytokine profile; Elderly onset; GM-CSF; GM-CSF receptor; Hereditary pulmonary alveolar proteinosis