title: Nicotine treatment improves Toll-like receptor 2 and Toll-like receptor 9 responsiveness in active pulmonary sarcoidosis.
abstract: BACKGROUND
  New evidence links nicotine to the regulation of T cell-mediated inflammation via a 7 nicotinic cholinergic receptor activation, and chronic nicotine exposure (smoking) reduces the incidence of granulomatous diseases. We sought to determine whether nicotine treatment was well tolerated while effectively normalizing immune responses in patients with active pulmonary sarcoidosis.
  
  
  METHODS
  Consenting adults with symptomatic sarcoidosis (n 5 13) were randomly assigned to receive 12 weeks of nicotine treatment plus conventional therapy or conventional therapy alone. Obtained blood cells were evaluated for their responsiveness to selected Toll-like receptor (TLR) and nucleotide oligomerization domain-like receptor ligands and T cell surface marker expression before and after nicotine treatment. Asymptomatic patients (n 5 6) and disease-free subjects (n 5 6) served as comparative control subjects. Adverse events were monitored for the duration of the study.
  
  
  RESULTS
  Compared with the asymptomatic group, symptomatic patients had impaired peripheral responses to TLR2, TLR4, and TLR9 ligands (anergy) and reduced peripheral populations of CD4 1 FoxP3 1 regulatory T cells (Tregs). Nicotine treatment was associated with restoration of TLR2 and TLR9 responsiveness, and expansion of Tregs, including the CD4 1 CD25 2 FoxP3 1 phenotype. There were no serious adverse events or signs of nicotine dependency.
  
  
  CONCLUSIONS
  Nicotine treatment in active pulmonary sarcoidosis was well tolerated and restored peripheral immune responsiveness to TLR2 and TLR9 agonists and expansion of FoxP3 1 Tregs, including a specific “preactivated” (CD25 2 ) phenotype. The immune phenotype of patients with symptomatic sarcoidosis treated with nicotine closely resembled that of asymptomatic patients, supporting the notion that nicotine treatment may be beneficial in this patient population.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, the Dorothy M. Davis Heart and Lung Research Institute, Columbus.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Julian
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, the Dorothy M. Davis Heart and Lung Research Institute, Columbus.
authors.forename: Guohong
authors.initials: G
authors.lastname: Shao
authors.affiliation: Department of Microbial Infection and Immunity and the Center for Microbial Interface Biology, Wexner Medical Center at The Ohio State University, Columbus.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, the Dorothy M. Davis Heart and Lung Research Institute, Columbus.
authors.forename: Qin
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, the Dorothy M. Davis Heart and Lung Research Institute, Columbus.
authors.forename: David G
authors.initials: DG
authors.lastname: Cosmar
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, the Dorothy M. Davis Heart and Lung Research Institute, Columbus.
authors.forename: Nitin Y
authors.initials: NY
authors.lastname: Bhatt
authors.affiliation: Department of Pulmonary, Allergy and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Culver
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Cincinnati Medical Center, Cincinnati, OH.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Baughman
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, the Dorothy M. Davis Heart and Lung Research Institute, Columbus.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Wood
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, the Dorothy M. Davis Heart and Lung Research Institute, Columbus. Electronic address: Elliott.Crouser@osumc.edu.
authors.forename: Elliott D
authors.initials: ED
authors.lastname: Crouser
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000494:pharmacology / Q000627:therapeutic use*; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D010641:Phenotype; D017565:Sarcoidosis, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000954:Antigens, Surface; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018722:Nicotinic Agonists; C495342:TLR2 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D009538:Nicotine