title: HMGB1/RAGE Signaling and Pro-Inflammatory Cytokine Responses in Non-HIV Adults with Active Pulmonary Tuberculosis.
abstract: BACKGROUND
  We aimed to study the pathogenic roles of High-Mobility Group Box 1 (HMGB1) / Receptor-for-Advanced-Glycation-End-products (RAGE) signaling and pro-inflammatory cytokines in patients with active pulmonary tuberculosis (PTB).
  
  
  METHODS
  A prospective study was conducted among non-HIV adults newly-diagnosed with active PTB at two acute-care hospitals (n = 80); age-and-sex matched asymptomatic individuals (tested for latent TB) were used for comparison (n = 45). Plasma concentrations of 8 cytokines/chemokines, HMGB1, soluble-RAGE, and transmembrane-RAGE expressed on monocytes/dendritic cells, were measured. Gene expression (mRNA) of HMGB1, RAGE, and inflammasome-NALP3 was quantified. Patients' PBMCs were stimulated with recombinant-HMGB1 and MTB-antigen (lipoarabinomannan) for cytokine induction ex vivo.
  
  
  RESULTS
  In active PTB, plasma IL-8/CXCL8 [median(IQR), 6.0(3.6-15.1) vs 3.6(3.6-3.6) pg/ml, P<0.001] and IL-6 were elevated, which significantly correlated with mycobacterial load, extent of lung consolidation (rs +0.509, P<0.001), severity-score (rs +0.317, P = 0.004), and fever and hospitalization durations (rs +0.407, P<0.001). IL-18 and sTNFR1 also increased. Plasma IL-8/CXCL8 (adjusted OR 1.12, 95%CI 1.02-1.23 per unit increase, P = 0.021) and HMGB1 (adjusted OR 1.42 per unit increase, 95%CI 1.08-1.87, P = 0.012) concentrations were independent predictors for respiratory failure, as well as for ICU admission/death. Gene expression of HMGB1, RAGE, and inflammasome-NALP3 were upregulated (1.2-2.8 fold). Transmembrane-RAGE was increased, whereas the decoy soluble-RAGE was significantly depleted. RAGE and HMGB1 gene expressions positively correlated with cytokine levels (IL-8/CXCL8, IL-6, sTNFR1) and clinico-/radiographical severity (e.g. extent of consolidation rs +0.240, P = 0.034). Ex vivo, recombinant-HMGB1 potentiated cytokine release (e.g. TNF-α) when combined with lipoarabinomannan.
  
  
  CONCLUSIONS
  In patients with active PTB, HMGB1/RAGE signaling and pro-inflammatory cytokines may play important roles in pathogenesis and disease manifestations. Our clinico-immunological data can provide basis for the development of new strategies for disease monitoring, management and control.
authors.affiliation: Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China.
authors.forename: Grace
authors.initials: G
authors.lastname: Lui
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Chun Kwok
authors.initials: CK
authors.lastname: Wong
authors.affiliation: Department of Microbiology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Margaret
authors.initials: M
authors.lastname: Ip
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Yi Jun
authors.initials: YJ
authors.lastname: Chu
authors.affiliation: Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China.
authors.forename: Irene M H
authors.initials: IM
authors.lastname: Yung
authors.affiliation: Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China.
authors.forename: Catherine S K
authors.initials: CS
authors.lastname: Cheung
authors.affiliation: Department of Microbiology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Imaging and Interventional Radiology, Prince of Wales Hospital, Hong Kong SAR, China.
authors.forename: Judy S Y
authors.initials: JS
authors.lastname: Lam
authors.affiliation: Department of Imaging and Interventional Radiology, Prince of Wales Hospital, Hong Kong SAR, China.
authors.forename: Ka Tak
authors.initials: KT
authors.lastname: Wong
authors.affiliation: Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong SAR, China.
authors.forename: Winnie W Y
authors.initials: WW
authors.lastname: Sin
authors.affiliation: Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong SAR, China.
authors.forename: Kin Wing
authors.initials: KW
authors.lastname: Choi
authors.affiliation: Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China.|Stanley Ho Center for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Nelson
authors.initials: N
authors.lastname: Lee
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D006678:HIV / Q000302:isolation & purification / Q000472:pathogenicity; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D016209:Interleukin-8 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases