Masaki Hirose1, Toru Arai1, Chikatoshi Sugimoto2, Takayuki Takimoto2, Reiko Sugawara2, Shojiro Minomo2, Sayoko Shintani2, Naoko Takeuchi2, Kanako Katayama2, Yasushi Inoue2, Tomoko Kagawa2, Takahiko Kasai3, Masanori Akira4, Yoshikazu Inoue5. 1. Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-Cho, Kita-Ku, Sakai City, Osaka, 591-8555, Japan. 2. Department of Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-Cho, Kita-Ku, Sakai City, Osaka, 591-8555, Japan. 3. Department of Pathology, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-Cho, Kita-Ku, Sakai City, Osaka, 591-8555, Japan. 4. Department of Radiology, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-Cho, Kita-Ku, Sakai City, Osaka, 591-8555, Japan. 5. Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-Cho, Kita-Ku, Sakai City, Osaka, 591-8555, Japan. giichiyi@me.com.
Abstract
BACKGROUND: Autoimmune pulmonary alveolar proteinosis (APAP) results from the suppression of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling by a neutralizing autoantibody against GM-CSF. B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are involved in immunoglobulin G production and are overproduced in various autoimmune disorders. We hypothesized that BAFF and/or APRIL levels would be elevated in serum and bronchoalveolar lavage fluid (BALF) and serum and BALF levels of BAFF and APRIL respond to the treatments (whole lung lavage (WLL) or inhalation of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF)) in patients with APAP. SUBJECTS AND METHODS: BAFF and APRIL levels in serum and BALF from 110 patients with APAP were measured at baseline and during and after treatment, using an enzyme-linked immunosorbent assay kit. We enrolled 34 healthy volunteers as serum cytokine controls, and 13 disease controls for BALF. Associations of BAFF and APRIL levels with clinical measures were assessed to clarify their clinical roles. RESULTS: In patients with APAP, serum BAFF and APRIL levels were significantly increased relative to healthy volunteers (p < 0.0001 and p < 0.05, respectively), and BALF BAFF and APRIL levels were significantly increased versus disease controls (p < 0.0001 and p < 0.01, respectively). Serum BAFF levels (but not APRIL levels) were significantly correlated with Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-D, SP-A, and lactate dehydrogenase (p < 0.0001). There was no significant correlation between serum BAFF or APRIL levels and anti-GM-CSF autoantibody. BAFF and APRIL were negatively correlated with single-breath diffusion capacity for carbon monoxide (DLco) (p = 0.004) and forced vital capacity (p = 0.04), respectively. BAFF (but not APRIL) in BALF was negatively correlated with vital capacity (p = 0.04) and DLco (p = 0.006). There were significant correlations between disease severity and BAFF levels in serum (p = 0.04) and BALF (p = 0.007). Serum levels of anti-GM-CSF autoantibody, BAFF, and APRIL were not significantly affected by WLL or inhalation of recombinant human GM-CSF. CONCLUSIONS: BAFF and APRIL levels of sera and BALF in APAP were significantly increased compared with healthy volunteer and disease control, and the BAFF and APRIL pathway might have important specific roles in pathogenesis of APAP. Our data suggest a new perspective of future treatment for APAP.
BACKGROUND:Autoimmune pulmonary alveolar proteinosis (APAP) results from the suppression of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling by a neutralizing autoantibody against GM-CSF. B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are involved in immunoglobulin G production and are overproduced in various autoimmune disorders. We hypothesized that BAFF and/or APRIL levels would be elevated in serum and bronchoalveolar lavage fluid (BALF) and serum and BALF levels of BAFF and APRIL respond to the treatments (whole lung lavage (WLL) or inhalation of recombinant humangranulocyte-macrophage colony-stimulating factor (GM-CSF)) in patients with APAP. SUBJECTS AND METHODS: BAFF and APRIL levels in serum and BALF from 110 patients with APAP were measured at baseline and during and after treatment, using an enzyme-linked immunosorbent assay kit. We enrolled 34 healthy volunteers as serum cytokine controls, and 13 disease controls for BALF. Associations of BAFF and APRIL levels with clinical measures were assessed to clarify their clinical roles. RESULTS: In patients with APAP, serum BAFF and APRIL levels were significantly increased relative to healthy volunteers (p < 0.0001 and p < 0.05, respectively), and BALF BAFF and APRIL levels were significantly increased versus disease controls (p < 0.0001 and p < 0.01, respectively). Serum BAFF levels (but not APRIL levels) were significantly correlated with Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-D, SP-A, and lactate dehydrogenase (p < 0.0001). There was no significant correlation between serum BAFF or APRIL levels and anti-GM-CSF autoantibody. BAFF and APRIL were negatively correlated with single-breath diffusion capacity for carbon monoxide (DLco) (p = 0.004) and forced vital capacity (p = 0.04), respectively. BAFF (but not APRIL) in BALF was negatively correlated with vital capacity (p = 0.04) and DLco (p = 0.006). There were significant correlations between disease severity and BAFF levels in serum (p = 0.04) and BALF (p = 0.007). Serum levels of anti-GM-CSF autoantibody, BAFF, and APRIL were not significantly affected by WLL or inhalation of recombinant humanGM-CSF. CONCLUSIONS:BAFF and APRIL levels of sera and BALF in APAP were significantly increased compared with healthy volunteer and disease control, and the BAFF and APRIL pathway might have important specific roles in pathogenesis of APAP. Our data suggest a new perspective of future treatment for APAP.
Entities:
Keywords:
Autoimmune pulmonary alveolar proteinosis; B cell‐activating factor; Biomarker
Authors: J A Gross; J Johnston; S Mudri; R Enselman; S R Dillon; K Madden; W Xu; J Parrish-Novak; D Foster; C Lofton-Day; M Moore; A Littau; A Grossman; H Haugen; K Foley; H Blumberg; K Harrison; W Kindsvogel; C H Clegg Journal: Nature Date: 2000-04-27 Impact factor: 49.962
Authors: M S Kavuru; A Malur; I Marshall; B P Barna; M Meziane; I Huizar; H Dalrymple; R Karnekar; M J Thomassen Journal: Eur Respir J Date: 2011-04-08 Impact factor: 16.671