B cell-activating factors in autoimmune pulmonary alveolar proteinosis

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.

Keywords: Autoimmune pulmonary alveolar proteinosis; B cell‐activating factor; Biomarker.

Fig. 1

Levels of BAFF and APRIL in 115 patients with APAP. Serum levels of BAFF (a) and APRIL (b) were significantly elevated in patients with APAP relative to healthy volunteers (p < 0.0001 and p < 0.05, respectively). Levels of BAFF (c) and APRIL (d) in BALF were significantly elevated in patients with APAP versus disease controls (p < 0.0001 and p < 0.01, respectively).  APAP, autoimmune pulmonary alveolar proteinosis; APRIL, a proliferation-inducing ligand; BAFF, B cell-activating factor; BALF, bronchial alveolar lavage fluid

Fig. 2

Change in serum levels of BAFF and APRIL before and after treatment with a rhGM-CSF inhalation therapy (N = 17) and b whole lung lavage (N = 16). Change in serum levels of APRIL before and after treatment with c rhGM-CSF inhalation (N = 17) and d whole lung lavage (N = 16). Abbreviations: BAFF, B cell-activating factor; APRIL, a proliferation-inducing ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor. Data were analyzed using the Steel’s test