BPIFB1 Is a Lung-Specific Autoantigen Associated with Interstitial Lung Disease

Autoimmunity targeting the lung-specific antigen BPIFB1 may be important to the pathogenesis of interstitial lung disease. Seeing the Forest by Examining the Trees Sometimes looking at something too closely obscures the big picture. However, when the big picture is too big, a reductionist approach may be best. Interstitial lung disease (ILD) is a complex and heterogeneous disorder, frequently associated with autoimmune syndromes. However, due in part to this heterogeneity, it remains unclear whether autoimmunity directly contributes to ILD. Now, Shum et al. attack this question by example—connecting one form of autoimmune disease, autoimmune polyglandular syndrome type 1 (APS1), with clinical ILD. The authors screened patients with APS1 and found autoantibodies to a lung-specific protein—BPIFB1—associated with the development of ILD in APS1 patients. They then extended these findings to non-APS1–associated ILD and found that 12 to 15% of patients also had these autoantibodies. The authors then examined a potential pathogenic mechanism of these autoantibodies in a mouse model of APS1, finding that similar autoantibodies and development of ILD resulted from a defect in thymic tolerance. Indeed, autoimmune targeting of BPIFB1 could cause ILD in mice without the autoimmune defect. These results suggest not only that ILD may be an autoimmune disorder in APS1 patients but also that autoimmunity may also contribute to pathology in a broader swath of ILD patients. Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes. Despite the connection between ILD and autoimmunity, it remains unclear whether ILD can develop from an autoimmune response that specifically targets the lung parenchyma. We examined a severe form of autoimmune disease, autoimmune polyglandular syndrome type 1 (APS1), and established a strong link between an autoimmune response to the lung-specific protein BPIFB1 (bactericidal/permeability-increasing fold-containing B1) and clinical ILD. Screening of a large cohort of APS1 patients revealed autoantibodies to BPIFB1 in 9.6% of APS1 subjects overall and in 100% of APS1 subjects with ILD. Further investigation of ILD outside the APS1 disorder revealed BPIFB1 autoantibodies present in 14.6% of patients with connective tissue disease–associated ILD and in 12.0% of patients with idiopathic ILD. The animal model for APS1, Aire−/− mice, harbors autoantibodies to a similar lung antigen (BPIFB9); these autoantibodies are a marker for ILD. We found that a defect in thymic tolerance was responsible for the production of BPIFB9 autoantibodies and the development of ILD. We also found that immunoreactivity targeting BPIFB1 independent of a defect in Aire also led to ILD, consistent with our discovery of BPIFB1 autoantibodies in non-APS1 patients. Overall, our results demonstrate that autoimmunity targeting the lung-specific antigen BPIFB1 may contribute to the pathogenesis of ILD in patients with APS1 and in subsets of patients with non-APS1 ILD, demonstrating the role of lung-specific autoimmunity in the genesis of ILD.