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

Abstract

Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes (1). Despite the connection between ILD and autoimmunity, it remains unclear whether ILD can develop from an autoimmune response that specifically targets the lung parenchyma. Here, we utilized a severe form of autoimmune disease, Autoimmune Polyglandular Syndrome Type 1 (APS1), to establish a strong link between an autoimmune response to the lung-specific protein BPIFB1 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 specifically present in 14.6% of patients with connective tissue disease-associated ILD and in 12.0% of patients with idiopathic ILD. Utilizing the animal model for APS1 to examine the mechanism of ILD pathogenesis, we found that Aire−/− mice harbor autoantibodies to a similar lung antigen named BPIFB9 that are a marker for ILD, and determined that a defect in thymic tolerance is responsible for the production of BPIFB9 autoantibodies and the development of ILD. Importantly, we also found that immunoreactivity targeting BPIFB1 independent of a defect in Aire also leads 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 be important 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.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy: Report of Seven Additional Sicilian Patients and Overview of the Overall Series from Sicily

“…In this study population, some very rare manifestations have been observed and previously described - in 1 case chronic demyelinating polyneuropathy [10,23] and in another pulmonary disease - with positivity of autoantibodies against the bronchial antigen KCNRG (potassium channel regulator) [24,25]. In the remaining cases of this series, neither neurological nor pulmonary symptoms were observed during the entire follow-up, although they were systematically sought.…”

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

“…Interestingly, in some patients autoantibodies to CYP21A2 can appear almost as early as the anti-cytokine autoantibodies [22]. Moreover, a perfect overlap between interstitial lung disease and autoantibodies to KCNRG and BPIFB1 has been described [123,125]. IA-2 autoantibodies are present only in patients with T1D, and CYP1A2-binding antibodies are specific for AIH.…”

“…Lung biopsy samples have suggested the autoimmune nature of the disease, including the presence of a severe peribronchiolar lymphoid infiltrate [123] that interestingly contains mainly B cells and plasma cells [124]. Two autoantibodies have shown a strong correlation with lung disease in APECED patients: potassium channel regulatory protein (KCNRG) [123,124] and bactericidal/permeability-increasing fold-containing B1 (BPIFB1) [125].…”

Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia

“…In humans, AIRE is primarily expressed in mTEC and its loss-of-function mutations cause the autoimmune polyendocrine syndrome type-1 (APS-1; OMIM #240300), which is marked by the survival and thymic export of self-reactive T eff cells (Mathis and Benoist 2009). Consequently, the syndrome is characterized by severe organspecific autoimmunity typically affecting parathyroid chief cells, steroidogenic cells of the adrenal cortex, pancreatic b-cells, gastric parietal cells, skin melanocytes, hepatocytes, gonads, and the lung (Shikama et al 2009;Shum et al 2013).…”