Date Published: March 7, 2019
Publisher: Public Library of Science
Author(s): Kirsten Anderson, Brenna Carey, Allison Martin, Christina Roark, Claudia Chalk, Marchele Nowell-Bostic, Brian Freed, Michael Aubrey, Bruce Trapnell, Andrew Fontenot, Gernot Zissel.
Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of pulmonary surfactant in alveolar macrophages and alveoli, resulting in respiratory impairment and an increased risk of opportunistic infections. Autoimmune PAP is an autoimmune lung disease that is caused by autoantibodies directed against granulocyte-macrophage colony-stimulating factor (GM-CSF). A shared feature among many autoimmune diseases is a distinct genetic association to HLA alleles. In the present study, we HLA-typed patients with autoimmune PAP to determine if this disease had any HLA association. We analyzed amino acid and allele associations for HLA-A, B, C, DRB1, DQB1, DPB1, DRB3, DRB4 and DRB5 in 41 autoimmune PAP patients compared to 1000 ethnic-matched controls and did not find any HLA association with autoimmune PAP. Collectively, these data may suggest the absence of a genetic association to the HLA in the development of autoimmune PAP.
Pulmonary alveolar proteinosis (PAP) is a rare syndrome comprising a heterogeneous group of diseases characterized by the accumulation of pulmonary surfactant in alveolar macrophages and the alveolar space [1, 2]. Eventually, surfactant accumulation results in respiratory impairment and/or failure as well as an increased risk of opportunistic infections . This syndrome occurs in individuals from ages 8 to 90 years, but it is most common in male smokers in the third to fourth decade [4, 5]. The catabolism of pulmonary surfactant in alveolar macrophages is controlled by granulocyte-macrophage-colony stimulating factor (GM-CSF) . GM-CSF is a cytokine that modulates the survival, differentiation, proliferation, and priming of myeloid cells . GM-CSF signaling can be disrupted by mutations in the GM-CSF gene [8, 9] or its receptors [10–13], as well as by neutralizing autoantibodies [2, 14, 15]. In this regard, autoimmune PAP is the disease that results from autoantibodies directed against GM-CSF, and the identification of neutralizing, polyclonal anti-GM-CSF autoantibodies in autoimmune PAP is an essential component of the disease diagnosis.
Based on the autoimmune nature of PAP, we hypothesized that a link existed between this disease and HLA. However, our study suggests that no such link exists. It remains possible that the lack of an association was due to the small sample size (47 patients). However, we did not note any trends towards association. As discussed above, our sample size should be sufficient to identify a strong positive association. However, it may not be large enough to definitively conclude the absence of an association. Previous studies in our laboratory have conclusively demonstrated the lack of an HLA association with as few as 150 patients . However, it should be noted that our methodology can identify a strong positive HLA association with only 50 patients . Our HEAP analysis consistently identified a strong, single amino acid HLA association in T1D and RA with as few as 20 subjects. Collectively, these data suggest that our sample size should be capable of detecting an association if one were present. However, due to sample size considerations, we were forced to limit our study to Caucasian patients. A larger study with a more diverse population would allow a more conclusive assessment and to include other ethnic minorities who represent more diverse HLA alleles.