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Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

ABSTRACT: Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR]?=?5.2; P?=?2.4?×?10^-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR?=?4.8; P?=?4.8?×?10^-12), followed by an additional independent risk allele at HLA-DP?1 amino acid position 8 (OR?=?0.28; P?=?3.4?×?10^-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (??=?0.32; P?=?0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.

SUBMITTER: Sakaue S

PROVIDER: S-EPMC7884840 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Sakaue Saori S Yamaguchi Etsuro E Inoue Yoshikazu Y Takahashi Meiko M Hirata Jun J Suzuki Ken K Ito Satoru S Arai Toru T Hirose Masaki M Tanino Yoshinori Y Nikaido Takefumi T Ichiwata Toshio T Ohkouchi Shinya S Ohkouchi Shinya S Hirano Taizou T Takada Toshinori T Miyawaki Satoru S Dofuku Shogo S Maeda Yuichi Y Nii Takuro T Kishikawa Toshihiro T Ogawa Kotaro K Masuda Tatsuo T Yamamoto Kenichi K Sonehara Kyuto K Tazawa Ryushi R Morimoto Konosuke K Takaki Masahiro M Konno Satoshi S Suzuki Masaru M Tomii Keisuke K Nakagawa Atsushi A Handa Tomohiro T Tanizawa Kiminobu K Ishii Haruyuki H Ishida Manabu M Kato Toshiyuki T Takeda Naoya N Yokomura Koshi K Matsui Takashi T Watanabe Masaki M Inoue Hiromasa H Imaizumi Kazuyoshi K Goto Yasuhiro Y Kida Hiroshi H Fujisawa Tomoyuki T Suda Takafumi T Yamada Takashi T Satake Yasuomi Y Ibata Hidenori H Hizawa Nobuyuki N Mochizuki Hideki H Kumanogoh Atsushi A Matsuda Fumihiko F Nakata Koh K Hirota Tomomitsu T Tamari Mayumi M Okada Yukinori Y

Nature communications 20210215 1

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p2 ...[more]

PMID: 33589587

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Project description:Pulmonary Alveolar Proteinosis (PAP) patients exhibit an acquired deficiency of biologically active granulocyte-macrophage colony stimulating factor (GM-CSF) attributable to GM-CSF specific autoantibodies. PAP alveolar macrophages are foamy, lipid-filled cells with impaired surfactant clearance and markedly reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPAR?) and the PPAR?-regulated ATP binding cassette (ABC) lipid transporter, ABCG1. An open label proof of concept Phase II clinical trial was conducted in PAP patients using rituximab, a chimeric murine-human monoclonal antibody directed against B lymphocyte specific antigen CD20. Rituximab treatment decreased anti-GM-CSF antibody levels in bronchoalveolar lavage (BAL) fluid, and 7/9 patients completing the trial demonstrated clinical improvement as measured by arterial blood oxygenation.This study sought to determine whether rituximab therapy would restore lipid metabolism in PAP alveolar macrophages.BAL samples were collected from patients pre- and 6-months post-rituximab infusion for evaluation of mRNA and lipid changes.Mean PPAR? and ABCG1 mRNA expression increased 2.8 and 5.3-fold respectively (p???0.05) after treatment. Lysosomal phospholipase A2 (LPLA2) (a key enzyme in surfactant degradation) mRNA expression was severely deficient in PAP patients pre-treatment but increased 2.8-fold post-treatment. In supplemental animal studies, LPLA2 deficiency was verified in GM-CSF KO mice but was not present in macrophage-specific PPAR? KO mice compared to wild-type controls. Oil Red O intensity of PAP alveolar macrophages decreased after treatment, indicating reduced intracellular lipid while extracellular free cholesterol increased in BAL fluid. Furthermore, total protein and Surfactant protein A were significantly decreased in the BAL fluid post therapy.Reduction in GM-CSF autoantibodies by rituximab therapy improves alveolar macrophage lipid metabolism by increasing lipid transport and surfactant catabolism. Mechanisms may involve GM-CSF stimulation of alveolar macrophage ABCG1 and LPLA2 activities by distinct pathways.

Dataset Information

Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Publications

Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

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