Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis

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

doi:10.1038/s41467-021-21011-y

Cited by 31 publications

(25 citation statements)

References 45 publications

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“…It will also be important to determine the distribution of auto-Abs against other cytokines in the general population. The East Asian predominance of auto-Abs against type II IFN reflects the higher frequency of predisposing HLA-DRB1 alleles in these populations ( Chi et al, 2013 ; Ku et al, 2016 ; Pithukpakorn et al, 2015 ), raising questions about possible HLA associations for other anti-cytokine auto-Abs, as suggested for anti–GM-CSF auto-Abs in PAP patients of Japanese ancestry ( Sakaue et al, 2021 ). Another fundamental question is the nature of the cytokine-specific Igs and their B cell epitopes, which are known only for auto-Abs against type II IFN ( Lin et al, 2016 ) and IL-6 ( Nanki et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…Most of the patients were male (72%) and of various ancestries. A recent genome-wide association study of autoimmune PAP in patients and controls of Japanese ancestry found that the HLA class II allele HLA-DRB1*08:03, which is common in Asian populations (e.g., 8.3% in Japanese individuals) but very rare or absent in other populations, including Europeans (e.g., 0.3% in Germans, 0% in Italians), was associated (P = 0.035) with high levels of anti–GM-CSF auto-Abs in patients, suggesting an underlying genetic predisposition for the production of these auto-Abs, at least in individuals of Asian ancestry ( Sakaue et al, 2021 ). In contrast, no HLA allele was associated with these auto-Abs in a study of 47 European patients with PAP ( Anderson et al, 2019 ).…”

Section: Neutralizing Auto-abs Against Gm-csfmentioning

confidence: 99%

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Human autoantibodies underlying infectious diseases

Puel

Bastard

Bustamante

et al. 2022

Journal of Experimental Medicine

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The vast interindividual clinical variability observed in any microbial infection—ranging from silent infection to lethal disease—is increasingly being explained by human genetic and immunological determinants. Autoantibodies neutralizing specific cytokines underlie the same infectious diseases as inborn errors of the corresponding cytokine or response pathway. Autoantibodies against type I IFNs underlie COVID-19 pneumonia and adverse reactions to the live attenuated yellow fever virus vaccine. Autoantibodies against type II IFN underlie severe disease caused by environmental or tuberculous mycobacteria, and other intra-macrophagic microbes. Autoantibodies against IL-17A/F and IL-6 are less common and underlie mucocutaneous candidiasis and staphylococcal diseases, respectively. Inborn errors of and autoantibodies against GM-CSF underlie pulmonary alveolar proteinosis; associated infections are less well characterized. In individual patients, autoantibodies against cytokines preexist infection with the pathogen concerned and underlie the infectious disease. Human antibody-driven autoimmunity can interfere with cytokines that are essential for protective immunity to specific infectious agents but that are otherwise redundant, thereby underlying specific infectious diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Neutralizing Auto-abs Against Gm-csfmentioning

confidence: 99%

Human autoantibodies underlying infectious diseases

Puel

Bastard

Bustamante

et al. 2022

Journal of Experimental Medicine

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“…We performed GWAS genotyping of the 2,520 COVID-19 cases and 3,341 controls using Infinium Asian Screening Array (Illumina, CA, USA). We applied stringent QC filters to the samples (sample call rate < 0.97, excess heterozygosity of genotypes > mean + 3SD, related samples with PI_HAT > 0.175, or outlier samples from East Asian clusters in principal component analysis with 1000 Genomes Project samples), and variants (variant call rate < 0.99, significant call rate differences between cases and controls with P < 5.0 × 10 -8 , deviation from Hardy-Weinberg equilibrium with P < 1.0 × 10 -6 , or minor allele count < 5), as described elsewhere 48 . Details of the QC for the mitochondrial variants are described elsewhere 21 .…”

Section: Methodsmentioning

confidence: 99%

Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan

Namkoong

Edahiro

Fukunaga

et al. 2021

Preprint

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To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 × 10-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

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“…A genetic predisposition to the appearance of anti-GM-CSF antibodies has long been suspected; genetic studies have provided con icting results depending on ethnicity or techniques used so far. [21,22]. Serum anti-GM-CSF autoantibody levels, unlike levels in bronchoalveolar uid, do not correlate with disease severity in patients with aPAP [23,24].…”

Section: Discussionmentioning

confidence: 95%

Neutralizing GM-CSF autoantibodies in pulmonary alveolar proteinosis, cryptococcal meningitis and severe nocardiosis

Salvator

Cheng

Rosen

et al. 2022

Preprint

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Background Anti GM-CSF autoantibodies (aAb) have been related to acquired pulmonary alveolar proteinosis (PAP) and described in cases of severe infections such as cryptococcosis and nocardiosis in previously healthy subjects. Whether there are different anti-GM-CSF autoantibodies corresponding to these phenotypes is unclear.MethodsPlasma samples gathered in the National Institute of Health from patients with anti GM-CSF aAb and either PAP (n=15), cryptococcal meningitis (n=15), severe nocardiosis (n=5) or overlapping phenotypes (n=6) were compared in terms of titer and neutralizing activity as assessed by inhibition of GM-CSF-induced intracellular phospho-STAT5 (pSTAT5) in monocytes.ResultsAnti GM-CSF aAb titers were higher in PAP patients compared to those with cryptococcosis (mean 495±464 ug/ml vs 197±159 ug/ml, p = 0.02); there was no difference with patients with nocardiosis (430±493 ug/ml) nor between the two type of infections. The concentration of anti-GM-CSF autoantibody resulting in 50% inhibition of GM-CSF-induced pSTAT5 (IC50) was not significantly different between groups of patients (2.46 ± 2.3, 3.7 ± 3.3 and 1.94 ± 1.1 ug/ml in PAP patients, cryptococcosis and nocardiosis patients, respectively). Nor was the concentration of GM-CSF necessary to induce 50% of maximal GM-CSF-induced pSTAT5 in presence of 10 ug/ml of anti-GM-CSF aAb (EC50). When studying longitudinal samples from patients with PAP or disseminated nocardiosis, the neutralizing effect of anti GM-CSF aAb was relatively constant over time despite targeted treatments and variations in aAb levels. ConclusionsDespite different clinical manifestations, anti-GM-CSF antibodies were similar across PAP, cryptococcosis and nocardiosis. Underlying host genetics and functional analyses may help further differentiate the biology of these conditions.

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Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis

Cited by 31 publications

References 45 publications

Human autoantibodies underlying infectious diseases

Human autoantibodies underlying infectious diseases

Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan

Neutralizing GM-CSF autoantibodies in pulmonary alveolar proteinosis, cryptococcal meningitis and severe nocardiosis

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