Whole-exome sequencing identifies susceptibility genes and pathways for idiopathic pulmonary fibrosis in the Chinese population

Genetic factors play a role in the risk of idiopathic pulmonary fibrosis (IPF). Specifically, MUC5B rs35705950 non-risk alleles and immunologic aberrations were associated with the IPF’s progression. However, rare genetic variants have not been systematically investigated in Chinese IPF patients. In this study, we aimed to improve understanding of the genetic architecture of IPF in the Chinese population and to assess whether rare protein-coding variants in the immunity pathway genes are enriched in the IPF patients with non-risk alleles at rs35705950. A case–control exome-wide study including 110 IPF patients and 60 matched healthy controls was conducted. rs35705950 was genotyped by Sanger sequencing. To identify genes enriched in IPF, gene-based association analyses were performed. Identified genes were included for further pathway analyses using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Associations between rs35705950 and genes enriched in the immunity pathway were also tested. 226 genes that were enriched with deleterious variants were identified in IPF patients. Out of them, 36 genes were significantly enriched in GO and KEGG pathways in the IPF. Pathway analyses implicated that these genes were involved in the immune response and cell adhesion. Rare protein-altering variants in genes related to the immunity pathway did not significantly differ between patients with a MUC5B risk allele and individuals without risk allele. We drafted a comprehensive mutational landscape of rare protein-coding variants in the Chinese IPF and identified genes related to immune response and cell adhesion. These results partially explain changes in gene expression involved in the immunity/inflammatory pathways in IPF patients

Real-world experiences: Efficacy and tolerability of pirfenidone in clinical practice.

BACKGROUND:The safety of pirfenidone on pulmonary fibrosis patients with other kinds of interstitial lung diseases (ILDs) in addition to idiopathic pulmonary fibrosis (IPF) is unknown. Furthermore, its effectiveness-related factors on IPF patients are not quite explored. METHODS:A retrospective study, on patients prescribed pirfenidone for pulmonary fibrosis, was conducted to assess effectiveness on IPF patients and tolerability of all patients with lung fibrosis. The effectiveness of pirfenidone was tested on 110 IPF subjects receiving treatment for ≥3 months by high-resolution computed tomography (HRCT). Response-linked factors and progression-free survival (PFS) were also analyzed. The data about safety outcomes and drug dose adjustments were collected from all included subjects. RESULTS:A total of 176 subjects were included: 117 were IPF, 19 connective tissue disease-associated interstitial lung disease (CTD-ILD), and 40 unclassifiable ILD. Out of the 110 IPF subjects, 89 subjects were assessed as stable and 21 as progressive, out of which 10 died of acute exacerbation and 11 progressed. The effectiveness was significantly related to their baseline body mass index (BMI). IPF subjects with BMI>25kg/m2 or diffusion capacity of carbon monoxide (DLco)>30% had higher PFS rate. The most common adverse events were skin-related and gastrointestinal-related. Drug discontinuation owing to adverse events occurred similarly in these three groups. CONCLUSION:Pirfenidone was well tolerated in most of the lung fibrosis patients besides IPF, with a similar pattern of adverse events. Nearly 80% of IPF subjects were assessed as stable. More benefits were seen in IPF patients with higher BMI or mild-to-moderate disease

Immunological Evidence for the Role of Mycobacteria in Sarcoidosis: A Meta-Analysis

<div><p>Background</p><p>Sarcoidosis is a granulomatous disease, the etiology of which is currently unknown. The role of mycobacteria in the etiology of sarcoidosis has been extensively investigated. In this meta-analysis, we assessed the immunological evidence of the possible role of mycobacteria in the pathogenesis and development of sarcoidosis.</p><p>Methods</p><p>We performed a systematic search of relevant articles from PubMed, Embase and Cochrane Library databases published between January 1990 and October 2015. Data extracted from the articles were analyzed with Review Manager 5.3 (Cochrane Collaboration, Oxford, UK).</p><p>Results</p><p>In this meta-analysis, 13 case-control studies (733 participants) were considered eligible according to our criteria. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). The positivity incidence of the immune response (either the cell-mediated response or humoral response) in sarcoidosis patients was significantly higher than that in controls, as determined using fixed-effects model. The odds ratio (OR) of the positivity incidence of T-cell response in the patients with sarcoidosis versus the controls with PPD- or unknown PPD status was 5.54 (95% CI 3.56–8.61); the ORs were 16.70 (95% CI 8.19–34.08) and 1.48 (95% CI 0.74–2.96) for the two subgroups with PPD- controls and unknown PPD status respectively. However, the OR of the positivity incidence in patients with sarcoidosis versus PPD+ controls (latent tuberculosis infection; LTBI) was 0.26 (95% 0.10–0.66). Regarding the humoral response, pooled analysis of the positivity incidence revealed an OR (95%CI) of 20.43 (5.53–75.53) for the patients with sarcoidosis versus controls; the ORs were 11.93 (95% CI 2.15–66.27) and 41.97 (95% CI 5.24–336.15) in two subgroups of controls with PPD- and unknown PPD statuses respectively. Data on heterogeneity and evidence of publication bias were examined.</p><p>Conclusions</p><p>This meta-analysis confirmed the existence of an association between mycobacteria (especially <i>M</i>.<i>tuberculosis</i>) and sarcoidosis. The current available evidence indicates that some insoluble mycobacterial antigens that preferentially within the body are involved in the pathogenesis of sarcoidosis rather than the whole mycobacteria and that they elicit a type IV immune response.</p></div

Forest plot of trials analyzing the positivity incidence of T-cell response to <i>M</i>. <i>tuberculosis</i> antigens in sarcoidosis patients versus PPD+ controls (LTBI).

<p>LTBI = latent tuberculosis infection.</p

Forest plot of trials analyzing the positivity incidence of the humoral response to <i>M</i>. <i>tuberculosis</i> antigens in sarcoidosis patients versus controls.

<p>Forest plot of trials analyzing the positivity incidence of the humoral response to <i>M</i>. <i>tuberculosis</i> antigens in sarcoidosis patients versus controls.</p

The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies.

<p>The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies.</p

Funnel plot assessing publication bias.

<p><b>a. Funnel plot for the studies on the T-cell response to <i>M</i>. <i>tuberculosis</i> antigens with controls of PPD- or unknown PPD status; b. Funnel plot for the studies on the T-cell response to <i>M</i>. <i>tuberculosis</i> antigens with PPD+ controls; c. Funnel plot for studies on the humoral response to <i>M</i>. <i>tuberculosis</i> antigens</b>. SA = sarcoidosis.</p

Flow diagram of assessment of studies identified in meta-analysis.

<p>Flow diagram of assessment of studies identified in meta-analysis.</p

B7H3-dependent myeloid-derived suppressor cell recruitment and activation in pulmonary fibrosis

http://deepblue.lib.umich.edu/bitstream/2027.42/175995/2/2022_MDSC-B7H3_TJ_Frontiers in Immunol.pdfPublished versionDescription of 2022_MDSC-B7H3_TJ_Frontiers in Immunol.pdf : Published versio