CD46 Protects against Chronic Obstructive Pulmonary Disease

BACKGROUND: Chronic obstructive pulmonary disease and emphysema develops in 15% of ex-smokers despite sustained quitting, while 10% are free of emphysema or severe lung obstruction. The cause of the incapacity of the immune system to clear the inflammation in the first group remains unclear. METHODS AND FINDINGS: We searched genes that were protecting ex-smokers without emphysema, using microarrays on portions of human lungs surgically removed; we found that loss of lung function in patients with chronic obstructive pulmonary disease and emphysema was associated with a lower expression of CD46 and verified this finding by qRT-PCR and flow cytometry. Also, there was a significant association among decreased CD46(+) cells with decreased CD4(+)T cells, apoptosis mediator CD95 and increased CD8(+)T cells that were protecting patients without emphysema or severe chronic obstructive pulmonary disease. CD46 not only regulates the production of T regulatory cells, which suppresses CD8(+)T cell proliferation, but also the complement cascade by degradation of C3b. These results were replicated in the murine smoking model, which showed increased C5a (produced by C3b) that suppressed IL12 mediated bias to T helper 1 cells and elastin co-precipitation with C3b, suggesting that elastin could be presented as an antigen. Thus, using ELISA from elastin peptides, we verified that 43% of the patients with severe early onset of chronic obstructive pulmonary disease tested positive for IgG to elastin in their serum compared to healthy controls. CONCLUSIONS: These data suggest that higher expression of CD46 in the lungs of ex-smoker protects them from emphysema and chronic obstructive pulmonary disease by clearing the inflammation impeding the proliferation of CD8(+) T cells and necrosis, achieved by production of T regulatory cells and degradation of C3b; restraining the complement cascade favors apoptosis over necrosis, protecting them from autoimmunity and chronic inflammation

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Protective genes.

a<p>mRNA expression tested in the same participants by microarray and quantitative RT-PCR which had either ^b lung resection for treatment of small peripheral cancer (n = 5); or ^c lung volume reduction surgery for emphysema (non-cancer, n = 4).</p>d<p>Values are expressed as average ± SD, P values are relative to control, calculated using two tailed T students test.</p>*<p>, p<0.0001;</p>†<p>, p<0.001;</p>‡<p>, p<0.01;</p>§<p>, p<0.05.</p

Inflammation in the murine smoking model.

<p>(A) Increased expression of CD46 in the lung tissue of no smoker mice compared to smoke exposed mice determined by IHC, arrow heads, and by western western blot on lung tissue homogenates of control mice or smoke-exposed mice (p = 0.02, n = 4, n = 4). (B) Increased deposition of C3b on lung tissue of control mice (n = 3) compared to smoke- exposed mice at 4 and 24 weeks (n = 3) determined by Western blot. Middle plot, immunoprecipitation of C3b from lung homogenate shows a significant increase of C3b deposition upon smoke exposure (p = 0.05). Elastin was stained and detected after stripping the membrane, showing significant increased co-precipitation with C3b (p = 0.01). Student t-test two tails was used to compare both groups; values in the plots represent average ± SD.</p

Quantification of CD46 levels.

<p>(A) Forward and side scatter plot of lung cells. Circles show the lymphocyte, macrophages and neutrophil populations. To the right a single color histograms showing expression of receptor CD46 from representative control, emphysema and end-stage participants. Pooled data from all participants (control, n = 4; emphysema, n = 4, end-stage n = 5) showing percent (median±SD) of total lung neutrophils, and macrophages expressing CD46; Cumulative values for lymphocytes showed a significative decrease (control, n = 6; emphysema, n = 7, end-stage n = 6, p<0.05) more patient were included with the same lung characteristics. (B) Gene expression of Casp 8, on the same patients, determined by qRT-PCR (median±SD) on emphysema patients with (n = 5) and without cancer (n = 4) shows no different expression level due to cancer away from the emphysemic region (p = 1). Mann-Whitney test was used to determine significant difference.</p

Kinetic of the inflammation in murine smoking model.

<p>Secretion of IL-12, C5a and IL-10, measured in mice bronchoalveolar lavage (BAL) of wild type (-▪-Wt), C5aR knockout (-•-C5ar−/−) and CXCR3 knockout (-○-CXCR3−/−) mice exposed at different times to cigarette smoke determined in Wt, C5ar−/− and CXCR3−/−. (A) Top plot show significantly less IL12 (average ± SD) secretion in C5aR −/− (*, p<0.001, n = 3) compared to Wt, while (B) CXCR3−/− shows significantly decrease C5a secretion (**, p = 0.02, n = 3) at 4 weeks smoke and (C) decreased IL10 (§, p = 0.03, and n = 3) relative to Wt (n = 6). P values were calculated using T student test, two tails.</p

治療によってFDG-PETにおける集積の変化を示した非結核性抗酸菌症の1例

症例は 64歳女性. 2006年 11月,検診にて胸部 X線異常を指摘された.胸部 CTで左舌区に consolidationを認め, FDG-PETでは SUV最大値 10.3と著明な集積を認めた.左 Bの経気管支生検で類上皮細胞肉芽腫を認め,気管支洗浄液から Mycobacteriumaviumが培養され,非結核性抗酸菌症と診断した.2007年 6月の胸部 CTで悪化を認めたため,多剤併用化学療法を開始した.同年 10月の胸部 CTで改善を認め,FDG-PETでは SUV最大値 3.9と集積の低下を認めた.自覚症状が乏しい非結核性抗酸菌症に対する適切な治療の導入基準は確立されていない.本症例は無症状であったが,短期間で胸部 CT所見の悪化がみられ, FDG-PETで SUVの著明高値を認めたため治療を行なった. FDG-PETは非結核性抗酸菌症の活動性を反映し,治療導入や効果判定に有用であった