Mutual Interaction of Basophils and T Cells in Chronic Inflammatory Diseases

Basophils are, together with mast cells, typical innate effector cells of allergen-induced IgE-dependent allergic diseases. Both cell types express the high affinity receptor for IgE (FcεR1), release histamine, inflammatory mediators and cytokines following FcεR1 cross-linking. Basophils are rare granulocytes in blood, lymphoid and non-lymphoid tissues and the difficulties to detect and isolate these cells has hampered the study of their biology and the understanding of their possible role in pathology. Furthermore, the existence of other FcεR1-expressing cells, including professional Ag-presenting dendritic cells, generated some controversy regarding the ability of basophils to express MHC Class II molecules, present Ag and drive naïve T cell differentiation into Th2 cells. The focus of this review is to present the recent advances on the interactions between basophils and peripheral blood and tissue memory Th1, Th2 and Th17 cells, as well as their potential role in IgE-independent non allergic chronic inflammatory disorders, including human inflammatory bowel diseases. Basophils interactions with the innate players of IgE-dependent allergic inflammation, particularly innate lymphoid cells, will also be considered. The previously unrecognized function for basophils in skewing adaptive immune responses opens novel perspectives for the understanding of their contribution to the pathogenesis of inflammatory diseases

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

CD47 fusion protein targets CD172a+ cells in Crohn’s disease and dampens the production of IL-1β and TNF

In mice, the transfer of CD172a(+) (SIRP-α) dendritic cells (DCs) elicits T cell–driven colitis, whereas treatment with CD47-Fc protein, a CD172a-binding agent, confers protection. The aim of this study was to elucidate the nature and functional properties of human CD172a(+) DCs in chronic intestinal inflammation. Here, we show that CD172a(+)CD11c(+) cells accumulate in the mesenteric lymph nodes (mLNs) and inflamed intestinal mucosa in patients with Crohn’s disease (CD). These cells are distinct from resident DCs and may coexpress markers typically associated with monocyte-derived inflammatory DCs such as CD14 and/or DC-SIGN, E-Cadherin, and/or CX(3)CR1. Spontaneous IL-1β and TNF production by HLA-DR(+) cells in CD tissues is restricted to those expressing CD172a. An avidity-improved CD47 fusion protein (CD47-Var1) suppresses the release of a wide array of inflammatory cytokines by CD172a(+) cells, which may include HLA-DR(−)CD172a(+) neutrophils, in inflamed colonic explant cultures and impairs the ability of HLA-DR(+)CD172a(+) cells to activate memory Th17 but not Th1 responses in mLNs. In conclusion, targeting CD172a(+) cells may represent novel therapeutic perspectives for patients with CD

Clinical Significance of Subcellular Localization of Maspin in Breast Carcinoma: An Immunohistochemical Study Using Two Different Antibodies

Background: Maspin is known to be a tumor suppressor protein: however, its prognostic value in patients with breast cancer remains controversial. The key influential factors contributing to this complexity may be the differences in antibodies used, as well as the positive criteria and sample size. To date, no study has investigated the prognostic significance of maspin expression by using two different antibodies in the same cohort. We aimed to clarify whether differences in antibodies could influence on the prognostic value of maspin in breast cancer patients. Methods: Immunohistochemical analyses using an anti-maspin antibody (clone G167-70) were performed on 164 resected specimens of invasive carcinoma of no special type (NOS). The correlation with clinicopathological factors was compared to previous results using clone EAW24, with longer follow-up duration. Results: The subcellular localization of maspin expression was as follows: cytoplasmic-only staining, 3 cases (1.8%), pancellular staining, 43 cases (26.2%); and no staining, 118 cases (72.0%). No nuclear-only staining was observed. There was no significant correlation between clinicopathological characteristics and the pancellualr expression of maspin. The pancellular expression group showed a significantly longer disease-free survival (DFS) than the other groups (P = 0.046). When clone EAW24 was used, the cytoplasmic-only staining group showed significantly shorter DFS than the pancellular staining group (P = 0.003). Conclusion: Clone EAW24 may be superior to clone G167-70 in selecting breast carcinoma with an aggressive phenotype, while clone G167-70 may be superior to clone EAW24 in selecting non-aggressive breast carcinoma

A Pilot Study of Transbronchial Biopsy Using Endobronchial Ultrasonography with a Guide Sheath in the Diagnosis of Peripheral Pulmonary Lesions in Patients with Interstitial Lung Disease

The occurrence of interstitial lung disease (ILD) with peripheral pulmonary lesions (PPLs) is closely linked to the development of lung cancer. Yet, the best diagnostic approach for identifying PPLs in patients with ILD remains elusive. This study retrospectively investigated the application of transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS) to the effective and safe diagnosis of PPLs when compared with conventional TBB. The study sample included a consecutive series of 19 patients with ILD who underwent conventional TBB or TBB using EBUS-GS at Tosei General Hospital between 1 April 2013 and 31 October 2015. The two techniques were compared based on diagnostic yield and associated complications. The diagnostic yield of EBUS-GS TBB was significantly higher than that of conventional TBB (p = 0.009), especially for small lesions (≤20 mm), lesions located in the lower lobes, lesions with a positive bronchus sign, and lesions visible by chest radiography (p = 0.010, p = 0.022, p = 0.006, and p = 0.002, respectively). There were no significant differences in complication rates. Therefore, EBUS-GS is an effective alternative for the diagnosis of PPLs in patients with ILD, without additional complications

Endobronchial Ultrasonography with a Guide Sheath Transbronchial Biopsy for Diagnosing Peripheral Pulmonary Lesions within or near Fibrotic Lesions in Patients with Interstitial Lung Disease

In patients with interstitial lung disease (ILD), the most frequent locations of lung cancer are within or near fibrotic lesions. However, the diagnostic yield for peripheral pulmonary lesions (PPLs) within or near fibrotic lesions using endobronchial ultrasonography with a guide sheath transbronchial biopsy (EBUS-GS TBB) may be unsatisfactory compared to that for PPLs distant from fibrotic lesions because of the difficulty in reaching the lesions. Our objectives were to evaluate the yield for PPLs using EBUS-GS TBB according to the proximity of PPLs to fibrotic lesions and to determine factors affecting the yield for PPLs. We retrospectively investigated 323 consecutive lesions using EBUS-GS TBB between 1 November 2014 and 31 December 2016. We identified PPLs with ILD in such lesions. PPLs with ILD were divided into PPLs within or near fibrotic lesions which met the criterion of PPLs, and of fibrotic lesions overlapping each other (PPLs-FL) and those distant from fibrotic lesions, which met the criterion of PPLs and the area of fibrotic lesion not overlapping each other (PPLs-NFL). Of the 323 lesions, 55 were included (31 PPLs-FL and 24 PPLs-NFL). The diagnostic yield for PPLs-FL was significantly lower than for PPLs-NFL (45.2% vs. 83.3%, p = 0.004). Multivariate analysis revealed that PPLs-NFL (odds ratio (OR) = 7.509) and a probe position within the lesion (OR = 4.172) were significant factors affecting diagnostic yield. Lesion’s positional relation to fibrotic lesions and the probe position were important factors affecting the successful diagnosis via EBUS-GS TBB in these patients

CD47 fusion protein targets CD172a+ cells in Crohn's disease and dampens the production of IL-1β and TNF.

In mice, the transfer of CD172a(+) (SIRP-α) dendritic cells (DCs) elicits T cell-driven colitis, whereas treatment with CD47-Fc protein, a CD172a-binding agent, confers protection. The aim of this study was to elucidate the nature and functional properties of human CD172a(+) DCs in chronic intestinal inflammation. Here, we show that CD172a(+)CD11c(+) cells accumulate in the mesenteric lymph nodes (mLNs) and inflamed intestinal mucosa in patients with Crohn's disease (CD). These cells are distinct from resident DCs and may coexpress markers typically associated with monocyte-derived inflammatory DCs such as CD14 and/or DC-SIGN, E-Cadherin, and/or CX3CR1. Spontaneous IL-1β and TNF production by HLA-DR(+) cells in CD tissues is restricted to those expressing CD172a. An avidity-improved CD47 fusion protein (CD47-Var1) suppresses the release of a wide array of inflammatory cytokines by CD172a(+) cells, which may include HLA-DR(-)CD172a(+) neutrophils, in inflamed colonic explant cultures and impairs the ability of HLA-DR(+)CD172a(+) cells to activate memory Th17 but not Th1 responses in mLNs. In conclusion, targeting CD172a(+) cells may represent novel therapeutic perspectives for patients with CD