Regulatory T Cells in Type 1 Autoimmune Pancreatitis

Autoimmune pancreatitis (AIP) is a newly recognized pancreatic disorder. Recently, International Consensus Diagnostic Criteria for AIP (ICDC) was published. In this ICDC, AIP was classified into Type 1 and Type 2. Patients with Type 1 AIP have several immunologic and histologic abnormalities specific to the disease, including increased levels of serum IgG4 and storiform fibrosis with infiltration of lymphocytes and IgG4-positive plasmacytes in the involved organs. Among the involved organs showing extrapancreatic lesions, the bile duct is the most common, exhibiting sclerosing cholangitis (IgG4-SC). However, the role of IgG4 is unclear. Recently, it has been reported that regulatory T cells (Tregs) are involved in both the development of various autoimmune diseases and the shift of B cells toward IgG4, producing plasmacytes. Our study showed that Tregs were increased in the pancreas with Type 1 AIP and IgG4-SC compared with control. In the patients with Type 1 AIP and IgG4-SC, the numbers of infiltrated Tregs were significantly positively correlated with IgG4-positive plasma cells. In Type 1 AIP, inducible costimulatory molecule (ICOS)+ and IL-10+ Tregs significantly increased compared with control groups. Our data suggest that increased quantities of ICOS+ Tregs may influence IgG4 production via IL-10 in Type 1 AIP

Cathelicidin-like Helminth Defence Molecules (HDMs) Absence of Cytotoxic, Anti-microbial and Anti-protozoan Activities Imply a Specific Adaptation to Immune Modulation

Host defence peptides (HDPs) are expressed throughout the animal and plant kingdoms. They have multifunctional roles in the defence against infectious agents of mammals, possessing both bactericidal and immune-modulatory activities. We have identified a novel family of molecules secreted by helminth parasites (helminth defence molecules; HDMs) that exhibit similar structural and biochemical characteristics to the HDPs. Here, we have analyzed the functional activities of four HDMs derived from Schistosoma mansoni and Fasciola hepatica and compared them to human, mouse, bovine and sheep HDPs. Unlike the mammalian HDPs the helminth-derived HDMs show no antimicrobial activity and are non-cytotoxic to mammalian cells (macrophages and red blood cells). However, both the mammalian- and helminth-derived peptides suppress the activation of macrophages by microbial stimuli and alter the response of B cells to cytokine stimulation. Therefore, we hypothesise that HDMs represent a novel family of HDPs that evolved to regulate the immune responses of their mammalian hosts by retaining potent immune modulatory properties without causing deleterious cytotoxic effects. © 2013 Thivierge et al

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

Immunolocalisation of the janus kinases (JAK)—signal transducers and activators of transcription (STAT) pathway in human epidermis

The janus kinases (JAK) and signal transducers and activators of the transcription (STAT) pathway have been shown to be activated by a number of cytokines or growth factors and to play significant roles in the differentiation of various cell types. In the present study, we investigated the distribution of the JAK–STAT pathway using immunohistochemistry in the human epidermis. Each element of the pathway showed abundant and differential expression in the epidermis. The differential distribution of the elements was most strikingly observed in the horny keratinised cell and granular layers of the epidermis. JAK2, JAK3, STAT1 and STAT5 were expressed in high amounts, and JAK1, TYK2, STAT2, STAT3, STAT4 and STAT6 to a much lesser extent in the horny cell layer. JAK3, TYK2, STAT2, STAT3, STAT4 and STAT6 were more abundantly expressed in the granular layer than the lower layers of the epidermis. JAK1, STAT1 and STAT5 were expressed at almost the same levels in the various layers of the epidermis. These results show that elements of the JAK–STAT pathway are abundantly and differentially expressed in the epidermis. It is suggested that each element of the pathway may play a role at a distinct stage of keratinocyte differentiation

Characteristics of a crater glacier at Ushkovsky volcano, Kamchatka, Russia, as revealed by the physical properties of ice cores and borehole thermometry

A glacier at the summit of Ushkovskyvolcano, Kamchatka peninsula, Russia, was studied in order to obtain information about the physical characteristics of a glacier that fills a volcanic crater. The glacier has a gentle surface and a concave basal profile with a maximum measured depth of 240 m at site K2. The annual accumulation rate was 0.54 m a-1 w.e., and the 10 m depth temperature was -15.8°C. A 211.70 m long ice core drilled at K2 indicates that (1) the site is categorized as a percolation zone, (2) the stress field in the glacier changes at 180 m depth from vertical and longitudinal compression with transversal extension, which is divergent flow, to a shear-dominated stress field, and (3) the frequent occurrence of ash layers can be a good tool for dating the ice core. The borehole temperature profiles were considered to be non-stationary, but the linear profile made it possible to estimate the basal temperature and the geothermal heat flux at K2. Assuming constant surface and the basal boundary-conditions, we constructed two depth-age relationships at K2. These predicted that the bottom ages of the ice core were about 511 or 603 years