In the last decade, the full picture of the role of innate lymphoid cells (ILCs) has been gradually revealed. ILCs are classified into 3 groups based on their transcription factors and cytokine ...production patterns, which mirror helper T-cell subsets. Unlike T cells and B cells, ILCs do not have antigen receptors. They promptly respond to multiple tissue-derived factors, such as cytokines and alarmins, and produce multiple proinflammatory and immunoregulatory cytokines. It has been reported that ILC-derived cytokines are important for the induction and regulation of inflammation. Accumulating evidence suggests that ILCs play substantial roles in protection against infection and the pathogenesis of inflammatory diseases, such as allergic diseases and autoimmune diseases. Different ILC subsets localize in distinct tissue/organ niches and receive tissue-derived signals on different types of inflammation, which allows them to acquire diverse phenotypes with specialized effector capacities. In this review we highlight the roles of ILCs in a variety of organs, such as the airway, skin, and gastrointestinal tract, in the context of allergic and nonallergic inflammation.
Background Bronchial epithelial barrier leakiness and type 2 innate lymphoid cells (ILC2s) have been separately linked to asthma pathogenesis; however, the influence of ILC2s on the bronchial ...epithelial barrier has not been investigated previously. Objective We investigated the role of ILC2s in the regulation of bronchial epithelial tight junctions (TJs) and barrier function both in bronchial epithelial cells of asthmatic patients and healthy subjects and general innate lymphoid cell– and ILC2-deficient mice. Methods Cocultures of human ILC2s and bronchial epithelial cells were used to determine transepithelial electrical resistance, paracellular flux, and TJ mRNA and protein expressions. The effect of ILC2s on TJs was examined by using a murine model of IL-33–induced airway inflammation in wild-type, recombination-activating gene 2 (Rag2) −/− , Rag2 −/− Il2rg −/− , and Rorasg/sg mice undergoing bone marrow transplantation to analyze the in vivo relevance of barrier disruption by ILC2s. Results ILC2s significantly impaired the epithelial barrier, as demonstrated by reduced transepithelial electrical resistance and increased fluorescein isothiocyanate–dextran permeability in air-liquid interface cultures of human bronchial epithelial cells. This was in parallel to decreased mRNAs and disrupted protein expression of TJ proteins and was restored by neutralization of IL-13. Intranasal administration of recombinant IL-33 to wild-type and Rag2 −/− mice lacking T and B cells triggered TJ disruption, whereas Rag2 −/− Il2rg −/− and Rorasg/sg mice undergoing bone marrow transplantation that lack ILC2s did not show any barrier leakiness. Direct nasal administration of IL-13 was sufficient to induce deficiency in the TJ barrier in the bronchial epithelium of mice in vivo. Conclusion These data highlight an essential mechanism in asthma pathogenesis by demonstrating that ILC2s are responsible for bronchial epithelial TJ barrier leakiness through IL-13.
Background
Morbidity and mortality from COVID‐19 caused by novel coronavirus SARS‐CoV‐2 is accelerating worldwide, and novel clinical presentations of COVID‐19 are often reported. The range of human ...cells and tissues targeted by SARS‐CoV‐2, its potential receptors and associated regulating factors are still largely unknown. The aim of our study was to analyze the expression of known and potential SARS‐CoV‐2 receptors and related molecules in the extensive collection of primary human cells and tissues from healthy subjects of different age and from patients with risk factors and known comorbidities of COVID‐19.
Methods
We performed RNA sequencing and explored available RNA‐Seq databases to study gene expression and co‐expression of ACE2, CD147 (BSG), and CD26 (DPP4) and their direct and indirect molecular partners in primary human bronchial epithelial cells, bronchial and skin biopsies, bronchoalveolar lavage fluid, whole blood, peripheral blood mononuclear cells (PBMCs), monocytes, neutrophils, DCs, NK cells, ILC1, ILC2, ILC3, CD4+ and CD8+ T cells, B cells, and plasmablasts. We analyzed the material from healthy children and adults, and from adults in relation to their disease or COVID‐19 risk factor status.
Results
ACE2 and TMPRSS2 were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA andPPIB), CD26 (DPP4), and related molecules were expressed in both epithelium and in immune cells. We also observed a distinct age‐related expression profile of these genes in the PBMCs and T cells from healthy children and adults. Asthma, COPD, hypertension, smoking, obesity, and male gender status generally led to the higher expression of ACE2‐ and CD147‐related genes in the bronchial biopsy, BAL, or blood. Additionally, CD147‐related genes correlated positively with age and BMI. Interestingly, we also observed higher expression of CD147‐related genes in the lesional skin of patients with atopic dermatitis.
Conclusions
Our data suggest different receptor repertoire potentially involved in the SARS‐CoV‐2 infection at the epithelial barriers and in the immune cells. Altered expression of these receptors related to age, gender, obesity and smoking, as well as with the disease status, might contribute to COVID‐19 morbidity and severity patterns.
ACE2 and TMPRSS2 expression is unique for the epithelial barrier sites, whereas CD147, cyclophilins, and CD26 are expressed in both, epithelial and immune cells. Age is a factor associated with the differential expression profiles of ACE2‐, CD147‐ and CD26‐related genes in the PBMCs and naive CD4+ T cells from healthy children and adults. Asthma, COPD, hypertension, smoking, obesity, and male gender generally lead to the higher expression of ACE2‐ and CD147‐related genes in the bronchial biopsy, BAL or blood.
Abbreviations: ACE2, angiotensin‐converting enzyme 2; AD, atopic dermatitis; BAL, bronchoalveolar lavage; COPD, chronic obstructive pulmonary disease; CypA, cyclophilin A; CypB, cyclophilin B; GLUT1, glucose transporter 1; ILC, innate lymphoid cell; MCTs, monocarboxylate transporters; NF‐ATs, nuclear factor of activated T cells; PBMCs, peripheral blood mononuclear cells; SARS‐CoV‐2; severe acute respiratory syndrome coronavirus 2; SLC6A19, sodium‐dependent neutral amino acid transporter B(0)AT1; S100A9, protein S100‐A9; TMPRSS2, transmembrane protease serine.
Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy with gastrointestinal symptoms such as vomiting and diarrhea. The development of international consensus ...guidelines for the diagnosis and management of FPIES in 2017 enabled us to compare patients worldwide, regardless of geographic variation in disease features. As a result, it has become clear that there is heterogeneity among patients with FPIES or that there are cases that partly fit the diagnostic criteria for FPIES but have different characteristics. This review highlights the heterogeneity in FPIES characteristics in terms of trigger foods, the age of onset, differences in geographic regions, and symptoms; it further proposes four disease entities, including acute FPIES in children, acute FPIES in adults, chronic FPIES, and early-onset neonatal FPIES, depending on the age of onset and presumed pathophysiology. The major symptoms at onset and trigger foods differ in acute FPIES in children, acute FPIES in adults, and chronic FPIES, whereas the disease entities may share a similar pathophysiology. Early-onset neonatal FPIES may have a different pathophysiology than acute or chronic FPIES, and may not necessarily fulfil the full diagnostic criteria for acute or chronic FPIES described in the international consensus guidelines. Due to the similarity in symptoms, early-onset neonatal FPIES may sometimes be misdiagnosed as necrotizing enterocolitis. We aim to increase awareness of FPIES among medical staff in pediatrics, neonatology, and internal medicine and promote research, to gain a better understanding of the heterogeneity and pathophysiology of FPIES.
Allergic asthma is an inflammatory disease characterized by lung eosinophilia controlled by type 2 cytokines. Cysteine proteases are potent triggers of allergic inflammation by causing barrier ...disruption in lung epithelial cells inducing the elevation of interleukin-5 (IL-5) and IL-13 from natural helper (NH) cells, a member of ILC2s, which leads to lung eosinophilia. In this study, we found that basophils play a crucial role in NH cell-mediated eosinophilic inflammation induced by protease allergens. Conditional deletion of basophils caused a resolution of the papain-induced eosinophilia and mucus production. Resolution of eosinophilia was also observed in mice lacking IL-4 specifically in basophils, indicating that basophil-derived IL-4 enhanced expression of the chemokine CCL11, as well as IL-5, IL-9, and IL-13 in NH cells, thus attracting eosinophils. These results demonstrate that IL-4 from basophils has an important role in the NH-derived cytokine and chemokine expression, subsequently leading to protease allergen-induced airway inflammation.
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•Basophils are essential for protease allergen-induced airway responses•Basophil-derived IL-4 controls ILC2-mediated eosinophilic inflammation•IL-4 is necessary for the expression of CCL11, IL-9, and IL-13 from NH cells•Interaction of basophils and ILC2 controls the IL-33 mediated allergic responses
The immune system in pregnancy is able to protect pregnant mothers and fetuses from pathogenic microorganisms even while permitting the mother to tolerate the semi-allogenic fetus. Trophoblasts, ...which are fetal-derived placental cells, play a central role on both sides of this duality at the maternal-fetal interface. In brief, the trophoblasts express pattern recognition receptors (PRRs) and are involved in the local innate immune response in the placenta. That response eliminates pathogenic microbes but also causes tissue damage. In this review, we summarize the research findings to date regarding the roles of those human trophoblast PRRs. Multiple types of PRRs (Toll-like receptors, Nod-like receptors, and RIG-I-like receptors) are expressed in the placenta and on trophoblasts. Trophoblasts’ PRRs participate in protecting the fetus against viruses, bacteria, and parasites by triggering production of proinflammatory cytokines and chemokines in the placenta. On the negative side, PRR signaling in trophoblasts can also initiate inflammation and trophoblast cell death, which can lead to placental inflammation-associated pregnancy complications such as preeclampsia, anti-phospholipid antibody syndrome, and miscarriage. Further elucidation of these dual roles of trophoblasts’ PRRs may shed light on the mechanisms by which fetuses are protected against congenital infections and also give us a better understanding of the etiologies of pregnancy complications, which can help us prevent/reduce adverse prenatal/neonatal outcomes.
•Trophoblasts express multiple types of pattern recognition receptors.•Trophoblasts contribute to host defense against pathogenic microbes through pattern recognition receptor signaling.•Trophoblasts' pattern recognition receptors are involved in the etiology of inflammation-associated pregnancy disorders.
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