RAG suppresses group 2 innate lymphoid cells

In Vivo Antagonistic Effects of Dexamethasone On Lenalidomide-Induced NK Cell Activation.

Inflammatory status might direct ILC and NK cells to IL-17 expressing ILC3 and NK subsets in Behcet's disease

Type I IFN Derived from Ly6Chi Monocytes Suppresses Type 2 Inflammation in a Murine Model of Atopic Dermatitis

Atopic dermatitis (AD) is a complex, multifactorial skin disease, characterized by pruritus and predominant Th2 inflammation. Innate immune cells may play a role in AD development and are composed of granulocytes, macrophages, innate-like T cells, and innate lymphoid cells. This study investigates the phenotypic and functional profile of circulating CLA+ natural killer (NK) cells and its role in the skin-homing to NK cells infiltrated in adults’ skin with AD. We selected 44 AD patients and 27 non-AD volunteers for the study. The results showed increased frequencies of both CLA+CD56bright and CLA+CD56dim NK cell populations in the peripheral blood, mainly in severe AD patients. Upon SEB stimulation, we observed an augmented percentage of CLA+CD56dim NK cells expressing CD107a, IFN-γ, IL-10, and TNF, reinforcing the role of staphylococcal enterotoxins in AD pathogenesis. Additionally, we demonstrated increased dermal expression of both NK cell markers NCAM-1/CD56 and pan-granzyme, corroborating the skin-homing, mostly in severe AD. Further studies are necessary to elucidate the potential role of NK cells in the chronification of the inflammatory process in AD skin, as well as their possible relationship with staphylococcal enterotoxins, and as practicable therapeutic targets.

Atopic dermatitis is a common chronic pruritic inflammatory disease of the skin involving neuro-immune communication. Neuronal mechanism-based therapeutic treatments remain lacking. We investigated the efficacy of intravenous lidocaine therapy on atopic dermatitis and the underlying neuro-immune mechanism. Pharmacological intervention, immunofluorescence, RNA-sequencing, genetic modification and immunoassay were performed to dissect the neuro-immune basis of itch and inflammation in atopic dermatitis-like mouse model and in patients. Lidocaine alleviated skin lesions and itch in both atopic dermatitis patients and calcipotriol (MC903)-induced atopic dermatitis model by blocking subpopulation of sensory neurons. QX-314, a charged NaV blocker that enters through pathologically activated large-pore ion channels and selectivity inhibits a subpopulation of sensory neurons, has the same effects as lidocaine in atopic dermatitis model. Genetic silencing NaV 1.8-expressing sensory neurons was sufficient to restrict cutaneous inflammation and itch in the atopic dermatitis model. However, pharmacological blockade of TRPV1-positive nociceptors only abolished persistent itch but did not affect skin inflammation in the atopic dermatitis model, indicating a difference between sensory neuronal modulation of skin inflammation and itch. Inhibition of activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons by lidocaine largely accounts for the therapeutic effect of lidocaine in the atopic dermatitis model. NaV 1.8+ sensory neurons play a critical role in pathogenesis of atopic dermatitis and lidocaine is a potential anti-inflammatory and anti-pruritic agent for atopic dermatitis. A dissociable difference for sensory neuronal modulation of skin inflammation and itch contributes to further understanding of pathogenesis in atopic dermatitis.

The human innate immune system plays critical roles in tumor surveillance and in immunoregulation within the tumor microenvironment. Natural killer (NK) cells are innate lymphoid cells that mediate tumor cell killing by antibody-dependent cell mediated cytotoxicity (ADCC), through direct recognition, and by the expression of chimeric antigen receptors that directly target tumors. However, NK cell subsets with regulatory functionality also contribute to the tumor immune suppressive environment that enables tumor growth. The balance between effector and regulatory NK cell subsets has been studied extensively in murine models of cancer, but there is a paucity of models to study human NK cell function in tumorigenesis, which is restricted primarily to in vitro experiments. Humanized mice are a powerful alternative to syngeneic mouse tumor models for the study of human immuno-oncology and have proven effective tools to test immunotherapies targeting T cells. However human NK cell development and survival in humanized mice are severely limited. Previous studies have demonstrated that injection or transient expression of human IL15 enables efficient development of functional human NK cells within immunodeficient mice that were engrafted with CD34+ HSC. Based on these results we established NSG mice that constitutively expresses human IL15. The NSG-Tg(Hu-IL15) mice were generated using a BAC containing the human IL15 gene, and express a physiological level of human IL15 (7.1 ± 0.3 pg/ml). To evaluate human NK cell development, 8 to 12-week-old NSG and NSG-Tg(Hu-IL15) mice received 200 cGy irradiation and were then injected intravenously with 1x105 CD34+ HSC derived from umbilical cord blood. No difference in overall survival of HSC-engrafted NSG-Tg(Hu-IL15) mice compared to NSG mice were observed during the experiment, indicating that expression of IL15 did not increase mortality. Levels of circulating human CD45+ cells, T cells and B cells were similar between the HSC-engrafted NSG-Tg(Hu-IL15) and NSG mice. Significantly higher levels of human CD56+ NK cells were found in NSG-Tg(Hu-IL15) mice as compared to NSG mice at all time points tested in the peripheral blood and within the spleen and bone marrow. A higher proportion of human CD56+ NK cells recovered from the blood and spleen of NSG-Tg(Hu-IL15) mice expressed granzyme A, granzyme B and perforin as compared to NK cells from NSG mice, suggesting that the NK cells were functional. Moreover, human NK cells enriched from the NSG-Tg(Hu-IL15) mice lysed K562 cells in an in vitro cytotoxicity assay. These data demonstrate that HSC-engrafted NSG mice expressing human IL15 support enhanced development of functional human NK cells and suggest that HSC-engrafted NSG-Tg(Hu-IL15) mice are a powerful model to study the role of NK cells in tumor-immune system interactions and to test immunotherapies targeting NK cells. Citation Format: Ken-Edwin Aryee, Lisa Burzenski, Dale L. Greiner, Raymond M. Welsh, Leonard D. Shultz, James G. Keck, Michael A. Brehm. Transgenic expression of human IL15 in NOD-scid IL2rgnull (NSG) mice enhances the development and survival of functional human NK cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5674.

NK cells as a possible new player in atopic dermatitis

BackgroundUncontrolled proliferation of metastatic solid tumors accounts for most cancer-related deaths. Metastatic tumors in the brain exemplify several key difficulties associated with researching and treating metastatic disease, including poor tissue...

Chapter 8 - Innate lymphoid cells in autoimmune diseases

Human innate lymphoid cells

Allergen challenge in allergic rhinitis rapidly induces increased peripheral blood type 2 innate lymphoid cells that express CD84

Daily cannabidiol and L-theanine beverage consumption does not alter anxiety, fatigue, cognitive function, or natural killer cell function: A randomized, controlled trial in healthy, young adults

The proposed pathogenesis of the cardiac manifestations of neonatal lupus (cardiac-NL) involves maternal autoantibodies to the RNPs SSA/Ro and SSB/La, enhanced by as-yet-unknown factors that likely involve dysregulation of both inflammatory and fibrotic fetal responses. This study was designed to improve the power to detect specific associations in genes with candidate biologic functions. Using data from our genome-wide association study of 116 Caucasian children with cardiac-NL and 3,351 Caucasian controls, we tested for enrichment of single-nucleotide polymorphism (SNP) associations in genes with candidate biologic functions related to fibrosis, immune function, apoptosis, T cell function, cell infiltration, innate immune cell function, interferon, Toll-like receptors, and calcium channels. After linkage disequilibrium pruning and exclusion of the extended HLA region, a total of 15,103 SNPs in 3,068 genes remained. A highly significant enrichment of P values was observed for genes related to fibrosis (P = 2.27 × 10(-9) ), apoptosis (P = 7.67 × 10(-7) ), and innate immune cell (P = 2.53 × 10(-6) ), immune (P = 5.01 × 10(-4) ), T cell (P = 2.23 × 10(-4) ), and interferon functions (P = 1.64 × 10(-3) ). The most significant non-HLA associations included the sialyltransferase gene ST8SIA2 (rs1487982; odds ratio 2.20 [95% confidence interval 1.52-3.19], P = 3.37 × 10(-5) ), the integrin gene ITGA1 (rs2432143; odds ratio 2.31 [95% confidence interval 1.54-3.45], P = 4.54 × 10(-5) ), and the complement regulator gene CSMD1 (rs7002001; odds ratio 2.41 [95% confidence interval 1.57-3.72], P = 6.33 × 10(-5) ). This study identified novel candidate genes associated with cardiac-NL and highlights the value of studying this cohort for advancing knowledge regarding the genetic etiology of this syndrome. Identification of causal alleles is expected to provide critical insight into the molecular mechanisms responsible for linking maternal autoantibodies to cardiac scarring in these fetuses/neonates.

This satellite symposium took place during the 49th annual meeting of the European Society for Dermatological Research (ESDR). Prof Dávila began the symposium by describing the immunology behind Type 2 inflammation as a complex interaction between environmental factors, immune response, and barrier dysfunction. He explained that the principal cells participating in innate Type 2 immunity are Type 2 innate lymphoid cells (ILC2), eosinophils, basophils, and mast cells, and that Th2 lymphocytes, dendritic cells (DC), and their main cytokines (IL-4, IL-5, and IL-13) comprise the adaptive arm of the Type 2 immune response and are essential in IgE-mediated reactions. Prof Seneschal followed by explaining that Type 2 inflammation in atopic dermatitis (AD) is a combination of immune and epidermal barrier components influenced by genetic and environmental factors. Epidermal barrier proteins are expressed in lower levels in AD, and other proteins are also dysregulated, disrupting tight junctions. Both lesional and nonlesional skin in patients with AD show epithelial barrier dysfunction, and inflammation can lead to a vicious cycle of itching and damage. Prof Dahlén concluded the meeting by explaining that airway inflammation is one of the major factors involved in Type 2 asthma, and this can be driven by an allergic route, involving mast cells, or a nonallergic route, involving ILC2. Inflammatory cytokines also increase mucus production, one of the main causes of asthma-related death. Recent studies of asthma immunology have suggested that ILC2 are subject to feedback modulation by prostaglandin D2 (PGD2), and that both IL-4 and IL-13 are involved in hyper-responsiveness in asthmatic lung tissue.

The pathogenesis of atopic dermatitis (AD) is understood to be crucially influenced by three main factors: dysregulation of the immune response, barrier dysfunction, and pruritus. In the lesional skin of AD, various innate immune cells, including Th2 cells, type 2 innate lymphoid cells (ILC2s), and basophils, produce Th2 cytokines [interleukin (IL)-4, IL-5, IL-13, IL-31]. Alarmins such as TSLP, IL-25, and IL-33 are also produced by epidermal keratinocytes, amplifying type 2 inflammation. In the chronic phase, not only Th2 cells but also Th22 and Th17 cells increase in number, leading to suppression of filaggrin expression by IL-4, IL-13, and IL-22, which further deteriorates the epidermal barrier function. Dupilumab, which targets IL-4 and IL-13, has shown efficacy in treating moderate to severe AD. Nemolizumab, targeting IL-31RA, effectively reduces pruritus in AD patients. In addition, clinical trials with fezakinumab, targeting IL-22, have demonstrated promising results, particularly in severe AD cases. Conversely, in murine models of AD, several cytokines, initially regarded as promising therapeutic targets, have not demonstrated sufficient efficacy in clinical trials. IL-33 has been identified as a potent activator of immune cells, exacerbating AD in murine models and correlating with disease severity in human patients. However, treatments targeting IL-33 have not shown sufficient efficacy in clinical trials. Similarly, thymic stromal lymphopoietin (TSLP), integral to type 2 immune responses, induces dermatitis in animal models and is elevated in human AD, yet clinical treatments like tezepelumab exhibit limited efficacy. Therapies targeting IL-1α, IL-5, and IL-17 also failed to achieve sufficient efficacy in clinical trials. It has become clear that for treating AD, IL-4, IL-13, and IL-31 are relevant therapeutic targets during the acute phase, while IL-22 emerges as a target in more severe cases. This delineation underscores the necessity of considering distinct pathophysiological aspects and therapeutic targets in AD between mouse models and humans. Consequently, this review delineates the distinct roles of cytokines in the pathogenesis of AD, juxtaposing their significance in human AD from clinical trials against insights gleaned from AD mouse models. This approach will improve our understanding of interspecies variation and facilitate a deeper insight into the pathogenesis of AD in humans.