FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)1-a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity2. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR-NF-κB-C/EBPβ signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Severe coronavirus disease 2019 (COVID-19) is linked to insufficient control of viral replication and excessive inflammation driven by an unbalanced immune response. Plasmacytoid dendritic cells (pDCs) are specialized in the rapid production of interferons in response to viral infections, and can also prime and activate T-cells. Conventional DCs (cDCs) are critical for the elimination of viral infections owing to their specialized ability to prime and activate T cells. We assessed the frequency and phenotype of pDCs and cDCs in survivors and non-survivors of COVID-19.
Patients with COVID-19 were enrolled, and 22 were included in this study. Peripheral whole blood was obtained during the 2nd week of illness, stained with antibodies specific for lineage markers, human leukocyte antigen-DR isotype (HLA-DR), CD11c, and CD123, and analyzed by flow cytometry. Patients were followed-up during hospital admission and grouped into survivors (n=17) and non-survivors (n=5) of COVID-19.
The ratio of pDCs to pre-cDCs was significantly lower (P=0.0005) in non-survivors compared to survivors. The frequency of pDCs was significantly higher than cDC2-like cells (P=0.0002) and pre-cDCs (P<0.0001) in survivors but not in non-survivors. HLA-DR expression level on pDCs and cDC2-like cells was lower in non-survivors compared to survivors (P=0.02 and P=0.058, respectively), and HLA-DR was inversely correlated with disease severity rating (pDCs: r= -0.47, P=0.027; cDC2-like cells: r= -0.45, P=0.037). CD123 expression level on pDCs was significantly lower (P=0.038) in non-survivors compared to survivors, and CD123 was inversely correlated with disease severity rating (r=-0.5, P=0.016). CD11c expression level on cDC2-like cells was significantly lower (P=0.03) in non-survivors compared to survivors, and CD11c was inversely correlated with disease severity rating (r=-0.47, P=0.025).
A lower frequency of pDCs compared to other circulating DCs, and lower expression levels of HLA-DR, CD123 or CD11c on DCs is associated with fatal COVID-19.
© 2022 Hasan et al.

The cytokine midkine (MK) is a growth factor that is involved in different physiological processes including tissue repair, inflammation, the development of different types of cancer and the proliferation of endothelial cells. The production of MK by primary human macrophages and monocyte-derived dendritic cells (MDDCs) was never described. We investigated whether MK is produced by primary human monocytes, macrophages and MDDCs and the capacity of macrophages and MDDCs to modulate the proliferation of endothelial cells through MK production. The TLR stimulation of human monocytes, macrophages and MDDCs induced an average of ≈200-fold increase in MK mRNA and the production of an average of 78.2, 62, 179 pg/ml MK by monocytes, macrophages and MDDCs respectively (p < 0.05). MK production was supported by its detection in CD11c+ cells, CLEC4C+ cells and CD68+ cells in biopsies of human tonsils showing reactive lymphoid follicular hyperplasia. JSH-23, which selectively inhibits NF-κB activity, decreased the TLR-induced production of MK in PMBCs, macrophages and MDDCs compared to the control (p < 0.05). The inhibition of MK production by macrophages and MDDCs using anti-MK siRNA decreased the capacity of their supernatants to stimulate the proliferation of endothelial cells (p = 0.01 and 0.04 respectively). This is the first study demonstrating that the cytokine MK is produced by primary human macrophages and MDDCs upon TLR triggering, and that these cells can stimulate endothelial cell proliferation through MK production. Our results also suggest that NF-κB plays a potential role in the production of MK in macrophages and MDDCs upon TLR stimulation. The production of MK by macrophages and MDDCs and the fact that these cells can enhance the proliferation of endothelial cells by producing MK are novel immunological phenomena that have potentially important therapeutic implications.

IgE and high-affinity IgE receptor (FcεRI) expression on basophils have been scarcely explored in patients with chronic inducible urticaria (CIndU).
To investigate baseline serum IgE and FcεRI expression on blood basophils in a large cohort of CIndU patients and its relationship to treatment response.
Baseline total serum IgE and basophil FcεRI expression measured by flow cytometry in 165 patients with CIndU was studied. The relationship of both parameters with the response to antihistamine and anti-IgE (omalizumab) treatment was considered in a subsample of CIndU patients. FcεRI expression in basophils was assessed by mean fluorescence intensity (MFI) and basophil FcεRI standardized density (receptors/cell).
The median FcεRI expression standardized per density in blood basophils was found significantly higher in patients with CIndU compared to HCs. A positive correlation was found between IgE serum levels and basophil FcεRI expression. Basal FcεRI expression was not related to antihistamine treatment response. However, it was related to omalizumab, and patients responding to omalizumab showed higher basal basophil expression of FcεRI levels. Non-responders to the antihistamine showed significantly higher IgE serum levels.
FcεRI receptor overexpression in patients with CIndU shows almost the same pattern than chronic spontaneous urticaria. It seems to be independent of CIndU subtypes. Although additional studies would be welcome, our work highlights the relevance of FcεRI receptor regulation in CIndU supporting autoimmune basophil and mast cell activation and may be a biomarker for response to anti-IgE therapy.
© 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.