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The small intestinal villus tip is the first point of contact for lumen-derived substances including nutrients and microbial products. Electron microscopy studies from the early 1970s uncovered unusual spatial organization of small intestinal villus tip blood vessels: their exterior, epithelial-facing side is fenestrated, while the side facing the villus stroma is non-fenestrated, covered by pericytes and harbors endothelial nuclei. Such organization optimizes the absorption process, however the molecular mechanisms maintaining this highly specialized structure remain unclear. Here we report that perivascular LGR5 +  villus tip telocytes (VTTs) are necessary for maintenance of villus tip endothelial cell polarization and fenestration by sequestering VEGFA signaling. Mechanistically, unique VTT expression of the protease ADAMTS18 is necessary for VEGFA signaling sequestration through limiting fibronectin accumulation. Therefore, we propose a model in which LGR5 +  ADAMTS18 + telocytes are necessary to maintain a “just-right” level and location of VEGFA signaling in intestinal villus blood vasculature to ensure on one hand the presence of sufficient endothelial fenestrae, while avoiding excessive leakiness of the vessels and destabilization of villus tip epithelial structures. The molecular mechanisms ensuring the specialized structure of small intestinal villus tip blood vessels are incompletely understood. Here the authors show that ADAMTS18 +  telocytes maintain a “just-right” level and location of VEGFA signaling on intestinal villus blood vessels, thereby ensuring the presence of endothelial fenestrae for nutrient absorption, while avoiding excessive leakiness and destabilization of villus tip epithelial structures.

Antibody-secreting plasma cells (PCs) arise rapidly during adaptive immunity to control infections. The early PCs are retained within the reactive lymphoid organ where their localization and homeostasis rely on extrinsic factors, presumably produced by local niche cells. While myeloid cells have been proposed to form those niches, the contribution by colocalizing stromal cells has remained unclear. Here, we characterized a subset of fibroblastic reticular cells (FRCs) that forms a dense meshwork throughout medullary cords of lymph nodes (LNs) where PCs reside. This medullary FRC type is shown to be anatomically, phenotypically, and functionally distinct from T zone FRCs, both in mice and humans. By using static and dynamic imaging approaches, we provide evidence that medullary FRCs are the main cell type in contact with PCs guiding them in their migration. Medullary FRCs also represent a major local source of the PC survival factors IL-6, BAFF, and CXCL12, besides also producing APRIL. In vitro, medullary FRCs alone or in combination with macrophages promote PC survival while other LN cell types do not have this property. Thus, we propose that this FRC subset, together with medullary macrophages, forms PC survival niches within the LN medulla, and thereby helps in promoting the rapid development of humoral immunity, which is critical in limiting early pathogen spread.

Stem and progenitor cells residing in the intestinal crypts drive the majority of colorectal cancers (CRCs), yet vascular contribution to this niche remains largely unexplored. VEGFA is a key driver of physiological and tumor angiogenesis. Accordingly, current anti-angiogenic cancer therapies target the VEGFA pathway. Here we report that in CRC expansion of the stem/progenitor pool in intestinal crypts requires VEGFA-independent growth and remodeling of blood vessels. Epithelial transformation induced expression of the endothelial peptide apelin, directs migration of distant venous endothelial cells towards progenitor niche vessels ensuring optimal perfusion. In the absence of apelin, loss of injury-inducible PROX1+ epithelial progenitors inhibited both incipient and advanced intestinal tumor growth. Our results establish fundamental principles for the reciprocal communication between vasculature and the intestinal progenitor niche and provide a mechanism for resistance to VEGFA-targeting drugs in CRCs.

Chronic lymphocytic leukaemia (CLL), the most common leukaemia in Germany, remains incurable; despite the availability of several systemic treatment options, patients often experience multiple relapses. The aim of this retrospective, observational study was to generate real-world evidence on the epidemiology, patient characteristics and treatment patterns of CLL in Germany, focussing on covalent Bruton’s tyrosine kinase inhibitor (cBTKi) and post-cBTKi treatments. Anonymised data from patients diagnosed with CLL (2012–2023) were harvested from one of the mandatory German Statutory Health Insurance sickness funds, AOK PLUS (the study population), and extrapolated to the German national population. There was an increase in CLL prevalence between 2012 and 2022, from 101.7 per 100,000 individuals (95% confidence interval [CI], 100.9–102.4) to 165.4 per 100,000 individuals (95% CI, 164.5–166.4), and incidence remained relatively stable in the German national population. One-third of the study population ( n  = 1616/4901) received treatment, and multiple treatment lines were common. Use of cBTKis (any line) increased between 2015 and 2022 in the German national population, from 2.4 per 100,000 individuals (95% CI, 2.3–2.5) to 15.7 per 100,000 individuals (95% CI, 15.4–16.0). Among 104 patients in the study population initiating post-cBTKi treatment, the most common (at any time) was another course of same/alternative cBTKi (53.8%), or anti-CD20 antibody (41.3%); 30.8% received venetoclax-based regimens at any time and 19.2% as a first post-cBTKi option. These real-world findings highlight the increasing prevalence of CLL in Germany, the need for multiple lines of treatment and the growing use of cBTKi therapies.

Bird breeder's lung disease is the most common form of hypersensitivity pneumonitis and is a rare entity in young children. We report three cases of children under 7 years of age in whom this diagnosis was confirmed early in the course of the disease. Three children aged 4.4 to 6.5 years presented with dry cough lasting for more than 1 month, dyspnoea, variable loss of appetite, weight loss, fatigue, fever and mild signs of respiratory distress. Chest X-ray films and CT scans showed a bilateral micronodular infiltrate. All three patients had strongly suggestive bronchoalveolar lavage fluid findings with lymphocytosis; two had elevated cell counts and decreased CD4/CD8 ratios. Lung biopsy confirmed the diagnosis in all children. Contact with allergens was identified in all children: two had spent holidays close to a farm in the previous month and one was living next to a pigeon house. In all children, avian precipitins were positive. The symptoms rapidly resolved after allergen avoidance and treatment with oral prednisone. Corticoid treatment was given between 11 and 15 weeks. One child relapsed and required long-term low-dose corticotherapy for 1 year. Lung function tests were normal in all three patients, 3.9 to 5.7 years after diagnosis. Bird breeder's lung disease is a rare entity but should be considered in young children presenting long lasting cough. While rapid allergen exclusion and start of treatment can avoid the evolution into irreversible lung fibrosis, clinical and biological evolution should be monitored carefully even after stopping corticoid treatment because of the possibility of relapse.