The SARS-CoV-2 infection causes severe respiratory involvement (COVID-19) in 5–20% of patients through initial immune derangement, followed by intense cytokine production and vascular leakage. Evidence of immune involvement point to the participation of T, B, and NK cells in the lack of control of virus replication leading to COVID-19. NK cells contribute to early phases of virus control and to the regulation of adaptive responses. The precise mechanism of NK cell dysregulation is poorly understood, with little information on tissue margination or turnover. We investigated these aspects by multiparameter flow cytometry in a cohort of 28 patients hospitalized with early COVID-19. Relevant decreases in CD56brightCD16+/- NK subsets were detected, with a shift of circulating NK cells toward more mature CD56dimCD16+KIR+NKG2A+ and “memory” KIR+CD57+CD85j+ cells with increased inhibitory NKG2A and KIR molecules. Impaired cytotoxicity and IFN-γ production were associated with conserved expression of natural cytotoxicity receptors and perforin. Moreover, intense NK cell activation with increased HLA-DR and CD69 expression was associated with the circulation of CD69+CD103+ CXCR6+ tissue-resident NK cells and of CD34+DNAM-1brightCXCR4+ inflammatory precursors to mature functional NK cells. Severe disease trajectories were directly associated with the proportion of CD34+DNAM-1brightCXCR4+ precursors and inversely associated with the proportion of NKG2D+ and of CD103+ NK cells. Intense NK cell activation and trafficking to and from tissues occurs early in COVID-19, and is associated with subsequent disease progression, providing an insight into the mechanism of clinical deterioration. Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches.

The US, Doppler and CT appearances in a patient with hemangiopericytoma of the greater omentum are presented. Ultrasound revealed a solid mass with heterogeneous echo pattern, well-defined margins and marked vascularity with low impedance flow (mean resistive index 0.42). The tumour was mobile. It was detected below the left kidney at the first US examination and had migrated into the pelvis 14 days later. At CT the tumour demonstrated strong but brief peripheral enhancement and a central hypodense scar.

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NK cells are generated from hematopoietic stem cells (HSC) residing in the bone marrow (BM), similar to other blood cells. Development toward mature NK cells occurs largely outside the BM through travel of CD34+ and other progenitor intermediates toward secondary lymphoid organs. The BM harbors multipotent CD34+ common lymphoid progenitors (CLPs) that generate T, B, NK, and Dendritic Cells and are devoid of erythroid, myeloid, and megakaryocytic potential. Over recent years, there has been a quest for single-lineage progenitors predominantly with the objective of manipulation and intervention in mind, which has led to the identification of unipotent NK cell progenitors devoid of other lymphoid lineage potential. Research efforts for the study of lymphopoiesis have almost exclusively concentrated on healthy donor tissues and on repopulation/transplant models. This has led to the widely accepted assumption that lymphopoiesis during disease states reflects the findings of these models. However, compelling evidences in animal models show that inflammation plays a fundamental role in the regulation of HSC maturation and release in the BM niches through several mechanisms including modulation of the CXCL12-CXCR4 expression. Indeed, recent findings during systemic inflammation in patients provide evidence that a so-far overlooked CLP exists in the BM (Lin − CD34 + DNAM-1 bright CXCR4 + ) and that it overwhelmingly exits the BM during systemic inflammation. These “inflammatory” precursors have a developmental trajectory toward surprisingly functional NK and T cells as reviewed here and mirror the steady state maintenance of the NK cell pool by CD34 + DNAM-1 − CXCR4 − precursors. Our understanding of NK cell precursor development may benefit from including a distinct “inflammatory” progenitor modeling of lymphoid precursors, allowing rapid deployment of specialized Lin − CD34 + DNAM-1 bright CXCR4 + -derived resources from the BM.

BackgroundCryopyrin associated periodic syndromes (CAPS) are a group of autoinflammatory diseases linked to gain-of-function mutations in the NLRP3 gene that cause uncontrolled IL-1β secretion. CINCA syndrome is the most severe CAPS disease characterized by central nervous system disabilities with a long-term risk of secondary amyloidosis.Proton pump inhibitors (PPIs), commonly used as inhibitors of gastric acid production, also display anti-inflammatory properties, making them promising drugs in sepsis and in inflammatory disorders.ObjectivesTo develop a novel NLRP3 knock-in (KI) mouse model of CAPS to evaluate amyloid deposition and to test alternative therapeutic approaches.MethodsWe generated KI mice by engineering N475K mutation associated with CAPS phenotype into mouse Nlrp3 gene. KI and Wild Type (WT) mice received PPIs or PBS intraperitoneally and were analyzed for survival, inflammation, cytokine secretion, and amyloidosis development. Cytokines secretion from bone marrow derived dendritic cells (BMDCs) and peritoneal macrophages (PMs) was evaluated by ELISA. Hystological analysis of all organs was evaluated by hematoxylin and eosin staining. Amyloid deposition was quantified through Congo Red staining.ResultsMutant NLRP3 KI mice displayed features that recapitulates the immunological and clinical phenotype of CAPS. These mice had systemic inflammation, with high levels of serum pro-inflammatory cytokines compared to WT controls. Hystological analysis revealed the presence of acute and chronic inflammatory cell infiltrates and amyloid deposits in spleen, liver and kidneys. As in CAPS monocytes, BMDCs and PM from KI mice showed a strong increase in IL-1β, IL-18, and IL-1α secretion and decreased levels in interleukin-1 receptor antagonist (IL-1Ra), the naturally occurring IL-1b inhibitor.PPIs treatment of KI mice showed a clear clinical impact with improvement of inflammatory conditions and regression of amyloid deposits. Remarkably, BMDCs and PMs from PPI-treated mice presented reduced secretion of pro-inflammatory cytokines and re-established the levels of IL-1RA.ConclusionNLRP3 KI mice display a CAPS phenotype with many characteristics of autoinflammation, including amyloidosis. The therapeutic effectiveness associated with lack of toxicity indicates that PPIs could represent relevant adjuvants to the anti-IL-1 drugs in IL-1 driven diseases.References[1] Gattorno M, Martini A. Beyond the NLRP3 inflammasome: autoinflammatory diseases reach adolescence. Arthritis Rheum. 2013;[2] Brydges SD, Mueller JL, McGeough MD, Pena CA, Misaghi A, Gandhi C Putnam CD, et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity. 2009;[3] Balza E, Piccioli P, Carta S, Lavieri R, Gattorno M, Semino Cet al. Proton pump inhibitors protect mice from acute sistemic inflammation and induce long-term cross-tolerance. Cell Death Dis. 2016.Disclosure of InterestsArinna Bertoni: None declared, Sonia Carta: None declared, Chiara Baldovini: None declared, Federica Penco: None declar...