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Familial forms of the severe immunoregulatory disease hemophagocytic lymphohistiocytosis (HLH) arise from biallelic mutations in the PRF1, UNC13D, STXBP2, and STX11 genes. Early and accurate diagnosis of the disease is important to determine the most appropriate treatment option, including potentially curative stem cell transplantation. The diagnosis of familial HLH (FHL) is traditionally based on finding biallelic mutations in patients with HLH symptoms and reduced natural killer (NK)-cell cytotoxicity. However, patients often have a low NK-cell count or receive immunosuppressive therapies that may render the NK-cell cytotoxicity assay unreliable. Furthermore, to fully understand the nature of a disease it is critical to directly assess the effect of mutations on cellular function; this will help to avoid instances in which carriers of innocuous mutations may be recommended for invasive procedures including transplantation. To overcome this diagnostic problem, we have developed a rapid and robust method that takes advantage of the functional equivalence of the human and mouse orthologues of PRF1, UNC13D, STX11, and STXBP2 proteins. By knocking out endogenous mouse genes in CD8+ T cells and simultaneously replacing them with their mutated human orthologues, we can accurately assess the effect of mutations on cell function. The wide dynamic range of this novel system allowed us to understand the basis of, otherwise cryptic, cases of FHL or HLH and, in some instances, to demonstrate that previously reported mutations are unlikely to cause FHL. This novel approach provides valuable new information to enable more accurate diagnosis and treatment of patients with HLH or FHL who inherit mutations of undetermined pathogenicity., (© 2023 by The American Society of Hematology.)

Niemann-Pick disease type C1 (NP-C1) is a rare lysosomal storage disorder resulting from mutations in an endolysosomal cholesterol transporter, NPC1. Despite typically presenting with pronounced neurological manifestations, NP-C1 also resembles long-term congenital immunodeficiencies that arise from impairment of cytotoxic T lymphocyte (CTL) effector function. CTLs kill their targets through exocytosis of the contents of lysosome-like secretory cytotoxic granules (CGs) that store and ultimately release the essential pore-forming protein perforin and proapoptotic serine proteases, granzymes, into the synapse formed between the CTL and target cell. We discovered that NPC1 deficiency increases CG lipid burden, impairs autophagic flux through stalled trafficking of the transcription factor EB (TFEB), and dramatically reduces CTL cytotoxicity. Using a variety of immunological and cell biological techniques, we found that the cytotoxic defect arises specifically from impaired perforin pore formation. We demonstrated defects of CTL function of varying severity in patients with NP-C1, with the greatest losses of function associated with the most florid and/or earliest disease presentations. Remarkably, perforin function and CTL cytotoxicity were restored in vitro by promoting lipid clearance with therapeutic 2-hydroxypropyl-β-cyclodextrin; however, restoration of autophagy through TFEB overexpression was ineffective. Overall, our study revealed that NPC1 deficiency has a deleterious impact on CTL (but not natural killer cell) cytotoxicity that, in the long term, may predispose patients with NP-C1 to atypical infections and impaired immune surveillance more generally., (© 2022 by The American Society of Hematology.)

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial disease of the lung tissue that causes symptoms such as coughing and asthma. It is caused by inflammatory factors and oxidative stress. In vivo model of IPF is induced by bleomycin (BLM,) a chemotherapeutic agent. We have investigated the effect of dapsone on bleomycin-induced IPF in adult male Wistar rats due to its anti-inflammatory and anti-oxidative stress effects. The animals were randomly divided into 5 groups (Control, BLM, BLM + dapsone 1, BLM + Dapsone 3, BLM + Dapsone 10). The control group received normal water and food. In the fibrosis group, bleomycin (BLM) (5 mg/kg) was used to induce pulmonary fibrosis by intratracheal administration. Three groups of animals were treated daily with single doses of 1, 3, and 10 mg dapsone by intraperitoneal injection 1 h after receiving BLM for 2 weeks. The activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and oxidative stress markers such as myeloperoxidase (MPO), malondialdehyde (MDA), protein carbonyl (PC) and nitrite were measured to evaluate bleomycin and therapeutic effect of dapsone. The histological assays of lung tissues were done by Hematoxylin-eosin (H & E) and Masson's trichrome staining. BLM reduced the activity of oxidative enzymes and increased the oxidative stress markers, while treatment with dapsone has reversed the results. In addition, the total number of cells as inflammatory cells such as neutrophils and eosinophils were examined. It has been indicated BLM increased these cells, and dapsone decreased them. The results of H & E and Masson's trichrome staining showed that dapsone reduced inflammation and alveolar wall thickness and BLM-induced pulmonary fibrosis. According to the findings of this study, dapsone seems to have therapeutic effects on pulmonary fibrosis through its anti-inflammatory and anti-oxidative stress properties and reduction of the toxic effects of bleomycin., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: The proportion of tuberculosis (TB) cases occurring in migrants in Europe is increasing. Extrapulmonary TB poses challenges in diagnosis and treatment and causes serious morbidity and mortality, yet its extent in migrant populations is unclear. We assessed patterns of extrapulmonary TB in migrants across the European Union (EU)/European Free Trade Association (EFTA). We investigated the proportion of extrapulmonary TB cases among migrants versus non-migrants, and variations by specific site of disease, reporting European region, and migrant region of origin., Methods: We carried out a cross-sectional secondary database analysis, utilizing 23 years of data collected between 1995 and 2017 from the European Surveillance System of the European Centre for Disease Prevention and Control for 32 EU/EFTA countries., Results: In total, 1 270 896 TB cases were included, comprising 326 987 migrants (25.7%) and 943 909 non-migrants (74.3%). Of TB cases among migrants, 45.2% (n = 147 814) were extrapulmonary compared to 21.7% (n = 204 613) among non-migrants (p < 0.001). Lymphatic, bone/joint and peritoneal/digestive TB were more common among migrant than non-migrant extrapulmonary cases. A lower proportion of extrapulmonary TB was seen in Eastern Europe (17.4%, n = 98 656 of 566 170) and Southern Europe (29.6%, n = 62 481 of 210 828) compared with Western (35.7%, n = 89 498 of 250 517) and Northern Europe (41.8%, n = 101 792 of 243 381). Migrants from South-East Asia and Sub-Saharan Africa were at highest risk of extrapulmonary disease, with 62.0% (n = 55 401 of 89 353) and 54.5% (n = 38 327 of 70 378) of cases, respectively, being extrapulmonary., Conclusions: Among TB cases in the EU/EFTA, extrapulmonary disease is significantly more common in migrants than in non-migrants. There is a need to improve clinical awareness of extrapulmonary TB and to integrate its detection into screening programmes., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)