Interleukin-17D and Nrf2 mediate initial innate immune cell recruitment and restrict MCMV infection.

Innate immune cells quickly infiltrate the site of pathogen entry and not only stave off infection but also initiate antigen presentation and promote adaptive immunity. The recruitment of innate leukocytes has been well studied in the context of extracellular bacterial and fungal infection but less during viral infections. We have recently shown that the understudied cytokine Interleukin (IL)-17D can mediate neutrophil, natural killer (NK) cell and monocyte infiltration in sterile inflammation and cancer. Herein, we show that early immune cell accumulation at the peritoneal site of infection by mouse cytomegalovirus (MCMV) is mediated by IL-17D. Mice deficient in IL-17D or the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an inducer of IL-17D, featured an early decreased number of innate immune cells at the point of viral entry and were more susceptible to MCMV infection. Interestingly, we were able to artificially induce innate leukocyte infiltration by applying the Nrf2 activator tert-butylhydroquinone (tBHQ), which rendered mice less susceptible to MCMV infection. Our results implicate the Nrf2/IL-17D axis as a sensor of viral infection and suggest therapeutic benefit in boosting this pathway to promote innate antiviral responses

Додатковий том «Словника української мови»

У статті подано історію роботи над Додатковим томом «Словника української мови» в 11-ти томах, описано джерела наповнення реєстру, структуру словникових статей, наведено приклади розробки статей різного типу – як нововведених слів, так і таких, що були в «Словнику української мови» і зазнали доповнення. Завдання лексикографів, які працювали над Додатковим томом, – відобразити динаміку лексичного шару української мови 1980-их рр. ХХ ст. – початку ХХІ ст. з акцентуванням її інноваційних й актуалізованих аспектів

Patient-reported outcomes with subcutaneous immunoglobulin in secondary immunodeficiency

Subcutaneous (SCIG) and intravenous immunoglobulin (IVIG) replacement are both used to prevent infections in patients with secondary immunodeficiency (SID). Compared with IVIG, SCIG has fewer systemic side effects and, additionally, facilitates home-based treatment. Shared decision-making practice should include discussion of aspects such as patient preference as well as the associated risks and benefits of treatment. We review the available evidence for the use of SCIG treatment in patients with SID, focusing on patient-reported outcomes (PROs). In most studies, there were improvements to health-related quality of life with SCIG treatment, compared with before initiating SCIG without prior IVIG treatment, or after switching to SCIG from IVIG treatment, or a no-SCIG/IVIG cohort. Treatment satisfaction with SCIG was similar between patients with SID and primary immunodeficiency disease. Patient preference and perception assessments highlighted the benefits of SCIG compared with IVIG, such as ease of use and administration, convenience, and time-effectiveness. In addition, many patients self-administered SCIG at home. Such aspects may be of specific benefit to patients with SID and hematological malignancy by reducing the risk of infection exposure in clinical settings. PRO data may be useful during shared decision-making discussions with patients with SID

Development of a primary care screening algorithm for the early detection of patients at risk of primary antibody deficiency

BACKGROUND: Primary antibody deficiencies (PAD) are characterized by a heterogeneous clinical presentation and low prevalence, contributing to a median diagnostic delay of 3-10 years. This increases the risk of morbidity and mortality from undiagnosed PAD, which may be prevented with adequate therapy. To reduce the diagnostic delay of PAD, we developed a screening algorithm using primary care electronic health record (EHR) data to identify patients at risk of PAD. This screening algorithm can be used as an aid to notify general practitioners when further laboratory evaluation of immunoglobulins should be considered, thereby facilitating a timely diagnosis of PAD. METHODS: Candidate components for the algorithm were based on a broad range of presenting signs and symptoms of PAD that are available in primary care EHRs. The decision on inclusion and weight of the components in the algorithm was based on the prevalence of these components among PAD patients and control groups, as well as clinical rationale. RESULTS: We analyzed the primary care EHRs of 30 PAD patients, 26 primary care immunodeficiency patients and 58,223 control patients. The median diagnostic delay of PAD patients was 9.5 years. Several candidate components showed a clear difference in prevalence between PAD patients and controls, most notably the mean number of antibiotic prescriptions in the 4 years prior to diagnosis (5.14 vs. 0.48). The final algorithm included antibiotic prescriptions, diagnostic codes for respiratory tract and other infections, gastro-intestinal complaints, auto-immune symptoms, malignancies and lymphoproliferative symptoms, as well as laboratory values and visits to the general practitioner. CONCLUSIONS: In this study, we developed a screening algorithm based on a broad range of presenting signs and symptoms of PAD, which is suitable to implement in primary care. It has the potential to considerably reduce diagnostic delay in PAD, and will be validated in a prospective study. Trial registration The consecutive prospective study is registered at clinicaltrials.gov under NCT05310604

Chitinase-like proteins promote IL-17-mediated neutrophilia in a tradeoff between nematode killing and host damage

Enzymatically inactive chitinase-like proteins (CLPs) such as BRP-39, Ym1 and Ym2 are established markers of immune activation and pathology, yet their functions are essentially unknown. We found that Ym1 and Ym2 induced the accumulation of neutrophils through the expansion of γδ T cell populations that produced interleukin 17 (IL-17). While BRP-39 did not influence neutrophilia, it was required for IL-17 production in γδ T cells, which suggested that regulation of IL-17 is an inherent feature of mouse CLPs. Analysis of a nematode infection model, in which the parasite migrates through the lungs, revealed that the IL-17 and neutrophilic inflammation induced by Ym1 limited parasite survival but at the cost of enhanced lung injury. Our studies describe effector functions of CLPs consistent with innate host defense traits of the chitinase family

IL-17-mediated antifungal defense in the oral mucosa is independent of neutrophils

Interleukin-17 (IL-17)-mediated immunity has emerged as a crucial host defense mechanism against Candida albicans infections in mucosal tissues and the skin. The precise mechanism by which the IL-17 pathway prevents fungal outgrowth has not been clarified. Neutrophils are critical for limiting fungal dissemination and IL-17 is generally thought to act by regulating neutrophil mobilization and trafficking to the site of infection. Using a mouse model of oropharyngeal candidiasis (OPC), we found that strikingly the IL-17 pathway is not required for the neutrophil response to C. albicans. Mice deficient for the IL-17 receptor subunits IL-17 receptor A (IL-17RA) or IL-17RC or mice depleted of IL-17A and IL-17F exhibited a normal granulocyte colony-stimulating factor (G-CSF) and CXC-chemokine response and displayed no defect in neutrophil recruitment or function. Instead, the inability of these mice to clear the fungus was associated with a selective defect in the induction of antimicrobial peptides (AMPs) in the epithelium that resulted in persistent fungal colonization. Importantly, this antifungal mechanism of IL-17A and IL-17F did not extend to the closely related family member IL-17C. Together, these data uncouple IL-17-dependent effector mechanisms from the neutrophil response and reveal a compartmentalization of the antifungal defense in the oral mucosa providing a new understanding of IL-17-mediated mucosal immunity against C. albicans

Additional file 1 of Development of a primary care screening algorithm for the early detection of patients at risk of primary antibody deficiency

Additional file 1: Table S1. Youden’s index per ICPC code

Additional file 3 of Development of a primary care screening algorithm for the early detection of patients at risk of primary antibody deficiency

Additional file 3: Figure S1. Data from the primary care electronic health record (EHR) on the number of diagnostic requests for leukocytes, C-reactive protein (CRP) and lung function tests. The censoring date is the date before which the EHR was screened. For most patients this is the date of data-extraction, November 2021. For immunodeficiency patients pre-diagnosis, the censoring date is the diagnosis date. For details on the censoring date, see “Methods” section

Additional file 2 of Development of a primary care screening algorithm for the early detection of patients at risk of primary antibody deficiency

Additional file 2: Table S2. Mean number of antibiotic prescriptions per ATCcode in the 4 years before the extraction date