Scandinavian Journal of Immunology最新文献

Distinct from the pulmonary circulation, the human respiratory mucosa is supplied by highly responsive, superficial, systemic microcirculations. In the early symptomatic phase of mucosal infections, circulating peptides-proteins of all sizes are released just beneath the epithelium and will soon appear on the mucosal surface. The traditional view is that mucosal injury must be involved in this plasma exudation process. However, well-controlled human in vivo observations demonstrate that the inflammatory plasma exudation response reflects non-injurious physiologic microvascular-epithelial cooperation. Crucially, although plasma exudation brings unfiltered plasma solutes without size restriction to the mucosal surface this occurs without reducing the protective epithelial barrier against inhaled molecules. Plasma exudation starts early and increases until viral or bacterial infections resolve. Plasma exudation therefore has the potential to slow down, or even prevent, progression to pneumonia and beyond. Plasma exudation would boost efficacy of a mature adaptive immunity by delivering circulating pathogen-neutralising antibodies undiluted to infection spots in the upper airways. Early mucosal infections would thus be dampened and development of lower airway infections prevented. Inferentially, this explains how treatment with vaccines still allows upper airway infections but prevent severe respiratory disease with alveolar and pulmonary circulation injury. Plasma exudation may also contribute to real-life protection against severe influenza/Covid-19 in airway mucosal diseases that exhibit plasma exudation hyperresponsiveness. Such hyperresponsiveness is inducible indicating feasibility of finding future treatments that increase the mucosal innate and adaptive immunity. Altogether, the present synthesis of literature suggests that plasma exudation is an important component of human respiratory mucosal antimicrobial immunity.

Common variable immunodeficiency disorders (CVID) are characterized by hypogammaglobulinemia and increased susceptibility to infections. However, non-infectious comorbidities (NICM) are also frequent manifestations of the disease. We search for distinctive immunophenotypes in CVID patients with NICM. Data were obtained from the clinical records and laboratory analyses of 42 CVID patients. Descriptive statistics, median comparisons, bivariate and multivariate analysis were performed. Median comparison of the immunological variables among patients with or without NICM revealed significant decreased levels of serum IgG, percentages of naïve CD4⁺ and CD8⁺ T cells, total B cells and CD56^dim NK cells in peripheral blood from CVID patients with NICM together with an increase in the percentages of effector memory (EM) CD4⁺ and terminally differentiated effector memory (EMRA) CD8⁺ T cells. By using logistic regressions, we determined the likelihood of exhibiting blood immunological abnormalities in patients with NICM vs. those without NICM. Finally, discriminant analyses and ROC curves established that percentages of CD4⁺ EM T cells and CD8⁺ EMRA T cells > 47.4% and 40.2% from the total CD4⁺ or CD8⁺ T cells, respectively, might be associated with NICM in CVID. These differences were also observed in CVID patients with Polyclonal lymphocytic infiltration. These data suggest subpopulations of effector T cells as potential biomarkers of NICM in CVID. Prospective studies are needed to determine the usefulness of our findings in the prognosis of CVID.

Primary immunodeficiency disorders (PIDDs) comprise a heterogeneous group of genetic conditions characterised by recurrent infections, immune dysregulation and increased susceptibility to malignancies. While clinical evaluation remains essential for diagnosis, genetic testing plays a pivotal role in confirming the diagnosis and guiding management. This cross-sectional study evaluates the diagnostic yield and clinical utility of targeted gene panel testing in patients with a strong clinical suspicion of PIDDs, within the framework of the Jeffrey Modell Foundation's 'Jeffrey's Insights' programme. Between 2022 and 2024, 104 patients without a prior genetic diagnosis were evaluated at the Department of Paediatric Allergy and Clinical Immunology, Başakşehir Çam and Sakura City Hospital, Türkiye. In 72 of 104 patients, the identified variants were consistent with clinical phenotypes. Pathogenic or likely pathogenic variants were identified in 41.3% of patients, increasing to 57.7% when including variants of uncertain significance (VUS) with high CADD scores. Genetic findings prompted reclassification of International Union of Immunological Societies (IUIS) categories in 25% of cases. Autosomal recessive inheritance and parental consanguinity were notable, reflecting regional genetic patterns. Failure to thrive and low switched memory B cell percentages were significantly associated with confirmed genetic diagnoses, while food allergy, viral skin infections and eczema were more common in genetically undiagnosed patients. These findings support the clinical value of targeted gene panels as an effective, accessible and informative tool in the diagnosis and classification of PIDDs, enhancing precision in patient care and enabling tailored therapeutic strategies.

Biological therapy is used to treat chronic inflammatory diseases (CIDs); however, up to 50% of patients fail to achieve an adequate clinical response. This study aimed to access the impact of obesity on clinical treatment response in CID patients after 14-16 weeks of biological therapy. This multicentre prospective cohort study enrolled 233 adults between 2017 and 2020 diagnosed with Crohn disease, ulcerative colitis (UC), rheumatoid arthritis, axial spondyloarthritis (PsA), psoriatic arthritis or psoriasis scheduled for biologic therapy. The main analysis population included patients with BMI data before treatment initiation, categorising patients as either obese (BMI ≥ 30 kg/m²) or non-obese (BMI < 30 kg/m²). The primary endpoint was the proportion of patients achieving clinical treatment response after 14-16 weeks. Main analyses were based on logistic regression with a factor for obesity, while adjusted for sex and age. Of the 228 patients eligible for the main analyses, 125 (55%) responded to biologic therapy. In the obese group (n = 59), 30 (51%) patients responded compared to the 95 (56%) individuals categorised as non-obese (n = 169), with no difference between groups (OR: 0.82, 95% CI: 0.43 to 1.60). This study did not find a lower likelihood of response to biologics in obese individuals compared with non-obese counterparts. Trial Registration: ClinicalTrials.gov identifier: NCT03173144.

Itaconate is a metabolite of the Krebs cycle, and endogenous itaconate is driven by a variety of innate signals that inhibit the production of inflammatory cytokines. The key mechanism of action of itaconate was initially found to be the competitive inhibition of succinate dehydrogenase (SDH), which inhibits the production of inflammatory factors, as well as its antioxidant effects. With increasing research, it was discovered that it modifies cysteine residues of related proteins through the Michael addition, such as modifying the Kelch-like ECH-associated protein 1 (KEAP1) protein and activating the nuclear factor erythroid 2-related factor 2 (NRF2) signalling pathway, as well as glycolytic enzymes and cellular pathway-associated factors that attenuate inflammatory responses and oxidative stress. It also acts on a variety of immune cells, affecting their function and activity, and has been increasingly shown to play a therapeutic role in a variety of inflammatory and autoimmune diseases through a combination of these mechanisms. In conclusion, there has been a great breakthrough in the research of itaconate, from the initial industrial application to the redefinition of the biological functions of itaconate. However, with the deepening of the research, we also found that there are more questions: the mechanism of action of itaconate, more functions of itaconate, clinical application of itaconate, and the use of itaconate still needs to be solved.

Nonspecific binding of monoclonal antibodies to Fcγ receptors (FcγRs) is a well-known root cause of unreliable results in flow cytometry. Over the past decade, liver Group 1 innate lymphoid cells (ILCs), including conventional natural killer (cNK) cells and type 1 ILCs (ILC1s), have been extensively studied by flow cytometry in various inflammatory liver disorders. In our previous work, we specifically evaluated changes in liver ILC1 numbers in two murine models of Toll-like receptor (TLR)-induced macrophage activation syndrome, a hyperinflammatory disorder with liver inflammation that is classified as a secondary form of hemophagocytic lymphohistiocytosis. Here, we follow up on a cell population that significantly expands during TLR triggering and resembles ILC1s, as they express CD49a and NK1.1 but lack expression of CD49b, a marker for cNK cells. However, detailed analysis revealed that these are CD49a⁺ monocytes/macrophages instead of ILC1s. During TLR triggering, their expression of FcγRIV increases significantly, leading to nonspecific binding of the frequently used PK136 anti-NK1.1 antibody, which cannot be blocked by standard Fcγ receptor blocking protocols. Instead, preincubation with anti-FcγRIV antibody or additional rat or mouse serum during antibody staining is necessary to prevent nonspecific anti-NK1.1 binding. Although we observed nonspecific binding of the anti-NK1.1 antibody in ex vivo applications, we confirmed that in vivo anti-NK1.1 only depletes truly NK1.1⁺ populations. In conclusion, we emphasise that studying NK1.1⁺ ILCs during inflammation by flow cytometry requires additional FcγRIV blocking reagents and careful exclusion of myeloid cells.

Muscle-specific tyrosine kinase antibody-positive myasthenia gravis (MuSKMG) is a rare subtype of MG that is often more refractory to immune treatment than acetylcholine receptor (AChR) antibody-positive MG. Therefore, novel therapeutic strategies are needed. We previously developed AChR-Fc, an Fc fusion protein that neutralises pathogenic autoantibodies and suppresses pathogenic B cells while preserving normal immunity, as a potential treatment for AChR antibody-positive MG. Subsequently, we conducted preliminary experiments on MuSK-Fc, a fusion protein targeting MuSKMG, using patient serum samples. This study examined whether MuSK-Fc binds to MuSK antibodies and inhibits MuSK antibody binding to MuSK. We found that MuSK-Fc specifically binds to MuSK antibodies and prevents their interaction with MuSK. These findings indicate that MuSK-Fc may neutralise pathogenic antibodies and suppress disease activity in MuSKMG.

Several studies have shown that infliximab and adalimumab ameliorate fatigue in inflammatory bowel disease. We investigated whether serum levels of these agents above or below a selected threshold influence fatigue severity. In this cross-sectional study, we measured serum concentrations (s-) of infliximab and adalimumab and corresponding anti-drug antibody levels. Therapeutic thresholds were defined as s-infliximab ≥ 5.0 mg/L and s-adalimumab ≥ 7.0 mg/L. Disease activity was assessed using the Harvey-Bradshaw Index for Crohn's disease, Partial Mayo Score for ulcerative colitis, and C-reactive protein (CRP) and faecal calprotectin levels for both conditions. Fatigue was assessed with the Fatigue Visual Analog Scale and Fatigue Severity Scale, and depression was evaluated with the Hospital Anxiety and Depression Scale, Depression subscale. Of 171 included patients (112 with Crohn's disease, 59 with ulcerative colitis), 66 (38.6%) were on infliximab and 105 (61.4%) were on adalimumab. Scores on the two fatigue scales were similar for serum values above versus below therapeutic thresholds for both drugs and did not differ with versus without anti-drug antibodies against either drug. CRP was numerically higher with infliximab levels below versus above the threshold (p = 0.06), whereas both CRP and faecal calprotectin were increased with adalimumab below versus above the threshold (p = 0.022, p = 0.0242). In patients with inflammatory bowel disease on maintenance therapy, s-infliximab and s-adalimumab levels below or above therapeutic thresholds or the presence of anti-drug antibodies did not affect fatigue severity. Trial Registration: ClinicalTrials.gov identifier: NCT02134054.