{"title":"Enhancing Primary Immunodeficiency Diagnosis: Findings From Targeted Genetic Testing in a Turkish Cohort.","authors":"Çiğdem Aydoğmus, Sibel Kaplan Sarıkavak, Burcu Cil, Özge Türkyılmaz Uçar, Pinar Gökmirza Özdemir, Serdar Al, Salim Can, Safa Barış, Jessica Quinn","doi":"10.1111/sji.70031","DOIUrl":"https://doi.org/10.1111/sji.70031","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"101 6","pages":"e70031"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yifan Xie, Qi Cheng, Meng Li Xu, Jing Xue, Huaxiang Wu, Yan Du
{"title":"Itaconate: A Potential Therapeutic Strategy for Autoimmune Disease.","authors":"Yifan Xie, Qi Cheng, Meng Li Xu, Jing Xue, Huaxiang Wu, Yan Du","doi":"10.1111/sji.70026","DOIUrl":"https://doi.org/10.1111/sji.70026","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"101 5","pages":"e70026"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amber De Visscher, Marte Vandeput, Bert Malengier-Devlies, Eline Bernaerts, Tania Mitera, Nele Berghmans, Philippe E Van den Steen, Carine Wouters, Patrick Matthys
{"title":"Upregulation of Fcγ Receptor IV on Activated Monocytes and Macrophages Causes Nonspecific Binding of the PK136 Anti-NK1.1 Antibody in Murine Models of Toll-Like Receptor-Induced Inflammation.","authors":"Amber De Visscher, Marte Vandeput, Bert Malengier-Devlies, Eline Bernaerts, Tania Mitera, Nele Berghmans, Philippe E Van den Steen, Carine Wouters, Patrick Matthys","doi":"10.1111/sji.70027","DOIUrl":"https://doi.org/10.1111/sji.70027","url":null,"abstract":"<p><p>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<sup>+</sup> 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<sup>+</sup> populations. In conclusion, we emphasise that studying NK1.1<sup>+</sup> ILCs during inflammation by flow cytometry requires additional FcγRIV blocking reagents and careful exclusion of myeloid cells.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"101 5","pages":"e70027"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Fusion Protein MuSK-Fc Functions as a Decoy to Block the Binding of Anti-MuSK Antibodies to MuSK.","authors":"Akiyuki Uzawa, Hiroyuki Akamine, Manato Yasuda, Hideo Handa, Etsuko Ogaya, Kentaro Kurumada, Yosuke Onishi, Satoshi Kuwabara","doi":"10.1111/sji.70033","DOIUrl":"https://doi.org/10.1111/sji.70033","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"101 5","pages":"e70033"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jessica S Kleer, Andrea Kieninger-Gräfitsch, Carlo Chizzolini, Uyen Huynh-Do, Camillo Ribi, Marten Trendelenburg
{"title":"Evaluation of the Impact of Anti-C1q Autoantibodies on Cardiovascular Outcomes in Systemic Lupus Erythematosus.","authors":"Jessica S Kleer, Andrea Kieninger-Gräfitsch, Carlo Chizzolini, Uyen Huynh-Do, Camillo Ribi, Marten Trendelenburg","doi":"10.1111/sji.70028","DOIUrl":"https://doi.org/10.1111/sji.70028","url":null,"abstract":"","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"101 5","pages":"e70028"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tore Grimstad, Arne Carlsen, Jan Terje Kvaløy, Nils Bolstad, David John Warren, Lars Aabakken, Knut E A Lundin, Lars Karlsen, Øyvind Steinsbø, Roald Omdal
{"title":"Fatigue in Inflammatory Bowel Disease: No Effect of Serum Concentrations of Infliximab, Adalimumab or Anti-Drug Antibodies During Maintenance Therapy.","authors":"Tore Grimstad, Arne Carlsen, Jan Terje Kvaløy, Nils Bolstad, David John Warren, Lars Aabakken, Knut E A Lundin, Lars Karlsen, Øyvind Steinsbø, Roald Omdal","doi":"10.1111/sji.70029","DOIUrl":"https://doi.org/10.1111/sji.70029","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"101 5","pages":"e70029"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Physiopathology of Allergic Asthma: A Comprehensive Review.","authors":"Najla Ghrairi, Youssef Zied Elhechmi","doi":"10.1111/sji.70032","DOIUrl":"https://doi.org/10.1111/sji.70032","url":null,"abstract":"<p><p>Allergic asthma is a chronic inflammatory airway disease characterised by airway hyperresponsiveness, reversible airflow obstruction and chronic inflammation. Environmental allergens trigger a series of immune responses driven by a Th2-dominated immune system, along with innate cells like innate lymphoid cells type 2 (ILC2) and effector cells such as mast cells, basophils and eosinophils. In addition to these immune pathways, genetic predisposition plays a crucial role in asthma onset. This review highlights the genetic basis of allergic asthma, the key immune responses, the mechanisms behind airway remodelling and advances in therapeutic strategies.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"101 5","pages":"e70032"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leon Cyranka, Ida Mariegaard, Beatrice Fageräng, Laura Pérez-Alós, Verena Harpf, Tom Eirik Mollnes, Peter Garred, Anne Rosbjerg
{"title":"Inhibition of Alternative and Terminal Complement Pathway Components Modulate the Immune Response Against Bacteria and Fungi in Whole Blood.","authors":"Leon Cyranka, Ida Mariegaard, Beatrice Fageräng, Laura Pérez-Alós, Verena Harpf, Tom Eirik Mollnes, Peter Garred, Anne Rosbjerg","doi":"10.1111/sji.70030","DOIUrl":"10.1111/sji.70030","url":null,"abstract":"<p><p>Complement activation plays a critical role in the inflammatory response to Escherichia coli and Aspergillus fumigatus conidia. However, the specific contributions of complement components, including anaphylatoxin receptors, remain unclear. Using an ex vivo lepirudin whole blood model, we examined the activation of all three complement pathways (C4c, C3bc, and sC5b-9) induced by these microbes. We also assessed granulocyte and monocyte receptor expression of CD11b, CD64, C3aR, C5aR1, and C5aR2, along with phagocytosis, leukocyte activation (MPO), and cytokine release. Additionally, we investigated selective inhibition of complement components FD, C3, C5, and C5aR1. Both microbes increased complement activation products (C3bc and sC5-9), CD11b and CD64 expression, MPO release, and proinflammatory cytokines (IL-1β, IL-6, IL-8, and TNF), while decreasing C3aR, C5aR1, and C5aR2 expression. Complement inhibition reduced CD11b and CD64 expression and partially restored C3aR and C5aR1 levels, with minimal effects on C5aR2. FD, C3, and C5 inhibition reduced downstream complement markers, with FD and C3 inhibition also reducing phagocytosis, and only C3 inhibition reducing MPO release. The cytokine response varied by microbe: E. coli triggered higher proinflammatory cytokines, and FD and C3 inhibition generally reduced cytokine release, while C5 inhibition was less effective. Interestingly, A. fumigatus-induced cytokines significantly increased with C5aR1 inhibition, highlighting immune response differences related to C5aR1 signalling in bacterial versus fungal infections. In conclusion, regulation of inflammation through FD, C3, C5, and C5aR1 underscores the immunoregulatory role of the complement system in anti-microbial immune responses.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"101 5","pages":"e70030"},"PeriodicalIF":4.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emanuel Fryk, Andrea Tompa, Alexander Lind, Rasmus Bennet, Maria Faresjö
{"title":"Inflammatory Immune Markers Associated With Thyroid Peroxidase Autoantibodies in Children Diagnosed With Both Type 1 Diabetes and Celiac Disease.","authors":"Emanuel Fryk, Andrea Tompa, Alexander Lind, Rasmus Bennet, Maria Faresjö","doi":"10.1111/sji.70015","DOIUrl":"10.1111/sji.70015","url":null,"abstract":"<p><p>Autoimmune thyroid disease (AITD) is associated with other autoimmune endocrine diseases such as type 1 diabetes (T1D) and celiac disease (CeD). Thyroid peroxidase autoantibodies (TPOA) are biomarkers of AITD but may also occur in patients with other autoimmune diseases. We examined cross-sectional correlations between TPOA and an array of immune markers in a cohort of 90 children with exclusively T1D (n = 27), CeD (n = 16) or a combination of these two diseases (n = 18), compared to a reference group of children without these diagnoses (n = 29). Children with exclusively T1D or T1D in combination with CeD had higher levels of TPOA with an overrepresentation among girls. The correlations between immune markers and TPOA were distinctly different between all study groups. In children with T1D, TPOA correlated mainly with the T helper 1 associated IFN-γ and pro-inflammatory IL-1β. In contrast, in children with combined diagnoses, TPOA was correlated with pro-inflammatory MCP-1, the acute phase proteins ferritin, fibrinogen, and serum albumin A, and adipocytokines resistin and visfatin. Children with exclusively CeD did not show the same strong association between immune markers and TPOA. In conclusion, TPOA positivity was mainly detected in patients with T1D and female sex. Several inflammatory markers correlated with TPOA, indicating a relation to autoimmune parameters in children with T1D, CeD or both, but preceding symptoms AITD.</p>","PeriodicalId":21493,"journal":{"name":"Scandinavian Journal of Immunology","volume":"101 4","pages":"e70015"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}