{"title":"High prevalence of autoantibodies neutralizing type I IFNs in Japanese patients with hepatitis C.","authors":"Maki Taniguchi, Chiaki Tao, Takaki Asano, Miyuki Tsumura, Ko Ko, Hiroko Kumada, Takanori Utsumi, Kosuke Noma, Fumiaki Sakura, Kosuke Ashihara, Moe Tamaura, Yoko Mizoguchi, Osamu Ohara, Dusan Bogunovic, Paul Bastard, Jean-Laurent Casanova, Junko Tanaka, Masataka Tsuge, Kazuaki Chayama, Shiro Oka, Satoshi Okada","doi":"10.70962/jhi.20250239","DOIUrl":"10.70962/jhi.20250239","url":null,"abstract":"<p><p>Autoantibodies neutralizing type I IFNs (AAN-I-IFNs) are being identified as major, common, and global determinants of a growing range of severe viral diseases. We examined whether persistent hepatitis C virus (HCV) infection, with or without IFN-α therapy, could induce AAN-I-IFNs. We tested 2,573 HCV patients aged 1-95 years (1,115 treated with IFN-α, 1,458 untreated) and 1,000 healthy controls. AAN-INF-α2 prevalence was significantly higher in hepatitis C patients (2.7%) than in healthy controls (0.7%) and was higher still in those treated with IFN-α (3.9%) than in untreated patients (1.9%) (P = 0.0053). A longitudinal study of 15 IFN-α-treated patients with AAN-IFN-α2 revealed that only one had AAN-IFN-α2 before IFN-α therapy and that 12 patients developed AAN-IFN-α2 in the year following treatment. However, 80% eventually became AAN-IFN-α2 negative. These findings suggest that chronic HCV infection, perhaps due to the chronic production of endogenous IFN-α, and exogenous IFN-α treatment promote the development of AAN-IFN-α2.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"2 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148979355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ambre Dethier, Fanny Bajolle, Paul Bastard, Laureline Berteloot, Romain Lévy, Filippo Consonni, Quentin Deletang, Eric Dannaoui, Olivier Raisky, Philippe Drabent, Jacinta Bustamante, Fréderic Rieux-Laucat, Anne Puel, Fanny Lanternier, Marie-Louise Frémond, Bénédicte Neven
{"title":"A fatal case of Aspergillus endocarditis in a pediatric patient with STING-associated vasculopathy.","authors":"Ambre Dethier, Fanny Bajolle, Paul Bastard, Laureline Berteloot, Romain Lévy, Filippo Consonni, Quentin Deletang, Eric Dannaoui, Olivier Raisky, Philippe Drabent, Jacinta Bustamante, Fréderic Rieux-Laucat, Anne Puel, Fanny Lanternier, Marie-Louise Frémond, Bénédicte Neven","doi":"10.70962/jhi.20250262","DOIUrl":"10.70962/jhi.20250262","url":null,"abstract":"<p><p>SAVI is a rare STING1 gain-of-function disorder causing systemic inflammation, vasculopathy, and interstitial lung disease. JAK inhibitors are first-line therapy. We report a SAVI patient on prolonged JAK inhibitors who developed opportunistic infections, including fatal Aspergillus endocarditis, underscoring therapeutic challenges.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"2 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149019501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"In Memoriam: Daniel L. Kastner, MD (1951-2026).","authors":"Sudhir Gupta, Raphaela Goldbach-Mansky, Ivona Aksentijevich","doi":"10.70962/jhi.20260153","DOIUrl":"https://doi.org/10.70962/jhi.20260153","url":null,"abstract":"<p><p>Dr. Daniel L. Kastner, former Scientific Director of the National Human Genome Research Institute (NHGRI), was a visionary physician-scientist whose discoveries transformed the understanding of innate immunity and established the modern field of autoinflammatory diseases. Early in his career, he led the International FMF Consortium in identifying mutations in the MEFV gene as the cause of familial Mediterranean fever, providing the first molecular basis for a hereditary periodic fever syndrome and fundamentally redefining the pathogenesis of inflammatory disease. He subsequently identified and characterized additional hereditary autoinflammatory disorders, developed the conceptual framework for autoinflammation, and demonstrated how the study of rare genetic diseases could reveal universal mechanisms governing human inflammation and immunity. As Chief of the Inflammatory Disease Section at the National Institute of Musculoskeletal and Skin Diseases and later at the NHGRI, he built an internationally recognized program that integrated clinical investigation, human genetics, and immunology to advance both scientific discovery and patient care. Dr. Kastner mentored generations of physician and scientists and inspired colleagues through his intellectual rigor, humility, wit, and generosity. He will be remembered as the founder of the field of autoinflammatory diseases, an extraordinary translational investigator, a dedicated mentor, and a compassionate physician whose discoveries transformed the lives of patients worldwide.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"2 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148946499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mattison P Stojcic, Makenzie A Manning, Miguel Galicchio, Manfred Hönig, Despina Moshous, Sven Kracker, Felipe Suarez, Ruben Martinez-Barricarte, Aidé Tamara Staines-Boone, Yuridia Salazar Gálvez, Edgar-Domingo Cordero-Chura, Estefany-Graciela Mamani-Velasquez, Jian Cui, Jeremie Rosain, Pandiarajan Vignesh, Sergio D Rosenzweig, Klaus Schwarz, Catherine M Biggs, Jacob Rozmus, Stuart E Turvey
{"title":"IRF4 p.T95R combined immunodeficiency: Clinical features and transplant outcomes.","authors":"Mattison P Stojcic, Makenzie A Manning, Miguel Galicchio, Manfred Hönig, Despina Moshous, Sven Kracker, Felipe Suarez, Ruben Martinez-Barricarte, Aidé Tamara Staines-Boone, Yuridia Salazar Gálvez, Edgar-Domingo Cordero-Chura, Estefany-Graciela Mamani-Velasquez, Jian Cui, Jeremie Rosain, Pandiarajan Vignesh, Sergio D Rosenzweig, Klaus Schwarz, Catherine M Biggs, Jacob Rozmus, Stuart E Turvey","doi":"10.70962/jhi.20260069","DOIUrl":"10.70962/jhi.20260069","url":null,"abstract":"<p><p>IRF4 is a transcription factor within the interferon regulatory factor family that controls key aspects of lymphocyte differentiation and adaptive immunity. The heterozygous IRF4 p.Thr95Arg (p.T95R) variant affecting the DNA-binding domain was recently identified to cause a new inborn error of immunity, but the longitudinal clinical course and therapeutic implications remain incompletely defined. We performed detailed clinical characterization and follow-up of all 10 known patients. Each presented with early-onset combined immunodeficiency characterized by hypo- or agammaglobulinemia and marked susceptibility to opportunistic infections. Pulmonary disease was universal, and gastrointestinal involvement was associated with a more severe clinical course. Four patients underwent hematopoietic stem cell transplantation; two survived, and two died. Notably, both deaths occurred in patients transplanted in the setting of active infection. These findings define IRF4 p.T95R as a profound combined immunodeficiency with high infectious burden and demonstrate that disease severity and intervention timing may contribute to transplant outcomes, supporting early diagnosis and timely transplantation before uncontrolled infection.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"2 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149140359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jenny A Patel, Nermina Saucier, Hwi M Gil, Elizabeth G Schmitz, Marianna B Ruzinova, Ayah Saffaf, Morey Blinder, Neha Mehta-Shah, Zachary D Crees, Megan A Cooper, Ofer Zimmerman
{"title":"Mosaic TLR8 gain-of-function in an elderly female treated with JAK inhibitor and adjunctive therapy.","authors":"Jenny A Patel, Nermina Saucier, Hwi M Gil, Elizabeth G Schmitz, Marianna B Ruzinova, Ayah Saffaf, Morey Blinder, Neha Mehta-Shah, Zachary D Crees, Megan A Cooper, Ofer Zimmerman","doi":"10.70962/jhi.20260113","DOIUrl":"10.70962/jhi.20260113","url":null,"abstract":"<p><p>We report severe neutropenia in a 77-year-old female with mosaic TLR8 gain-of-function due to a novel variant. Treatment with ruxolitinib, prednisone, and GM-CSF resulted in clinical improvement. This case expands the phenotypic spectrum beyond pediatric and male cohorts, highlighting mosaicism in late-onset immune dysregulation.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"2 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13603065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149043363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Signe Bedsted Clemmensen, Nanna Mørk, Julie A Jensen, Lisbeth Aagaard Larsen, Bettina Bundgaard, Marianne Nygaard, Michelle Møhlenberg, Morten K Skouboe, Adrian Gervais, Paul Bastard, Anne Puel, Aurelie Cobat, Jean-Laurent Casanova, Kaare Christensen, Trine H Mogensen
{"title":"Autoantibodies neutralizing type I interferons in older twin pairs: Low concordance.","authors":"Signe Bedsted Clemmensen, Nanna Mørk, Julie A Jensen, Lisbeth Aagaard Larsen, Bettina Bundgaard, Marianne Nygaard, Michelle Møhlenberg, Morten K Skouboe, Adrian Gervais, Paul Bastard, Anne Puel, Aurelie Cobat, Jean-Laurent Casanova, Kaare Christensen, Trine H Mogensen","doi":"10.70962/jhi.20260142","DOIUrl":"10.70962/jhi.20260142","url":null,"abstract":"<p><p>Autoantibodies (auto-Abs) neutralizing type I interferons (IFN-I) underlie various life-threatening viral infections, and the prevalence of these auto-Abs rises sharply between 65 and 70 years of age. We investigated the familial aggregation of neutralizing IFN-I auto-Abs by assessing concordance rates in Danish older twins, including 3,270 twins aged 65-96 years in a sample comprising 1,318 intact twin pairs (2,636 individuals) and 634 twins from broken twin pairs (634 individuals). Neutralizing IFN-I auto-Abs were detected in 1.5% (50/3,270) of all twins tested, including 1.4% (37/2,636) in twins from intact pairs and 2.1% (13/634) in twins from broken pairs. A total of 50 twins had neutralizing IFN-I auto-Abs, including one concordant monozygotic pair and 35 discordant pairs, yielding a low overall concordance rate. A slight, but nonsignificant, increase in mortality was associated with harboring neutralizing IFN-I auto-Abs. Collectively, these findings do not reveal any familial aggregation of IFN-I auto-Abs, arguing against a strong germline genetic etiology of IFN-I auto-Abs in older adults.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"2 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149140358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anna-Lena Neehus, Vijay G Sankaran, Jean-Laurent Casanova, Jacinta Bustamante
{"title":"Human inborn errors of the phagocyte respiratory burst: Chronic granulomatous disease and beyond.","authors":"Anna-Lena Neehus, Vijay G Sankaran, Jean-Laurent Casanova, Jacinta Bustamante","doi":"10.70962/jhi.20260106","DOIUrl":"10.70962/jhi.20260106","url":null,"abstract":"<p><p>The phagocyte respiratory burst is an effector mechanism of immunity by which granulocytes, monocytes, and other myeloid cells generate reactive oxygen species (ROS). Inborn errors of core phagocyte NADPH oxidase components (gp91phox, p22phox, p47phox, and p67phox) underlie most cases of chronic granulomatous disease, characterized by severe, recurrent bacterial and fungal infections. An expanding spectrum of inborn errors of immunity (IEIs) has been identified that affect molecules that trigger (IFN-γ, TNF, and their signaling pathways) or control NADPH oxidase assembly and activation (EROS, p40phox, PKCδ, RAC2, and DOCK2), thereby impairing ROS production. Studies of these genetic disorders, which include infection, autoinflammation, and autoimmunity, have identified crucial pathways governing the induction, regulation, assembly, priming, activation, and function of the phagocyte NADPH oxidase complex. We review here the diverse IEIs affecting phagocyte ROS production, highlighting disorders in which ROS generation is absent, reduced, or subset-specific, and the corresponding cellular, immunological, and clinical phenotypes.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"2 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148993646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Edoardo Galli, Christoph T Berger, Thomas Daikeler, Anne-Kathrin Peyer Kauffmann, Marc Emmenegger, Armin Droll, Andrea Egger, Michael Sinnreich, Mike Recher
{"title":"Antibody deficiency in myotonic dystrophy type 1: A differential diagnosis below the radar.","authors":"Edoardo Galli, Christoph T Berger, Thomas Daikeler, Anne-Kathrin Peyer Kauffmann, Marc Emmenegger, Armin Droll, Andrea Egger, Michael Sinnreich, Mike Recher","doi":"10.70962/jhi.20250223","DOIUrl":"10.70962/jhi.20250223","url":null,"abstract":"<p><p>Myotonic dystrophy type 1 is a rare, underdiagnosed genetic neuromuscular disorder that is often accompanied by hypogammaglobulinemia, serving as a crucial diagnostic clue. We report the clinical and immunophenotypic features of two patients and discuss the underlying pathogenesis.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"2 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Work participation in inborn errors of immunity: The dual burden on patients and caregivers.","authors":"Federica Pulvirenti, Mayla Sgrulletti, Klara Radovic, Marco Lecis, Gloria Mantuano, Cinzia Milito, Alessandro Aiuti, Isabella Quinti, Viviana Moschese","doi":"10.70962/jhi.20260077","DOIUrl":"https://doi.org/10.70962/jhi.20260077","url":null,"abstract":"<p><p>Despite improved survival, occupational challenges in with inborn errors of immunity (IEI) patients and their families remain unmeasured. We conducted a nationwide cross-sectional survey promoted by AIP and ImmunITA, including 420 IEI adults and 110 caregivers, integrating occupational data with patient-reported outcome measures. Multivariable models assessed employment and productivity determinants. Overall, 67% of patients were employed, yet half reported reduced capacity, unsafe environments, limited career progression, and stigma. Unemployment was associated with female sex, disability, and lower education. Nondisclosure affected one-fourth of patients and one-fifth of caregivers. Work impairment reached 39%; absenteeism was driven by healthcare demands, while presenteeism was associated with disease burden, psychological distress, and immune dysregulation, but not the Ig administration route. Caregivers showed 34% work impairment, with absenteeism linked to care intensity and presenteeism to psychological distress, patient health, and child caregiving. Child caregivers had greater time demands and more part-time employment. In conclusion, IEI substantially impair work productivity, supporting integration of occupational needs into care to improve social inclusion.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"2 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13689748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149248483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Highly neutralizing anti-IFN-ω autoantibodies underlie severe pediatric adenovirus infection.","authors":"Chen-Xuan Kang, Jing-Ya Ding, Yu-Fang Lo, Tsai-Yi Wu, Han-Po Shih, Jhan-Jie Peng, Kung-Wei Lin, You-Ning Lin, Chia-Chi Lo, Shao-Hsuan Hsia, Jainn-Jim Lin, En-Pei Lee, Oi-Wa Chan, Yhu-Chering Huang, Chih-Jung Chen, Tzou-Yien Lin, Cheng-Lung Ku, Chen-Yen Kuo","doi":"10.70962/jhi.20250255","DOIUrl":"https://doi.org/10.70962/jhi.20250255","url":null,"abstract":"<p><p>Neutralizing autoantibodies (auto-Abs) against type I IFNs (IFN-α and IFN-ω) have emerged as major acquired risk factors for severe viral infections. Human adenovirus (HAdV) is highly prevalent in children and can cause severe pneumonia, but the host determinants of disease severity remain poorly understood. We describe here a 5-year-old child with life-threatening HAdV-B7 pneumonia requiring intensive care who carried high-titer anti-IFN-ω auto-Abs of the IgG1 and IgG3 subclasses. Peripheral blood mononuclear cells produced normal amounts of IFN-α and IFN-ω ex vivo; however, IFN-ω was undetectable in the plasma during acute illness. Functional assays demonstrated that the patient's plasma strongly neutralized IFN-ω, abolishing its antiviral signaling and protective effects, resulting in high levels of adenovirus replication and virus-induced cytotoxicity. These findings implicate anti-IFN-ω auto-Abs in severe adenoviral infection and support immunological screening of pediatric patients with unexplained severe viral pneumonia, which may guide targeted management.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"2 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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