{"title":"Disease associations for rare immune genetic variants require statistical or rule-based support.","authors":"Paul E Gray, Stuart G Tangye, Edwin P Kirk","doi":"10.70962/jhi.20260099","DOIUrl":"10.70962/jhi.20260099","url":null,"abstract":"<p><p>Validating weak gene-disease associations requires statistical support from large case-control studies. In contrast, strong (e.g., monogenic) gene-disease associations may be established from relatively few affected individuals, when independent orthogonal evidence converges. Here, we examine four publications associating heterozygous variants in five genes-TNIP1, P2RY8, BLK, BANK1, and SH2B3-with autoimmune disease (predominantly systemic lupus erythematosus [SLE]). While we do not dispute the molecular findings of these studies, we do not accept the proposed disease associations, which lack case-control evidence and where high minor allele frequencies in non-disease populations, indicate that the genotypes are far too common to represent Mendelian disease alleles. Additionally, 8 of 18 alleles were searchable in UK Biobank, and none showed enrichment in SLE. Until further evidence emerges, caution is warranted in ascribing disease association to heterozygous genotypes in TNIP1, P2RY8, BLK, BANK1, and SH2B3, and linkage to patients in clinical pedigrees should not be taken as inferring a monoallelic inborn error of immunity.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221325","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}
{"title":"Pretransplant immune dysregulation and survival after HSCT in pediatric inborn errors of immunity.","authors":"Andrés Soffia, Arturo Borzutzky, Cristián Sotomayor","doi":"10.70962/jhi.20260093","DOIUrl":"10.70962/jhi.20260093","url":null,"abstract":"<p><p>Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many inborn errors of immunity (IEIs), but the prognostic role of pretransplant immune dysregulation in pediatric patients remains unclear. We retrospectively studied 29 pediatric patients with genetically confirmed IEI undergoing HSCT between 2021 and 2025. Immune dysregulation was quantified using IDDA v2.1; HCT-CI and PARI were also calculated. 2-year overall survival (OS) was 79%, and event-free survival was 59%. Higher IDDA v2.1 scores were associated with inferior OS in univariate analysis (HR: 2.23 per five-point increase, P = 0.043) and remained associated in an exploratory multivariable model (HR: 2.76, P = 0.041). Harrell's C-statistic for OS was 0.722 for IDDA v2.1, 0.661 for HCT-CI, and 0.772 for PARI. Exploratory quadrant analyses suggested that IDDA v2.1 provides complementary information, identifying patients classified as lower risk by comorbidity indices who nonetheless had adverse outcomes. These findings support IDDA v2.1 as an adjunct pretransplant risk stratification tool in pediatric IEI.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221326","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}
Madhavi Lakkaraja, Erica G Schmitt, Amika K Sood, Karin Chen, Arunkumar J Modi, James W Verbsky, Troy Torgerson, Ghassan Wahbeh, Aleksandra Petrovic, K Scott Baker, Megan A Cooper, Lauri M Burroughs
{"title":"Hematopoietic cell transplantation using treosulfan-based conditioning for IL-10 receptor deficiency.","authors":"Madhavi Lakkaraja, Erica G Schmitt, Amika K Sood, Karin Chen, Arunkumar J Modi, James W Verbsky, Troy Torgerson, Ghassan Wahbeh, Aleksandra Petrovic, K Scott Baker, Megan A Cooper, Lauri M Burroughs","doi":"10.70962/jhi.20260123","DOIUrl":"10.70962/jhi.20260123","url":null,"abstract":"<p><p>IL-10 receptor deficiency is a life-threatening inborn error of immunity associated with early-onset inflammatory bowel disease. Hematopoietic cell transplantation (HCT) using treosulfan-based conditioning resulted in excellent survival with full donor engraftment. Importantly, anakinra effectively served as a bridge to HCT.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13671123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198234","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}
Laure Delaval, Karim Dorgham, Jehane Fadlallah, Emilie Corvilain, Pierre-Emmanuel Rautou, Eric Oksenhendler, Claire Fieschi, Guy Gorochov, Marion Malphettes
{"title":"Higher serum sCD14 is an independent biomarker for porto-sinusoidal vascular disease risk in CVID.","authors":"Laure Delaval, Karim Dorgham, Jehane Fadlallah, Emilie Corvilain, Pierre-Emmanuel Rautou, Eric Oksenhendler, Claire Fieschi, Guy Gorochov, Marion Malphettes","doi":"10.70962/jhi.20260066","DOIUrl":"10.70962/jhi.20260066","url":null,"abstract":"<p><p>Serum soluble CD14 (sCD14) is used as a surrogate marker for bacterial translocation. This cohort study demonstrates that higher baseline sCD14 levels are an independent biomarker for porto-sinusoidal vascular disease risk in patients with common variable immunodeficiency.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13674294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198384","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}
V Koneti Rao, Anna Šedivá, Virgil A S H Dalm, Alessandro Plebani, Catharina Schuetz, Anna Shcherbina, Antonio Trizzino, Yulia Zharankova, Alanvin Orpia, Elaine Kulm, Julia Körholz, Vassilios Lougaris, Yulia Rodina, Jason Bradt, Anurag Relan, Gulbu Uzel
{"title":"Open-label extension study of leniolisib in activated PI3Kδ syndrome: Long-term efficacy and safety.","authors":"V Koneti Rao, Anna Šedivá, Virgil A S H Dalm, Alessandro Plebani, Catharina Schuetz, Anna Shcherbina, Antonio Trizzino, Yulia Zharankova, Alanvin Orpia, Elaine Kulm, Julia Körholz, Vassilios Lougaris, Yulia Rodina, Jason Bradt, Anurag Relan, Gulbu Uzel","doi":"10.70962/jhi.20260040","DOIUrl":"10.70962/jhi.20260040","url":null,"abstract":"<p><p>Activated phosphoinositide 3-kinase delta syndrome (APDS) is an inborn error of immunity characterized by immune deficiency and dysregulation. Leniolisib is a selective phosphoinositide 3-kinase delta inhibitor approved to treat APDS in patients ≥12 years old. We report final results from a single-arm, open-label extension study in 37 patients with APDS (NCT02859727). Median leniolisib exposure was 4.3 years (range, 1.2-7.0 years). Adverse events (AE) were reported in 34 patients; 87% were grade 1. Serious AEs, reported in 10 patients, were deemed unrelated to leniolisib. Two patients discontinued treatment due to AEs: cardiac arrest and Hodgkin's lymphoma. There were significant reductions in annual infection (P = 0.0005) and respiratory infection (P = 0.0017) rates per year of treatment. Immunoglobulin replacement therapy (IRT) use significantly decreased per year of treatment (P = 0.0095). Clinically meaningful improvements in general health scores from the 36-Item Short Form Survey were observed. Overall, long-term use of leniolisib was generally well tolerated, and infections and IRT use reduced over time.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187648","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}
Sophia Marie Armbruster, Andres Caballero-Oteyza, Oliver Bartsch, Tiziana Lorenzini, Hassan Abolhassani, Samantha Chan, Luis Ignacio González Granado, Victor Garcia-Bustos, Marta Dafne Cabañero Navalon, Nazanin Fathi, Nima Rezaei, Mathieu Fusaro, Roger Colobran, Kaan Boztug, Michele Proietti, Bodo Grimbacher
{"title":"Genotype-phenotype analysis in 333 individuals with heterozygous variants in NFKB1.","authors":"Sophia Marie Armbruster, Andres Caballero-Oteyza, Oliver Bartsch, Tiziana Lorenzini, Hassan Abolhassani, Samantha Chan, Luis Ignacio González Granado, Victor Garcia-Bustos, Marta Dafne Cabañero Navalon, Nazanin Fathi, Nima Rezaei, Mathieu Fusaro, Roger Colobran, Kaan Boztug, Michele Proietti, Bodo Grimbacher","doi":"10.70962/jhi.20260076","DOIUrl":"https://doi.org/10.70962/jhi.20260076","url":null,"abstract":"<p><p>Heterozygous germline variants in NFKB1 can be classified into variants with \"known protein defect\" and \"unknown protein effect.\" However, beyond this, NFKB1 variants may be additionally categorized into at least eight distinct variant classes. We conducted a literature review of 67 papers reporting on NFKB1 variants and included four additional individuals, carrying previously unreported NFKB1 variants. We identified 333 individuals with unique variants in NFKB1. Our compiled data revealed that there is no sex predilection, the penetrance-including all heterozygous carriers-was 78%, and the mean age of onset for the \"known protein defect cohort\" was 21.2 years. Individuals harboring variants with a known protein defect demonstrated a higher frequency of malignancies and autoimmune disorders. However, these individuals were less frequently classified as affected than individuals with variants with unknown protein defect. Carriers of whole NFKB1 gene deletions had a significantly higher penetrance to being designated as \"affected,\" but beyond this, the clinical manifestations did not differ between variant classes.</p>","PeriodicalId":521015,"journal":{"name":"Journal of human immunity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225583","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}
Dan Tomomasa, Tomoko Uehara, Tomotada Takayama, Madoka Nishimura, Ryosuke Wakatsuki, Xi Yang, Satoshi Okada, Akihiro Fujimoto, Hirokazu Kanegane
{"title":"A possible founder IRAK4 variant in Okinawa, Japan.","authors":"Dan Tomomasa, Tomoko Uehara, Tomotada Takayama, Madoka Nishimura, Ryosuke Wakatsuki, Xi Yang, Satoshi Okada, Akihiro Fujimoto, Hirokazu Kanegane","doi":"10.70962/jhi.20260119","DOIUrl":"10.70962/jhi.20260119","url":null,"abstract":"<p><p>A cluster of cases of IRAK4 deficiency has been identified in Okinawa Prefecture, Japan. All affected families carry the homozygous c.123_124insA variant, suggesting a founder effect and supporting the implementation of targeted newborn screening of IRAK4 deficiency in Okinawa.</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/PMC13576643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148972923","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}
Renan César Sbruzzi, Adrian Gervais, Eduarda Sgarioni, Silvia Gress, Helena Suñé Lehmen, Martina Schroeder Wissmann, Bibiana Sampaio de Oliveira Fam, Nathan A Cadore, Mariléa F Feira, Osvaldo Artigalás, Giovanna Câmara Giudicelli, Lucy Bizien, Aurélie Cobat, Qian Zhang, Anne Puel, Paul Bastard, Jean-Laurent Casanova, Fernanda S L Vianna
{"title":"Autoantibodies neutralizing type I interferons in COVID-19 patients from southern Brazil.","authors":"Renan César Sbruzzi, Adrian Gervais, Eduarda Sgarioni, Silvia Gress, Helena Suñé Lehmen, Martina Schroeder Wissmann, Bibiana Sampaio de Oliveira Fam, Nathan A Cadore, Mariléa F Feira, Osvaldo Artigalás, Giovanna Câmara Giudicelli, Lucy Bizien, Aurélie Cobat, Qian Zhang, Anne Puel, Paul Bastard, Jean-Laurent Casanova, Fernanda S L Vianna","doi":"10.70962/jhi.20260096","DOIUrl":"10.70962/jhi.20260096","url":null,"abstract":"<p><p>Inborn errors of type I IFN (IFN-I) immunity and neutralizing autoantibodies (auto-Abs) against IFN-I (AAN-I-IFNs) impair antiviral immunity and underlie critical COVID-19. Their impact on disease severity in different populations, such as Latin American populations, remains to be better understood. This study assessed the presence of AAN-I-IFNs (anti-IFN-α2, anti-IFN-ω, and anti-IFN-β) in a cohort of 458 COVID-19 patients from southern Brazil, stratified as mild (n = 224) versus non-mild (n = 234), or survivors (n = 369) versus deceased (n = 89). AAN-I-IFNs were detected in 17 patients (3.7%), with increasing prevalence across disease severity, present in one (0.4%) mild case and 16 (6.8%) hospitalized cases (P = 0.006); and eight (2.2%) survivors and nine (10.1%) deceased cases (P = 0.008). Anti-IFN-α2 and anti-IFN-ω auto-Abs were most frequently detected, while anti-IFN-β auto-Abs were found in one patient. Our findings highlight the role of AAN-I-IFNs underlying COVID-19 severity in a southern Brazilian population.</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/PMC13641011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149122981","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}
Derrick H Y Chong, Caroline Spaner, Ibrahim Elsharawi, Mark Trinder, Haya Al Bitar, Mariam Goubran, Amelia Perrotta, Rachael Horner, Dilys Chen, Jennifer Corpuz, Kun Huang, Trudy Taylor, Ian Marie Lano, Kerri Purdy, Jan P Dutz, Sylvia Pasternak, Richard I Crawford, Luke Y C Chen
{"title":"Skin biopsy in adult-onset Still's disease: A specific, rapid, and widely available diagnostic test.","authors":"Derrick H Y Chong, Caroline Spaner, Ibrahim Elsharawi, Mark Trinder, Haya Al Bitar, Mariam Goubran, Amelia Perrotta, Rachael Horner, Dilys Chen, Jennifer Corpuz, Kun Huang, Trudy Taylor, Ian Marie Lano, Kerri Purdy, Jan P Dutz, Sylvia Pasternak, Richard I Crawford, Luke Y C Chen","doi":"10.70962/jhi.20260088","DOIUrl":"10.70962/jhi.20260088","url":null,"abstract":"<p><p>Adult-onset Still's disease (AOSD) is a diagnostic challenge, as its features overlap with many inflammatory syndromes and no single finding is diagnostic. Skin biopsies showing dyskeratotic keratinocytes (DKs) in the superficial epidermis, including the horny layer, are thought to be highly specific for AOSD but are not included in current diagnostic or classification criteria. We conducted a retrospective clinicopathological study of 16 adults with confirmed AOSD and skin biopsies from a Canadian rare diseases program, and developed a differential diagnosis for superficial DKs using expert consensus and literature review. Clinical morphology varied, but histopathology was similar: 12 of 16 patients had DKs or necrotic keratinocytes in the upper epidermis. Superficial DKs have been reported in conditions distinct from AOSD, but not in its major mimics. Skin biopsy is low-cost, minimally invasive, and widely available and should be performed early in suspected AOSD; superficial DKs should be added to future diagnostic and classification criteria.</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/PMC13587882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148993658","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":"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}
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