Journal of Clinical Immunology最新文献

{"title":"The Targets of Immune Adverse Events in Cancer Immunotherapy by Combined Check-point Inhibitors Resemble those Seen in IPEX Patients.","authors":"Maria Francisca Moraes-Fontes, Jocelyne Demengeot, António Coutinho","doi":"10.1007/s10875-025-01929-4","DOIUrl":"https://doi.org/10.1007/s10875-025-01929-4","url":null,"abstract":"<p><strong>Introduction: </strong>Specific determinants of target-organ damage in autoimmune diseases are complex and multifactorial, several genetic and environmental factors are recognized but mostly remain unknown. Immunotherapy with \"check-point inhibitors\" (CPI) is complicated by immune related adverse events (IRAE), occurring in a large fraction of patients, with organ-specific inflammation of immunologic aetiology. We hypothesized that such IRAE are associated to regulatory T cell (Treg) dysfunction. To start testing this hypothesis, we have now compared organ targets of CPI-induced IRAE with those described in IPEX (Immune dysregulation polyendocrinopathy enteropathy X-linked) patients carriers of deleterious mutations in the Foxp3 gene leading to deficient/absent Treg.  METHOD: We compared the frequency of autoimmune diseases (AID) in three groups of conditions: CPI-induced IRAE, IPEX patients, and the General Population (GP) through a PubMed search from 01/01/1998 to 31/05/2024. For each group, and each autoimmune disease, the highest reported frequency was selected, listed in reference to CPI-IRAE and classified from the highest to lowest prevalence. Identified were enteropathy, rash (eczema or other dermatitis), transaminitis/hepatitis, hypothyroidism, increased lipase/exocrine pancreatitis, arthralgia/inflammatory arthritis, hypophysitis, adrenal insufficiency, type 1 diabetes mellitus, haemolytic anaemia, Sjögren´s syndrome, polymyalgia rheumatica, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis.  RESULTS: While dermatitis and thyroid disease are also the most frequent AID in the GP, the latter, together with enteropathy, hepatitis, and adrenal insufficiency are much more frequent in CPI-IRAE and IPEX. Of note, the most frequent systemic AID in the GP such as de novo Sjögren´s syndrome, polymyalgia rheumatica, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis are extremely rare in CPI-IRAE (few case reports) and not described in IPEX.</p><p><strong>Conclusion: </strong>Our finding provides further evidence for the possibility that the functional inhibition/inactivation of Treg is a plausible contributing mechanism in the physiopathology of CPI-IRAE.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"141"},"PeriodicalIF":5.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency.","authors":"Li Wang, Jing Xiao, Rui Gan, Xuemei Tang, Junfeng Wu","doi":"10.1007/s10875-025-01939-2","DOIUrl":"10.1007/s10875-025-01939-2","url":null,"abstract":"<p><strong>Objective: </strong>Mutations in the HOIP gene, encoding Heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1) interacting protein, a key component of the linear ubiquitination chain assembly complex (LUBAC), affect the activation of the NF-κB pathway and result in autoinflammation and immunodeficiency. To date, only three patients with HOIP mutations have been reported in the English literature. This study aimed to identify the genetic cause in a 1-year-6-month-old boy with early-onset autoinflammation and immunodeficiency.</p><p><strong>Methods: </strong>Clinical manifestations and immunological phenotypes were assessed in a Chinese patient with novel compound heterozygous mutations in HOIP. Swiss-PdbViewer was used to predict the pathogenicity of the mutations. HOIP and LUBAC protein levels were evaluated by western blot. Immunological phenotypes and intracellular NF-κB phosphorylation in T and B cells were analyzed by flow cytometry, and the interferon (IFN) signature was assessed using quantitative reverse transcription PCR (RT-qPCR).</p><p><strong>Results: </strong>The patient experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period, requiring repeated hospitalizations. Targeted gene sequencing identified novel compound heterozygous mutations in HOIP (c.1654 C > T, p.Gln552Ter; c.3038 A > C, p.His1013Pro). These mutations significantly reduced HOIP and LUBAC protein expression and altered the HOIP protein structure. Immunophenotyping revealed a reduction in CD8 + T cells, central memory (CD8 CM) and effector memory (CD8 EM) T cells, and CD4 + T cells. Subset analysis of CD4 + T cells showed decreased T follicular helper cells (Tfh) and increased IL-17-producing T helper (Th17) cells. The patient also exhibited a higher percentage of naïve B cells and a lower percentage of memory B cells, alongside impaired NF-κB phosphorylation in T and B cells upon LPS stimulation. The expression of the patient's interferon-stimulated gene (ISG) was markedly higher than that of healthy controls.</p><p><strong>Conclusion: </strong>HOIP mutations may lead to multiple immune abnormalities, impaired NF-κB activation, and activation of the type I interferon pathway. These findings highlight the diversity of HOIP mutations and expand the clinical spectrum of associated diseases.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"135"},"PeriodicalIF":5.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Five CGD-Linked CYBB Mutations in Chinese Patients: Insights Into Predicting IFN-γ Treatment Efficacy.","authors":"Yi-Xin Liao, Lu Xia, Ping Liu, Xin-Hua Li, Li-Pin Liu, Li Xu, Di Tian, Dong-Ling Shi, Xiao-Man Guo, Xue Mei, Satoshi Okada, Ya-Bin Liu, Fei-Fei Wang, Xiao-Chuan Wang, Chen Zhao, Xiao-Hong Fan, Jin-Qiao Sun, Tie-Fu Liu, Yun Ling","doi":"10.1007/s10875-025-01926-7","DOIUrl":"10.1007/s10875-025-01926-7","url":null,"abstract":"<p><strong>Background: </strong>The CYBB gene encodes the gp91-phox protein, a critical component of the NADPH oxidase complex involved in pathogen clearance. Mutations in CYBB are associated with chronic granulomatous disease (CGD), leading to recurrent bacterial infections.</p><p><strong>Objective: </strong>To understand the genetic causes of Chinese CGD patients.</p><p><strong>Methods: </strong>Exome sequencing was used to identify mutations in CGD patients' PBMCs, confirmed by Sanger sequencing. Neutrophil respiratory burst capacity was analyzed to correlate with clinical treatment efficacy.</p><p><strong>Results: </strong>We identified five CYBB mutations in six CGD patients from five unrelated Chinese families, including two novel mutations (c.1507A > G:p.T503A, c.1587_1605del:p.529_535del), two rare mutations without functional characterization (c.43A > G:p.I15V, c.125C > A:p.T42K), and one recently reported in a different ethnicity (c.252G > T:p.A84A). Our analysis revealed that these mutations had varying effects on CYBB expression, demonstrating that the synonymous c.252G > T mutation is indeed a splicing mutation, resulting in exon 3 deletion and minimal protein expression. Neutrophils from all patients exhibited defective mitogen-stimulated respiratory bursts. However, only neutrophils with the I15V mutation responded to interferon-γ (IFN-γ) treatment, significantly improving the respiratory capacity defect. Consistent with this, the patient with the I15V mutation showed clinical improvement after two weeks of IFN-γ and anti-bacterial co-treatment.</p><p><strong>Conclusion: </strong>Our findings underscore the diverse effects of CYBB mutations on protein expression and function. More importantly, they suggest that assessing the IFN-γ-mediated potentiation of respiratory burst response in patient's neutrophils is an effective way to predict the therapeutic efficacy of IFN-γ in treating CGD cases, particularly those with non-tuberculous mycobacteria (NTM) and Mycobacterium tuberculosis (TB).</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"131"},"PeriodicalIF":5.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Insights into the Clinical Features, Genetic Spectrum and Clonal Evolution of Patients Carrying NLRP3 Mosaicism.","authors":"Nuria Bonet, Jose M Mascaro, Laura Hurtado-Navarro, Diego Angosto-Bazarra, Jose Luis Callejas-Rubio, Daniel Clemente, Alejandro Souto, Olalla Lima, Natalia Palmou-Fontana, Eulalia Baselga, Santiago Jiménez-Treviño, Agustin Remesal, Marta Andreu-Barasoain, Luis Fernandez-Dominguez, Josep Riera-Monroig, Maria Aparicio, Juan Garcia-Herrero, David Pesqué, Maria Teresa Sanchez-Calvin, Jose Miguel Lezana-Rosales, Maria Correyero-Plaza, Julio Garcia-Villalba, Victor Bolaño, Sara Peiro, Mar Diaz, Alexandru Vlagea, Daniel Lorca, Virginia Fabregat, Maria Carmen Anton, Susana Plaza, Luis Ignacio Gonzalez-Granado, Concepción Postigo, Jose Maria Garcia-Ruiz de Morales, Enrique Gómez de la Fuente, Estibaliz Iglesias, Javier Gomez-Roman, Caritina Vázquez-Triñanes, Juan Carlos Lopez-Robledillo, Norberto Ortego-Centeno, Ana María Giménez-Arnau, Josep M Campistol, Hafid Laayouni, Iñaki Ortiz de Landazuri, Jordi Yagüe, Eva Gonzalez-Roca, Anna Mensa-Vilaro, Oscar Fornas, Eduardo Ramos, Pablo Pelegrin, Ferran Casals, Juan I Arostegui","doi":"10.1007/s10875-025-01922-x","DOIUrl":"10.1007/s10875-025-01922-x","url":null,"abstract":"<p><p>NLRP3 mosaicism is a well-established mechanism causing the monogenic autoinflammatory disease named cryopyrin-associated periodic syndromes (CAPS). The number of reported patients with NLRP3 mosaicism is small, and the knowledge about the long-term disease behavior is limited. Herein we assembled the largest cohort of individuals with NLRP3 mosaicism reported to date to obtain additional evidence that strengthens the understanding of this disease. The novel genetic data were obtained by using Sanger and next-generation sequencing methods, whereas in vitro analyses determined the functional consequences of detected variants. A total of seventeen individuals with NLRP3 mosaicism were enrolled, with 16/17 experiencing different CAPS phenotypes. An overrepresentation of late-onset forms was detected (37.5%). Overall, clinical manifestations, analytical results, and outcomes of treatments were markedly similar to those detected in patients with germline variants. A large mutational diversity was identified, with 16 different variants among 17 individuals. Two main patterns of mosaicism (extended vs. myeloid-restricted) were detected, with the last one overrepresented in the late-onset group. The evaluation of mosaicism over time identified three different patterns, being the group with stable mosaicism the largest one. Collected evidence supports the marked similarities among patients carrying somatic or germline NLRP3 variants. The overrepresentation of NLRP3 mosaicism in late-onset forms should be considered in patients with inflammatory manifestations starting in adulthood. Analysis of mosaicism at the biological level confirms the two known patterns of corporal distribution and reveals that mosaicism remains stable over time in most patients, but it may also vary during the course of the disease.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"134"},"PeriodicalIF":5.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Potential Therapeutic Agents for Type I Interferonopathy Using iPSC-Based Disease Modeling.","authors":"Bunki Natsumoto, Hirofumi Shoda, Motonori Tsuji, Makoto Otsu, Hideki Taniguchi, Kazuhiko Yamamoto, Keishi Fujio","doi":"10.1007/s10875-025-01933-8","DOIUrl":"10.1007/s10875-025-01933-8","url":null,"abstract":"<p><strong>Purpose: </strong>Type I interferonopathy encompasses disorders marked by systemic inflammation and neurological involvement, arising from genetic mutations that result in the upregulation of type I IFN signaling through various mechanisms. Currently, therapeutic options are limited, and no standard therapy exists. This study aims to develop a strategy for identifying new therapeutic targets for type I interferonopathy using induced pluripotent stem cells (iPSCs).</p><p><strong>Methods: </strong>The IFIH1 R779H variant was introduced into iPSCs through genome editing. RNA sequencing of iPSC-derived dendritic cells (DCs) was performed, and differentially expressed genes (DEGs) were identified. IFN-α secretion, reactive oxygen species (ROS), and mitochondrial oxygen consumption rate (OCR) were analyzed in iPSC-derived DCs. An in silico prediction of compounds binding to the OAS-like domain was conducted. Candidate compounds were evaluated for their ability to inhibit IFN secretion from IFIH1 R779H-mutated iPSC-derived DCs.</p><p><strong>Results: </strong>Transcriptome analysis indicated upregulation of the IFN-related and metabolic pathways. IFIH1 R779H-mutated iPSC-derived DCs exhibited increased OCR and ROS generation, and blocking mitochondrial metabolism significantly reduced excessive IFN-α secretion. Among the DEGs, PML was upregulated, and targeting this gene with arsenic trioxide (ATO), a PML antagonist, suppressed IFN-α secretion from IFIH1 R779H-mutated iPSC-derived DCs. Additionally, bisantrene, phthalylsulfathiazole and ganaplacide were predicted to bind to the RNA binding groove of OAS-like domain of human OASL in silico, effectively inhibiting IFN-α secretion from IFIH1 R779H-mutated DCs.</p><p><strong>Conclusion: </strong>Our iPSC-based disease modeling and drug investigation approach provides a robust platform for validating the efficacy and toxicity of candidate therapeutic agents for rare and intractable human diseases such as type I interferonopathy.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"140"},"PeriodicalIF":5.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CVID Enteropathy Is Difficult To Treat and Shows a Heterogeneous Histopathology.","authors":"Noah M Juliana, Mirjam Severs, Jan Willem Marsden, Joris M van Montfrans, Pauline M Ellerbroek, Miangela M Lacle, Virgil A S H Dalm, Amir Abelmoumen, Helen L Leavis","doi":"10.1007/s10875-025-01920-z","DOIUrl":"10.1007/s10875-025-01920-z","url":null,"abstract":"<p><strong>Purpose: </strong>Enteropathy is a non-infectious complication in Common Variable Immune Deficiency (CVID) associated with increased morbidity and mortality. We characterized this group of CVID enteropathy (CVID-E) patients and investigated the effectiveness of immunosuppressive treatments on its clinical course.</p><p><strong>Method: </strong>We identified patients with CVID-E in two academic teaching hospitals and obtained informed consents. Using electronic patient health care records, we retrospectively collected clinical information in the national Primary immunodeficiency disorder database until 01-2023.</p><p><strong>Results: </strong>We included 39 patients with CVID-E. Bronchiectasis (69.2%) and lymphoproliferation (46.1%) were the most frequent co-occurring symptoms. The most common endoscopy findings concerned inflammation (72.2%) and erythema (69.4%); The most prevalent histopathologic findings were IBD-like inflammation (55.6%), indiscriminate chronic inflammation (47.2%) and indiscriminate active inflammation (38.9%). We assessed 88 events of treatment response in the 25 treated patients. Overall treatment response was poor, however there were 31 events of remission observed, ranging from partial to sustained remission. Of these 26 were the result of tumor necrosis factor inhibitors (TNFi) or thiopurines, either as monotherapy or in combination with other immunosuppressive treatment. 10 patients achieved complete remission.</p><p><strong>Conclusion: </strong>In this study, we describe a cohort of CVID-E patients including related comorbidity, clinical course and response to therapy. CVID-E patients frequently develop other, sometimes severe comorbidities. Our study confirms the alleged heterogeneity regarding endoscopic and histopathological findings, and in one third of patients even multiple distinct abnormalities co-occurred in the same biopsy. We found azathioprine and/or TNFi to be the most effective current treatment.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"129"},"PeriodicalIF":5.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\".","authors":"Pankaj Dwivedi, Kishor Deshpande, Trupti Dhabale, Atul Kapse, Anand Pathak","doi":"10.1007/s10875-025-01928-5","DOIUrl":"10.1007/s10875-025-01928-5","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"132"},"PeriodicalIF":5.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Child with Chronic Mucocutaneous Candidiasis Harbors a Novel Gain-of-Function Mutation in STAT1.","authors":"Yang Xiang, Shuo Sun, Hong Wang, Chia-Chi Lo, Jie Wu, Wei-Te Lei, Fengming Li, Xiaodong Liu, Ningning Dang, Cheng-Lung Ku, Jing Guo","doi":"10.1007/s10875-025-01937-4","DOIUrl":"10.1007/s10875-025-01937-4","url":null,"abstract":"<p><strong>Objective: </strong>Germline heterozygous gain-of-function (GOF) mutations in STAT1 impair IL-17-mediated immunity, resulting in carriers' susceptibility to chronic mucocutaneous candidiasis (CMC). JAK inhibitors have shown therapeutic effectiveness in patients with STAT1-GOF mutations.</p><p><strong>Methods: </strong>The mutation was detected using whole-exome sequencing (WES) and confirmed by Sanger sequencing. The functional impact of the mutation was verified by luciferase reporter assay. The phosphorylation level of STAT1 in patient cells, the phenotyping of leukocyte subtypes, and serum cytokine levels were determined by flow cytometry.</p><p><strong>Results: </strong>The patient with CMC harbors a heterozygous missense mutation in STAT1 (c.1078G > C, p.V360L). This mutation was functionally validated as a GOF mutation based on functional analysis of the variant and enhanced phosphorylation upon IFN-γ stimulation in the patient's cells. Additionally, the patient demonstrated a decreased proportion of CD4 + T cells, NK cells, and Th17 cells. Flow cytometry analysis revealed a significant decrease in the expression of IL-17 A in CD4 + T cells from the patient. Serological test results showed that the patient's IgM level was decreased, while the levels of IL-2, IL-5, IL-6 and TNF-α were elevated. Topical application of ruxolitinib demonstrated therapeutic efficacy.</p><p><strong>Conclusions: </strong>The present study reports a pediatric patient with CMC who carries a novel GOF mutation in STAT1. This mutation may impair IL-17 immunity, which could potentially increase the patient's susceptibility to CMC. However, further research is needed to elucidate the underlying mechanism. Although ruxolitinib shows potential as a therapeutic option for CMC, its clinical efficacy requires further validation through experimental studies and long-term patient follow-up.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"137"},"PeriodicalIF":5.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Cause of CIDP: Homozygous Hotspot Mutation, c.793 C > T in CASP8 Gene.","authors":"Kamal Sharma, Ana Flores, Paul Maertens","doi":"10.1007/s10875-025-01931-w","DOIUrl":"10.1007/s10875-025-01931-w","url":null,"abstract":"<p><strong>Background: </strong>Caspase-8 enzyme deficiency (CED) is a rare autosomal recessive inborn error of immunity with autoimmune lymphoproliferative syndromes (ALPS), deficient extrinsic apoptosis and hyperactivation of the mammalian target of rapamycin (mTOR) pathway.</p><p><strong>Methods: </strong>Features of our patient with early onset chronic inflammatory demyelinating polyneuropathy (CIDP) are presented in detail. We report features of ALPS due to CED (ALPS-CED) in 6 patients in previous literature and our patient with the homozygous hotspot mutation, c.793 C > T in the CASP8 gene, and demonstrate that such mutation is a novel cause of CIDP.</p><p><strong>Results: </strong>Our patient fits the spectrum of genetic disorders causing ALPS with dysregulation of the mTOR pathway. Autoimmune lymphoproliferative syndrome with FAS mutations (ALPS-FAS) is also associated with hyperactivation of the mTOR pathway but hematologic symptoms are more severe than ALPS-CED. Both ALPS-FAS and ALPS-CED lead to autoimmunity and improve with use of mTOR inhibitors. ALPS-FAS is characterized by the elevation of alpha beta-double negative T-cells (DNT) and hypergammaglobulinemia, while such features are not prominent in ALPS-CED. Patients with ALPS-CED not only suffer from ALPS but also present with an immune deficiency and a chronic inflammatory state both related to non-apoptotic functions of caspase-8.</p><p><strong>Conclusions: </strong>Both ALPS-FAS and ALPS-CED are characterized by deficient extrinsic apoptosis and dysregulation of the mTOR pathway. Compared to ALPS-FAS, the phenotype of ALPS-CED is more complex due to a more diffuse dysfunction of the non-apoptotic pathways. To our knowledge, early onset CIDP in a patient with homozygous hotspot mutation, c.793 C > T in CASP8, has not been reported previously.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"130"},"PeriodicalIF":5.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity.","authors":"Huda Alajlan, Amer Al-Mazrou, Hibah Alruwaili, Safia Sumayli, Ali Almehaidib, Khalid Alsaleem, Sawsan Abu Awwad, Hazem Ghebeh, Monther Al-Alwan, Anas M Alazami, Hamoud Al-Mousa","doi":"10.1007/s10875-025-01938-3","DOIUrl":"10.1007/s10875-025-01938-3","url":null,"abstract":"<p><p>Phosphatidylinositol 3-kinases (PI3Ks) are heterodimeric lipid kinases that are involved in a diverse array of cellular functions such as growth, metabolism, and migration. Mutations in PIK3CD, which encodes an immune-specific catalytic subunit of PI3K, cause both dominant (activating) and recessive (loss of function) immune deficiencies in humans. Here we report a family with three affected children carrying a novel bi-allelic, truncating mutation in PIK3CD. All three patients exhibited chronic diarrhea and recurrent sinopulmonary infections. Immunoblot confirmed loss of protein along with reduced expression of the associated p85α regulatory subunit. Immune phenotyping showed B cell dysregulation with abnormally high levels of naïve cells. In vitro functional testing of CD19 + and enriched naïve B cells revealed impaired proliferation, and reduction in class-switch recombination upon CD40L and IL-21 stimulation. Our data raise the possibility that PI3K-related dysregulation in human B cells may be broader than in mouse models, where class-switch recombination can still occur with external T cell help. Our study substantially increases the limited number of patients known to have immune deficiency due to loss of PIK3CD.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"139"},"PeriodicalIF":5.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}