Alajlan H, Al-Mazrou A, Alruwaili H
… +8 more, Sumayli S, Almehaidib A, Alsaleem K, Awwad SA, Ghebeh H, Al-Alwan M, Alazami AM, Al-Mousa H
J Clin Immunol
· 2025 Sep · PMID 41026257
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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-sp...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.
Natsumoto B, Shoda H, Tsuji M
… +4 more, Otsu M, Taniguchi H, Yamamoto K, Fujio K
J Clin Immunol
· 2025 Sep · PMID 41026253
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PURPOSE: 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...PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Segura-Tudela A, Nieto-López C, Bermejo-Olivera FJ
… +8 more, Andara LA, Arroyo-Ródenas J, Dueñas-Prieto L, Alfocea-Molina Á, Paz-Artal E, Pleguezuelo D, Cabrera-Marante O, Allende LM
J Clin Immunol
· 2025 Sep · PMID 41026241
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Inborn errors of immunity (IEI) are a heterogeneous group of genetic disorders that disrupt the normal development and function of the immune system. These diseases not only increase susceptibility to infections but also...Inborn errors of immunity (IEI) are a heterogeneous group of genetic disorders that disrupt the normal development and function of the immune system. These diseases not only increase susceptibility to infections but also significantly elevate the risk of developing malignancies and autoimmune diseases. The interplay between immune dysregulation, chronic inflammation, and altered cellular homeostasis in IEI can lead to aberrant cellular proliferation and self-reactive immune responses. Malignancy in IEI often arises due to the immune system's failure to effectively eliminate transformed cells, predisposing patients to lymphomas, leukemias and solid tumors. Autoimmune diseases in IEI can result from defective T-regulatory cell function, impaired central or peripheral tolerance mechanisms or B-cell dysregulation leading to autoantibody production. This work was a retrospective study of 173 adults with IEI suspicion who underwent genetic sequencing between 2005 and 2023. A significant increase of malignancies was observed in patients with a molecular diagnosis (w_MolDx) compared to those without (wo_MolDx). Notably, hematologic malignancies were predominant in the w_MolDx cohort, whereas solid tumors were more frequently observed in the wo_MolDx group. In contrast, the correlation between autoimmune diseases and molecular diagnosis was less evident when comparing w_MolDx and wo_MolDx patients. Understanding the complex relationship between IEI, malignancies and autoimmunity is crucial for optimizing patient management. Early diagnosis of IEI allows for timely interventions, including hematopoietic stem cell transplantation, gene therapy and targeted immunomodulatory therapies, which can mitigate the risk of both malignancies and autoimmune complications.
Bonet N, Mascaro JM, Hurtado-Navarro L
… +48 more, Angosto-Bazarra D, Callejas-Rubio JL, Clemente D, Souto A, Lima O, Palmou-Fontana N, Baselga E, Jiménez-Treviño S, Remesal A, Andreu-Barasoain M, Fernandez-Dominguez L, Riera-Monroig J, Aparicio M, Garcia-Herrero J, Pesqué D, Sanchez-Calvin MT, Lezana-Rosales JM, Correyero-Plaza M, Garcia-Villalba J, Bolaño V, Peiro S, Diaz M, Vlagea A, Lorca D, Fabregat V, Anton MC, Plaza S, Gonzalez-Granado LI, Postigo C, de Morales JMG, de la Fuente EG, Iglesias E, Gomez-Roman J, Vázquez-Triñanes C, Lopez-Robledillo JC, Ortego-Centeno N, Giménez-Arnau AM, Campistol JM, Laayouni H, de Landazuri IO, Yagüe J, Gonzalez-Roca E, Mensa-Vilaro A, Fornas O, Ramos E, Pelegrin P, Casals F, Arostegui JI
J Clin Immunol
· 2025 Sep · PMID 41026232
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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...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.
Qian M, Zhou J, Chen P
… +11 more, Jiang N, Wang T, Chen X, Xu H, Zhou F, Yang Y, Lin X, Yang Q, Shao L, Ruan Q, Zhang W
J Clin Immunol
· 2025 Sep · PMID 41026231
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Mendelian susceptibility to mycobacterial disease (MSMD) is a rare clinical syndrome that is characterized by selective vulnerability to intracellular pathogens. Deficiency in IL12RB1 is the most common type of MSMD but...Mendelian susceptibility to mycobacterial disease (MSMD) is a rare clinical syndrome that is characterized by selective vulnerability to intracellular pathogens. Deficiency in IL12RB1 is the most common type of MSMD but the heterogeneity of its clinical Manifestation Makes precise diagnosis difficult. Here, we report a previously healthy 29 year-old woman who had suffered from disseminated infection with Mycobacterium tilburgii, which is a rare, unculturable environmental mycobacteria, for over 2 years. We used whole exome sequencing to detect a novel compound heterozygous variant in the IL12RB1 gene. Immunological analysis of the patient's peripheral lymphocytes showed a barely detectable level of IL-12Rβ1, a reduced population of follicular helper T (Tfh) cells and impaired production of IFN-γ in response to IL-12/IL-23 stimulation. Metagenomic next-generation sequencing was used to identify the causative pathogen and to analyze drug susceptibility. The infection was contained by a combination of anti-mycobacterial drugs and IFN-γ supplementary treatment. An RNA-seq analysis, using follow-up blood samples, revealed the limited success of these treatments over 6 months. Our findings support the screening for inherited immunological problems in patients with difficult-to-treat mycobacterial infections. The suboptimal response to prolonged anti-mycobacterial drugs and IFN-γ supplementation warrants the development of novel therapeutic strategies for MSMD patients.
Gumusburun R, Yıldırım O, Karakoc M
… +19 more, Okan K, Inan S, Dalgıc CT, Akten HS, Bogatekin G, Bulut G, Demir M, Aytac H, Camyar A, Ozısık M, Demir D, Soyer N, Soylu M, Uysal FE, Aykut A, Durmaz A, Ozgul S, Sin AZ, Ardeniz O
J Clin Immunol
· 2025 Sep · PMID 40993321
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PURPOSE: Inborn Errors of Immunity (IEI) often lead to recurrent infections, immune dysregulation, and an increased risk of malignancies. Due to the heterogeneity in IEI presentations, personalized monitoring is essentia...PURPOSE: Inborn Errors of Immunity (IEI) often lead to recurrent infections, immune dysregulation, and an increased risk of malignancies. Due to the heterogeneity in IEI presentations, personalized monitoring is essential for early detection of non-infectious complications. This study aims to document the characteristics and prevalence of malignancies in IEI patients. METHODS: A retrospective review of 355 patients diagnosed with IEI at the Adult Allergy and Immunology Clinic of Ege University was conducted. Data on demographics, clinical presentations, laboratory results, and immunological and genetic profiles of patients with malignancies were analyzed. RESULTS: A total of 40 patients with neoplasia (F/M: 18/22; median age: 51.58 years, range: 18-91) were evaluated. The median ages at IEI symptom onset, diagnosis, and neoplasm diagnosis were 16.5, 45, and 39.5 years, respectively. Malignancy was diagnosed in 60% of patients before IEI, with referrals for low immunoglobulin levels and/or severe infections, and for a genetic profile suggestive of immunodeficiency. The prevalence of malignancy in the overall cohort was 10.42% (37/355), while it was significantly higher in the common variable immunodeficiency (CVID) subgroup, reaching 20.44% (28/137). Lymphoma was the most common malignancy at 45.9%, primarily non-Hodgkin lymphoma (NHL) at 40.5%, with diffuse large B-cell lymphoma (DLBCL) as a key subtype; carcinomas were the second most common at 35.1%. Hematologic malignancies were significantly more frequent among patients with CVID (90.5%), whereas non-hematologic malignancies predominated in the non-CVID group (77.8%) (p = 0.024). Lymphoproliferation was more common in hematologic malignancies (85.7%) compared to non-hematologic malignancies (25.0%) (p < 0.001). Genetic variants were identified in 61% of cases, with 37% classified as pathogenic or likely pathogenic, including variants in TNFRSF13B/TACI, CCDC40, PLCG2, ATM, CARD11, CHEK2, CNV, COPB1, HPS5, LYST, MAPK8IP1, NBS1, NF1, NFKBIA, PI4KA, POLE, SPI1, and TAP2. CONCLUSIONS: Findings confirm that NHL, particularly DLBCL, is the most prevalent malignancy in this cohort. Given the link between malignancies and underlying IEI, immunologic evaluation is recommended, particularly for NHL patients. The observed predominance of hematologic malignancies among CVID patients and the association with lymphoproliferation further emphasize the need for heightened malignancy surveillance and early immunologic workup in this subgroup. Further research on biomarkers for malignancy prediction in IEI is warranted.
Bargir UA, Setia P, Desai M
… +47 more, S C, Dalvi A, Shinde S, Gupta M, Jodhawat N, Jose A, Goriwale M, Yadav RM, Vedpathak D, Temkar L, Shabrish S, Hule G, Gowri V, Taur P, Athavale A, Jijina F, Bhatia S, Shukla A, Kalra M, Sivasankaran M, Balaji S, Jain P, Sharma S, Gangadharan H, Narula G, Sharma R, Kini P, Mangalani M, Zanwar A, Chaudhary H, Chaudhary NK, Khurana U, Bavdekar A, Subramaniam G, Raj R, Saniyal S, Shah N, Petiwala T, Kumar P, Pai V, Bhattad S, Sengupta A, Soneja M, Upase D, Ganapule A, Talukdar I, Madkaikar M
J Clin Immunol
· 2025 Aug · PMID 40856873
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Common Variable Immunodeficiency (CVID) is a heterogeneous disorder characterized by impaired antibody production and recurrent infections. In this study we investigated the clinical and immunological features of CVID in...Common Variable Immunodeficiency (CVID) is a heterogeneous disorder characterized by impaired antibody production and recurrent infections. In this study we investigated the clinical and immunological features of CVID in Indian patients and develops a machine learning model for predicting disease severity. We retrospectively analyzed 150 patients diagnosed with CVID over a decade at a tertiary care center in India. The median age of diagnosis was 18 years, with a male predominance (62%). The majority of patients (66.6%) had a severe phenotype, with recurrent respiratory tract infections being the most common clinical manifestation (84.2%). Gastrointestinal complications were observed in 45% of patients, while autoimmune manifestations were seen in 21%. All patients exhibited hypogammaglobulinemia. IgA levels varied, with 7.8% normal and 14.5% undetectable. IgM levels were decreased in 85.5% of patients. B-cell analysis revealed 64.4% had reduced class-switched memory B cells, with 21.7% showing very low levels. Nine adult patients presented with late-onset combined immunodeficiency. Genetic testing, performed on 52 patients, identified underlying monogenic causes in 29 pediatric and 15 adult patients. LRBA deficiency was the most common genetic defect, found in seven pediatric and three adult patients. We developed a novel machine learning-based severity prediction model for CVID patients, utilizing readily available lymphocyte subsets, class-switched memory B cell counts, and serum immunoglobulin levels to provide an accessible and robust tool for predicting disease severity using Ameratunga's clinical severity score. Random Forest outperformed other models across all metrics, achieving an accuracy of 0.853 (95% CI: 0.840-0.866). Feature importance analysis across all models identified Th-Tc ratio, CD19, and IgM levels as the most influential predictors for severity prediction. Our study highlights the diverse clinical and immunological features of CVID in Indian patients, emphasizing the need for early diagnosis and individualized management strategies. The machine learning model developed using commonly available immune parameters provide a robust tool for predicting disease severity, potentially guiding treatment strategies to improve patient outcomes.
Blom M, Duintjer AJ, Jamee M
… +36 more, de Gier M, Bloomfield M, Klocperk A, Kralickova P, Karaca NE, Boyarchuk O, Čižnár P, Jeseňák M, Sharapova S, Skopovets E, Gonzalez-Granado LI, Palmeri S, Volpi S, Nalda AM, Tello SR, Soler-Palacín P, Abolhassani H, Pulvirenti F, Cinicola B, Wintergerst U, de Bree GJ, van den Berg JM, Leavis HL, Vermont C, Dalm VASH, van Aerde K, Henriet S, Jolink H, Potjewijd J, Lankester A, Mukherjee CR, Berghuis D, Pac M, Shillitoe BMJ, Gennery AR, van der Burg M
J Clin Immunol
· 2025 Aug · PMID 40853601
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PURPOSE: Patients with (X-linked) agammaglobulinemia (XLA) suffer from severe, recurrent infections potentially leading to life-threatening complications such as sepsis, meningoencephalitis and chronic lung disease. Earl...PURPOSE: Patients with (X-linked) agammaglobulinemia (XLA) suffer from severe, recurrent infections potentially leading to life-threatening complications such as sepsis, meningoencephalitis and chronic lung disease. Early diagnosis and timely treatment can prevent infections and secondary complications, emphasizing a role for early detection of XLA via newborn screening (NBS). Our international multicenter survey study aimed to evaluate self-reported outcomes and parental perspectives in XLA patients to determine whether an early diagnosis is associated with better quality of life (QoL). METHODS: QoL-questionnaires included the PedsQL for children and SF-36, CVID_QOL, PADQOL-16 for adults. A new questionnaire was specifically developed for parents about an early diagnosis of XLA. RESULTS: In total, 88 adult and 65 pediatric XLA patients, and 69 parents from 14 countries completed the survey. Patients with an early diagnosis reported less severe, recurrent infections and less hospitalization (p < 0.05). QoL was significantly lower in multiple health domains for pediatric and adult patients with a late diagnosis compared to the general population. Patients with an early diagnosis reported similar QoL outcomes compared to the general population. Parents showed immense support for NBS for XLA stating that an early diagnosis prevents emotional insecurity, health damage, unnecessary diagnostics and allows early access to medical care and informed family planning. CONCLUSION: Our study has shown supportive evidence to pursue an early diagnosis of XLA from both a self-reported clinical, health related QoL and parental perspective. The main plea from patients and parents is to achieve an early diagnosis for XLA and severe B-lymphocyte deficiencies with NBS.
Gao H, Zhao Y, Chen S
… +16 more, Zhang Z, Yang F, Chen Z, Wang L, Yang J, He S, Tang C, Zheng S, Guan C, Xu Y, Tang L, Zhang A, Maurer M, Lee D, Ma L, Luo X
J Clin Immunol
· 2025 Aug · PMID 40848077
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Hereditary angioedema with normal C1 inhibitor (HAE-nC1-INH) is a rare and genetically heterogeneous disorder with an incomplete molecular understanding. This study aimed to identify novel genetic variants associated wit...Hereditary angioedema with normal C1 inhibitor (HAE-nC1-INH) is a rare and genetically heterogeneous disorder with an incomplete molecular understanding. This study aimed to identify novel genetic variants associated with HAE-nC1-INH, characterize their clinical manifestations, and evaluate real-world treatment responses. Whole-exome sequencing of 27 HAE patients, including eight with HAE-nC1-INH, identified four previously unreported MYOF variants and additional pathogenic variants in KNG1 and HS3ST6, expanding the genetic spectrum of the disease. MYOF variants were associated with recurrent edema episodes, often with prolonged duration. The HS3ST6 variant was linked to refractory angioedema with non-resolving lower extremity involvement, highlighting atypical, persistent clinical phenotypes beyond the classical self-limiting presentation of HAE. Lanadelumab effectively reduced attack frequency in most patients; however, the variability in treatment response, particularly in MYOF and HS3ST6 carriers, highlights the need for individualized therapeutic approaches. These findings provide new insights into the genetic and clinical complexity of HAE-nC1-INH and emphasize the importance of genetic testing in refining diagnosis and optimizing treatment strategies, contributing to a more precise understanding of hereditary angioedema.
Liu Q, Zhang A, Bai Y
… +7 more, Yang X, Liu X, Yang L, Ying Y, Luo X, Fang F, Liu C
J Clin Immunol
· 2025 Aug · PMID 40788322
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PURPOSE: The Ezrin-Radixin-Moesin (ERM) family member moesin (MSN) plays a crucial role in reversibly linking F-actin to the cell membrane. Patients carrying MSN gene mutations consistently exhibit immunodeficiencies. Ho...PURPOSE: The Ezrin-Radixin-Moesin (ERM) family member moesin (MSN) plays a crucial role in reversibly linking F-actin to the cell membrane. Patients carrying MSN gene mutations consistently exhibit immunodeficiencies. However, due to the scarce number of reported cases worldwide, the mechanism by which MSN mutation leads to immune function defects remains unclear. This study aims to profile the immunological features in MSN mutant patients elaborately. METHODS: In this article, we present a case study of a patient with c.511 C > T, p.Arg171Trp (p.R171W) mutation on the MSN gene. We analyzed abnormalities in peripheral immune cell subsets by quantitative analysis, morphological examination, and functional molecule assessment during various infection states. Using total internal reflection fluorescence microscopy (TIRFm), we visualized BCR clusters and F-actin dynamics in B cells, revealing valuable insights into B cell activation and the link between F-actin aggregation and BCR signaling in MSN mutant patients. RESULTS: The results suggest that the MSN c.511 C > T, p.Arg171Trp (p.R171W) mutation affects the proliferation, differentiation, metabolism, and adhesion functions in peripheral immune cells, as well as the maturation process in bone marrow cells. Additionally, we elucidate the impact of MSN mutation on B cell and T cell metabolism and propose a potential diagnostic indicator for patients with MSN gene mutations. CONCLUSION: Our findings support the diagnosis of primary immunodeficiency and provide detailed insights into changes occurring in immune cells, especially B cells. Overall, our study adds to the diagnosis and pathogenesis of X-linked moesin-associated immunodeficiency (X-MAID).
Dong L, Sun B, Min Q
… +17 more, Meng X, Li Y, Yu M, Wen Z, Wu X, Hu Z, Zhang R, Feng X, Luan Y, Lu C, Wang W, Hui X, Hou J, Sun J, Cai S, Wang X, Wang JY
J Clin Immunol
· 2025 Aug · PMID 40751765
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The interleukin-2 receptor γ (IL-2Rγ, or γc) is a crucial component of several cytokine receptor complexes. Deficiencies in γc lead to X-linked severe combined immunodeficiency (X-SCID), characterized by recurrent infect...The interleukin-2 receptor γ (IL-2Rγ, or γc) is a crucial component of several cytokine receptor complexes. Deficiencies in γc lead to X-linked severe combined immunodeficiency (X-SCID), characterized by recurrent infections due to the absence or dysfunction of T and NK cells, and nonfunctional B cells. Missense variants in the γc extracellular region are linked to atypical X-SCID with normal counts of T, B, and NK cells and less severe symptoms, yet the underlying cellular and molecular mechanisms are not well understood. This study describes a case of atypical X-SCID with a missense variant (c.420 A > T, p.R140S) in the γc extracellular domain, associated with recurrent bacterial, fungal, and viral infections. We found that the R140S variant leads to reduced surface expression and variably affects cytokine receptor signaling. Specifically, STAT5 phosphorylation and proliferation in CD4 T and CD8 T cells are impaired in response to IL-7, a cytokine essential for T cell survival, proliferation and function. Notably, γc predominantly localizes to the endoplasmic reticulum, in contrast to WT γc, which is found in acidic compartments. Despite this mislocalization, γc does not trigger unfolded protein responses, and its protein stability and degradation pathways remain unaffected. Nevertheless, cells expressing high levels of γc exhibited a competitive disadvantage in culture compared to those expressing WT γc, resulting in the enrichment of cells expressing lower levels of γc. These findings extend our understanding of how mutations in the extracellular domain of γc can lead to reduced protein expression and influence the pathophysiology of atypical X-SCID.
Tian Z, Chen R, Jia Y
… +6 more, Jiang J, Dai R, An Y, Tang X, Zhao X, Zhou L
J Clin Immunol
· 2025 Aug · PMID 40748513
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BACKGROUND AND OBJECTIVES: Germline pathogenic variants in the mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) encodes a caspase-like protease that plays a crucial role in the caspase recruitment...BACKGROUND AND OBJECTIVES: Germline pathogenic variants in the mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) encodes a caspase-like protease that plays a crucial role in the caspase recruitment domain (CARD)-B-cell lymphoma 10 (BCL10)-MALT1 (CBM) complex. This complex mediates the activation of nuclear factor-kB (NF-kB) pathway and are associated with diverse human diseases including combine immunodeficiency (CID), lymphoproliferation and others. This study aimed to determine the underlying cause of immune deficiency and immune dysregulation in a patient presented with recurrent respiratory infections, aphthous ulcers, dermatitis, chronic diarrhea, failure to thrive and early death. METHODS: Clinical and laboratory records were reviewed. Patients underwent next-generation sequencing (NGS), and analysis of genomic DNA was performed on the patient and her parents. Lymphocyte subsets, MALT1 expression and NF-kB signaling was evaluated by flow cytometry, RT-PCR and immunoblotting. RESULTS: The patient carried a novel pathogenic biallelic loss-of-function variant in MALT1 (c.1411G > A; p.D471N) located in the caspase-like domain, leading to severely reduced MALT1 protein expression. Impaired CBM-mediated NF-κB activation was confirmed by reduced phosphorylation of the p65 subunit, resulting in deficient production of IL-2 and TNF-α. This functional defect caused lower Tfr and Treg cells, a normal proportion of Tfh cells, with higher expression of activation markers PD-1 and ICOS. The patient displayed low NK cell and B cell counts, together with a developmental block at the transitional B cell stage. Additionally, the proportion of marginal zone-like B cells (MZB-like) was markedly decreased, indicating impaired B cell differentiation. CONCLUSIONS: Human MALT1 deficiency causes profound CID by impairing CBM-mediated NF-kB signaling and MALT1-paracaspase activity. Consistent with the reported variants located in the caspase-like domain, our patient presented with an inflammatory phenotype, supporting the notion that the MALT1 D471N mutation phenocopies a partial loss of both MALT1 scaffolding function and paracaspase activity. Prompt hematopoietic stem cell transplantation (HSCT) is highly recommended as an effective therapy for MALT1 deficiency.
Bar-On Z, Reuven O, Lev A
… +15 more, Simon AJ, Salaymeh W, Shalom A, Somech R, Barel O, Porges S, Javasky E, Molho-Pessach V, Granot Z, Bijaoui D, Neuman T, Tal Y, Baniyash M, Berger M, Shamriz O
J Clin Immunol
· 2025 Aug · PMID 40748410
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PURPOSE: Baraitser-Winter syndrome type 1 (BRWS1) is a rare disorder characterized by intellectual disability, short stature, facial dysmorphism, cortical malformations, macrothrombocytopenia, and recurrent infections. B...PURPOSE: Baraitser-Winter syndrome type 1 (BRWS1) is a rare disorder characterized by intellectual disability, short stature, facial dysmorphism, cortical malformations, macrothrombocytopenia, and recurrent infections. BRWS1 is caused by loss-of-function variants in ACTB, leading to β-actin deficiency. Given the essential role of the actin cytoskeleton in T-cell activation, the immunological consequences of ACTB mutations remain unexplored. Here, we characterize immune dysfunction associated with a novel ACTB variant in a patient with BRWS1. METHODS: Whole-exome sequencing identified a heterozygous ACTB p.Gln360ProfsTer4 variant in a patient with BRWS1 and combined immunodeficiency. Functional studies were performed in HEK293T cells transfected with wild-type and mutant ACTB constructs. Patient-derived T cells were analyzed for immunological synapse formation, cytokine production, activation, and proliferation. The therapeutic effects of exogenous IL-2 and dupilumab were evaluated. RESULTS: The mutant β-actin protein was rapidly degraded and exerted a dominant-negative effect on wild-type β-actin, thereby disrupting cytoskeletal integrity. Patient-derived T cells demonstrated defective immunological synapse formation, reduced intra-synaptic IL-2 levels, and impaired activation and proliferation. Supplementation with exogenous IL-2 partially restored T-cell function in vitro. Notably, dupilumab treatment led to significant clinical and immunological improvement, suggesting a role in restoring immune regulation. CONCLUSION: BRWS1 represents a novel primary immune regulatory disorder. Our findings highlight actinopathy-driven immunodeficiency as a target for therapeutic intervention, with broader implications for cytoskeletal disorders.
Ferron E, Jullien M, Braud M
… +15 more, David G, Fourgeux C, Bastien M, Salameh P, Willem C, Legrand N, Walencik A, Guillaume T, Peterlin P, Garnier A, Lebourgeois A, Gagne K, Poschmann J, Chevallier P, Retière C
J Clin Immunol
· 2025 Jul · PMID 40728766
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Natural Killer (NK) cells naturally recognize and eliminate leukemic cells. However, the molecular interactions that govern these responses are diverse due to the large number of activating and inhibitory NK receptors th...Natural Killer (NK) cells naturally recognize and eliminate leukemic cells. However, the molecular interactions that govern these responses are diverse due to the large number of activating and inhibitory NK receptors that modulate NK functions and the diversity of corresponding ligands that are differentially expressed in acute lymphoblastic and myeloblastic leukemias. We identified resting NKG2A NK cells and NKG2AKIR NK cell subsets as the most effective in eliminating lymphoid and myeloid leukemic cells respectively. The NKG2AKIRCD57 cell subsets show high expression of activating receptors and a functional transcriptomic profile, but differ in KIR2DL5 expression. The frequency of KIR2DL5 NK cells increases with the number of expressed KIR. Furthermore, KIR2DL5 is preferentially co-expressed with KIR2DL1 and is negatively regulated by NKG2A. Of note, CD57 expression, regardless of the NK cell subset considered, is associated with reduced receptor expression, consistent with its reduced cytotoxic potential. Furthermore, molecular interactions between NK cells and leukemic cells influence NK cell responses, particularly the inhibitory KIR2DL5-PVR axis. The integration of these data is of importance for the optimization of NK cell-based immunotherapies, as the selection of NK cell donors represents a key parameter for the improvement of these therapies.
J Clin Immunol
· 2025 Jul · PMID 40711631
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BACKGROUND: The assessment of polysaccharide responsiveness via vaccination is pivotal in the evaluation of patients for primary immunodeficiency. However, the applicability of current guidelines provided by the American...BACKGROUND: The assessment of polysaccharide responsiveness via vaccination is pivotal in the evaluation of patients for primary immunodeficiency. However, the applicability of current guidelines provided by the American Academy of Allergy, Asthma & Immunology (AAAAI) has been subject to scrutiny. METHODS: We conducted a prospective study involving 120 healthy Danish adult blood donors. Antibodies targeting pneumococcal capsular polysaccharide serotypes were quantified using a multianalyte bead immunoassay before and four to eight weeks post-vaccination. Polysaccharide responsiveness in donors was assessed according to AAAAI guidelines. RESULTS: Remarkably, only a minority of participants (2.5%) demonstrated a normal polysaccharide response per AAAAI criteria. This finding prompted us to advocate for an alternative approach based on percentile rankings relative to a reference population. Polysaccharide Responsiveness Percentile (PRP) was not significantly associated with age, sex, vaccine batch, or the duration between vaccination and antibody measurements in our cohort supporting its robustness, generalizability, and potential for standardized clinical application. CONCLUSION: Our study unveils significant limitations of the AAAAI guidelines, highlighting the imperative for a more robust and adaptable approach. By introducing a novel PRP assessment method, we aim to enhance the accuracy and reliability of immune function evaluations.
Briones AC, Marin AV, Chaparro-García R
… +7 more, López-Nevado M, Abia D, Estevez-Benito I, Chacón-Arguedas D, Fernández-Malavé E, Cardenas PP, Regueiro JR
J Clin Immunol
· 2025 Jul · PMID 40711587
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BACKGROUND: The CD247 chain of the T-cell receptor (TCR) is essential for normal T cell development and function. Reported CD247-deficient patients showed severe immunodeficiency despite the presence of two populations o...BACKGROUND: The CD247 chain of the T-cell receptor (TCR) is essential for normal T cell development and function. Reported CD247-deficient patients showed severe immunodeficiency despite the presence of two populations of peripheral T cells, most with low TCR levels carrying the germline variant and a few with higher TCR levels due to somatic reversion. However, the revertant T cells remained a minority and did not improve the patients' clinical status. PURPOSE: To compare the capability of somatic revertant variants of CD247 germline changes (p.M1T and p.Q70X) to restore TCR expression and function. METHODS: CD247 wild-type (WT) and p.Q70L/W/Y somatic variants were individually introduced in CD247-deficient mouse (MA5.8), human mutant (PM1T), and CRISPR/Cas9-generated Jurkat (ZKO) T cell lines by nucleofection or transduction. RESULTS: MA5.8 mouse T cells do not accurately model human CD247 deficiencies, as Q70X restores TCR expression in MA5.8 but not in human cells. In human cell models, all somatic revertant variants restored TCR expression with varying degrees (WT = Q70L > Q70W > Q70Y). In contrast, TCR-induced activation events, such as CD69/CD25 upregulation, showed a different hierarchy (WT = Q70W > Q70L = Q70Y). Furthermore, all CD247 somatic variants failed to induce TCR-mediated ZAP70 tyrosine phosphorylation compared to WT. CONCLUSION: Somatic reversions, such as those detected in patients with pathogenic CD247 germinal changes, display a discordant capability to rescue TCR expression versus function. These findings shed light on the role of CD247 in TCR expression and function during human T cell development, with implications for immunodeficiencies, as well as for the biological consequences of CD247 somatic mosaicism.
Wu J, Li L, Ten W
… +9 more, Wang Y, Liu R, Hu B, Tan J, Dong F, Shi K, Zhang H, Su L, Hu W
J Clin Immunol
· 2025 Jul · PMID 40705100
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PURPOSE: Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare vasculitis characterized by increased eosinophils in human tissues and peripheral blood. In this case, we present a 53-year-old female patient with...PURPOSE: Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare vasculitis characterized by increased eosinophils in human tissues and peripheral blood. In this case, we present a 53-year-old female patient with EGPA. By this case and literature review, we want to explain the early manifestations, diagnosis, and management of EGPA, which will help clinicians to understand the disease and attach importance to the possibility of dupilumab-induced EGPA, to improve the early diagnosis rate of EGPA, and reduce misdiagnosis and missed diagnosis. METHODS: The diagnostic criteria for EGPA established by the American Rheumatology Association (ACR) in 2022 were used; these criteria encompass clinical presentation, laboratory tests, and pathological biopsy. In addition, we conducted a comprehensive literature review on this case. RESULT: We present a 53-year-old female patient who developed severe peripheral neuropathic pain after the administration of dupilumab for the treatment of refractory asthma and sinusitis. The patient's symptoms, laboratory examination findings, and nasopharyngeal biopsy pathology results collectively support the diagnosis of EGPA. When dupilumab was converted to mepolizumab combined with glucocorticoid, her peripheral neuropathic pain and asthma symptoms were dramatically relieved. Our literature review also provides a detailed discussion on the relationship between Dupilumab and EGPA. CONCLUSION: We present a case of EGPA with peripheral neuropathic pain induced by Dupilumab, and mepolizumab has a good therapeutic effect on this patient. Our literature review shows that although dupilumab is effective in treating eosinophilic airway inflammatory diseases, clinicians must pay attention to the possibility of dupilumab inducing or aggravating EGPAs.