Pub Date : 2025-07-20DOI: 10.1016/j.clim.2025.110568
Yang Liu , Sumiao Liu , Ying Liu, Qian Li, Ke Xu
Objectives
To evaluate infection risk associated with hypogammaglobulinemia in patients with systemic lupus erythematosus (SLE).
Methods
We retrospectively analyzed 242 cases of hypogammaglobulinemia identified among 3565 hospitalized SLE patients between 2014 and 2024. Of these, 133 experienced infections, while 109 remained infection-free and served as controls.
Results
Infection rates were comparable among patients with low IgG (60.0 %), IgM (56.3 %) and IgA (57.7 %) levels. Multivariate logistic regression identified low body weight, fever, medication discontinuation, lymphopenia, reduced lymphocyte count, elevated CRP levels, and decreased Th cell and NK cell counts as independent predictors of infection. During follow-up, immunoglobulin levels recovered in most patients, with rates at two years of 76.0 % for IgA, 43.8 % for IgG, and 26.2 % for IgM. Immunoglobulin normalization was associated with reduced infection risk.
Conclusion
Hypogammaglobulinemia increases infection risk in SLE due to multifactorial immune dysfunction. Modifiable clinical and immunologic factors, along with immunoglobulin recovery, may represent actionable targets for intervention.
{"title":"Infection risk associated with hypogammaglobulinemia in patients with systemic lupus erythematosus: Real-world evidence from 2014 to 2024","authors":"Yang Liu , Sumiao Liu , Ying Liu, Qian Li, Ke Xu","doi":"10.1016/j.clim.2025.110568","DOIUrl":"10.1016/j.clim.2025.110568","url":null,"abstract":"<div><h3>Objectives</h3><div>To evaluate infection risk associated with hypogammaglobulinemia in patients with systemic lupus erythematosus (SLE).</div></div><div><h3>Methods</h3><div>We retrospectively analyzed 242 cases of hypogammaglobulinemia identified among 3565 hospitalized SLE patients between 2014 and 2024. Of these, 133 experienced infections, while 109 remained infection-free and served as controls.</div></div><div><h3>Results</h3><div>Infection rates were comparable among patients with low IgG (60.0 %), IgM (56.3 %) and IgA (57.7 %) levels. Multivariate logistic regression identified low body weight, fever, medication discontinuation, lymphopenia, reduced lymphocyte count, elevated CRP levels, and decreased Th cell and NK cell counts as independent predictors of infection. During follow-up, immunoglobulin levels recovered in most patients, with rates at two years of 76.0 % for IgA, 43.8 % for IgG, and 26.2 % for IgM. Immunoglobulin normalization was associated with reduced infection risk.</div></div><div><h3>Conclusion</h3><div>Hypogammaglobulinemia increases infection risk in SLE due to multifactorial immune dysfunction. Modifiable clinical and immunologic factors, along with immunoglobulin recovery, may represent actionable targets for intervention.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"280 ","pages":"Article 110568"},"PeriodicalIF":4.5,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144686317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ferroptosis is an iron-dependent cell death characterized by elevated levels of reactive oxygen species (ROS) and the peroxidation of membrane lipids, leading to cellular destruction. This phenomenon results from a disruption in the balance between oxidative and antioxidative processes, with oxidation involving iron and lipid metabolism, and antioxidation primarily relying on GPX4. Multiple myeloma (MM) is a hematological malignancy characterized by uncontrolled plasma cell growth, accounting for 1.3 % of all malignancies. Despite advancements in treatment, MM still has a poor prognosis. Research indicates that malignant MM cells are susceptible to ferroptosis, suggesting that this process may serve as a novel therapeutic strategy to enhance the efficacy of treatment for MM. This review explores current insights into the cellular mechanisms of ferroptosis and its role in eliminating multiple myeloma cells, as well as its effectiveness alongside conventional drugs like Bortezomib.
{"title":"Iron-dependent cell death: Unlocking Ferroptosis as a key to multiple myeloma therapy","authors":"Fatemeh Karimian , Melika Khademi , Amirsalar Nikkhah Bahrami , Maryam Nabigol , Fatemeh Mikanik , Mehdi Bakhtiyaridovvombaygi , Nader Vazifeh Shiran","doi":"10.1016/j.clim.2025.110570","DOIUrl":"10.1016/j.clim.2025.110570","url":null,"abstract":"<div><div>Ferroptosis is an iron-dependent cell death characterized by elevated levels of reactive oxygen species (ROS) and the peroxidation of membrane lipids, leading to cellular destruction. This phenomenon results from a disruption in the balance between oxidative and antioxidative processes, with oxidation involving iron and lipid metabolism, and antioxidation primarily relying on GPX4. Multiple myeloma (MM) is a hematological malignancy characterized by uncontrolled plasma cell growth, accounting for 1.3 % of all malignancies. Despite advancements in treatment, MM still has a poor prognosis. Research indicates that malignant MM cells are susceptible to ferroptosis, suggesting that this process may serve as a novel therapeutic strategy to enhance the efficacy of treatment for MM. This review explores current insights into the cellular mechanisms of ferroptosis and its role in eliminating multiple myeloma cells, as well as its effectiveness alongside conventional drugs like Bortezomib.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"280 ","pages":"Article 110570"},"PeriodicalIF":3.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-11DOI: 10.1016/j.clim.2025.110563
Fatima Zaman , Xianming Zhu , Joanne H. Hunt , Gracie Rozek , Yolanda Eby , Sarah Hussain , Niraj M. Desai , Sander Florman , Meenakshi M. Rana , Rachel Friedman-Moraco , Marcus R. Pereira , Shikha Mehta , Peter Stock , Alexander Gilbert , Jonathan Hand , Michele I. Morris , Valentina Stosor , Sapna A. Mehta , Catherine B. Small , Joanna Schaenman , Aaron A.R. Tobian
Kidney transplantation from donors with HIV has recently become standard clinical practice, but the plasma inflammatory profile is not well characterized. Thirty-two cytokines and chemokines were evaluated among donors with HIV (n = 63) and without HIV (n = 41). Wilcoxon rank sum test was used to compare cytokines between groups. Donors with and without HIV were generally similar in terms of characteristics, except those with HIV had a non-significantly lower kidney donor profile index, reflecting better graft survival, creatinine, and body mass index. Most cytokine and chemokine levels were similar between groups. However, median IL-8 levels were higher (p < 0.0015) in donors without HIV (32.6 pg/mL, IQR = 13.8–394.9) compared to donors with HIV (15.1 pg/mL, IQR = 8.4–35.5). There were no significant correlations between cytokine and chemokine concentrations and CD4 counts or HIV viral load. In summary, inflammatory profiles were similar or lower among donors with HIV compared to donors without HIV supporting the safety of this emerging kidney transplantation practice.
{"title":"Inflammation among kidney transplant donors with and without HIV: Multicenter HOPE in Action Consortium","authors":"Fatima Zaman , Xianming Zhu , Joanne H. Hunt , Gracie Rozek , Yolanda Eby , Sarah Hussain , Niraj M. Desai , Sander Florman , Meenakshi M. Rana , Rachel Friedman-Moraco , Marcus R. Pereira , Shikha Mehta , Peter Stock , Alexander Gilbert , Jonathan Hand , Michele I. Morris , Valentina Stosor , Sapna A. Mehta , Catherine B. Small , Joanna Schaenman , Aaron A.R. Tobian","doi":"10.1016/j.clim.2025.110563","DOIUrl":"10.1016/j.clim.2025.110563","url":null,"abstract":"<div><div>Kidney transplantation from donors with HIV has recently become standard clinical practice, but the plasma inflammatory profile is not well characterized. Thirty-two cytokines and chemokines were evaluated among donors with HIV (<em>n</em> = 63) and without HIV (<em>n</em> = 41). Wilcoxon rank sum test was used to compare cytokines between groups. Donors with and without HIV were generally similar in terms of characteristics, except those with HIV had a non-significantly lower kidney donor profile index, reflecting better graft survival, creatinine, and body mass index. Most cytokine and chemokine levels were similar between groups. However, median IL-8 levels were higher (<em>p</em> < 0.0015) in donors without HIV (32.6 pg/mL, IQR = 13.8–394.9) compared to donors with HIV (15.1 pg/mL, IQR = 8.4–35.5). There were no significant correlations between cytokine and chemokine concentrations and CD4 counts or HIV viral load. In summary, inflammatory profiles were similar or lower among donors with HIV compared to donors without HIV supporting the safety of this emerging kidney transplantation practice.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"280 ","pages":"Article 110563"},"PeriodicalIF":4.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-11DOI: 10.1016/j.clim.2025.110564
Johanna Bodin , Anja Bråthen Kristoffersen , Tove Karin Herstad , Gro Tunheim , Sabin Bhandari , Anna Hayman Robertson , Ratnadeep Mukherjee , Unni Cecilie Nygaard , Fredrik Oftung , Lisbeth M. Næss
While severe COVID-19 is well-characterized, immune profiles of non-hospitalized, non-vaccinated individuals are less investigated. High-dimensional single-cell profiling and multiplex serum marker analysis characterized immune profiles according to outcome during acute infection and six months later. Lower IL-1RA and HGF levels, higher CD57+TIGIT+NKT, CD57+GrB+NKT, CD16+TIGIT+NK and CD4+CD57+GrB+ effector T-cell levels characterized asymptomatic infection. PMA + ionomycin induced higher frequencies of polyfunctional CD4+ and CD8+ effector T-cells in asymptomatic compared to moderate disease. Absence of multiple long-term symptoms was associated with higher CD16+TIGIT+NK-cell frequency, lower HGF levels and persisting high memory B and regulatory NK subpopulation levels. Higher frequency of CD16+TIGIT+ NK cells was in common for non-infected, asymptomatic, and individuals without multiple long-term symptoms. Compared to infected individuals, non-infected cases showed higher pre-existing T-cell responses to hCoV and SARS-CoV-2 peptides. This study contributes to increased understanding of protective immune responses in non-hospitalized COVID-19 cases, emphasizing the role of defined NK and T-cell subpopulations.
{"title":"High-dimensional immune profiling identifies circulating NK and T cell subpopulations associated with asymptomatic COVID-19 and absence of multiple long-term symptoms","authors":"Johanna Bodin , Anja Bråthen Kristoffersen , Tove Karin Herstad , Gro Tunheim , Sabin Bhandari , Anna Hayman Robertson , Ratnadeep Mukherjee , Unni Cecilie Nygaard , Fredrik Oftung , Lisbeth M. Næss","doi":"10.1016/j.clim.2025.110564","DOIUrl":"10.1016/j.clim.2025.110564","url":null,"abstract":"<div><div>While severe COVID-19 is well-characterized, immune profiles of non-hospitalized, non-vaccinated individuals are less investigated. High-dimensional single-cell profiling and multiplex serum marker analysis characterized immune profiles according to outcome during acute infection and six months later. Lower IL-1RA and HGF levels, higher CD57<sup>+</sup>TIGIT<sup>+</sup>NKT, CD57<sup>+</sup>GrB<sup>+</sup>NKT, CD16<sup>+</sup>TIGIT<sup>+</sup>NK and CD4<sup>+</sup>CD57<sup>+</sup>GrB<sup>+</sup> effector T-cell levels characterized asymptomatic infection. PMA + ionomycin induced higher frequencies of polyfunctional CD4<sup>+</sup> and CD8<sup>+</sup> effector T-cells in asymptomatic compared to moderate disease. Absence of multiple long-term symptoms was associated with higher CD16<sup>+</sup>TIGIT<sup>+</sup>NK-cell frequency, lower HGF levels and persisting high memory B and regulatory NK subpopulation levels. Higher frequency of CD16<sup>+</sup>TIGIT<sup>+</sup> NK cells was in common for non-infected, asymptomatic, and individuals without multiple long-term symptoms. Compared to infected individuals, non-infected cases showed higher pre-existing T-cell responses to hCoV and SARS-CoV-2 peptides. This study contributes to increased understanding of protective immune responses in non-hospitalized COVID-19 cases, emphasizing the role of defined NK and T-cell subpopulations.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"280 ","pages":"Article 110564"},"PeriodicalIF":4.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human Herpesvirus 8 (HHV-8) poses a significant risk in solid organ transplant recipients (SOTRs). HHV-8 is implicated in both neoplastic and non-neoplastic conditions. This study investigates immune dysregulation in HHV-8-infected SOTRs by analysing cytokine profiles and virus-specific T cell responses across different clinical manifestations. Our findings reveal a progressive decline in HHV-8-specific T cell responses correlating with disease severity, alongside a distinct cytokine signature. KICS patients exhibit heightened inflammation with elevated IL-6, IL-10, IFNα, TNFα, IL-1β, IL-17 A, IDO, sCD14, and immune exhaustion markers (PD-1, LAG-3), whereas KS is associated with angiogenic and macrophage activation factors (HGF, CD163). Given these insights, monitoring HHV-8 DNAemia, inflammatory cytokines, and T cell functionality is crucial for early detection and risk stratification. This study underscores the importance of immune monitoring in transplant recipients, paving the way for targeted interventions to mitigate HHV-8-associated complications.
{"title":"Immune profiling in solid organ transplant recipients with HHV-8 infection: Identification of immunological biomarkers for KICS and Kaposi's sarcoma","authors":"Rosalia Busà , Francesca Timoneri , Monica Miele , Mariangela Di Bella , Andrea Cona , Salvatore Castelbuono , Mattia Emanuela Ligotti , Alessia Gallo , Francesca Pecoraro , Giuseppe Randazzo , Caterina Amato , Clara Pipia , Giandomenico Amico , Valentina Agnese , Pier Giulio Conaldi , Mario Luppi , Alessandra Mularoni , Matteo Bulati","doi":"10.1016/j.clim.2025.110562","DOIUrl":"10.1016/j.clim.2025.110562","url":null,"abstract":"<div><div>Human Herpesvirus 8 (HHV-8) poses a significant risk in solid organ transplant recipients (SOTRs). HHV-8 is implicated in both neoplastic and non-neoplastic conditions. This study investigates immune dysregulation in HHV-8-infected SOTRs by analysing cytokine profiles and virus-specific T cell responses across different clinical manifestations. Our findings reveal a progressive decline in HHV-8-specific T cell responses correlating with disease severity, alongside a distinct cytokine signature. KICS patients exhibit heightened inflammation with elevated IL-6, IL-10, IFNα, TNFα, IL-1β, IL-17 A, IDO, sCD14, and immune exhaustion markers (PD-1, LAG-3), whereas KS is associated with angiogenic and macrophage activation factors (HGF, CD163). Given these insights, monitoring HHV-8 DNAemia, inflammatory cytokines, and T cell functionality is crucial for early detection and risk stratification. This study underscores the importance of immune monitoring in transplant recipients, paving the way for targeted interventions to mitigate HHV-8-associated complications.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"280 ","pages":"Article 110562"},"PeriodicalIF":4.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144604458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-10DOI: 10.1016/j.clim.2025.110561
Weicheng Shen , Shengyan Cui , Yanqi Xia , Luo Duan , Yunpeng Dou , Han Zhao , Leixin Liu , Wei Wang , Ye Cui , Yan Chen , Jie Liu , Zhe Lv , Chris J. Corrigan , Huihui Yuan , Ying Sun
B-1 cells are derived from a subpopulation of B lymphocytes which have a specific developmental process, unique phenotype and location, and distinct functions in comparison with conventional B-2 cells. The origin of B-1 cells is not completely clear, with two existing hypotheses concerning their lineage and differentiation pathways. B-1 cells are located principally in the peritoneal and pleural cavities, but are also distributed in secondary lymphoid tissues, at mucosal sites and in the blood and bone marrow. B-1 cells regulate immune responses and maintain homeostasis by secretion of natural antibodies (nAbs), and participate in the adaptive immune response through phagocytosis and presentation of antigens to T cells. B-1 cells are associated with many diseases including autoimmune, infectious and inflammatory diseases. This review focuses on the origin and biological functions of B-1 cells as well as their involvement in human disease, and discusses advances in the understanding of the heterogeneity of B-1 cells under specific pathophysiological features, as partly clarified by single-cell sequencing analysis.
{"title":"Origin, functions, heterogeneity and associated diseases of B-1 cells","authors":"Weicheng Shen , Shengyan Cui , Yanqi Xia , Luo Duan , Yunpeng Dou , Han Zhao , Leixin Liu , Wei Wang , Ye Cui , Yan Chen , Jie Liu , Zhe Lv , Chris J. Corrigan , Huihui Yuan , Ying Sun","doi":"10.1016/j.clim.2025.110561","DOIUrl":"10.1016/j.clim.2025.110561","url":null,"abstract":"<div><div>B-1 cells are derived from a subpopulation of B lymphocytes which have a specific developmental process, unique phenotype and location, and distinct functions in comparison with conventional B-2 cells. The origin of B-1 cells is not completely clear, with two existing hypotheses concerning their lineage and differentiation pathways. B-1 cells are located principally in the peritoneal and pleural cavities, but are also distributed in secondary lymphoid tissues, at mucosal sites and in the blood and bone marrow. B-1 cells regulate immune responses and maintain homeostasis by secretion of natural antibodies (nAbs), and participate in the adaptive immune response through phagocytosis and presentation of antigens to T cells. B-1 cells are associated with many diseases including autoimmune, infectious and inflammatory diseases. This review focuses on the origin and biological functions of B-1 cells as well as their involvement in human disease, and discusses advances in the understanding of the heterogeneity of B-1 cells under specific pathophysiological features, as partly clarified by single-cell sequencing analysis.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"280 ","pages":"Article 110561"},"PeriodicalIF":4.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-10DOI: 10.1016/j.clim.2025.110565
Samantha A.M. Tromp , Ester M.M. van Leeuwen , Machiel H. Jansen , Arjan J. Kwakernaak , Marije K. Bomers , René E. Jonkers , Resie M.L. van Spaendonk , Taco W. Kuijpers , Godelieve J. de Bree
Background
Genetic variants in Cytotoxic T-Lymphocyte-associated protein 4 (CTLA4) and LPS responsive beige-like anchor protein (LRBA), involved in the same biological pathways, are implicated as monogenic causes of Common Variable Immunodeficiency Disorder (CVID). The pitfall in the recognition of CVID possibly related to CTLA-4 haploinsufficiency or LRBA deficiency is a clinical picture that is very heterogeneous. In the present study, we illustrate this challenge by means of clinical and immunological analysis of five patients with novel genetic variants in CTLA4 and LRBA.
Methods
Whole-exome sequencing (WES) was performed to identify genetic variants in the currently known immune genes in patients. Extensive immunophenotyping, lymphocyte proliferation assays and expression of CTLA-4 and a panel of 17 co-stimulatory molecules, both in rest and upon activation, were performed to gain insight into the impact of the genetic variants on B and T cell phenotype and function.
Results
A novel heterozygous variant in CTLA4 (c.457 + 5G > A) was identified in three members of a single family, all presenting with different clinical manifestations. In two additional patients, two genetic variants in LRBA (c.1771 T > C; c.2450-3C > A) were found, of which one is novel as well. The B cell phenotype was naïve with absence of non-switched and switched memory B cells in all patients except of the genetically affected elderly woman without any clinical manifestations. CD4 and CD8 T cell numbers and phenotype were normal. Differentiation of B cells into antibody secreting cells in vitro was reduced, especially in response to T cell-independent stimulation. The T cells showed impaired upregulation of CTLA-4 expression, which was most pronounced in CD4+CD25+FoxP3+ regulatory T cells, which helped to biologically support the genetic diagnosis.
Conclusion
The described novel genetic variants in CTLA4 and LRBA show immunological impact and are therefore likely to underly an immune dysregulation syndrome with a highly variable clinical presentation. Apart from the immunophenotypic abnormal findings in activated T cells, the intrinsic B cell defect aids in the interpretation of novel genetic variants in these two genes in the context of a highly suspected clinical presentation.
{"title":"Novel pathogenic variants in CTLA4 and LRBA immune dysregulation: Reduced CTLA-4 expression with normal expression of co-stimulatory surface molecules","authors":"Samantha A.M. Tromp , Ester M.M. van Leeuwen , Machiel H. Jansen , Arjan J. Kwakernaak , Marije K. Bomers , René E. Jonkers , Resie M.L. van Spaendonk , Taco W. Kuijpers , Godelieve J. de Bree","doi":"10.1016/j.clim.2025.110565","DOIUrl":"10.1016/j.clim.2025.110565","url":null,"abstract":"<div><h3>Background</h3><div>Genetic variants in Cytotoxic T-Lymphocyte-associated protein 4 (<em>CTLA4</em>) and LPS responsive beige-like anchor protein (<em>LRBA</em>), involved in the same biological pathways, are implicated as monogenic causes of Common Variable Immunodeficiency Disorder (CVID). The pitfall in the recognition of CVID possibly related to CTLA-4 haploinsufficiency or LRBA deficiency is a clinical picture that is very heterogeneous. In the present study, we illustrate this challenge by means of clinical and immunological analysis of five patients with novel genetic variants in <em>CTLA4</em> and <em>LRBA</em>.</div></div><div><h3>Methods</h3><div>Whole-exome sequencing (WES) was performed to identify genetic variants in the currently known immune genes in patients. Extensive immunophenotyping, lymphocyte proliferation assays and expression of CTLA-4 and a panel of 17 co-stimulatory molecules, both in rest and upon activation, were performed to gain insight into the impact of the genetic variants on B and T cell phenotype and function.</div></div><div><h3>Results</h3><div>A novel heterozygous variant in <em>CTLA4</em> (c.457 + 5G > A) was identified in three members of a single family, all presenting with different clinical manifestations. In two additional patients, two genetic variants in <em>LRBA</em> (c.1771 T > C; c.2450-3C > A) were found, of which one is novel as well. The B cell phenotype was naïve with absence of non-switched and switched memory B cells in all patients except of the genetically affected elderly woman without any clinical manifestations. CD4 and CD8 T cell numbers and phenotype were normal. Differentiation of B cells into antibody secreting cells in vitro was reduced, especially in response to T cell-independent stimulation. The T cells showed impaired upregulation of CTLA-4 expression, which was most pronounced in CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> regulatory T cells, which helped to biologically support the genetic diagnosis.</div></div><div><h3>Conclusion</h3><div>The described novel genetic variants in <em>CTLA4</em> and <em>LRBA</em> show immunological impact and are therefore likely to underly an immune dysregulation syndrome with a highly variable clinical presentation. Apart from the immunophenotypic abnormal findings in activated T cells, the intrinsic B cell defect aids in the interpretation of novel genetic variants in these two genes in the context of a highly suspected clinical presentation.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"280 ","pages":"Article 110565"},"PeriodicalIF":4.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-09DOI: 10.1016/j.clim.2025.110557
Katarina Mirjačić Martinović , Ana Vuletić , Nevena Tišma Miletić , Milica Nedeljković , Suzana Matković , Vladimir Jurišić
Therapeutical blockade of programmed cell death protein 1 (PD-1) axis may enhance anti-tumor immunity and especially natural killer (NK) cells activity. In 32 BRAF wild type (wt) metastatic melanoma (MM) patients before and after every 12 weeks of therapy with PD-1 inhibitor, Pembrolizumab, we analyzed the percentage of T cell subsets, NK cells and CD14+HLA-DR− monocytes, the expression of CD107a degranulation marker, activating NKG2D, NKp46, DNAM-1 and inhibitory CD158a receptors on NK cells by Flow cytometry, until one year or disease progression (DP). The patients with disease control (non-DP patients) had significant increase in lymphocyte count, percentage of NK cells, increased expression of CD107a, NKG2D, NKp46, but decreased CD158a on NK cells during Pembrolizumab therapy compared to pretherapy values. Patients with DP had increased neutrophil number, increased percentage of immunosuppressive CD14+HLA-DR− monocytes, as well as increased CD158a expression on NK cells. In MM patients with disease control, contrary to DP patients blocking of PD-1 inhibitory molecule may increase NK cell cytotoxicity through enhancement of NK cell degranulation and activating receptor expression. Therefore, our findings show that NK cells and their receptors in MM patients may be potential biomarkers of response to Pembrolizumab.
{"title":"Analyses of peripheral blood NK cells in response to anti-PD-1 therapy in metastatic melanoma patients","authors":"Katarina Mirjačić Martinović , Ana Vuletić , Nevena Tišma Miletić , Milica Nedeljković , Suzana Matković , Vladimir Jurišić","doi":"10.1016/j.clim.2025.110557","DOIUrl":"10.1016/j.clim.2025.110557","url":null,"abstract":"<div><div>Therapeutical blockade of programmed cell death protein 1 (PD-1) axis may enhance anti-tumor immunity and especially natural killer (NK) cells activity. In 32 BRAF wild type (wt) metastatic melanoma (MM) patients before and after every 12 weeks of therapy with PD-1 inhibitor, Pembrolizumab, we analyzed the percentage of T cell subsets, NK cells and CD14<sup>+</sup>HLA-DR<sup>−</sup> monocytes, the expression of CD107a degranulation marker, activating NKG2D, NKp46, DNAM-1 and inhibitory CD158a receptors on NK cells by Flow cytometry, until one year or disease progression (DP). The patients with disease control (non-DP patients) had significant increase in lymphocyte count, percentage of NK cells, increased expression of CD107a, NKG2D, NKp46, but decreased CD158a on NK cells during Pembrolizumab therapy compared to pretherapy values. Patients with DP had increased neutrophil number, increased percentage of immunosuppressive CD14<sup>+</sup>HLA-DR<sup>−</sup> monocytes, as well as increased CD158a expression on NK cells. In MM patients with disease control, contrary to DP patients blocking of PD-1 inhibitory molecule may increase NK cell cytotoxicity through enhancement of NK cell degranulation and activating receptor expression. Therefore, our findings show that NK cells and their receptors in MM patients may be potential biomarkers of response to Pembrolizumab.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"280 ","pages":"Article 110557"},"PeriodicalIF":4.5,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-08DOI: 10.1016/j.clim.2025.110560
Taylor Wesley, Callie Rose, Jessica Ding, Kirstin Parkin
Myasthenia gravis is an autoimmune disease that impairs neuromuscular transmission through autoantibodies, most commonly targeting acetylcholine receptors (AChR). While clinical scores like the Quantitative Myasthenia Gravis Score (QMGS) and the Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) are commonly used in trials, there is no gold standard biomarker for evaluating treatment efficacy. This scoping review aimed to identify which biomarkers are most frequently used in randomized controlled trials (RCTs) for non-surgical treatments of generalized myasthenia gravis. We searched five databases for English-language RCTs published before May 9, 2024. Of 6685 screened texts, 33 met inclusion criteria. A total of 33 distinct biomarkers were tracked across studies, with AChR antibodies, IgG, and IL-2 most frequently reported. Biomarkers were measured inconsistently and at varied intervals, limiting cross-study comparability. The lack of standardized biomarker use hinders the ability to assess treatment efficacy and perform meta-analyses. We recommend developing consensus guidelines to improve future trial quality.
{"title":"Measuring efficacy for myasthenia gravis treatments: A review of biomarkers used in clinical trials","authors":"Taylor Wesley, Callie Rose, Jessica Ding, Kirstin Parkin","doi":"10.1016/j.clim.2025.110560","DOIUrl":"10.1016/j.clim.2025.110560","url":null,"abstract":"<div><div>Myasthenia gravis is an autoimmune disease that impairs neuromuscular transmission through autoantibodies, most commonly targeting acetylcholine receptors (AChR). While clinical scores like the Quantitative Myasthenia Gravis Score (QMGS) and the Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) are commonly used in trials, there is no gold standard biomarker for evaluating treatment efficacy. This scoping review aimed to identify which biomarkers are most frequently used in randomized controlled trials (RCTs) for non-surgical treatments of generalized myasthenia gravis. We searched five databases for English-language RCTs published before May 9, 2024. Of 6685 screened texts, 33 met inclusion criteria. A total of 33 distinct biomarkers were tracked across studies, with AChR antibodies, IgG, and IL-2 most frequently reported. Biomarkers were measured inconsistently and at varied intervals, limiting cross-study comparability. The lack of standardized biomarker use hinders the ability to assess treatment efficacy and perform meta-analyses. We recommend developing consensus guidelines to improve future trial quality.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"280 ","pages":"Article 110560"},"PeriodicalIF":4.5,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-07DOI: 10.1016/j.clim.2025.110558
Xukang Gao , Min Xu , Hao Xiao , Zeping Han , Zhutao Wang , Guoqiang Sun , Dai Zhang , Qiu Shuangjian , Ning Ren , Chenhao Zhou , Yong Yi
Neutrophils, constituting 50–70 % of circulating leukocytes, serve as first responders in innate immunity. In recent years, as research into the tumor immune microenvironment has intensified, the role of neutrophils in tumor has gained increasing attention. Studies have shown that neutrophils are involved in tumor growth, metastasis, angiogenesis, and immune regulation. However, because tumor-associated neutrophils (TANs) often exhibit dual-edged effects and significant heterogeneity, it remains challenging to determine whether they act as allies or adversaries. This review systematically summarizes the classification and functions of neutrophils in tumor. Additionally, the current challenges in tumor-associated neutrophils are discussed, aiming to provide new insights for the development of neutrophil-related immunotherapies.
{"title":"Tumor-associated neutrophils: a complex role in cancer","authors":"Xukang Gao , Min Xu , Hao Xiao , Zeping Han , Zhutao Wang , Guoqiang Sun , Dai Zhang , Qiu Shuangjian , Ning Ren , Chenhao Zhou , Yong Yi","doi":"10.1016/j.clim.2025.110558","DOIUrl":"10.1016/j.clim.2025.110558","url":null,"abstract":"<div><div>Neutrophils, constituting 50–70 % of circulating leukocytes, serve as first responders in innate immunity. In recent years, as research into the tumor immune microenvironment has intensified, the role of neutrophils in tumor has gained increasing attention. Studies have shown that neutrophils are involved in tumor growth, metastasis, angiogenesis, and immune regulation. However, because tumor-associated neutrophils (TANs) often exhibit dual-edged effects and significant heterogeneity, it remains challenging to determine whether they act as allies or adversaries. This review systematically summarizes the classification and functions of neutrophils in tumor. Additionally, the current challenges in tumor-associated neutrophils are discussed, aiming to provide new insights for the development of neutrophil-related immunotherapies.</div></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"280 ","pages":"Article 110558"},"PeriodicalIF":4.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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