Clinical And Experimental Immunology[JOURNAL]
Sun
200 papers
Characterization of T-bet expressing B cells in lupus patients indicates a putative prognostic and therapeutic value of these cells for the disease.
Sachinidis A, Trachana M, Taparkou A … +8 more , Gavriilidis G, Vasileiou V, Keisaris S, Verginis P, Adamichou C, Boumpas D, Psomopoulos F, Garyfallos A
Clin Exp Immunol · 2025 Jan · PMID 39918986 · Full text
OBJECTIVE: To investigate whether T-bet+ B cells, as well as age-associated B cells/ABCs (CD19 + CD21-CD11c + T-bet+) and double-negative B cells/DN (CD19 + IgD-CD27- CXCR5-T-bet+), serve as prognostic and/or therapeutic...
OBJECTIVE: To investigate whether T-bet+ B cells, as well as age-associated B cells/ABCs (CD19 + CD21-CD11c + T-bet+) and double-negative B cells/DN (CD19 + IgD-CD27- CXCR5-T-bet+), serve as prognostic and/or therapeutic tools for systemic lupus erythematosus (SLE) in humans. METHODS: Flow cytometry was used for enumerating T-bet+ B cells and ABCs/DN subsets, found in the peripheral blood of 10 healthy donors and 22 active SLE patients. Whole blood assay cultures, combined with in vitro pharmacological treatments, were performed to evaluate the effects of hydroxychloroquine, anifrolumab, and fasudil (a ROCK kinase inhibitor) on T-bet+ B cells' percentage. Moreover, previously published single-cell RNA sequencing (scRNA-seq) data were used in a meta-analysis to allow characterization of genes and pathways associated with the biology of T-bet in B cells. RESULTS: T-bet+ B cells displayed an expansion in SLE patients [1.47 (1.9-0.7) vs 10.85 (37.4-3.6)]. Similarly, both ABCs and DN were found to be expanded. Interestingly, percentages of T-bet+ B cells positively correlated with patients' SLEDAI scores (rs = 0.55, P = 0.007). Cell culture experiments conducted revealed that all three agents tested can deplete T-bet + B cells (without affecting the cell viability of lymphocytes, T cells, and B cells). According to bioinformatics analyses, T-bet is highly expressed in two B-cell clusters with pathogenic characteristics for SLE (designated as atypical memory B cells and activated naïve B cells). These clusters can be targeted for therapeutic interventions. CONCLUSIONS: T-bet+ B cells can serve as a putative prognostic biomarker of lupus severity. Circumstantial data suggest that these cells may promote disease pathogenesis and may represent a novel therapeutic target.
Application of whole-exome sequencing to predict inborn errors of immunity in pediatric severe infections and sepsis.
Moundir A, Aissaoui O, Akhrichi N … +7 more , Allaoui A, Benhsaien I, Jouanguy E, Casanova JL, El Bakkouri J, Ailal F, Bousfiha AA
Clin Exp Immunol · 2025 Jan · PMID 39918293 · Full text
Increasing evidence supports the involvement of inborn errors of immunity in severe infections, but little is known about the prevalence of these genetic defects in children with sepsis. Due to the limited understanding...
Increasing evidence supports the involvement of inborn errors of immunity in severe infections, but little is known about the prevalence of these genetic defects in children with sepsis. Due to the limited understanding of the molecular and immunological mechanisms driving sepsis, genetic testing is rarely used in routine diagnostics to identify genetic susceptibility to the condition. We performed a prospective observational study on previously healthy children hospitalized for severe infections, including sepsis. Patients underwent immunophenotyping and whole-exome sequencing, followed by in silico analysis to identify potentially causal variants. We assembled a cohort of 194 previously healthy children, including 149 (77%) patients with severe infection and 45 (23%) with sepsis. Our cohort was marked by a high frequency of respiratory tract infections (35%), bloodstream infections (20%), and central nervous system infections (16%). The genetic investigation identified 28 potentially causal variants, 18 (64%) are classified as variants with uncertain significance, and 10 (36%) are likely pathogenic variants. Of 45 patients with sepsis, 6 (13%) had potentially causal genetic variants. Similarly, 22/149 (15%) patients with severe infection presented potentially causal genetic variants. Whole-exome sequencing predicted the impairment of various immune mechanistic pathways such as immune dysregulation defects, antibody deficiencies, and combined immunodeficiencies (18% each). We found no clear association between genetic variants and the studied parameters: organ failure, microbe identification, immunoglobulin levels, and lymphocyte subset numbers. Although whole-exome sequencing is a valuable tool for detecting inborn errors of immunity underlying sepsis and unexplained severe infections, it could be selectively recommended for patients with a strong clinical suspicion of genetic abnormalities, balancing its diagnostic value with its cost and complexity.
How do large-scale population studies inform vaccine evaluations in England?
Kirsebom FCM, Hall V, Stowe J
Clin Exp Immunol · 2025 Jan · PMID 39910973 · Full text
Large-scale population studies are important to monitor and evaluate aspects of a vaccination programme including vaccine coverage, real-world effectiveness, and post-licensure vaccine safety. These types of epidemiologi...
Large-scale population studies are important to monitor and evaluate aspects of a vaccination programme including vaccine coverage, real-world effectiveness, and post-licensure vaccine safety. These types of epidemiological studies often come under the remit of public health agencies, such as the UK Health Security Agency (UKHSA) in England, which are required to undertake surveillance of vaccine-preventable diseases, including via seroepidemiological studies and data linkage studies using national-level electronic healthcare data. An individual-level national vaccine register with an accurate denominator can be the key to gaining insights into vaccine coverage, effectiveness, and safety. During the coronavirus disease 2019 pandemic, England's first vaccine register was developed. This enabled timely estimates of real-world vaccine effectiveness in the whole population of England, as well as enabling epidemiological investigations of rare potential risks from vaccines in specific populations. Population-based research studies, including prospective cohort studies, are complementary to surveillance and combined, enable more comprehensive assessments. As there was an unprecedented investment into research studies and infrastructure during the pandemic, the scale of these studies meant they were able to contribute to vaccine programme evaluations in a way that had not been possible for previous vaccine programmes. In this review, we summarise the different large-scale surveillance and research studies that have been used to evaluate and inform vaccine policy from the time of the first data linkage studies undertaken in England in the 1990s to the present-day post-COVID-19 pandemic.
Correction to: Antibody-mediated glomerulonephritis in mice: the role of endotoxin, complement and genetic background.
Clin Exp Immunol · 2025 Jan · PMID 39846897 · Full text
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Functional validation of a novel STAT3 'variant of unknown significance' identifies a new case of STAT3 GOF syndrome and reveals broad immune cell defects.
Mackie J, Suan D, McNaughton P … +5 more , Haerynck F, O'Sullivan M, Guerin A, Ma CS, Tangye SG
Clin Exp Immunol · 2025 Jan · PMID 39836489 · Full text
INTRODUCTION: Signal transducer and activator of transcription 3 (STAT3) orchestrates crucial immune responses through its pleiotropic functions as a transcription factor. Patients with germline monoallelic dominant nega...
INTRODUCTION: Signal transducer and activator of transcription 3 (STAT3) orchestrates crucial immune responses through its pleiotropic functions as a transcription factor. Patients with germline monoallelic dominant negative or hypermorphic STAT3 variants, who present with immunodeficiency and/or immune dysregulation, have revealed the importance of balanced STAT3 signaling in lymphocyte differentiation and function, and immune homeostasis. Here, we report a novel missense variant of unknown significance in the DNA-binding domain of STAT3 in a patient who experienced hypogammaglobulinemia, lymphadenopathy, hepatosplenomegaly, immune thrombocytopenia, eczema, and enteropathy over a 35-year period. METHODS: In vitro demonstration of prolonged STAT3 activation due to delayed dephosphorylation, and enhanced transcriptional activity, confirmed this to be a novel pathogenic STAT3 gain-of-function variant. Peripheral blood lymphocytes from this patient, and patients with confirmed STAT3 Gain-of-function Syndrome, were collected to investigate mechanisms of disease pathogenesis. RESULTS: B cell dysregulation was evidenced by a loss of class-switched memory B cells and a significantly expanded CD19hiCD21lo B cell population, likely influenced by a skewed CXCR3+ TFH population. Interestingly, unlike STAT3 dominant negative variants, cytokine secretion by activated peripheral blood STAT3 GOF CD4+ T cells and frequencies of Treg cells were intact, suggesting CD4+ T cell dysregulation likely occurs at sites of disease rather than the periphery. CONCLUSION: This study provides an in-depth case study in confirming a STAT3 gain-of-function variant and identifies lymphocyte dysregulation in the peripheral blood of patients with STAT3 gain-of-function syndrome. Identifying cellular biomarkers of disease provides a flow cytometric-based screen to guide validation of additional novel STAT3 gain-of-function variants as well as provide insights into putative mechanisms of disease pathogenesis.
B cells recruitment promotes M2 macrophage polarization to inhibit inflammation during wound healing.
Yin Y, Wu S
Clin Exp Immunol · 2025 Jan · PMID 39821004 · Full text
Wound healing causes heavy economic burdens for families and society, becoming a critical issue in the global healthcare system. While the role of immune cells in the wound-healing process is well-established, the involv...
Wound healing causes heavy economic burdens for families and society, becoming a critical issue in the global healthcare system. While the role of immune cells in the wound-healing process is well-established, the involvement of B cells remains poorly understood. This study aims to elucidate the essentiality of B cells in wound repair. Our findings demonstrate a rise in B-cell population during the early stage of wound healing, which further intensifies during the later stage. We employed anti-CD20 antibodies to deplete B cells in mice and created a whole skin excisional wound mice model, analyzing wound closure over 12 days. B cells were isolated from the animals' spleen and co-cultured with macrophages from bone marrow. The polarization of M1 and M2 macrophages was analyzed by real-time qPCR and flow cytometry. The wound healing process in mice was observed to be considerably delayed following the elimination of B cells. The wounds exhibited a state of inflammation primarily characterized by the presence of pro-inflammatory M1 macrophages. The decrease in M2 macrophages within the local wound area resulted in impairment of the wound repair mechanism. B-cell-macrophage co-culture system revealed that B cells effectively induce the polarization of macrophages towards M2-like phenotype. Furthermore, we found that follicular B cells play predominant role in modulating the polarization of M2 macrophages. Consequently, our findings indicate that B cells can be recruited to the wound site and facilitate the polarization of M2-like macrophages, thereby accelerating the healing process during wound healing.
Proteomic analysis reveals dysregulation of peripheral blood neutrophils in patients with Multiple Sclerosis.
Smith KJ, Lim Z, Vermeren S … +5 more , Miron VE, Dimeloe S, Davidson DJ, Williams A, Gwyer Findlay E
Clin Exp Immunol · 2025 Jan · PMID 39817476 · Full text
Multiple Sclerosis (MS) is a complex auto-inflammatory disease affecting the brain and spinal cord, which results in axonal de-myelination and symptoms including fatigue, pain, and difficulties with vision and mobility....
Multiple Sclerosis (MS) is a complex auto-inflammatory disease affecting the brain and spinal cord, which results in axonal de-myelination and symptoms including fatigue, pain, and difficulties with vision and mobility. The involvement of the immune system in the pathology of MS is well established, particularly the adaptive T cell response, and there has been a particular focus on the IL-17-producing subset of Th17 cells and their role in driving disease. However, the importance of innate immune cells has not been so well characterized. Here we focussed on neutrophils, which are innate immune cells and rapid responders to inflammation, and which have recently been linked to other chronic autoimmune conditions. Multiple strands of evidence in patients with MS and in mice with the experimental autoimmune encephalomyelitis MS model suggest neutrophils may play a role in driving MS inflammation. Here, we performed proteomic analysis on neutrophils from patients with MS and healthy donors, revealing striking differences. In particular, granule proteins were significantly more abundant in the MS neutrophils compared to the healthy controls, with a particular overabundance of proteins in primary and secondary granules. In addition, members of the MAVS signalling pathway were differently regulated compared to healthy donor cells. Finally, we find that MS neutrophils do not suppress T cell activation equivalently to healthy neutrophils, and in particular are unable to suppress expression of CD161 on the T cells, indicative of a suppression of Th17 differentiation. We propose that neutrophil dysregulation in MS may contribute to dysfunctional T cell responses.
Investigating T-cell-derived extracellular vesicles as biomarkers of disease activity, axonal injury, and disability in multiple sclerosis.
Zagrodnik JL, Blandford SN, Fudge NJ … +6 more , Arsenault ST, Anthony S, McGrath L, Clift F, Stefanelli M, Moore CS
Clin Exp Immunol · 2025 Jan · PMID 39798086 · Full text
INTRODUCTION: Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system, whereby clinical disease activity is primarily monitored by magnetic resonance imaging. METHODS: Giv...
INTRODUCTION: Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system, whereby clinical disease activity is primarily monitored by magnetic resonance imaging. METHODS: Given the limitations associated with implementing and acquiring novel and emerging imaging biomarkers in routine clinical practice, the discovery of biofluid biomarkers may offer a more simple and cost-effective measure that would improve accessibility, standardization, and patient care. Extracellular vesicles (EVs) are nanoparticles secreted from cells under both homeostatic and pathological states, and have been recently investigated as biomarkers in MS. The objectives of this study were to longitudinally measure levels of specific immune cell-derived EVs in MS and provide evidence that EV sub-populations may serve as biomarkers of disease activity, axonal injury, and/or clinical disability. RESULTS: Our results demonstrate that the rate of clinical disability in MS negatively correlates with changes in circulating CD3+ EVs within the plasma. Additionally, numbers of CD4+ EVs decrease in individuals with increasing pNfL levels overtime whereby the magnitude of the pNfL increase negatively correlates with changes in plasma CD4+ and CD8+ EVs. Finally, when applying NEDA-3 criteria to define active versus stable disease, individuals with active disease had significantly elevated CD4+ and CD8+ EVs compared to stable disease. CONCLUSION: In summary, the analysis of specific immune cell-derived EV subsets may provide a method to monitor disability accumulation, disease activity, and axonal injury in MS, while also providing insights into the pathophysiology and cellular/molecular mechanisms that influence progression.
Single-cell analysis of lung epithelial cells reveals age and cell population-specific responses to SARS-CoV-2 infection in ciliated cells.
Osborn RM, Anderson CS, Leach JR … +4 more , Chu C, Dewhurst S, Mariani TJ, Thakar J
Clin Exp Immunol · 2025 Jan · PMID 39780400 · Full text
INTRODUCTION: The ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evade antiviral immune signaling in the airway contributes to the severity of coronavirus disease 2019 (COVID-19). Additionally...
INTRODUCTION: The ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evade antiviral immune signaling in the airway contributes to the severity of coronavirus disease 2019 (COVID-19). Additionally, COVID-19 is influenced by age and has more severe presentations in older individuals. Hence we investigate the role of innate immune signaling as a function of lung development and age. METHOD: We investigated the transcriptome of the airway epithelium using pediatric and adult lung tissue samples from the LungMAP Human Tissue Core Biorepository. Specifically, lung lobes were digested and cultured into a biomimetic model of the airway epithelium on an air-liquid interface. Cells were then infected with SARS-CoV-2 and subjected to single-cell RNA sequencing. The data was analyzed using Seurat, scType, Monacle and tools to infer cell-cell communication. RESULTS: The clustering analysis identified following six cell populations: club cells, proliferating epithelial cells, multiciliated precursor cells, ionocytes, and two biologically distinct clusters of ciliated cells (FOXJ1high and FOXJ1low). Interestingly, the two ciliated cell clusters showed different infection rates and enrichment of processes involved in ciliary biogenesis and function; we observed a cell-type-specific suppression of innate immunity in infected cells from the FOXJ1low subset. We also identified a significant number of genes that were differentially expressed in lung cells derived from children as compared to adults, suggesting the differential pathogenesis of SARS-CoV-2 infection in children versus adults. CONCLUSION: This work reveals age dependent differences in the lung epithelial cell response to SARS-CoV-2 infection. The results can be used to identify drug targets to modulate molecular signaling cascades that mediate an innate immune response.
Neuro-Behçet's disease: an update of clinical diagnosis, biomarkers, and immunopathogenesis.
Zhan H, Cheng L, Li Y
Clin Exp Immunol · 2025 Jan · PMID 39774671 · Full text
Neuro-Behçet's disease (NBD) is a more severe but rare symptom of Behçet's disease, which is mainly divided into parenchymal NBD (p-NBD) involving brain stem, spinal cord, and cerebral cortex. Non-p-NBD manifests as intr...
Neuro-Behçet's disease (NBD) is a more severe but rare symptom of Behçet's disease, which is mainly divided into parenchymal NBD (p-NBD) involving brain stem, spinal cord, and cerebral cortex. Non-p-NBD manifests as intracranial aneurysm, cerebral venous thrombosis, peripheral nervous system injuries, and mixed parenchymal and non-parenchymal disease. p-NBD is pathologically characterized by perivasculitis presenting with cerebrospinal fluid (CSF) pleocytosis, elevated total protein, and central nervous system (CNS) infiltration of macrophages and neutrophils, which are subdivided into acute and chronic progressive stages according to relapsing-remitting courses and responses to steroids. The diagnosis of NBD depends heavily on clinical features and magnetic resonance imaging (MRI) findings. The lack of laboratory biomarkers has hindered standard diagnostics. CSF interleukin (IL)-6 is the most investigated dimension of NBD and correlates with NBD activity, therapeutic responses, and prognosis. Further investigations have focused on inflammatory biomarkers that reflect the activation of innate and adaptive immune responses. Higher levels of CSF migration inhibitory factor and immunosuppressive acidic protein indicated the activation of macrophages in the CNS; increased IL-17, IL-10, T-bet/GATA-3, and retinoic acid related orphan receptor (ROR)-γt/Foxp3 ratios, marking the disrupted scale of the Th1/Th2 and Th17/Treg axis; and elevated B-cell activating factor of the TNF family (BAFF) and IgA/IgM intrathecal synthesis, suggesting that B cells play a dominant role in NBD. CNS destruction and degeneration as a consequence of neuroinflammatory cascades were confirmed by elevated CSF levels of NFL, β2MG, and MBP. Autoantibodies, including anti-STIP-1, anti-Mtch1, anti-B-Crystallin, and anti-m-Hsp65, provide substantial evidence for autoimmune essence and underlying microbiological infections in NBD immunopathogenesis. We summarized opinions on the clinical diagnosis, biomarkers, and pathological findings of NBD.
Geographic disparities impacting oral vaccine performance: Observations and future directions.
Burke RM, Ramani S, Lynch J … +6 more , Cooper LV, Cho H, Bandyopadhyay AS, Kirkwood CD, Steele AD, Kang G
Clin Exp Immunol · 2025 Jan · PMID 39774633 · Full text
Oral vaccines have several advantages compared with parenteral administration: they can be relatively cheap to produce in high quantities, easier to administer, and induce intestinal mucosal immunity that can protect aga...
Oral vaccines have several advantages compared with parenteral administration: they can be relatively cheap to produce in high quantities, easier to administer, and induce intestinal mucosal immunity that can protect against infection. These characteristics have led to successful use of oral vaccines against rotavirus, polio, and cholera. Unfortunately, oral vaccines for all three diseases have demonstrated lower performance in the highest-burden settings where they are most needed. Rotavirus vaccines are estimated to have >85% effectiveness against hospitalization in children <12 months in countries with low child mortality, but only ~65% effectiveness in countries with high child mortality. Similarly, oral polio vaccines have lower immunogenicity in developing country settings compared with high-resource settings. Data are more limited for oral cholera vaccines, but suggest lower titers among children compared with adults, and, for some vaccines, lower efficacy in endemic settings compared with non-endemic settings. These disparities are likely multifactorial, and available evidence suggests a role for maternal factors (e.g. transplacental antibodies, breastmilk), host factors (e.g. genetic polymorphisms-with the best evidence for rotavirus-or previous infection), and environmental factors (e.g. gut microbiome, co-infections). Overall, these data highlight the rather ambiguous and often contradictory nature of evidence on factors affecting oral vaccine response, cautioning against broad extrapolation of outcomes based on one population or one vaccine type. Meaningful impact on performance of oral vaccines will likely only be possible with a suite of interventions, given the complex and multifactorial nature of the problem, and the degree to which contributing factors are intertwined.
The potential of autologous patient-derived circulating extracellular vesicles to improve drug delivery in rheumatoid arthritis.
Moskovitch O, Anaki A, Caller T … +11 more , Gilburd B, Segal O, Gendelman O, Watad A, Mehrian-Shai R, Mintz Y, Segev S, Shoenfeld Y, Popovtzer R, Amital H, Halpert G
Clin Exp Immunol · 2025 Jan · PMID 39756417 · Full text
Recognizing the need for innovative therapeutic approaches in the management of autoimmune diseases, our current investigation explores the potential of autologous extracellular vesicles (EVs), derived from the blood of...
Recognizing the need for innovative therapeutic approaches in the management of autoimmune diseases, our current investigation explores the potential of autologous extracellular vesicles (EVs), derived from the blood of rheumatoid arthritis patients, to serve as therapeutic vectors to improve drug delivery. We found that circulating EVs derived from arthritic mice (collagen-induced arthritis model) express the joint/synovia homing receptor, αVβ3 integrin. Importantly, both autologous labeled EVs, derived from the blood of arthritic mice (collagen antibody-induced arthritis model) and healthy mice-derived EVs, exhibit targeted migration toward inflamed synovia without infiltrating healthy joints, as demonstrated by an in vivo imaging system. Furthermore, EVs derived from plasma of rheumatoid arthritis patients show an overexpression of αV integrin and are effectively taken up by lipopolysaccharides/tumor necrosis factor alpha (TNFα)-induced activated human synovial cell line in vitro, although interestingly the uptake of healthy EVs was found to be significantly increased. Notably, arthritic mice-derived circulating EVs, strongly express murine glucose transporter 1, which in turn can facilitate their binding to glucose-coated gold nanoparticles (previously shown to be conjugated with drugs for improved drug delivery). The significance of our results, lies in the identification of autologous tissue homing EVs as promising vectors, offering a novel avenue to enhance targeted delivery of anti-inflammatory/rheumatic drugs in rheumatoid arthritis treatment.
A multi-centre UK-based survey on angioedema secondary to acquired C1 inhibitor deficiency.
Morsi H, Huissoon A, Grammatikos A … +50 more , Whyte AF, Manson A, Ekbote A, Sivadasan A, Boulton APR, Herwadkar A, Anantharachagan A, Price A, Steele C, Stroud C, Chopra C, Arnold D, Eren E, Cleave E, Drewe E, Moon E, Zinser E, Hayman G, Alachkar H, Ghanta H, Bourne H, Abdelhakam I, Dempster J, Townsend K, Sooriyakumar K, Lorenzo L, Dziadzio M, Ahuja M, Prasinou M, Frleta-Gilchrist M, Zhang M, Thomas M, Vijayadurai P, Vaitla PM, Sargur R, Herriot R, Yellon RL, Murng SHK, Drinkwater S, Denness S, Denman S, Elkhalifa S, Savic S, Kiani-Alikhan S, Coulter TI, El-Shanawany T, Rahman T, Garcez T, Yong PFK, Jain R
Clin Exp Immunol · 2025 Jan · PMID 39756409 · Full text
BACKGROUND: Acquired angioedema due to C1-inhibitor deficiency (AAE-C1-INH) is very rare compared to its prototype, hereditary angioedema. An updated characterization of the AAE-C1-INH cohort in the UK is required to inf...
BACKGROUND: Acquired angioedema due to C1-inhibitor deficiency (AAE-C1-INH) is very rare compared to its prototype, hereditary angioedema. An updated characterization of the AAE-C1-INH cohort in the UK is required to inform management. OBJECTIVES: To describe the disease burden of AAE-C1-INH, long-term prophylaxis (LTP) and the clinical, immunochemical, and treatment profiles of AAE-associated diseases in the UK. METHOD: Retrospective data on 117 AAE-C1-INH patients were collected using a national survey proforma across 25/34 Adult Clinical Immunology and Allergy centres in the UK. Other European cohorts were compared. RESULTS: The median age at AAE-C1-INH diagnosis was 65 years with 3.4% of patients diagnosed below 40 years. The median delay in diagnosis was 1 year. Antifibrinolytics and attenuated androgens showed comparable efficacy to LTP, at 88.9% and 89.5%, respectively. A haematological disorder was identified in 83.8% of AAE-C1-INH patients compared to 3.4% of autoimmune diseases. The predominant haematological disorders were splenic marginal zone lymphoma 34% followed by MGUS 16%. The severity of angioedema did not depend on the associated disease. Anti-C1INH-autoantibodies testing was limited to 23.1%. Rituximab monotherapy was effective in treating 9/9 splenic marginal zone lymphoma and 1/2 MGUS-associated AAE-C1-INH. Rituximab efficacy was independent of anti-C1INH-autoantibodies detection with response in 3/3 seronegative and 4/4 seropositive patients. CONCLUSION: The diagnosis of AAE-C1-INH should not be overlooked below the age of 40 years. The choice of oral LTP should be informed by the propensity to side effects. B cell depletion could be considered in treating monoclonal B cell disorder-associated-AAE-C1-INH in the absence of haematological indications. Further studies are required to address the clinical utility of anti-C1INH-autoantibodies.
Mouse CD8+ T cell subsets differentially generate IL-17-expressing cells in the colon epithelium and lamina propria.
Ge C, Tong Q, Zheng S … +3 more , Liu L, Tian L, Luo H
Clin Exp Immunol · 2025 Jan · PMID 39745881 · Full text
Colon-resident CD8+ T cells actively contribute to gut homeostasis and the pathogenesis of inflammatory bowel disease. However, their heterogeneity in generating IL-17-expressing CD8+ T cells, i.e. Tc17 cells, has not be...
Colon-resident CD8+ T cells actively contribute to gut homeostasis and the pathogenesis of inflammatory bowel disease. However, their heterogeneity in generating IL-17-expressing CD8+ T cells, i.e. Tc17 cells, has not been thoroughly revealed. This study aims to characterize the abilities of mouse colonic intraepithelial (IE) and lamina propria (LP) CD8+ T cell subsets to differentiate into Tc17 cells. Using flow cytometry, we found that normal TCRβ+CD4-CD8αα+ cells (CD8αα T cells) and TCRβ+CD4-CD8αβ T cells, (CD8αβ T cells), either IE or LP, expressed abundant granzymes and IFN-γ but minute IL-17A. Under the in vitro Tc17-inducing condition, IE CD8αα T cells showed the weakest Tc17 differentiation ability and LP CD8αβ T cells exhibited the strongest Tc17 differentiation ability, whereas IE CD8αβ T cells and LP CD8αα T cells demonstrated moderate Tc17 differentiation abilities. The expression of IL-6 receptor, TGF-β receptor, TCR signaling indicators, CD161, and IL-23 receptor was low in IE CD8αα T cells, median in IE CD8αβ T cells and LP CD8αα T cells, but high in LP CD8αβ T cells. IE CD8αα T cells weakly induced the expression of chemokines, cytokines, and host defense mediators in colonic epithelial cells while LP CD8αβ T cells showed a robust up-regulatory effect. Furthermore, these colonic CD8+ T cell subsets also exhibited different abilities to generate Tc17 cells in inflamed colons. Collectively, LP CD8αβ T cells have the strongest Tc17 differentiation ability and might play a more significant role than the other subsets in Tc17-mediated immunity or inflammation in the colon.
The role of neutrophils in allergic disease.
Trayer J, Isaza-Correa J, Kelly L … +4 more , Kelleher M, Hourihane J, Byrne A, Molloy E
Clin Exp Immunol · 2025 Jan · PMID 39721985 · Full text
Neutrophils are short-lived cells of the innate immune system and represent 50-70% of the circulating leucocytes. Their primary role is antimicrobial defence which they accomplish through rapid migration to sites of infl...
Neutrophils are short-lived cells of the innate immune system and represent 50-70% of the circulating leucocytes. Their primary role is antimicrobial defence which they accomplish through rapid migration to sites of inflammation followed by phagocytosis, degranulation, and the release of neutrophil extracellular traps (NETosis). While previously considered terminally differentiated cells, they have been shown to have great adaptability and to play a role in conditions ranging from cancer to autoimmunity. This review focuses on their role in allergic disease. In particular: their role as potential amplifiers of type 1 hypersensitivity reactions leading to anaphylaxis; their involvement in alternative pathways of food and drug allergy; their role in allergic rhinitis and asthma and neutrophil dysfunction in atopic dermatitis. The use of potential biomarkers and therapeutic targets is also discussed with a view to guiding future research.
Type I interferon and mitochondrial dysfunction are associated with dysregulated cytotoxic CD8+ T cell responses in juvenile systemic lupus erythematosus.
Radziszewska A, Peckham H, Restuadi R … +11 more , Kartawinata M, Moulding D, de Gruijter NM, Robinson GA, Butt M, Deakin CT, Wilkinson MGL, Wedderburn LR, Jury EC, Rosser EC, Ciurtin C
Clin Exp Immunol · 2025 Jan · PMID 39719886 · Full text
Juvenile systemic lupus erythematosus (JSLE) is an autoimmune condition which causes significant morbidity in children and young adults and is more severe in its presentation than adult-onset SLE. While many aspects of i...
Juvenile systemic lupus erythematosus (JSLE) is an autoimmune condition which causes significant morbidity in children and young adults and is more severe in its presentation than adult-onset SLE. While many aspects of immune dysfunction have been studied extensively in adult-onset SLE, there is limited and contradictory evidence of how cytotoxic CD8+ T cells contribute to disease pathogenesis and studies exploring cytotoxicity in JSLE are virtually non-existent. Here, we report that CD8+ T cell cytotoxic capacity is reduced in JSLE versus healthy controls, irrespective of treatment or disease activity. Transcriptomic and serum metabolomic analysis identified that this reduction in cytotoxic CD8+ T cells in JSLE was associated with upregulated type I interferon (IFN) signalling, mitochondrial dysfunction, and metabolic disturbances when compared to controls. Greater interrogation of the influence of these pathways on altered cytotoxic CD8+ T cell function demonstrated that JSLE CD8+ T cells had enlarged mitochondria and enhanced sensitivity to IFN-α leading to selective apoptosis of effector memory (EM) CD8+ T cells, which are enriched for cytotoxic mediator-expressing cells. This process ultimately contributes to the observed reduction in CD8+ T cell cytotoxicity in JSLE, reinforcing the growing evidence that mitochondrial dysfunction is a key pathogenic factor affecting multiple immune cell populations in type I IFN-driven rheumatic diseases.
Detection of antibodies to infliximab in routine care: a 4-year French retrospective study.
Bertin D, Aghzadi J, Balandraud N … +3 more , Roman C, Serrero M, Desplat-Jégo S
Clin Exp Immunol · 2025 Jan · PMID 39714327 · Full text
Despite its wide use to treat various inflammatory diseases, infliximab becomes ineffective in some patients due to inadequate drug levels and production of anti-drug antibodies (ADA). The aim of this study was to compar...
Despite its wide use to treat various inflammatory diseases, infliximab becomes ineffective in some patients due to inadequate drug levels and production of anti-drug antibodies (ADA). The aim of this study was to compare the prevalence and ADA levels in a large cohort of patients. ADA and infliximab (IFX) through levels measured by enzyme-linked immunosorbent assay were collected from 505 patients within a period of 4 years. The results indicate that (i) 13.5% of patients produce ADA, (ii) male patients were more likely to produce ADA at levels above 10 000 ng/ml than female patients, (iii) ADA levels were lower when associated with immunosuppressant drugs, (iv) there was an inverse relationship between ADA presence and IFX detection, and (v) no correlation was observed between ADA levels and number of injections or brand of IFX administered. This study improves our understanding of the factors promoting IFX immunogenicity and highlights the need to develop personalized treatment strategies.
Comparative efficacy of leniolisib (CDZ173) versus standard of care on rates of respiratory tract infection and serum immunoglobulin M (IgM) levels among individuals with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS): an externally controlled study.
Whalen J, Chandra A, Kracker S … +9 more , Ehl S, Seidel MG, Gulas I, Dron L, Velummailum R, Nagamuthu C, Liu S, Tutein Nolthenius J, Maccari ME
Clin Exp Immunol · 2025 Jan · PMID 39673396 · Full text
Leniolisib, an oral, targeted phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, was well-tolerated and efficacious versus placebo in treating individuals with activated PI3Kδ syndrome (APDS), an ultra-rare inborn error...
Leniolisib, an oral, targeted phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, was well-tolerated and efficacious versus placebo in treating individuals with activated PI3Kδ syndrome (APDS), an ultra-rare inborn error of immunity (IEI), in a 12-week randomised controlled trial. However, longer-term comparative data versus standard of care are lacking. This externally controlled study compared the long-term effects of leniolisib on annual rate of respiratory tract infections and change in serum immunoglobulin M (IgM) levels versus current standard of care, using data from the leniolisib single-arm open-label extension study 2201E1 (NCT02859727) and the European Society for Immunodeficiencies (ESID) registry. The endpoints were chosen following feasibility assessment considering comparability and availability of data from both sources. Baseline characteristics between groups were balanced through inverse probability of treatment weighting. The leniolisib-treated group included 37 participants, with 62 and 49 participants in the control group for the respiratory tract infections and serum IgM analyses, respectively. Significant reductions in the annual rate of respiratory tract infections (rate ratio: 0.34; 95% confidence interval [CI]: 0.19, 0.59) and serum IgM levels (treatment effect: -1.09 g/L; 95% CI: -1.78, -0.39, P = 0.002) were observed in leniolisib-treated individuals versus standard of care. The results were consistent across all sensitivity analyses, regardless of censoring, baseline infection rate definition, missing data handling, or covariate selection. These novel data provide an extended comparison of leniolisib treatment versus standard of care, highlighting the potential for leniolisib to deliver long-term benefits by restoring immune system function and reducing infection rate, potentially reducing complications and treatment burden.
Exploring the relation between TGF-β pathway activity and response to checkpoint inhibition in patients with metastatic melanoma.
van Ravensteijn SG, Amir AL, Tauriello DVF … +7 more , van Herpen CML, Boers-Sonderen MJ, Wesseling YJW, van Brussel AGC, Keizer DM, Verheul HMW, Bol KF
Clin Exp Immunol · 2025 Jan · PMID 39668127 · Full text
INTRODUCTION: Immune checkpoint inhibition (ICI) is highly effective for the treatment of melanoma, but intrinsic resistance is present in a subgroup of patients. TGF-β pathway activity may play a role in this resistance...
INTRODUCTION: Immune checkpoint inhibition (ICI) is highly effective for the treatment of melanoma, but intrinsic resistance is present in a subgroup of patients. TGF-β pathway activity may play a role in this resistance by preventing T-cells from entering the tumor microenvironment, causing immune escape. We investigated the association of TGF-β signal transduction pathway activity with resistance to ICI treatment in advanced melanoma. Furthermore, other pathway activities were analyzed to better understand their potential role in ICI resistance. METHOD: The activity of 8 signaling pathways (TGF-β, Hedgehog, MAPK, AR, NOTCH, PI3K, JAK/STAT1-2, and NFkB) was analyzed from tumor tissue from patients with advanced melanoma. Pathway activity scores (PAS) were explored for associations with survival and response to ICI in 34 patients (19 non-responders and 15 responders). A second, independent method to investigate the predictive value of TGF-β pathway activation was conducted by determining levels of phosphorylated SMAD2. RESULTS: The mean TGF-β PAS of responders vs non-responders was 53.9 vs 56.8 (P = 0.265). No significant relation with progression-free survival was detected for TGF-β activity (P = 0.078). No association between pSMAD2 staining and treatment response or survival was identified. In contrast, Hedgehog scores of responders versus non-responders were 35.7 vs 41.6 (P = 0.038). High Hedgehog PAS was the sole significant predictor of resistance to ICI (OR 0.88, P = 0.033) and worse progression-free survival (HR 1-1.1, P = 0.012). CONCLUSION: TGF-β pathway activation showed no significant relation with treatment response to ICI or survival in patients with advanced melanoma. Hedgehog PAS was identified as a possible biomarker associated with both treatment response and survival.
Effects of cladribine on intrathecal and peripheral B and plasma cells.
Allen-Philbey K, Stephenson S, Doody G … +15 more , MacDougall A, Aboulwafaali M, Ammoscato F, Andrews M, Gnanapavan S, Giovannoni G, Grigoriadou S, Hickey A, Holden DW, Lock H, Papachatzaki M, Redha I, Baker D, Tooze R, Schmierer K
Clin Exp Immunol · 2025 Jan · PMID 39663507 · Full text
INTRODUCTION: Cladribine is a deoxyadenosine analogue that can penetrate the blood-brain barrier. It is used to treat multiple sclerosis (MS). However, the mechanistic understanding of the effect of this highly effective...
INTRODUCTION: Cladribine is a deoxyadenosine analogue that can penetrate the blood-brain barrier. It is used to treat multiple sclerosis (MS). However, the mechanistic understanding of the effect of this highly effective therapy on B cells and plasma cells in the central nervous system compartment is limited. The CLADRIPLAS study examined the effect of cladribine on peripheral and intrathecal B and plasma cell biology in people with MS. METHODS: Thirty-eight people with progressive MS ineligible for- or rejecting-treatment with licenced therapies were recruited and supplied a baseline lumbar puncture. Those exhibiting gadolinium-enhancing or new/enlarging T2 magnetic resonance imaging lesions and/or elevated neurofilament levels were offered subcutaneous cladribine (Litak®). Seven people were eligible; one person died before treatment, and only five completed the first year of treatment. Twenty-two ineligible people were willing to provide a repeat lumbar puncture 12 months later. RESULTS: The CLADRIPLAS study found no evidence of a difference in the odds of a positive cerebrospinal fluid oligoclonal band result between the cladribine-treated and untreated group. This is probably explained by microarray and in vitro studies, which demonstrated that plasmablasts and notably long-lived plasma cells are relatively resistant to the cytotoxic effect of cladribine compared with memory B cells at physiological concentrations. This was consistent with the loss of intracellular deoxycytidine kinase during antibody-secreting cell differentiation. CONCLUSION: CLADRIPLAS indicates that cerebrospinal fluid oligoclonal bands are not rapidly eliminated in most people with MS. This may be explained by the relative lack of direct cytotoxic action of cladribine on long-lived plasma cells.
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