Clinical And Experimental Immunology[JOURNAL]
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200 papers
Could we discuss the molecular signature of immune dysregulation?
Bildik HN, Yaz I, Esenboga S … +1 more , Cagdas D
Clin Exp Immunol · 2026 Jul · PMID 42400499 · Publisher ↗
INTRODUCTION: Immune dysregulation (ID), defined as aberrant immune activation or suppression, may result in autoimmune or inflammatory disorders, lymphoproliferative malignancies, and allergic diseases. Apoptosis, nucle...
INTRODUCTION: Immune dysregulation (ID), defined as aberrant immune activation or suppression, may result in autoimmune or inflammatory disorders, lymphoproliferative malignancies, and allergic diseases. Apoptosis, nuclear factor-κB (NFκB), and phosphoinositide 3-kinase (PI3K) pathways are major pathways involved in ID. OBJECTIVE: This study aimed to assess ID using targeted inflammatory gene-expression profiles in comparison with controls. METHODS: We grouped patients according to presenting features: autoimmune lymphoproliferative syndrome (ALPS) (group 1), immune cytopenia (group 2), and EBV-associated lymphoproliferation (group 3). We established real-time quantitative polymerase chain reaction (RT-qPCR) analysis for selected genes (CASP8, CASP10, FAS, FASL, AKT, MAP3K7, MAP3K14, mTOR, NFKB1, NFKB2, NFKBIA, and TRAF3) involved in inflammatory pathways, and calculated gene expression fold changes using the logarithmic Delta-Delta Ct (2^(-delta delta CT)) method. RESULTS: The median age of symptom onset in group 1 (n=10), group 2 (n=12), and group 3 (n=10) was 9.3 (0.5-38.7), 5.7 (0.7-19), 22.5 (0.7-45) years, respectively (p=0.181). The median age at hospital admission was 12 (1.9-38.7), 9.4 (2.3-35), and 34.8 (0.9-54.7) years in groups 1, 2, and 3, respectively (p=0.152). There was a significant difference between patient and control groups (p<0.05), but none among patient groups regarding targeted gene expression (relative quantification values). According to ROC curve analysis, the most discriminative target genes are NFKB2, MAP3K7, AKT, mTOR, NFKB1, and FAS. CONCLUSION: We propose an ID signature that includes targeted gene expression profiles (NFKB1, NFKB2, MAP3K7, AKT, mTOR, and FAS) and suggest using these specific gene expressions as a biomarker for diagnosis and therapy response in ID.
The many faces of cytokine storm syndrome: immunopathogenic mechanisms and clinical implications for a better patient management.
Ruscitti P
Clin Exp Immunol · 2026 Jul · PMID 42387291 · Publisher ↗
Cytokine storm syndrome is a life-threatening hyperinflammatory condition characterized by excessive and dysregulated immune activation, leading to multiorgan dysfunction and poor clinical outcomes if not promptly recogn...
Cytokine storm syndrome is a life-threatening hyperinflammatory condition characterized by excessive and dysregulated immune activation, leading to multiorgan dysfunction and poor clinical outcomes if not promptly recognized and adequately treated. Rather than representing a single disease entity, cytokine storm syndrome is increasingly understood as a final common pathogenic pathway shared by a broad spectrum of clinical conditions converging on overlapping immunopathological mechanisms driven by sustained cytokine production, immune-cell hyperactivation, and failure of immune-regulatory pathways. The clinical presentation of cytokine storm syndrome is characterized by rapidly progressive nature, multisystem involvement, and the diagnostic challenges arising from nonspecific symptoms and overlapping laboratory features. Hyperferritinaemia emerges as a central laboratory hallmark with both diagnostic and potential pathogenic relevance. Therapeutic management of cytokine storm syndrome requires early recognition and is guided by three core principles: supportive care for organ dysfunction, control of underlying triggers, and timely immunomodulatory or immunosuppressive interventions. Overall, cytokine storm syndrome represents a complex and heterogeneous clinical syndrome in which improved mechanistic understanding, biomarker development, and tailored therapeutic strategies are essential to optimize patient outcomes.
PD-1 Engagement and Circulating Th17 Effector Activity During Secukinumab Treatment in Plaque Psoriasis.
Zhang M, Feng X, Yan K … +3 more , Zhou J, Shen L, Zhang Z
Clin Exp Immunol · 2026 Jun · PMID 42376866 · Publisher ↗
INTRODUCTION: Plaque psoriasis (PP) is a chronic immune-mediated inflammatory disease driven by dysregulation of the IL-23/Th17/IL-17 axis. Although IL-17A targeted biologics achieve robust clinical efficacy, how cytokin...
INTRODUCTION: Plaque psoriasis (PP) is a chronic immune-mediated inflammatory disease driven by dysregulation of the IL-23/Th17/IL-17 axis. Although IL-17A targeted biologics achieve robust clinical efficacy, how cytokine blockade is accompanied by systemic immune remodeling during disease control remains incompletely understood. The objective was to characterize changes in circulating T-cell subsets associated with clinical response to IL-17A blockade and to examine the relationship between PD-1 engagement and Th17 effector activity. METHODS: Longitudinal immune profiling was performed in seven patients with PP before and after achieving a 90% reduction in the Psoriasis Area and Severity Index (PASI 90) following secukinumab treatment. Circulating T-cell subsets, PD-1 expressing populations, and cutaneous lymphocyte antigen positive (CLA+) T cells were quantified by flow cytometry, with plasma cytokine profiling. Ex vivo T-cell responses to the PD-1 agonist peresolimab were assessed in an independent cohort. RESULTS: At baseline, patients exhibited reduced frequencies of regulatory T cells compared with healthy controls. Following PASI 90, circulating Th17 and Th2 cell frequencies increased despite minimal sustained changes in plasma cytokines, indicating dissociation between effector T-cell expansion and soluble mediators during IL-17A blockade. Circulating CD4+CLA+T cells were partially restored. Treatment was accompanied by increased frequencies of PD-1 expressing CD4+T-cell subsets, which showed an inverse association with disease activity over time. Ex vivo PD-1 engagement selectively reduced IL-17A producing CD4+ T cells, with limited effects on IFN-γ. CONCLUSIONS: PD-1 likely restrains Th17 activity during IL-17A blockade, a hypothesis that warrants validation in larger cohorts. Successful therapy in PP appears to reflect immune reorganization through PD-1/Th17 interactions, rather than systemic suppression.
Henoch-Schoenlein purpura (HSP) like lesions in IL12RB1 and IL12B defects - A multi-centric experience from India.
Sharma Y, Nadig P, Das J … +14 more , Iyengar V, Loganathan SK, Chougule A, Gowri V, Taur P, Pilania R, Dhaliwal M, Sharma S, Chatterjee D, Suri D, Desai M, Singh S, Vignesh P, Rawat A
Clin Exp Immunol · 2026 Jun · PMID 42366588 · Publisher ↗
INTRODUCTION: Mendelian Susceptibility to Mycobacterial Disease (MSMD), caused by IL12RB1 or IL12B mutations, typically presents with intra-cellular infections such as BCG-adenitis or Salmonella. Rarely, patients with IL...
INTRODUCTION: Mendelian Susceptibility to Mycobacterial Disease (MSMD), caused by IL12RB1 or IL12B mutations, typically presents with intra-cellular infections such as BCG-adenitis or Salmonella. Rarely, patients with IL12RB1/IL12B defects can exhibit cutaneous manifestations like Henoch-Schonlein purpura (HSP). This study aimed to evaluate such vasculitic manifestations in genetically confirmed cases with MSMD in India and review the literature for similar associations. METHODS: We included nine patients with genetically proven MSMD presenting with features of HSP-like small vessel vasculitis from pediatric immunology clinics across three tertiary care centers in India. Clinical, laboratory, histopathological, and genetic data were recorded using a structured proforma. Skin biopsy findings, IgA levels, renal involvement, and infection history were analyzed. Additionally, a literature review was performed using PubMed, Scopus, and Google Scholar databases to identify similar reported cases. RESULTS: In our cohort, 8 patients had IL12RB1 defect, and one had IL12B defect. All had maculopapular purpuric rash in lower limbs, predominantly in the anterior aspect of legs and posterior thighs resembling the rash of HSP. Leukocytoclastic vasculitis (LCV) was observed in 77.7% patients (n=7), with 2 out of 5 had IgA deposits in dermo-epidermal junction. Concurrent infections due to Salmonella sp. and Pandorea apista were documented in 44.4% (n=4) and 22.2% (n=2), respectively. Treatment focused on antimicrobial therapy led to clinical improvement. CONCLUSION: The HSP-like vasculitic rash usually occurred in setting of underlying bacterial infections in patients with particularly IL12RB1/IL12B defects. These skin lesions can also be considered as one of the potential clinical clues for underlying IL12RB/IL12B defects.
Case Series on the Efficacy of Daratumumab in Treating Patients with Anti-Interferon-Gamma Autoantibodies.
Tan KL, Chandana Ghanta H, Blake L … +8 more , Ceron-Gutierrez L, Cusack TP, Doffinger R, Jenner M, Sharma S, Soo XY, Eren E, Yong PFK
Clin Exp Immunol · 2026 Jun · PMID 42363739 · Publisher ↗
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Deleterious germline CARD11 gain-of-function variants alter human B-cell and CD4+ T-cell differentiation and function.
Nguyen T, Kallarakal MA, Ludgate JL … +6 more , Morison IM, Su HC, Arjunaraja S, Snow AL, Ma CS, Tangye SG
Clin Exp Immunol · 2026 Jan · PMID 42284456 · Full text
CARD11 is a scaffold protein expressed primarily in hematopoietic tissues, shaping key processes in B and T cells via regulation of Ag-linked signaling pathways, including NF-κB, mTOR, JNK, and AKT. Heterozygous, gain-of...
CARD11 is a scaffold protein expressed primarily in hematopoietic tissues, shaping key processes in B and T cells via regulation of Ag-linked signaling pathways, including NF-κB, mTOR, JNK, and AKT. Heterozygous, gain-of-function (GOF) variants in its encoding gene, CARD11, are implicated in a human disorder characterized by frequent upper respiratory infections, poor responses to polysaccharide vaccines, vulnerability to certain opportunistic viruses, and polyclonal B-cell expansion, likely predisposing these patients to lymphoma. Over the past decade, several studies have elucidated some of the B-cell functional defects that likely underlie the patients' infectious phenotype. However, the potential contributions of CARD11 GOF variants to subpopulations of T cells have not been explored in detail. Therefore, our study sought to investigate the effect of increased CARD11 activity on the development, maturation, activation, differentiation, and effector function of adaptive lymphocytes from a cohort of five individuals harboring monoallelic CARD11 GOF variants through detailed ex vivo immunophenotyping and in vitro analyses. Our findings revealed intrinsic requirements for CARD11 in activation, differentiation, and effector function of human naïve B cells. Contrary to previous reports, intact CARD11 activity is also required for multiple aspects of CD4+ T-cell homeostasis alongside its notable role in the humoral immune response. Overall, these results shed light on mechanisms underlying disease pathogenesis due to not only CARD11 GOF variants but also LOF variants and reveal opportunities to consider targeted therapies in CARD11 GOF patients.
Clinical, genetic, and functional characterization of novel NFKB1 variants in Chinese patients with primary immunodeficiency.
Zhang J, Cai H, Zhu T … +1 more , Shen M
Clin Exp Immunol · 2026 Jan · PMID 42252100 · Full text
The nuclear factor κB (NF-κB)-related disorders encompassed not only common variable immunodeficiency but also manifestations of autoinflammation, autoimmunity, and malignancies. While most cases have been reported in Eu...
The nuclear factor κB (NF-κB)-related disorders encompassed not only common variable immunodeficiency but also manifestations of autoinflammation, autoimmunity, and malignancies. While most cases have been reported in European populations, reports in the Chinese population are sparse. Clinical data and genetic variants from four Chinese patients with NFKB1 variants, alongside four previously reported cases, were analyzed and compared with an international cohort. Additionally, comprehensive in vitro functional assays-including immunoblotting, transcript analyses, dual-luciferase reporter, and co-immunoprecipitation assays-were conducted to explore the molecular defects of the novel variants. Our cohort included three men and one woman, all presenting with recurrent fever and hypogammaglobulinemia. Three patients experienced recurrent sinopulmonary infections, accompanied by decreased B cells and NK cells, while two patients developed pneumonia, bronchiectasis, and hepatitis. Three novel NFKB1 (NM_003998) variants were identified: c.559C > T (p. Arg187Trp), c.1509del (p. Glu504Argfs*19), and c.1753-11_1760del (p. Thr585Alafs*9). Functional analyses revealed distinct pathomechanisms: the frameshift/splicing variants drive classical haploinsufficiency via nonsense-mediated mRNA decay (NMD), triggering compensatory inflammatory hyperactivation; conversely, the p.Arg187Trp missense variant maintains protein stability and heterodimerization but strictly abolishes DNA-binding capacity. Compared to a previously reported cohort, Chinese patients were predominantly male, had a later median age of onset and diagnosis. Notably, Chinese patients exhibited a higher prevalence of hepatitis (25%) and cirrhosis (12.5%), potentially reflecting the high endemicity of hepatitis B virus in China. They also showed increased rates of viral infections, sepsis, and bronchiectasis, with more pronounced reductions in NK and B cells. In contrast, autoimmune diseases and bronchitis were less frequent than in the foreign cohort. This study represents the first and largest case series of Chinese patients with NF-κB1-related diseases, providing molecular characterization for three novel variants. In this limited case series, the observed delayed onset and frequent hepatic complications in our cohort may reflect regional factors, such as HBV endemicity, or ascertainment bias. Our findings underscore that suspected AOSD accompanied by hypogammaglobulinemia warrants immediate genetic investigation. Early diagnosis is essential to prioritize immunoglobulin replacement and prevent fatal complications from immunosuppressive therapy.
Bispecific MASP-2/3 antibody provides superior renoprotection over monotherapy in pristane-induced lupus nephritis.
Tu T, Wang C, Li Z … +3 more , Fu W, Tan Y, Zhao M
Clin Exp Immunol · 2026 Jan · PMID 42213887 · Full text
Lupus nephritis (LN) is a major cause of organ damage in systemic lupus erythematosus and is driven in part by overactivation of the lectin pathway (LP) and alternative pathway (AP) of complement. Mannan-binding lectin-a...
Lupus nephritis (LN) is a major cause of organ damage in systemic lupus erythematosus and is driven in part by overactivation of the lectin pathway (LP) and alternative pathway (AP) of complement. Mannan-binding lectin-associated serine protease-2 (MASP-2) initiates LP through C4/C2 cleavage, whereas MASP-3 enables AP amplification by activating pro-factor D. We hypothesized that concurrent inhibition of both proteases would provide superior renoprotection compared with single-pathway blockade in established disease. Female BALB/c mice with pristane-induced LN received anti-MASP-2, anti-MASP-3, bispecific antibodies, or vehicle for 4 weeks. Bispecific MASP-2/3 inhibition produced greater improvements in albuminuria, renal activity index, and glomerular C3d and C5b-9 deposition than either monotherapy. Functional assays confirmed selective LP suppression with MASP-2 blockade and AP suppression with MASP-3 blockade, whereas dual inhibition maximally reduced both pathways and their downstream complement effectors. Kidney transcriptomics demonstrated broad down-regulation of complement, coagulation, and inflammatory gene networks. Together, these findings indicate that bispecific MASP-2/3 blockade provides robust complement-directed protection in established LN and may represent an effective therapeutic strategy for complement-mediated kidney disease.
Optimization of a parallel CAR for B-cell lymphoma via ITAM attenuation and target specificity validation.
Kausar F, Davis C, Larcombe-Young D … +6 more , Bove C, Farzaneh F, Graham C, Benjamin R, Davies DM, Maher J
Clin Exp Immunol · 2026 Jan · PMID 42200445 · Full text
Second-generation CAR T-cells have transformed the management of B-cell malignancy. However, in vivo functional persistence is often limited, highlighting a key mechanism of treatment failure. We have engineered a parall...
Second-generation CAR T-cells have transformed the management of B-cell malignancy. However, in vivo functional persistence is often limited, highlighting a key mechanism of treatment failure. We have engineered a parallel (p)CAR platform that delivers dual CD28 and 4-1BB co-stimulation via a co-expressed CAR and chimeric co-stimulatory receptor (CCR). To target CD19, we employed an avidity-optimized FMC63 scFv to direct CAR specificity while utilizing an unmodified FMC63 scFv to target the CCR. Here, we describe the late-stage optimization of this system for Phase 1 clinical evaluation. First, we confirmed that the avidity-optimized scFv lacked off-target specificity. To minimize risk of insertional mutagenesis and immunogenicity, respectively, we transitioned from a gammaretrovirus to a third-generation lentiviral expression vector and removed epitope tags used to discriminate between CAR and CCR expression. Most strikingly, we found that inactivation of immune tyrosine activation motif 2 and 3 within our pCAR prototype markedly potentiated efficacy in xenograft-bearing NSG mice. Mechanistically, this resulted from increased pCAR T-cell functional persistence and organ infiltration, with enhanced local clearance of malignant B-cells. These data set the scene for evaluation of this iteratively honed pCAR candidate in a clinical trial in relapsed/refractory B-cell non-Hodgkin's lymphoma.
Cholesteatoma-an immune disease.
Khatiwada A, Mohammed ME, Dumitriu IE … +1 more , Baruah P
Clin Exp Immunol · 2026 Jan · PMID 42189704 · Full text
Cholesteatoma is abnormal epithelial tissue in the middle ear cleft and an important cause of chronically discharging ears and hearing loss. Its proximity to important middle ear structures and the brain can lead to sign...
Cholesteatoma is abnormal epithelial tissue in the middle ear cleft and an important cause of chronically discharging ears and hearing loss. Its proximity to important middle ear structures and the brain can lead to significant complications. Cholesteatoma presents both as congenital and acquired types and can occur both in children and adults. The mainstay of treating cholesteatoma is a destructive surgery with attendant morbidity. Despite radical surgery cholesteatomas can recur, sometimes repeatedly, causing a significant impact on quality of life. The role of inflammation in cholesteatoma is an area of keen interest. However, immune processes are highly complex, and while various individual components of the process have been studied in cholesteatoma, we are far from a cohesive understanding of the role of immune cells and inflammation pathways in the pathogenesis of cholesteatoma. Better understanding of its immune-pathogenesis would enable identification of disease-modifying therapies and novel pharmacological targets. In this review, we provide a detailed overview of the existent knowledge and recent developments on immune cells and inflammatory pathways implicated in cholesteatoma pathogenesis, progression, and damaging bone eroding properties. As cholesteatoma surgery is inherently destructive with poor hearing results, there is a definite necessity for new treatments to reduce the surgical burden and enable functional preservation in the management of this condition. We focus on the current and future areas of research that could lead to new therapies targeting inflammation and bring about a step change in the management of this aggressive ear condition.
Immunometabolism crosstalk between regulatory T cells and glucose homeostasis of type 1 diabetes.
Nodehi M, Veisi Malekshahi Z, Rahimnia R … +3 more , Verdi J, Vousooghi N, Seyhoun I
Clin Exp Immunol · 2026 Jan · PMID 42166641 · Full text
Type 1 diabetes mellitus (T1D) is an autoimmune disease that is associated with the loss of pancreatic β cells. Regulatory T cells (Tregs) play a critical role in the maintenance of immune tolerance; however, the number...
Type 1 diabetes mellitus (T1D) is an autoimmune disease that is associated with the loss of pancreatic β cells. Regulatory T cells (Tregs) play a critical role in the maintenance of immune tolerance; however, the number and function of Tregs have been found to be compromised in T1D. Genetic changes in FOXP3, as well as the role of hyperglycaemia and the accumulation of advanced glycation end products, have been proposed as potential mechanisms for the dysfunction of Tregs. However, the current understanding suggests that the role of the metabolic reprogramming associated with hyperglycaemia is more likely to be a potential mechanism for the instability of Tregs rather than a well-established primary mechanism for the development of T1D. Several therapeutic strategies have been explored in experimental models for the management of autoimmune diseases associated with Tregs dysfunction. These include the administration of low-dose interleukin-2, metformin, and dietary or microbiome-based therapies. These therapies have been found to modulate the immune system; however, the efficacy of these therapies for the management of T1D is to be established. In the present review article, the current understanding of the role of the interrelationship between hyperglycaemia, metabolic reprogramming, and Tregs-mediated immune tolerance in the pathogenesis of type 1 diabetes is reviewed.
Depletion and recovery of IgG following treatment with an anti-FcRn antibody and IdeS in pigtail macaques.
Rzasa KM, Zikos J, Penney T … +8 more , Schiro FR, Doyle-Meyers LA, Aye PP, Veazey RS, Hoxie JA, Maness NJ, Magnani DM, Ackerman ME
Clin Exp Immunol · 2026 Jan · PMID 42162557 · Full text
Antibodies are central players in adaptive immunity, providing protection against a wide array of pathogens through mechanisms such as neutralization, opsonization, recruitment of effector immune cells, complement activa...
Antibodies are central players in adaptive immunity, providing protection against a wide array of pathogens through mechanisms such as neutralization, opsonization, recruitment of effector immune cells, complement activation, and engagement. However, in other contexts, these same effector functions can contribute to immunopathology, particularly when antibodies are developed against self-antigens, resulting in autoimmunity. Understanding the role antibodies play in preventing or causing disease is often supported by studies in model systems wherein manipulation of immunoglobulin G (IgG) levels can be used as an experimental tool. Here, we report in simian immunodeficiency virus (SIV) infected pigtail macaques (Macaca nemestrina) the capacity of two orthogonal strategies to systemically deplete IgG: treatment with a primatized neonatal Fc receptor blocking antibody (anti-FcRn) modelled on rozanolixizumab that restricts IgG rescue and recycling, and administration of the IgG protease IdeS that cleaves the Fc domain. Under the conditions evaluated, we observed more rapid and effective, although not necessarily more durable, IgG depletion mediated by IdeS, reducing levels by 74.1-95.1%, compared with a lesser reduction of 31.3-66.9% with anti-FcRn treatment. We observed a similar degree of depletion, comparable kinetics of rebound among SIV antigen-specific fractions as total IgG, but differential balance among IgG subclasses following treatment in some cases. In sum, this study in a non-human primate model describes the efficacy and downstream impacts of new tools to modify humoral immune states, providing insight into the balance between protective and pathological effects of IgG antibodies.
CD137 deficiency patients: two new patients and review of the literature.
Genc Ozbay Z, Kocali B, Ilgun Gurel D … +9 more , Yaz I, Ulum B, Aktas D, Ozogul E, Soyak Aytekin E, Esenboga S, Uner A, Kuskonmaz B, Cagdas D
Clin Exp Immunol · 2026 Jan · PMID 42144872 · Full text
CD137 (4-1BB, TNFRSF9) plays a crucial role in T-cell activation, proliferation, and antiviral immunity. Biallelic TNFRSF9 variants cause CD137 deficiency, a rare inborn error of immunity characterized by Epstein-Barr vi...
CD137 (4-1BB, TNFRSF9) plays a crucial role in T-cell activation, proliferation, and antiviral immunity. Biallelic TNFRSF9 variants cause CD137 deficiency, a rare inborn error of immunity characterized by Epstein-Barr virus (EBV)-induced hemophagocytic lymphohistiocytosis (HLH) and lymphoproliferation/malignancy. In this study, we aimed to characterize the clinical, immunological, and genetic spectrum of CD137 deficiency to provide insights into patient management. We recruited two patients carrying the same homozygous large deletion encompassing exons 1-6 of the TNFRSF9 gene and reviewed previously reported cases. The genetic defect was identified by whole-exome sequencing and confirmed by multiplex ligation-dependent probe amplification. Reported variants included missense, splice-site, and frameshift variants, large deletions, and compound heterozygous variants. A total of 14 patients, including the two newly reported cases, exhibited recurrent sinopulmonary infections and EBV viremia. HLH occurred in four patients (28.5%), including both newly reported patients, while lymphoma developed in seven patients (50%). Most patients were of Middle Eastern origin, and parental consanguinity was documented in 12 of 14 patients (85%). Hematopoietic stem cell transplantation (HSCT) was performed in 35.7% (5/14) of patients, with a median age of 9 years (range, 7-17 years) among four reported cases. All transplanted patients were alive at the last follow-up, whereas mortality occurred exclusively among non-transplanted patients, including EBV-positive cases. These findings expand the phenotypic and mutational spectrum of CD137 deficiency and highlight the importance of incorporating copy number variant analysis into exome-based diagnostic pipelines when conventional single-nucleotide variant analysis is inconclusive. HSCT remains the only potentially curative treatment, and early molecular diagnosis is essential to enable timely consideration of HSCT and to mitigate life-threatening EBV-driven immunopathology.
A bioluminescent inhibition immunoassay for detecting GM-CSF inhibitory activity in serum.
Bradhurst P, Stoyanov A, Rosen LB … +3 more , Holland SM, Guy TV, Urriola N
Clin Exp Immunol · 2026 Jan · PMID 42132313 · Full text
Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) are the cause of autoimmune pulmonary alveolar proteinosis (aPAP). They are also found in the serum/plasma of previously immunocompetent pa...
Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) are the cause of autoimmune pulmonary alveolar proteinosis (aPAP). They are also found in the serum/plasma of previously immunocompetent patients with disseminated Cryptococcus spp. infection (typically spp. gattii) and disseminated Nocardia spp. infection. Detection of this autoantibody is generally performed through an antibody binding assay, followed by a live-cell-based pSTAT5 neutralization to confirm functional significance of detected autoantibodies. The requirement for a live-cell-based assay increases the technical difficulty of diagnosis and means that this testing is generally only offered in specialist research centres. We report a bioluminescent immunoassay (BLIA) platform, which accurately detects inhibition of GM-CSF detection in serum. The BLIA method has previously been described in detail to detect anti-cytokine autoantibodies against IFNγ. The BLIA platform was able to distinguish 24 blinded disease control samples with 100% accuracy when compared with gold standard testing. We sought referrals for patients with aPAP, Cryptococcus spp. Infection, and Nocardia spp. infection to test the performance of this assay. Positive results were seen in 100% of patients with clinically confirmed aPAP and a proportion of patients with disseminated Cryptococcus or Nocardia spp. infection. We conclude that the BLIA is technically simple, rapid, and easily automatable and could be easily employed in a diagnostic laboratory. The performance characteristics of the BLIA result in rapid and accurate screening of patients with these uncommon autoantibody-mediated conditions, allowing for quick diagnosis and referral for specialist management.
From T-cell defect to tumorigenesis: Epstein-Barr virus-associated smooth muscle tumors in ITK deficiency.
Oussama K, Idrissi Fawzi F, Benhsaien I … +9 more , Bennani Guebessi N, Aadam Z, Elamine A, Salam S, Karkouri M, Elbakkouri J, Bousfiha AA, Alzemmouri M, Ailal F
Clin Exp Immunol · 2026 Jan · PMID 42132280 · Full text
Interleukin-2-inducible T-cell kinase (ITK) is critical for T-cell receptor signaling and antiviral immunity. ITK deficiency is a rare combined immunodeficiency, classically linked to Epstein-Barr virus (EBV)-driven lymp...
Interleukin-2-inducible T-cell kinase (ITK) is critical for T-cell receptor signaling and antiviral immunity. ITK deficiency is a rare combined immunodeficiency, classically linked to Epstein-Barr virus (EBV)-driven lymphoproliferation, with only two previous reports of EBV-associated smooth muscle tumors (EBV-SMT). We report a 13-year-old boy with recurrent respiratory infections and bilateral adrenal masses. Immunophenotyping, targeted gene panel sequencing, histopathology, immunohistochemistry, and EBV in situ hybridization were performed to investigate underlying immunodeficiency and tumor etiology. Computational modeling assessed the functional impact of the identified ITK variant. The patient exhibited CD4+ T-cell lymphopenia and markedly reduced regulatory T cells. Histopathology and immunohistochemistry confirmed bilateral adrenal leiomyomas, and EBV in situ hybridization demonstrated EBV infection within tumor cells despite negative blood EBV serology, indicating tissue-restricted viral persistence. Genetic analysis revealed a novel homozygous ITK variant (c.1673C>T; p.Pro558Leu) in the kinase domain, predicted to destabilize the protein and impair T-cell receptor signaling. This represents the first African case of ITK deficiency complicated by EBV-SMT, expanding the recognized tumor spectrum and highlighting that EBV can remain localized within tissue despite negative systemic serology. The combination of CD4+ T-cell lymphopenia and Treg reduction underscores ITK's critical role in antiviral immunity and tumor surveillance. Tissue-based EBV detection is essential for accurate diagnosis in immunodeficient patients presenting with SMTs.
Suppressor of cytokine signaling 1 haploinsufficiency in a patient with granulomatous lymphocytic interstitial lung disease and inflammatory bowel disease-like disease.
Sonmez G, Yaz I, Ustun C … +6 more , Sahin A, Aliyeva G, Babaoglu E, Ozden G, Halacli SO, Cagdas D
Clin Exp Immunol · 2026 Jan · PMID 42102262 · Full text
Suppressor of cytokine signaling 1 (SOCS1) haploinsufficiency is an inborn error of immunity with dysregulated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling and heterogeneous autoim...
Suppressor of cytokine signaling 1 (SOCS1) haploinsufficiency is an inborn error of immunity with dysregulated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling and heterogeneous autoimmune, infectious, and inflammatory phenotypes; its spectrum and management remain unclear. We report a 29-year-old woman with a novel heterozygous SOCS1 variant (c.494C>T; p.Pro165Arg) identified by whole-exome sequencing. Variant impact was assessed in silico (combined annotation dependent depletion, conservation mapping, AlphaFold3, and PremPS) and functionally by measuring total and phosphorylated STAT1 (p-STAT1) expression in patient vs control cells at baseline and after interferon-γ stimulation. We also reviewed data from 20 previously reported SOCS1-deficient patients. The patient had granulomatous lymphocytic interstitial lung disease (GLILD), rheumatoid arthritis, inflammatory bowel disease-like enteropathy, and hypogammaglobulinemia, initially diagnosed with common variable immune deficiency. GLILD responded to rituximab; sirolimus was ineffective for enteropathy. Segregation revealed an asymptomatic father carrying the same variant. The patient was found to have an additional heterozygous TACI gene variant. Poststimulation flow cytometry showed higher STAT1 [24.7 vs 5.8 median fluorescence intensity (MFI)] and p-STAT1 (43.4 vs 2.4 MFI) levels; however, these differences were not statistically significant (P > 0.05). Structural modeling predicted Src homology 2 domain destabilization (ΔΔG + 1.16 kcal/mol). Literature synthesis for SOCS1 deficiency patients (n = 21) showed median symptom onset of 8 years (range 5 months to 44 years), autoimmune diseases (immune thrombocytopenia, psoriasis, etc.), and frequent immunophenotypic abnormalities: lymphopenia 4/8 (50%); high IgE 5/7 (71.4%); low CD3+ 11/17 (64.7%); CD4+ 6/19 (31.5%); CD8+ 5/17 (29.4%); B cells 5/17 (29.4%); and natural killer (NK) cells 4/19 (21%). SOCS1 haploinsufficiency presents heterogeneous phenotypes with variable penetrance. Early genetic testing and targeted interventions, such as JAK inhibitors or cytokine-blocking biologics, may improve outcomes.
Heterogeneity between insulin and proinsulin in the potency for insulin autoantibodies in newly diagnosed type 1 diabetes children.
Parsian P, Bennet R, Tsai CT … +4 more , Ramelius A, Lernmark Å, Jönsson J, BDD Study Group
Clin Exp Immunol · 2026 Jan · PMID 42084337 · Full text
Autoantibodies against insulin (IAA) are early appearing markers of autoimmunity against the pancreatic islet beta cells and predict progression to type 1 diabetes if additional islet autoantibodies also develop. It is s...
Autoantibodies against insulin (IAA) are early appearing markers of autoimmunity against the pancreatic islet beta cells and predict progression to type 1 diabetes if additional islet autoantibodies also develop. It is still controversial if proinsulin rather than insulin is the primary autoantibody. The aim of the present study was to compare the half-maximal concentration (IC50) between insulin and proinsulin to displace the binding of insulin to insulin autoantibodies (IAA) in the Antibody Detection by Agglutination PCR (ADAP) assay. IC50 as a measure of potency to displace insulin binding to IAA was determined in 36 newly diagnosed type 1 diabetes children. The ability of either insulin or proinsulin to displace IAA was heterogenous. Proinsulin curves were consistently right-shifted relative to insulin as median IC50 was 21.0 nM (IQR 14.9-25.1) for insulin and 26.1 nM (IQR 12.3-37.5) for proinsulin. A significant age × sex interaction was observed (F (1,31) = 14.3, P < 0.001), indicating that IC50 for both insulin and proinsulin increased with age in boys but decreased in girls. It may reflect whether autoantibodies to insulin or proinsulin were first appearing or of variable maturation from the time of initiation through progression to clinical onset. It was concluded that the IC50 of insulin and proinsulin for IAA was comparable in children with newly diagnosed type 1 diabetes. The ADAP IAA assay should prove useful to determine whether insulin or proinsulin is the primary target at the time of seroconversion to IAA.
Concurrent central nervous system infection with Candida and Mycobacterium intracellulare in CARD9 deficiency: immunological insights from a single case.
Shigemura T, Nagumo H, Kobayashi N … +7 more , Agematsu K, Saito T, Kurata T, Asaka S, Yamaguchi T, Kosho T, Nakazawa Y
Clin Exp Immunol · 2026 Jan · PMID 42068233 · Full text
Caspase recruitment domain-containing protein 9 (CARD9) deficiency is classically characterized by chronic mucocutaneous candidiasis (CMC) and invasive Candida infections, including central nervous system (CNS) disease....
Caspase recruitment domain-containing protein 9 (CARD9) deficiency is classically characterized by chronic mucocutaneous candidiasis (CMC) and invasive Candida infections, including central nervous system (CNS) disease. Susceptibility to mycobacterial infection has not been considered a defining feature of CARD9 deficiency. We describe a patient with a typical clinical phenotype of CARD9 deficiency associated with compound heterozygous variants in CARD9, initially presenting with CMC and later manifesting CNS candidiasis, complicated by a concurrent CNS infection caused by Mycobacterium intracellulare. This unexpected finding prompted detailed immunological analyses to determine whether the mycobacterial infection represented a coincidental event or reflected an underlying susceptibility. Immunological studies demonstrated preserved neutrophil nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species production, whereas bactericidal/permeability-increasing protein (BPI) was uniquely and markedly reduced among neutrophil antimicrobial proteins. In parallel, monocyte-derived dendritic cells exhibited impaired tumor necrosis factor-α (TNF-α) production in response to mycobacterial stimulation, suggesting impaired cytokine responses downstream of CARD9. These findings suggest that impaired dendritic cell cytokine responses to mycobacteria, together with markedly reduced neutrophil BPI content, may have contributed to the development of M. intracellulare infection in this patient. Our study highlights a potential mechanism underlying susceptibility to mycobacterial infection in CARD9 deficiency.
Immunological dysfunction associated with SARS-CoV-2 persistence in immunocompromised patients.
Johannsen IM, Vibholm LK, Frattari GS … +15 more , Rosas-Umbert M, Tarpgaard IH, Storgaard M, Juhl AK, Pedersen ML, Iversen EF, Andersen NB, Ebsen TS, Svensgaard SNH, Andreas M, Asdahl P, Leth S, Rasmussen TA, Schleimann MH, Tolstrup M
Clin Exp Immunol · 2026 Jan · PMID 41961589 · Full text
Advances in coronavirus disease 2019 management has led to decreases in disease burden; however, immunocompromised patients continue to experience prolonged or persistent infections. We investigated immunological factors...
Advances in coronavirus disease 2019 management has led to decreases in disease burden; however, immunocompromised patients continue to experience prolonged or persistent infections. We investigated immunological factors associated with time to viral clearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in immunocompromised patients. By integrating clinical follow-up data, SARS-CoV-2-specific humoral and cellular response data, and single-cell RNA transcriptomic data, we uncovered differential immune responses between patients exhibiting short or long time-to-clearance (TTC), both at diagnosis and later during infection. We found that prolonged infection was associated with reduced SARS-CoV-2-specific humoral responses (P = 0.035) and diminished development of CD4+ and CD8+ T-cell activation (P = 0.045 and P = 0.038, respectively) despite levels of interferon-γ-producing T cells not being negatively affected. Baseline transcriptional profiles revealed increased immunological engagement of CD8+ cytotoxic T and natural killer (NK) cells among patients with prolonged TTC, potentially to compensate for impaired functional T-cell activation. Differential gene expression further pointed towards features of impaired T-cell functionality and exhaustion as contributors to prolonged TTC, including enrichment of NEAT1, CD52, and IL12RB2 in Long TTC patients. Our findings indicate that impaired viral clearance in some immunocompromised patients reflects an actively engaged yet dysregulated immune response. This underscores the complexity of immune dysfunction in this population and highlights the need for targeted interventions to restore effective, antiviral immunity, with a particular focus on regaining functional activation of antigen-specific T cells.
PSMB8 stratifies therapy response in eosinophilic esophagitis.
Wei X, Degen S, Hironimus T … +22 more , Rechenauer T, Yankouskaya K, Rückel A, Schmid M, Rieger D, Ehrsam C, Regensburger AP, Schnell A, Rabe A, Schmidt-Choudhury A, Tannapfel A, De Laffolie J, Schumann S, Schwerd T, Hoelz H, Allabauer I, Gupta P, Krebs W, Hartmann A, Woelfle J, Rieker R, Hoerning A
Clin Exp Immunol · 2026 Jan · PMID 41954923 · Full text
Proton pump inhibitors (PPIs) are an effective first-line treatment for eosinophilic esophagitis (EoE). However, half of the patients are refractory to PPI therapy, and predictive markers for therapy decision are lacking...
Proton pump inhibitors (PPIs) are an effective first-line treatment for eosinophilic esophagitis (EoE). However, half of the patients are refractory to PPI therapy, and predictive markers for therapy decision are lacking. Thus, this study aimed to investigate the differences in esophageal immunologic transcriptome between PPI-non-responders and PPI-responders and identify molecular biomarkers to guide therapy decisions. Forty-eight pediatric EoE patients were enrolled and classified due to PPI-therapy response. Pre-treatment esophagus biopsy was collected for gene expression analysis, differentially expressed genes (DEGs) between PPI-responders and non-responders were identified, followed by gene enrichment and protein-protein interaction network analyses. Expression of identified hub genes was confirmed by immunohistochemistry in an extended cohort comprising 62 patients. PPI-non-responders and responders exhibit a partially different transcriptomic profile, as 12 DEGs were up-regulated and one down-regulated. These DEGs are closely related to antigen processing and presentation function. PSMB8 was identified as a hub gene differing between these two groups, and immunohistochemistry confirmed significantly increased expression in PPI-non-responders (P < 0.0001). Notably, receiver operating characteristic curves curve analysis of PSMB8 reveals it as highly predictive for PPI response (sensitivity/specificity: 0.61/1.00). PPI-non-responding EoE patients exhibited a more profound dysregulation of gene expression. PSMB8 represents a promising esophageal biomarker for predicting therapy response in pediatric EoE.
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