Blog

Front Immunol. 2025 Jun 2;16:1594636. doi: 10.3389/fimmu.2025.1594636. eCollection 2025.

ABSTRACT

BACKGROUND: Hyper-IgM syndrome (HIGM) is a genetic immunodeficiency characterized by elevated to normal IgM levels and decreased IgG, IgA, and IgE. The overlapping clinical presentations of different gene mutations complicate diagnosis and management.

OBJECTIVE: This study aims to elucidate the clinical implications of concurrent AICDA and IKBKB homozygous variants in a pediatric patient diagnosed with hyper-IgM syndrome.

METHODS: We present immunological and genetic analysis of a Tunisian patient with two homozygous variants of uncertain significance (VUSs) in the IKBKB and AICDA genes, suspected of causing hyper-IgM and immune deficiency. We conducted functional tests to ascertain the pathogenicity of IKBKB and AICDA mutations and to provide a definitive diagnosis and appropriate management.

RESULTS: Genetic analysis identified two homozygous variants: AICDA (p.W80S) and IKBKB (p.R77Q). Immunophenotyping and functional studies found greatly reduced class-switched memory B cells and somatic hypermutations but normal T cell responses and NFkB activation.

CONCLUSION: The simultaneous presence of multiple homozygous VUSs emphasizes a major challenge in the genetic diagnosis of highly consanguinous patients. Functional workup as well as familial segregation studies are needed to clarify variant pathogenicity and provide a definitive diagnosis and tailored treatment strategies for these patients. Our studies suggest that the AICDA p.W80S variant is pathogenic, while the IKBKB p.R77Q variant is likely benign.

PMID:40529371 | PMC:PMC12171361 | DOI:10.3389/fimmu.2025.1594636

Arthritis Rheumatol. 2025 Jun 16. doi: 10.1002/art.43283. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the efficacy of tight-control, rapid escalation to TNF inhibition in early axial spondyloarthritis (axSpA) in relation to gut inflammation.

METHODS: GO-GUT (NCT03270501) was a prospective, open-label, 52-week trial in treatment-naïve axSpA patients with less than 1 year of symptom duration and high disease activity. At baseline patients underwent ileocolonoscopy with histopathological evaluation of the gut mucosa. Next, all patients received two different NSAIDs in optimal dose for a period of 4 weeks. If inactive disease, defined as Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP <1.3) or clinically important improvement (ΔASDAS-CRP score ≥ 1.1 resulting in low disease activity (ASDAS-CRP <2.1)) was not achieved, monotherapy with 50mg golimumab every 4 weeks was initiated. Patients were followed until achieving sustained clinical remission (ASDAS-CRP <1.3 at two consecutive visits with 12 weeks interval) or end of trial. Upon achievement of sustained clinical remission, all medication was discontinued and the possibility of drug-free remission was evaluated.

RESULTS: Fifty-eight patients were included in the trial. Microscopic gut inflammation was present in 28.6% of patients, predominantly acute inflammation. An escalation of therapy to golimumab was required for 72.7% of patients. The primary study endpoint of sustained clinical remission was reached by 61.8% of patients, irrespective of gut inflammation. Treatment discontinuation resulted in disease relapse within 1 year in 78.1% of patients.

CONCLUSIONS: Applying a treat-to-target approach in treatment-naïve early axSpA allows to induce high rates of sustained clinical remission, regardless of the presence of microscopic gut inflammation.

PMID:40524500 | DOI:10.1002/art.43283

Scand J Immunol. 2025 Jun;101(6):e70031. doi: 10.1111/sji.70031.

ABSTRACT

Primary immunodeficiency disorders (PIDDs) comprise a heterogeneous group of genetic conditions characterised by recurrent infections, immune dysregulation and increased susceptibility to malignancies. While clinical evaluation remains essential for diagnosis, genetic testing plays a pivotal role in confirming the diagnosis and guiding management. This cross-sectional study evaluates the diagnostic yield and clinical utility of targeted gene panel testing in patients with a strong clinical suspicion of PIDDs, within the framework of the Jeffrey Modell Foundation’s ‘Jeffrey’s Insights’ programme. Between 2022 and 2024, 104 patients without a prior genetic diagnosis were evaluated at the Department of Paediatric Allergy and Clinical Immunology, Başakşehir Çam and Sakura City Hospital, Türkiye. In 72 of 104 patients, the identified variants were consistent with clinical phenotypes. Pathogenic or likely pathogenic variants were identified in 41.3% of patients, increasing to 57.7% when including variants of uncertain significance (VUS) with high CADD scores. Genetic findings prompted reclassification of International Union of Immunological Societies (IUIS) categories in 25% of cases. Autosomal recessive inheritance and parental consanguinity were notable, reflecting regional genetic patterns. Failure to thrive and low switched memory B cell percentages were significantly associated with confirmed genetic diagnoses, while food allergy, viral skin infections and eczema were more common in genetically undiagnosed patients. These findings support the clinical value of targeted gene panels as an effective, accessible and informative tool in the diagnosis and classification of PIDDs, enhancing precision in patient care and enabling tailored therapeutic strategies.

PMID:40518733 | DOI:10.1111/sji.70031

J Allergy Clin Immunol. 2025 Jun 11:S0091-6749(25)00624-4. doi: 10.1016/j.jaci.2025.06.001. Online ahead of print.

NO ABSTRACT

PMID:40513623 | DOI:10.1016/j.jaci.2025.06.001

J Neuroimmunol. 2025 Jun 7;406:578662. doi: 10.1016/j.jneuroim.2025.578662. Online ahead of print.

ABSTRACT

Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disorder that often presents with recurrent infections and autoimmune complications, leading to diagnostic delays. This case report presents two adult male patients, ages 44 and 42, with prolonged histories of recurrent pneumonia, sinusitis, meningitis, and autoimmune encephalitis. Both cases were initially mismanaged due to the isolated treatment of symptoms, delaying the diagnosis of CVID. Comprehensive diagnostic evaluations eventually revealed low immunoglobulin levels, confirming the diagnosis. These cases highlight the importance of early recognition and a multidisciplinary approach to managing patients with recurrent infections and unusual presentations.

PMID:40505342 | DOI:10.1016/j.jneuroim.2025.578662

Sci Rep. 2025 Jun 11;15(1):20042. doi: 10.1038/s41598-025-02472-3.

ABSTRACT

Pulmonary infection is common in connective tissue diseases (CTDs) patients because of immunodeficiency. The basic characteristics of pathogens in this set of patients may differs from immunocompetent patients and largely unclear. We aimed to understand these characteristics by metagenomic next-generation sequencing (mNGS) detection in bronchoalveolar lavage fluid (BALF) from CTDs and explored the primary disease features of this group of patients. Eighty-one CTD patients who were suspected pulmonary infection and received mNGS of BALF as well as conventional microbiologic testing (CMT) were enrolled consecutively. We analysed the types of CTDs, whether accompanied with interstitial lung disease, comparison between performance of mNGS and CMT, and distribution of clinically relevant pathogens, etc. Of the 81 cases, 62 were clinically diagnosed with pulmonary infection. Among all patients, idiopathic inflammatory myopathy accounted for the highest proportion of cases infected, especially anti-MDA5 dermatomyositis and anti-synthetase syndrome. Patients in the pulmonary infection group had been previously treated with higher percentages of anti-rheumatic drugs than those in the non-infection group. The sensitivity of mNGS was higher than that of CMT (80.6% vs. 66.1%). Among the microbes detected by mNGS, the most common bacterial pathogen was Pseudomonas aeruginosa, and the most frequently fungi was Pneumocystis jirovecii. As for the specific pathogens, mNGS had great advantages over CMT in identifying Pneumocystis jirovecii. Idiopathic inflammatory myopathy was the disease most susceptible to pulmonary infections among CTDs. mNGS showed high efficiency for the detection of pathogens that cause pneumonia in BALF from patients with CTDs, especially for Pneumocystis jirovecii.

PMID:40500273 | DOI:10.1038/s41598-025-02472-3

Front Immunol. 2025 May 26;16:1601776. doi: 10.3389/fimmu.2025.1601776. eCollection 2025.

ABSTRACT

STAT3-hyper IgE syndrome (STAT3-HIES) is a primary immunodeficiency disorder caused by dominant-negative mutations in STAT3, leading to defects in Th17 cell differentiation, immune regulation, and tissue repair. Patients are susceptible to recurrent infections and vascular abnormalities, such as vasculopathy and pseudoaneurysms. While involvement of cerebral, bronchial, and coronary arteries has been reported, hepatic artery involvement is rare. We describe a 25-year-old woman with genetically confirmed STAT3-HIES who presented with biliary hemorrhage secondary to a ruptured hepatic pseudoaneurysm. Emergency transcatheter arterial embolization successfully controlled the hemorrhage, and the patient was discharged without complications. Systemic vascular screening revealed an asymptomatic right coronary artery dilation, necessitating medical management with statin therapy. This case highlights hepatic pseudoaneurysm as a rare but life-threatening vascular complication in STAT3-HIES. Given the potential for multi-organ vasculopathy, systemic vascular screening by contrast-enhanced CT or MRI is crucial for early detection and management. Further research is needed to elucidate the mechanisms underlying vasculopathy in STAT3-HIES and establish optimal screening strategies to improve patient outcomes.

PMID:40491905 | PMC:PMC12146391 | DOI:10.3389/fimmu.2025.1601776

Acta Derm Venereol. 2025 Jun 9;105:adv41318. doi: 10.2340/actadv.v105.41318.

ABSTRACT

Inborn errors of immunity are rare diseases and 50-80% present with dermatological manifestations. This study evaluated difficult-to-treat cutaneous human papillomavirus infections and their associations with immunological defects. Patients were recruited from the Dermatological Outpatient Clinic over 2 years. Patients reporting persistent common warts and/or a combination of molluscum contagiosum or more than 2 flat warts, with a clinical assessment of severe or persistent skin infection, met the clinical severity criteria for inclusion. Resistance to several therapies was also considered. A total of 632 patient records were analysed to clinically characterize the warts, laboratory data, treatments used and their responses, comorbidities, and family history. Among these, 459 cases were initially excluded from further evaluation. A questionnaire was provided by phone to 173 patients, among whom 47 patients were selected for an in-person consultation. Of these, 6 met the criteria for further evaluation. Immunological tests revealed neutropenia, low levels of immunoglobulin isotypes (IgA, IgM, and IgG), and reduced frequency of lymphocyte subsets. Family history, flat warts, and associated recurrent viral infections suggested the need for further immunological evaluation. Criteria are proposed for identifying patients with cutaneous warts that warrant additional evaluation for potential inborn errors of immunity.

PMID:40488587 | DOI:10.2340/actadv.v105.41318

J Transl Autoimmun. 2025 May 15;10:100292. doi: 10.1016/j.jtauto.2025.100292. eCollection 2025 Jun.

ABSTRACT

BACKGROUND: Anti-γ interferon autoantibody (AIGA) syndrome is a widespread and grossly underestimated immunodeficiency disorder characterized by high mortality rates and a lack of standardized diagnostic methods. A highly accurate AIGA biomarker that meets the requirements of absolute quantification is urgently needed to enable the early diagnosis and treatment monitoring of the disease. In our study, we aimed to identify the primary components of AIGAs, determine their function, and develop a novel diagnostic method.

METHODS: Immune repertoire sequencing and a retrospective antibody subtype index analysis were performed for typical patients. Affinity chromatography was used to isolate and purify IgGs from AIGAs in the plasma of AIGA(+) patients. The clinical application value of chromatography for testing AIGAs was evaluated in a prospective clinical cohort.

RESULTS: A total of 114 eligible subjects were enrolled. Immune repertoire sequencing revealed that 74 % of the AIGA(+) patients had IgG clone types, with the somatic hypermutation (SHM) analysis being the most informative. We isolated AIGAs from the blood and interpreted their affinity and major components completely. Based on the results of this prospective cohort study, AIGAs, an absolute quantitative biomarker, were significantly better than the ELISA method (Delong test, P = 0.0018).

CONCLUSIONS: Patients with AIGA syndrome have abnormally elevated IgG levels, with IgG3 subtypes dominating. The disorder is characterized by the rapid acquisition of polyclonal AIGAs. The obtained AIGAs had a good neutralization capacity and potential as absolute quantitative biomarkers.

PMID:40485903 | PMC:PMC12143649 | DOI:10.1016/j.jtauto.2025.100292

Neuron. 2025 Jun 4:S0896-6273(25)00363-0. doi: 10.1016/j.neuron.2025.05.016. Online ahead of print.

ABSTRACT

Inborn errors of immunity (IEI), as congenital chronic disorders, are often associated with neurobehavioral symptoms, traditionally considered secondary to patient burden. Their origin, however, has yet to be addressed. Here, we found that IEI-associated genes are expressed in neural lineages during human brain development, and in the absence of immunological challenges, IEI mutations directly impair neurodevelopmental trajectories, leading to psychomotor defects. Warts hypogammaglobulinemia immunodeficiency myelokathexis (WHIM) mice-bearing a mutation causing Cxcr4 hyperactivation-show developmental foliation defects of the cerebellum correlating with sensorimotor and affective dysfunctions, which recapitulate the alterations described in patients. WHIM cerebella single-cell profiling revealed major transcriptional deregulation in granule cell progenitors, whose aberrant proliferation and migration induce foliation and circuit defects. AMD3100 intracerebroventricular injection rescues both morphological and behavioral defects, demonstrating their brain-specific and Cxcr4-dependent origin. Collectively, our findings highlight the relevance of neurodevelopmental implications underlying psychomotor IEI manifestations, broadening our understanding of these conditions beyond immune dysfunctions.

PMID:40482638 | DOI:10.1016/j.neuron.2025.05.016