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Clin Exp Immunol. 2025 Jan 21:uxaf005. doi: 10.1093/cei/uxaf005. Online ahead of print.

ABSTRACT

INTRODUCTION: 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 de-phosphorylation, 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 peripheral blood of patients with STAT3 Gain-of-function Syndrome. Identifying cellular biomarkers of disease provide 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.

PMID:39836489 | DOI:10.1093/cei/uxaf005

Elife. 2025 Jan 21;13:RP94420. doi: 10.7554/eLife.94420.

ABSTRACT

PIK3R1 encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β, or p110δ. Constitutional PIK3R1 mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction. We sought to investigate this. In dermal fibroblasts from an APDS2 patient, we found no increased PI3K signalling, with p110δ expression markedly reduced. In preadipocytes, the APDS2 variant was potently dominant negative, associating with Irs1 and Irs2 but failing to heterodimerise with p110α. This attenuation of p110α signalling by a p110δ-activating PIK3R1 variant potentially explains co-incidence of gain-of-function and loss-of-function PIK3R1 phenotypes.

PMID:39835783 | DOI:10.7554/eLife.94420

Front Immunol. 2025 Jan 6;15:1519345. doi: 10.3389/fimmu.2024.1519345. eCollection 2024.

ABSTRACT

BACKGROUND: The Aryl Hydrocarbon Receptor (AhR) pathway significantly influences immune cell regulation, impacting the effectiveness of immunotherapy and patient outcomes in melanoma. However, the specific downstream targets and mechanisms by which AhR influences melanoma remain insufficiently understood.

METHODS: Melanoma samples from The Cancer Genome Atlas (TCGA) and normal skin tissues from the Genotype-Tissue Expression (GTEx) database were analyzed to identify differentially expressed genes, which were intersected with a curated list of AhR-related pathway genes. Prognostic models were subsequently developed, and feature genes were identified. Advanced methodologies, including Gene Set Enrichment Analysis (GSEA) and immune cell infiltration analysis, were employed to explore the biological significance of these genes. The stability of the machine learning models and the relationship between gene expression and immune infiltrating cells were validated using three independent melanoma datasets. A mouse melanoma model was used to validate the dynamic changes of the feature genes during tumor progression. The relationship between the selected genes and drug sensitivity, as well as non-coding RNA interactions, was thoroughly investigated.

RESULTS: Our analysis identified a robust prognostic model, with four AhR-related genes (MAP2K1, PRKACB, KLF5, and PIK3R2) emerging as key contributors to melanoma progression. GSEA revealed that these genes are involved in primary immunodeficiency. Immune cell infiltration analysis demonstrated enrichment of CD4⁺ naïve and memory T cells, macrophages (M0 and M2), and CD8⁺ T cells in melanoma, all of which were associated with the expression of the four feature genes. Importantly, the diagnostic power of the prognostic model and the relevance of the feature genes were validated in three additional independent melanoma datasets. In the mouse melanoma model, Map2k1 and Prkacb mRNA levels exhibited a progressive increase with tumor progression, supporting their role in melanoma advancement.

CONCLUSIONS: This study presents a comprehensive analysis of AhR-related genes in melanoma, highlighting MAP2K1, PRKACB, KLF5, and PIK3R2 as key prognostic markers and potential therapeutic targets. The integration of bioinformatics and machine learning provides a robust framework for enhancing prognostic evaluation in melanoma patients and offers new avenues for the development of treatments, particularly for those resistant to current immunotherapies.

PMID:39835132 | PMC:PMC11743449 | DOI:10.3389/fimmu.2024.1519345

J Allergy Clin Immunol. 2025 Jan 16:S0091-6749(25)00016-8. doi: 10.1016/j.jaci.2025.01.005. Online ahead of print.

ABSTRACT

BACKGROUND: The Clinical Genome Resource (ClinGen) is an international collaborative effort between scientists and clinicians, diagnostic and research laboratories as well as the patient community. Using a standardized framework, ClinGen has established guidelines to classify gene-disease relationships as Definitive, Strong, Moderate, and Limited based on available scientific and clinical evidence. When the genetic and functional evidence for a gene-disease relationship has conflicting interpretations or contradictory evidence, they can be Disputed or Refuted.

OBJECTIVES AND METHODS: The ClinGen Antibody Deficiencies Gene Curation Expert Panel (AD-GCEP), using the ClinGen framework, has classified genes related to Primary Antibody Deficiencies (PAD) that primarily affect B cell development and/or function and accounts for the largest proportion of Inborn Errors of Immunity (IEI) or Primary Immunodeficiencies (PIDs).

RESULTS: The AD-GCEP curated a total of 65 genes associated with humoral immune defects to validate 74 gene-disease relationships. Of these, 40 gene-disease relationships were classified as Definitive, 1 as Strong, 16 as Moderate, 15 as Limited, and two as Disputed. The curation process involved the review of 490 patient records and 3,546 associated Human Phenotype Ontology (HPO) entries. The most frequently observed HPO terms related to PAD was decreased circulating antibody (Ab) level, pneumonia and lymphadenopathy.

CONCLUSIONS: These curations represent the first effort by the Immunology Clinical Domain Working Group (CDWG) of ClinGen to provide a comprehensive genetic and phenotypic revision of genetic disorders affecting humoral immunity, and these were reviewed and approved by experts in the field. The curations are publicly available at www.clinicalgenome.org.

PMID:39826876 | DOI:10.1016/j.jaci.2025.01.005

Microbiome. 2025 Jan 16;13(1):12. doi: 10.1186/s40168-024-01982-y.

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent infections. Significant morbidity and mortality are caused by immune dysregulation complications (CVIDid), which affect around one-third of CVID patients and have a poorly understood etiology. Here, we investigate the hypothesis that gut microbial dysbiosis contributes to the inflammation underlying CVIDid.

RESULTS: Bacterial invasion of colonic crypts was observed in CVID (3/15) and X-linked agammaglobulinemia (XLA, 1/3), but not in healthy control (HC, 0/9) biopsies. Fecal gut microbiota was characterized using 16S rRNA-targeted amplicon sequencing. Increased bacterial load, decreased alpha diversity and distinct beta diversity were observed in CVIDid (n = 42) compared to HC (n = 48), and similar results were seen in CVID with IgA deficiency (n = 40) compared to HC. CVIDid and CVID-IgA showed enrichment of the genus Enterococcus, and in vitro studies confirmed the inflammatory potential of Enterococcus gallinarum and Enterococcus hirae in patient monocytes.

CONCLUSIONS: This study further supports the hypothesis that a dysregulated gut microbiota, with IgA deficiency as an important driving factor, contributes to systemic inflammation in primary antibody deficiency, and introduces enterococci as potential pathobionts in CVIDid. Video Abstract.

PMID:39819634 | DOI:10.1186/s40168-024-01982-y

Science. 2025 Jan 17;387(6731):234-235. doi: 10.1126/science.adv9833. Epub 2025 Jan 16.

ABSTRACT

An obscure gene editor was used to restore a missing liver enzyme in an infant with a devastating metabolic condition.

PMID:39818894 | DOI:10.1126/science.adv9833

J Neurol. 2025 Jan 15;272(2):110. doi: 10.1007/s00415-024-12766-7.

ABSTRACT

Ataxia-Telangiectasia (A-T) is a very rare multisystem disease of DNA repair, associated with progressive disabling neurological symptoms, respiratory failure, immunodeficiency and cancer predisposition, leading to premature death. There are no curative treatments available for A-T but clinical trials have begun. A major limiting factor in effectively evaluating therapies for A-T is the lack of suitable outcome measures and biomarkers. We have performed a systematic review to collect the information currently available on biomarkers for A-T both in patients and preclinical studies. We have identified 56 reports discussing potential A-T biomarkers in both pre-clinical models and patients. These studies report on diagnostic biomarkers but prognostic biomarkers and responsive markers of clinical status are currently lacking. Some biomarkers of neurodegeneration in A-T show promise, including non-invasive neuroimaging biomarkers. Some biomarkers of oxidative stress and responsive markers to radiotherapy and steroid treatment have potential value in clinical trials. The formation of the A-T biomarker working group with international experts is an important step forward to facilitate the sharing of materials, data and expertise with the common goal of finding effective biomarkers for A-T.

PMID:39812834 | DOI:10.1007/s00415-024-12766-7

J Exp Med. 2025 Feb 3;222(2):e20240843. doi: 10.1084/jem.20240843. Epub 2025 Jan 15.

ABSTRACT

IKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. The absence of IKKα causes fetal encasement syndrome in humans, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and causes combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were loss-of-function. Non-canonical NF-κB activation was profoundly diminished in stromal and immune cells while the canonical pathway was unexpectedly partially impaired. Reintroducing wt CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of biallelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding, and suggesting IKKα’s role in canonical NF-κB target gene expression in humans.

PMID:39812688 | DOI:10.1084/jem.20240843

Blood Adv. 2025 Jan 14:bloodadvances.2024014639. doi: 10.1182/bloodadvances.2024014639. Online ahead of print.

ABSTRACT

Immune Thrombocytopenia (ITP) is a heterogenous autoimmune disorder diagnosed by excluding other conditions. Misdiagnosis of primary ITP occurs in patients with inherited thrombocytopenia and primary immunodeficiency syndromes. This study investigates whether genetic testing for inherited thrombocytopenia or primary immunodeficiency can enhance diagnostic accuracy in ITP, and guide treatment strategies. We performed whole genome sequencing or targeted panel sequencing on peripheral blood samples in a cohort of 80 participants with chronic ITP, utilising the ThromboGenomics (TG) Panel (n=72) and the Genomics of Rare Immune Disorders (GRID) panel (n=50) consisting of genes known to cause bleeding and platelet disorders (BPDG) or primary immunodeficiency syndromes (PIDG) respectively. A replication cohort of 73 patients underwent clinical genomics testing with either the R90 (BPDG, n=35) or R15 (PIDG, n=50) NHS Genomics panels. Known pathogenic or likely pathogenic, disease-causing, variants were identified in 9 patients in the first cohort (11% CI:5-20); 7 patients (10% CI:4-19) in BPDG and 2 patients (4% CI:1-14) in PIDG. Additionally, 26 patients (32.5%) carried variants of uncertain significance (VUS). In the replication cohort, 8% (CI:2-20) and 9% (CI:2- 23) of patients had a pathogenic variant identified on the R15 (PIDG) or R90 panel (BPDG) respectively. The findings impacted clinical management such as avoidance of immunosuppression (ANKRD26, GP1BB, ETV6, TUBB1, ITGB3) and eligibility for allogeneic stem cell transplantation (UNC13D). Our findings demonstrate that genomic sequencing identifies diagnostically relevant variants in patients with chronic ITP. Identification of these variants can guide treatment decisions and improve patient outcome.

PMID:39808791 | DOI:10.1182/bloodadvances.2024014639

Turk J Pediatr. 2024 Nov 26;66(6):786-791. doi: 10.24953/turkjpediatr.2024.4602.

ABSTRACT

BACKGROUND: Griscelli syndrome (GS) is a rare genetic disorder characterized by oculocutaneous albinism and variable immune dysfunction. Among three distinct types of GS, occurring due to different genetic mutations; GS type 1 presents with neurological manifestations, hemophagocytic lymphohistiocytosis (HLH) generally develops in GS type 2, and GS type 3 primarily exhibits oculocutaneous albinism. HLH, a life-threatening condition with excessive immune activation, may occur secondary to various triggers, including infections, and develop in different tissues, as well as in the testis, similar to Erdheim-Chester disease.

CASE: After referral at 19 days of age with restlessness, left testicular swelling, and erythema, an infant was diagnosed with bilateral hydrocele with left testicular torsion by testicular ultrasound, leading to a left orchiectomy. Pathology showed testicle and spermatic cord hemorrhagic necrosis. A week later, the infant presented with right testicular swelling and hepatosplenomegaly. He had silvery gray hair. We administered broad-spectrum antibiotics for increased acute phase reactants. Viral panels, including cytomegalovirus and Epstein-Barr virus, were negative. Laboratory findings indicated cholestasis and disseminated intravascular coagulation. Bone marrow aspiration revealed hemophagocytosis and increased histiocytes. Microscopic hair examination supported the diagnosis of GS. Sanger sequencing revealed the homozygous mutation c.217T>G (p.W73G) in RAB27A.

CONCLUSION: Prompt diagnosis and treatment of HLH are crucial to prevent progression to multi-organ failure and death. This case highlights the diverse tissue involvement and diagnostic challenges in Griscelli syndrome type 2.

PMID:39807742 | DOI:10.24953/turkjpediatr.2024.4602