bims-actimu 2025-11-23 papers

Issue of 2025–11–23
five papers selected by
Elodie Busch, University of Strasbourg

Genes Immun. 2025 Nov 17.

Molecular analysis and immunological characterization of a founder mutation causing ARPC1B deficiency.

Megan M Dobrose, Meltem Ece Kars, Jareb J Perez-Caraballo, Colleen M Roark, Christine Mariskanish, Oscar Zavaleta-Martinez, Noemi Gomez-Hernandez, Saul Oswaldo Lugo-Reyes, Yuval Itan, Lizbeth Blancas-Galicia, Rubén Martínez-Barricarte.

Actin-Related Protein Complex 1B (ARPC1B) is a subunit of the ARP2/3 complex that is predominately expressed in hematopoietic cells and is involved in the regulation of actin polymerization. ARPC1B deficiency leads to combined immunodeficiency (CID) with symptoms of eczema, allergies, inflammation, recurrent infection, and thrombocytopenia. We characterize the disease-causing variant c.899_944del (p.E300Gfs*7) on the ARPC1B gene that originated from a founder effect in an indigenous American population. We showed that this variant impairs protein expression leading to a complete deficiency of ARPC1B. Additionally, we used mass cytometry to thoroughly analyze the effects of this mutation on the frequencies of immune populations. Our findings suggest that ARPC1B is critical for class switching since our ARPC1B-deficient patient had reduced frequencies of class-switched memory B cells. Furthermore, the frequencies of total CD4+, CD8+, and γδ T cells were reduced, consistent with an essential function of ARPC1B in T cell development. Overall, this study advances the knowledge of the c.899_944del ARPC1B mutation and the understanding of the role of ARPC1B in the immune system.

DOI: https://doi.org/10.1038/s41435-025-00368-w

Iran J Allergy Asthma Immunol. 2025 Oct 29. 24(6): 799-807

Measuring Dedicator of Cytokinesis 8 (DOCK8) Expression as a Flow Cytometry Biomarker for DOCK8 Deficiency Detection.

Maryam Moradi, Mahsa Yousefpour Marzbali, Nazanin Nazari, Zahra Chavoshzadeh, Seyed Alireza Mahdaviani, Mahnaz Sadeghi-Shabestari, Nima Rezaei.

The autosomal recessive form of hyperimmunoglobulin E syndrome (AR-HIES), caused by mutations in the DOCK8 (Dedicator of Cytokinesis 8) gene, presents a wide range of clinical manifestations and phenotypically overlaps with several types of combined immunodeficiency disorders characterized by elevated serum IgE levels. Due to the high rates of morbidity and mortality, as well as the potential curability through hematopoietic stem cell transplantation (HSCT), early and accurate differential diagnosis of this syndrome is crucial for optimal management and improved prognosis. Flow cytometry tests can be beneficial for early diagnosis of many inborn errors of immunity (IEIs), including this syndrome. This study, conducted for the first time on Iranian patients, investigated the expression of the DOCK8 protein. DOCK8 expression was assessed by flow cytometry in 14 patients (6 males and 8 females) with a clinical diagnosis of DOCK8 deficiency. The diagnosis was ultimately confirmed through genetic testing. The results showed that DOCK8 expression in patients was significantly lower compared to the healthy control group. Flow cytometric evaluation of DOCK8 protein expression offers a rapid and efficient diagnostic method with a sensitive detection range suitable for many cases. This approach can facilitate the diagnosis of DOCK8 deficiency, thereby enabling timely and effective disease management.

Keywords: Flow cytometry; Hyper IgE; Immunodeficiencies; Inborn errors of immunity

DOI: https://doi.org/10.18502/ijaai.v24i6.20158

Cureus. 2025 Oct;17(10): e94783

X-linked Multisystem Autoinflammatory Disease With Immune Dysregulation in a Pediatric Patient: A Rare Case and Review of the Literature.

Sara Laranja, Inês Piscalho, Matilde Caetano, Inês Coelho, Luísa Gaspar, Maria João Virtuoso.

X-linked multisystem autoinflammatory disease with immune dysregulation (ADMIDX) is a rare X-linked recessive disorder with only a few cases described in the literature. It typically presents with variable cytopenias and systemic or organ-specific autoinflammatory features. We report the case of a 10-year-old male with recurrent febrile episodes, seizures, splenomegaly, and elevated proinflammatory cytokines. Given the suspicion of an autoinflammatory condition, a genetic panel was performed, identifying a hemizygous mutation in the DOCK11 gene, subsequently associated with ADMIDX. As the patient remains clinically stable, a conservative "watchful waiting" approach has been adopted. This report aims to raise awareness among pediatricians and emphasize the diagnostic challenges posed by this rare condition.

Keywords: autoinflammatory disease; dock11 deficiency; immune dysregulation; recurrent fever; x-linked disease

DOI: https://doi.org/10.7759/cureus.94783

J Physiol. 2025 Nov 16.

Mechanics of blunting of actin-myosin interaction dynamics by the actinopathy-causing mutation E334Q in cytoskeletal γ-actin.

Irene Pertici, Valentina Buonfiglio, Johannes N Greve, Elena Battirossi, Duccio Fanelli, Dietmar J Manstein, Pasquale Bianco.

Cellular processes such as cytokinesis, apoptosis and migration rely heavily on the myosin-based contractility of the γ-actin network in the submembrane cortex. Direct measurements of γ-actin-myosin interactions through morphological and depletion investigations remain elusive. Here, we use a synthetic nanomachine, consisting of an array of myosin motors carried on a nanopositioner and brought to interact with an actin filament attached to a bead trapped in the focus of dual laser optical tweezers. The nanomachine is able to mimic the loading conditions of γ-actin-myosin interactions in situ, allowing measurements of the maximum steady force (F0) and of the shortening velocity against loads < F0. Comparative measurements are conducted on wild-type γ-actin and γ-actin carrying the E334Q mutation, associated with non-muscle actinopathies. Our results show that the force of the single actin-myosin interaction is 2.5 pN for the wild-type actin and is halved by the mutation. The kinetics of motor attachment-detachment, underpinning the rate of isometric force rise and the force-velocity relation, are also reduced by a factor of two, resulting in a reduction of the maximum nanomachine power to one-fifth. The identification and quantitative definition of the loss of basic function caused by the E334Q γ-actin mutation serve as a starting point for understanding the chain of remodelling events leading to the pathological phenotype and demonstrate the potential of the nanomachine for targeted therapeutic interventions. KEY POINTS: Mutations in cytoskeletal actin cause rare pathologies classified as non-muscle actinopathies (NMAs), including the Baraitser-Winter cerebrofrontofacial syndrome characterized by neural cortex abnormalities leading to facial dysmorphism, developmental delay and organ malformations. Cytoskeleton dynamics control cell morphology and migration and rely on the interaction of non-muscle myosin II with cytoskeletal γ-actin, but the system's mechanical performance and its blunting by NMA-causing mutations in γ-actin have still to be defined. Here, a synthetic nanomachine is used to record the relevant mechano-kinetic parameters of the γ-actin-myosin interaction under physiological loading conditions. Quantitative estimates of these parameters for wild-type and E334Q mutant γ-actin suggest that strong defects in the actin-myosin interaction mechanics may be one of the main molecular mechanisms leading to the pathological phenotype. This paper lays the groundwork for the quantitative definition of the basic function altered by NMA-causing mutations and the evaluation of targeted therapies.

Keywords: actinopathies; cytoskeletal actin; cytoskeletal actin mutants

DOI: https://doi.org/10.1113/JP289622