bims-actimu 2025-11-16 papers

Issue of 2025–11–16
four papers selected by
Elodie Busch, University of Strasbourg

Int J Hematol. 2025 Nov 12.

Advancements in gene therapy for Wiskott-Aldrich syndrome: from early trials to emerging approaches.

Luana de Mambro, Roberta Sessa Stilhano.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disorder characterized by microthrombocytopenia, eczema, recurrent infections, and immune dysregulation, affecting approximately 1 in 100,000 live births. While the disorder was historically fatal in early childhood, advances in hematopoietic stem cell transplantation (HSCT), gene therapy, and supportive care have improved survival, though morbidity remains high. Mutations in the WAS gene disrupt the WAS protein (WASp), which is essential for actin cytoskeleton dynamics, thereby impairing immune cell function. Over 466 mutations correlate with disease severity, from severe classic WAS to milder X-linked thrombocytopenia (XLT). Supportive therapies manage symptoms, while HSCT offers a cure for severe cases. Gene therapy has emerged as a promising alternative, with early gamma-retroviral trials showing efficacy but also a risk of leukemogenesis. Third-generation lentiviral vectors with self-inactivating LTRs (long terminal repeats) demonstrate improved safety and immune restoration in clinical trials. This review evaluates the evolution of gene therapy for WAS, from early trials to emerging genome editing approaches, assessing their efficacy, safety, and potential to transform clinical outcomes.

Keywords: Gene therapy; Lentiviral vectors; WAS gene; Wiskott–Aldrich syndrome

DOI: https://doi.org/10.1007/s12185-025-04099-6

J Neurovirol. 2025 Nov 12.

Progressive multifocal leukoencephalopathy in a young adult with DOCK8 deficiency: a case of JC virus reactivation in primary immunodeficiency.

Laura Naydovich, Joseph R Berger, Pavle S Milutinovic.

Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV) reactivation in the setting of impaired cellular immunity. While commonly associated with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and immunosuppressive therapies, PML can also arise in primary immunodeficiency disorders. We report a case of PML in a young adult with autosomal recessive hyper-IgE syndrome (AR-HIES) due to DOCK8 deficiency, highlighting the importance of considering genetic immunodeficiencies in cases of JCV-PML without known iatrogenic or acquired causes.

Keywords: DOCK8 deficiency; Hyper-IgE syndrome; JC virus reactivation; Primary immunodeficiency; Progressive multifocal leukoencephalopathy

DOI: https://doi.org/10.1007/s13365-025-01279-2

J Clin Immunol. 2025 Nov 10. 45(1): 156

Combined Immunodeficiency Associated with Two Novel CARMIL2 Mutations: A Case Series.

Saja I Abu Ghannam, Celina R Andonie, Tala Mahmoud Hamadna, Lila H Abu-Hilal, Rabee S Adwan.

Combined immunodeficiency due to CARMIL2 mutations is a rare autosomal recessive primary immunodeficiency characterized by impaired T-cell activation and function, leading to diverse clinical manifestations. Fewer than 50 cases have been reported worldwide. We describe the clinical and genetic features of five patients from Palestine with homozygous CARMIL2 mutations, including the first documented case of recurrent visceral leishmaniasis associated with this gene defect. This retrospective case series was conducted using whole-exome sequencing to confirm the diagnosis. All patients exhibited significant immunologic symptoms, including chronic dermatitis, cutaneous warts, recurrent respiratory infections, and mucocutaneous candidiasis. Two developed cytomegalovirus-related disease. Genetic analysis revealed two novel homozygous variants: NM_001317026.3:c.1865 C > T (p.Ala622Val) in four patients, and c.1973 C > T (p.Ala658Val) in one. Notably, one adult male developed recurrent visceral leishmaniasis, an unusual presentation not previously reported in the context of CARMIL2 deficiency. Consanguinity was identified in two families. All patients required immunomodulatory therapy, and four were evaluated for hematopoietic stem cell transplantation. This case series underscores the clinical heterogeneity of CARMIL2-associated immunodeficiency and highlights the importance of genetic testing in patients with recurrent or atypical infections, particularly in populations with a high prevalence of consanguinity. The novel link to visceral leishmaniasis expands the known phenotypic spectrum of this condition.

Keywords: Carmil2 mutation; Combined immunodeficiency; Novel mutation.; Primary immunodeficiency disorders; Visceral leishmaniasis

DOI: https://doi.org/10.1007/s10875-025-01956-1

Science. 2025 Nov 13. 390(6774): 728-734

Branched actin networks mediate macrophage-dependent host-microbiota homeostasis.

Luiz Ricardo C Vasconcellos, Shaina Chor Mei Huang, Alejandro Suarez-Bonnet, Simon Priestnall, Probir Chakravarty, Sunita Varsani-Brown, Matthew L Winder, Kathleen Shah, Naoko Kogata, Brigitta Stockinger, Michael Way.

Branched actin networks formed by the Arp2/3 complex are essential for immune system function. Patients with loss-of-function mutations in the ARPC5 subunit of the Arp2/3 complex develop inflammation and immunodeficiency after birth, leading to early mortality. The basis for these phenotypes remains obscure. We found that loss of ARPC5, but not the ARPC5L isoform, in the mouse hematopoietic system caused early-onset intestinal inflammation after weaning. This condition was initiated by microbiota breaching the ileal mucosa and led to systemic inflammation. ARPC5-deficient macrophages and neutrophils infiltrated the ileum but failed to restrict microbial invasion. Specifically, macrophages that lack ARPC5 struggled to phagocytose and kill intracellular bacteria. Our results highlight the indispensable role of ARPC5-containing, but not ARPC5L-containing, Arp2/3 complexes in mononuclear phagocyte function and host-microbiota homeostasis.

DOI: https://doi.org/10.1126/science.adr9571