bims-actimu 2025-08-31 papers

Issue of 2025–08–31
two papers selected by
Elodie Busch, University of Strasbourg

Front Genet. 2025 ;16 1584681

Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry.

Zahra Chavoshzadeh, Shahrzad Fallah, Vahide Zeinali, Samin Sharafian, Samaneh Delavari, Mehrnaz Mesdaghi, Reda Djidjik, Brahim Belaid, Aydan Ikinciogullari, Sule Haskologlu, Figen Dogu, Ferah Genel, Nesrin Gulez, Safa Baris, Ahmet Ozen, Elif Karakoc-Aydiner, Ayça Kiykim, Zeynep Meric, Necil Kutukculer, Ayse Aygun, Guzide Aksu, Neslihan Edeer Karaca, Mehmet Geyik, Sevgi Keles, Ismail Reisli, Sukru Nail Guner, Rachida Boukari, Saliha Hakem, Reda Belbouab, Mohamed-Ridha Barbouche, Imen Ben-Mustapha, Najla Mekki, Meriem Ben-Ali, Ali Sobh, Marwa Elnagdy, Kamel Djenouhat, Azzeddine Tahiat, Hiba Mohammed Shendi, Amna Alkuwaiti, Gulnara Nasrullayeva, Tariq Alfars, Nashat Alsukaiti, Michel Massaad, Cybel Mehawej, Andre Megarbane, Carla Irani, Gehad Elghazali, Salem Al-Tamemi, Nisreen Khalifa, Raed Alzyoud, Sara Sebnem Kilic Gultekin, Hulya Kose, Hedieh Khodaverdy, Bibi Shahin Shamsian, Narges Eslami, Tooba Momen, Roya Sherkat, Soheila Aleyasin, Hossein Esmaeilzadeh, Hamid Ahanchian, Fereshte Salami, Saba Fekrvand, Loïc Dupre, Hans D Ochs, Nima Rezaei, Waleed Al-Herz, Hassan Abolhassani.

Background: The majority of monogenic inborn errors of immunity presenting as actinopathies were reported originally from the Middle East and North Africa (MENA) countries indicating a high prevalence of these entities in the region. However, their prognosis is unclear due to rarity and lack of comprehensive treatment outcomes.
Methods: We evaluated clinical, immunological, and genetic abnormalities associated with 15 genetic entities of actinopathies. Based on the function of mutant genes in actin-regulatory pathways, patients were classified into CDC42- and RAC2-related subcategories.
Results: A total of 503 individuals (29.5% females) from 17 countries were considered with a median age of 120 months. Although most patients presented initially with allergic phenotypes (37.7%), the most prevalent manifestations throughout the lifespan were infection in respiratory tracts (72.2%). Primary clinical diagnosis was mainly combined immunodeficiencies (48.3%) and the majority of cases were molecularly assigned to the CDC42 pathway (64.8%). The most common genetic defects were reported within the DOCK8 (n = 209) followed by the WAS (n = 94) and the CARMIL2 (n = 15) genes. Hematopoietic stem cell transplantation (HSCT) was conducted on 24.0% of patients, which significantly improved survival in patients with defects in WAS, DOCK8 and DOCK2. Overall mortality was 23.0%, mainly due to sepsis and malignancy.
Conclusion: Patients with defects in RAC2-associated regulators of actin usually present with late-onset symptoms due to normal immune profiles, but a higher rate of EBV and HPV infections, autoimmune cytopenia, asthma, and lymphoproliferation compared to defects in the CDC42 pathway. The severity of mutations in patients of the CDC42 group helps to estimate the prognosis of the disease and prioritization of HSCT.

Keywords: actinopathies; eosinophilia; genetic; immune dysregulation; inborn errors of immunity; primary immunodeficiency; thrombocytopenia

DOI: https://doi.org/10.3389/fgene.2025.1584681

3 Biotech. 2025 Sep;15(9): 302

Mechanistic understanding of Wiskott-Aldrich syndrome protein (WASp)-mediated epigenetic regulation of T helper cell differentiation in acute leukemia.

R Pradeep, Sudeshna Rakshit, Geetha Shanmugam, Amit Choudhary, Ramya Ramesh, Jaikumar G Ramamoorthy, Reena Gulati, Deepak Amalnath, Prabhu Manivannan, Smita Kayal, Saptak Banerjee, Koustav Sarkar.

Wiskott-Aldrich syndrome protein (WASp) is exclusively expressed in hematopoietic cells, yet its role in leukemia remains poorly defined. This study investigates the epigenetic regulation of key immune genes by T helper (TH) cell transcription factors. Human CD4⁺ T cells from healthy donors and patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) were transfected with control CRISPR (CO), WASp knockout (WKO), and WASp overexpression (WOE) plasmids. Flow cytometry confirmed intracellular WASp staining in CO, WKO, and WOE CD4⁺ T cells. WOE leads to elevated mRNA levels of TH1-associated transcription factors, such as TBX21 and IFNγ. Notably, TBX21 enrichment increased significantly in WOE cells, while no such enrichment was observed for GATA3, RORC, or FOXP3. In addition, aberrant accumulation of R-loops at key gene loci, including TBX21, STAT1, ATM, and H2AFX, was prominently observed in WKO cells but not in WOE conditions. DNA methylation increased WKO cells but m6A levels were elevated under WOE conditions. Immunofluorescence analysis revealed much higher WASp expression in WOE but increased γH2A.X fluorescence in WKO. We found WASp stably interacts with the STAT1 binding region in the TBX21 promoter by molecular docking studies. Nitric oxide, reactive oxygen species, and glutathione levels were higher in WKO cells, while lactate dehydrogenase levels were increased in WOE samples. These findings collectively imply that WOE in acute leukemia promotes TH1 cell activity in a significant manner through epigenetic regulation and could be a potential therapeutic target.
Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-025-04474-4.

Keywords: Acute leukemia; CRISPR–Cas9; Epigenetic regulation; Methylation; T helper (TH) cell; Wiskott–Aldrich syndrome protein

DOI: https://doi.org/10.1007/s13205-025-04474-4