bims-actimu 2025-02-16 papers

Issue of 2025–02–16
two papers selected by
Elodie Busch, University of Strasbourg

Front Immunol. 2024 ;15 1507494

Case report: Advanced age at transplantation and pre-emptive treatment with dupilumab in DOCK8 deficiency.

Sophia Trombello, Andrea Jarisch, Andre Willasch, Eva Rettinger, Julia Fekadu-Siebald, Dirk Holzinger, Roland Adelmann, Peter Bader, Shahrzad Bakhtiar.

Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency (CID) due to biallelic mutations in the gene encoding DOCK8. Major clinical phenomena are recurrent severe infections of the lungs and skin, atopic eczema, and predisposition to malignancy leading to a poor prognosis. Typical findings include highly elevated IgE and eosinophilia. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is indicated as the only curative treatment option. We present a patient with advanced disease undergoing alloHSCT at the age of 11 years after individualized pre-treatment using dupilumab and rituximab resulting in a decrease in IgE levels and clinical improvement of the skin condition. Additionally, in a review of the literature, we summarize morbidity and outcome in DOCK8-deficient patients older than 8 years of age receiving alloHSCT. Life-threatening infections, malignancy, and disease-related complications with organ damage pre-transplant are challenging in older DOCK8-deficient patients. The therapeutic role of dupilumab in DOCK8 deficiency should be evaluated in larger studies.

Keywords: DOCK8-deficiency; alloHSCT; combined immunodeficiency; dupilumab; omalizumab

DOI: https://doi.org/10.3389/fimmu.2024.1507494

Biol Direct. 2025 Feb 08. 20(1): 21

Inhibition of RAC1 activator DOCK2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activation.

Jianli Qiu, Yitong Qu, Yinli Li, Cancan Li, Junling Wang, Lu Meng, Xiaojin Jing, Jiangping Fu, Yan Xu, Yuna Chai.

BACKGROUND: The Rho GTPase Rac family small GTPase 1 (RAC1) is considered a promising fibrotic therapeutic target, but the role of its activator, dedicator of cytokinesis 2 (DOCK2), in liver fibrosis is largely unknown. This study aimed to investigate the expression and role of DOCK2 in cholestasis-induced liver fibrosis and to further explore the potential mechanisms.
RESULTS: Cholestasis was induced in male C57BL/6 mice by bile duct ligation (BDL). DOCK2 knockdown was achieved by tail vein injection of adenovirus containing DOCK2-targeting shRNA. The effect of DOCK2 knockdown on cholestatic liver injury was evaluated at different time points after BDL. Hepatic DOCK2 expression gradually increased after BDL. Knockdown of DOCK2 reduced the necrotic area in BDL liver and downregulated serum levels of liver injury indicators. At 3d post-BDL (acute phase), DOCK2 knockdown alleviated M1 macrophage inflammation in the liver, as evidenced by reduced infiltrating iNOS + macrophages and inflammatory cytokines and mitigated NLRP3 inflammasome activation. At 14d post-BDL (chronic phase), DOCK2 knockdown suppressed hepatic stellate cell (HSC) activation and liver fibrosis as indicated by decreased α-SMA + HSCs and extracellular matrix deposition. In vitro experiments further demonstrated that DOCK2 knockdown suppressed M1 macrophage polarisation and HSC to myofibroblast transition, accompanied by inhibition of RAC1 activation.
CONCLUSIONS: In summary, this study demonstrates for the first time that the RAC1 activator DOCK2 regulates M1 macrophage polarisation and hepatic stellate cell activation to promote cholestasis-induced liver inflammation and fibrosis, suggesting that DOCK2 may be a potential therapeutic target in cholestatic liver injury.

Keywords: Cholestasis; DOCK2; Hepatic stellate cell; Liver fibrosis; Macrophage polarisation; RAC1

DOI: https://doi.org/10.1186/s13062-025-00612-3