bims-actimu 2024-09-29 papers

Issue of 2024‒09‒29
five papers selected by
Elodie Busch, University of Strasbourg

Cureus. 2024 Aug;16(8): e67658

Wiskott-Aldrich Syndrome: A Report of a Rare X-Linked Disorder.

Manojkumar G Patil, Sarita Verma, Om Prasanth Reddy Avuthu, Kannan Subramanian, Sampada Tambolkar, Shailaja V Mane.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive genetic disorder marked by eczema, thrombocytopenia, and immunodeficiency. The associated immune dysregulation increases the risk of autoimmune disorders and lymphoid malignancies. WAS results from mutations in the WAS protein gene on the short arm of the X chromosome. Here, we present the case of a seven-month-old male, born to non-consanguineous parents with no significant birth or family history. The child had height, weight, and head circumference below the third percentile for age and presented with recurrent mild upper respiratory infections, mild eczema, and thrombocytopenia. Despite symptomatic treatment and clinical improvement, platelet counts continued to decline. A provisional diagnosis of immune thrombocytopenia was made, and intravenous immunoglobulin was administered, which halted the downward trend but did not improve platelet counts. Autoimmune testing revealed strong positivity for antinuclear antibodies (ANA). Given the early-onset thrombocytopenia, anemia, and failure to thrive, autoimmune lymphoproliferative syndrome was suspected. However, T cell subset analysis was normal. A bone marrow biopsy suggested myelodysplastic syndrome or myeloproliferative neoplasm, but molecular studies were negative. Due to the early-onset autoimmunity and strongly positive ANA, genetic testing via whole exome sequencing confirmed the diagnosis of WAS.

Keywords: clinical hematology; hematopoietic stem cell transplant; pediatrics & neonatology; whole-exome sequencing; x-linked inheritance

DOI: https://doi.org/10.7759/cureus.67658

Scand J Immunol. 2024 Sep 20. e13408

Somatic reversion in Wiskott-Aldrich syndrome: Case reports and mechanistic insights.

Rashmi Rikhi, Suprit Basu, Kanika Arora, Koon-Wing Chan, Ankur Kumar Jindal, Amit Rawat, Yu-Lung Lau, Deepti Suri.

This report describes two brothers from India and a Chinese patient with somatic reversion of an inherited deleterious mutation in the WAS gene. Both the Indian siblings had inherited a single nucleotide deletion causing a frameshift mutation (c.1190del, p.Pro397Argfs*48) (variant 1: marked in blue) from the mother. Another variant (variant 2: marked in red), a 12-nucleotide deletion at position 1188-1199 (c.1188_1199del, p.P401_P404del) was also found, which resulted in restoration of the frame and subsequent rescue of the protein sequence. DNA sequencing from buccal mucosal cells revealed only the inherited variant (variant 1), while no reversion mutation was identified in the mucosal cells. Similarly, the Chinese patient was found to have a novel germline 14-base duplication (ACGAAAATGCTTGG) c.120_132 + 1dup (variant 1). This resulted in abolishment of the original splice junction coupled with the creation of a new junction 14 bases 3' and a frameshift mutation with predicted protein truncation p. Thr45Aspfs*. DNA from the patient's PBMC showed co-existence of wild-type and mutated sequences, but only the mutant was present in the buccal cells. Genomic and mRNA analysis of the isolated CD3+ T lymphocytes, CD3- mononuclear cells, and EBV-transformed B lymphocytes indicated that the reverant variant (germline variant was restored to wild-type sequence) were selectively found in CD3+ T lymphocytes.

DOI: https://doi.org/10.1111/sji.13408

MedComm (2020). 2024 Oct;5(10): e747

Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4+ T cells.

Panpan Jiang, Siyu Zhao, Xiaoyu Li, Shiyan Hu, Shuhan Chen, Yinming Liang, Lichen Zhang, Liaoxun Lu, Guofeng Fang, Lu Yang, Yanmei Huang, Heather Miller, Fei Guan, Jiahui Lei, Chaohong Liu.

Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency disease caused by mutations in exon 45 of the DOCK8 gene. The clinical signs primarily consist of increased serum IgE levels, eczema, repeated skin infections, allergies, and upper respiratory tract infections. Using CRISPR/Cas9 technology, we generated a DOCK8 exon 45 mutation in mice, mirroring the mutation found in patients. The results indicated that DOCK8 mutation impairs peripheral T cell homeostasis, disrupts regulatory T cells (Tregs) development, increases ICOS expression in Tregs within peripheral lymph nodes (pLn), and promotes Th17 cell differentiation within the spleen and pLn. Upon virus infection, DOCK8 mutation CD4+ T cells have a Th2 effector fate. RNA-bulk sequencing data revealed alternations in the mTOR pathway of DOCK8 mutant CD4+ T cells. We observed that DOCK8 mutation upregulates the glycolysis levels in CD4+ T cells, which is related to the Akt/mTOR/S6/HIF-1α pathway. In summary, our research elucidates that DOCK8 regulates the differentiation of helper T cells by modulating the glycolytic pathway in CD4+ T cells, thereby advancing the comprehension and offering potential treatment of diseases in DOCK8-deficient patients.

Keywords: DOCK8; T cell; differentiation; glycolytic

DOI: https://doi.org/10.1002/mco2.747

Curr Opin Pediatr. 2024 Sep 26.

Hematopoietic cell transplantation for inborn errors of immunity: an update on approaches, outcomes and innovations.

Olatundun Williams.

PURPOSE OF REVIEW: Allogeneic hematopoietic cell transplantation (HCT) is a curative option for many for inborn errors of immunity (IEI). This review highlights recent progress in the field of HCT for IEI.RECENT FINDINGS: Alternative donor transplantation continues to expand donor options for patients with IEI. Reduced intensity and reduced toxicity conditioning approaches are being investigated and optimized. Immunomodulatory bridging therapies are yielding impressive progress in outcomes for primary immune regulatory disorders (PIRD) but require further study in prospective trials. Single-institution, multicenter and consortium studies have improved our understanding of factors that affect overall outcomes in IEI and outcomes in Wiskott-Aldrich syndrome (WAS), chronic granulomatous disease (CGD) and PIRD in particular. Data show that second HCT offers a viable chance of cure to some IEI patients. Late effects in IEI HCT survivors are being better characterized. Preclinical studies of chemo(radiation)-free HCT strategies hold promise for decreasing HCT toxicity.
SUMMARY: Improvements in our understanding of HCT donor choice, conditioning regimen, immunomodulatory bridging therapies, diagnostic and post-HCT surveillance testing and late effects continue to yield advancements in the field of HCT for IEI.

DOI: https://doi.org/10.1097/MOP.0000000000001407

Cytoskeleton (Hoboken). 2024 Sep 27.

Multifaceted role of the actin-binding protein WIP: Promotor and inhibitor of tumor progression and dissemination.

Jorge Alonso-Eiras, Ines M Anton.

Cancer cells depend on actin cytoskeleton reorganization to achieve hallmark malignant functions including abnormal activation, proliferation, migration and invasiveness. (Neural)-Wiskott-Aldrich Syndrome protein ((N-)WASP) binds actin and forms a complex with the WASP-interacting protein (WIP), which plays a critical role in regulating the actin cytoskeleton, through (N)-WASP-dependent and independent functions. Mutations in the WIP gene (WIPF1) lead to severe early onset immunodeficiency in humans and severe autoimmunity and shortened lifespan in mice. This review covers the available evidence about the physiological role of WIP in different tissues and its contribution to human disease, focusing on cancer. In solid tumors overexpression of WIP has mostly been associated with tumor initiation, progression and dissemination through matrix degradation by invadopodia, while a suppressive function has been shown for WIP in certain hematological cancers. Interestingly, a minority of studies suggest a protective role for WIP in specific tumor contexts. These data support the need for further research to fully understand the mechanisms underlying WIP's diverse functions in health and disease and raise important questions for future work.

Keywords: (N‐)WASP; WIP; actin cytoskeleton; cancer metastasis; immunodeficiency

DOI: https://doi.org/10.1002/cm.21935