Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation

He, Minghui; Saeed, Mezida B.; Record, Julien; Keszei, Márton; Pinho, Lia Gonçalves; Vasconcelos-Fontes, Larissa; D'Aulerio, Roberta; Vieira, Rhaissa Calixto; Oliveira, Mariana M.S.; Geyer, Chiara E.; Bohaumilitzky, Lena; Thiemann, Meike; Deordieva, Ekaterina; Buedts, Lieselot; Lopes, Joao Pedro; Pershin, Dmitriy; Hammarström, Lennart; Lei, Yu; Zhao, Xiaodong; Cunningham‐Rundles, Charlotte; Thrasher, Adrian J.; Burns, Siobhan O.; Cotta-de-Almeida, Vinı́cius; Liu, Chaohong; Shcherbina, Anna; Vandenberghe, Peter; Westerberg, Lisa S.

doi:10.1016/j.jaci.2021.07.033

Cited by 5 publications

(12 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the increased propensity to be degraded, WASp‐L270P and WASp‐I294T, murine WASp‐L272P and WASp‐I296T, induce increased actin dynamics that contribute to increased cellular stiffness but also increased cellular dynamics 51,52,110 . This is at least partly due to increased phosphorylation of the Tyr291 (murine Tyr293‐WASp) and localization to cellular membranes 53,110 . Engineered phospho‐mimicking and phospho‐disrupting mutations of Tyr293‐WASp show increased F‐actin, together providing the cellular concept for the critical role of the Tyr291 for regulation of WASp activity and stability 50,52,111 …”

Section: Mechanistic Insight For Therapeutic Benefitmentioning

confidence: 99%

“…Importantly, lentiviral‐mediated gene therapy restores B‐cell tolerance in WAS 191,198,199 . XLN patients have normal levels of naïve B cells and plasmablasts, although they have reduced IgA switching, proliferation, and memory B cells 53 . WASp‐L272P and WASp‐I296T XLN B cells show alteration in actin polymerization, reduced proliferation, increased apoptosis, and increased genomic instability (Figure 4).…”

Section: Cellular Insight For Therapeutic Benefitmentioning

confidence: 99%

“…[47][48][49][50][51][52] Six unique XLN mutations have been identified to date with amino acid mutations WAS-L270P, I294T, S272P, I290T, R268W, and F271S. 53 All patients have congenital neutropenia and treatment with G-CSF restores a number of blood neutrophils. Because of the possible genetic instability of many hematopoietic cells, 50,52,53 G-CSF should be given with some caution to the development of myelodysplastic syndrome and leukemia as seen upon long-term usage of G-CSF to treat neutropenia patients.…”

Section: Wa S -Rel Atedd Is E a S E S:loss -Of-fun C Tionandg Ain -Of...mentioning

confidence: 99%

“…and localization to cellular membranes. 53,110 Engineered phosphomimicking and phospho-disrupting mutations of Tyr293-WASp show increased F-actin, together providing the cellular concept for the critical role of the Tyr291 for regulation of WASp activity and stability. 50,52,111 The increasing knowledge about WASp interactors and how they regulate WASp has prompted the investigation of new approaches to stabilize or increase WASp degradation.…”

Section: Mutationsinwas/xlt/xlnaffectwasp Stability and Autoinhibitionmentioning

confidence: 99%

“…A major clinical unmet need and a remaining hurdle to solve is the restoration of WASp expression in platelets to prevent thrombocytopenia in XLT patients and restore platelet counts upon gene therapy of WAS patients. XLN patients are treated on demand with G‐CSF and caution should be taken to prevent malignant transformation as XLN mutations in WAS have been associated with genomic instability 50,52–54 …”

Section: Was‐related Diseases: Loss‐of‐function and Gain‐of‐function ...mentioning

confidence: 99%

See 4 more Smart Citations

Understanding immunoactinopathies: A decade of research on WAS gene defects

Vieira

Pinho

Westerberg

2023

Pediatric Allergy Immunology

Self Cite

View full text Add to dashboard Cite

Immunoactinopathies caused by mutations in actin‐related proteins are a growing group of inborn errors of immunity (IEI). Immunoactinopathies are caused by a dysregulated actin cytoskeleton and affect hematopoietic cells especially because of their unique capacity to survey the body for invading pathogens and altered self, such as cancer cells. These cell motility and cell‐to‐cell interaction properties depend on the dynamic nature of the actin cytoskeleton. Wiskott‐Aldrich syndrome (WAS) is the archetypical immunoactinopathy and the first described. WAS is caused by loss‐of‐function and gain‐of‐function mutations in the actin regulator WASp, uniquely expressed in hematopoietic cells. Mutations in WAS cause a profound disturbance of actin cytoskeleton regulation of hematopoietic cells. Studies during the last 10 years have shed light on the specific effects on different hematopoietic cells, revealing that they are not affected equally by mutations in the WAS gene. Moreover, the mechanistic understanding of how WASp controls nuclear and cytoplasmatic activities may help to find therapeutic alternatives according to the site of the mutation and clinical phenotypes. In this review, we summarize recent findings that have added to the complexity and increased our understanding of WAS‐related diseases and immunoactinopathies.

show abstract

Section: Mechanistic Insight For Therapeutic Benefitmentioning

confidence: 99%

Section: Cellular Insight For Therapeutic Benefitmentioning

confidence: 99%

Section: Wa S -Rel Atedd Is E a S E S:loss -Of-fun C Tionandg Ain -Of...mentioning

confidence: 99%

Section: Mutationsinwas/xlt/xlnaffectwasp Stability and Autoinhibitionmentioning

confidence: 99%

Section: Was‐related Diseases: Loss‐of‐function and Gain‐of‐function ...mentioning

confidence: 99%

See 3 more Smart Citations

Understanding immunoactinopathies: A decade of research on WAS gene defects

Vieira

Pinho

Westerberg

2023

Pediatric Allergy Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

Controlled WASp activity regulates the proliferative response for Treg cell differentiation in the thymus

Vasconcelos‐Fontes,

Vieira,

et al. 2024

Eur J Immunol

Self Cite

View full text Add to dashboard Cite

The Wiskott–Aldrich syndrome protein (WASp) regulates actin cytoskeletal dynamics and function of hematopoietic cells. Mutations in the WAS gene lead to two different syndromes; Wiskott–Aldrich syndrome (WAS) caused by loss‐of‐function mutations, and X‐linked neutropenia (XLN) caused by gain‐of‐function mutations. We previously showed that WASp‐deficient mice have a decreased number of regulatory T (Treg) cells in the thymus and the periphery. We here evaluated the impact of WASp mutations on Treg cells in the thymus of WAS and XLN mouse models. Using in vitro Treg differentiation assays, WAS CD4 single‐positive thymocytes have decreased differentiation to Treg cells, despite normal early signaling upon IL‐2 and TGF‐β stimulation. They failed to proliferate and express CD25 at high levels, leading to poor survival and a lower number of Foxp3+ Treg cells. Conversely, XLN CD4 single‐positive thymocytes efficiently differentiate into Foxp3+ Treg cells following a high proliferative response to IL‐2 and TGF‐β, associated with high CD25 expression when compared with WT cells. Altogether, these results show that specific mutations of WASp affect Treg cell development differently, demonstrating a critical role of WASp activity in supporting Treg cell development and expansion.

show abstract

Not too little, not too much: the impact of mutation types in Wiskott-Aldrich syndrome and RAC2 patients

Hsu

2023

Clinical and Experimental Immunology

View full text Add to dashboard Cite

Summary Primary immune deficiencies (PIDs) are genetic disorders impacting the appropriate development or functioning of any portion of the immune system. The broad adoption of high-throughput sequencing has driven discovery of new genes as well as expanded phenotypes associated with known genes. Beginning with the identification of WAS mutations in patients with severe Wiskott-Aldrich Syndrome, recognition of WAS mutations in additional patients has revealed phenotypes including isolated thrombocytopenia and X-linked neutropenia. Likewise RAC2 patients present with vastly different phenotypes depending on the mutation - ranging from reticular dysgenesis or severe neutrophil dysfunction with neonatal presentation to later onset common variable immune deficiency. This review examines genotype-phenotype correlations in patients with WAS (Wiskott-Aldrich Syndrome) and RAC2 mutations, highlighting functional protein domains, how mutations alter protein interactions, and how specific mutations can affect isolated functions of the protein leading to disparate phenotypes.

show abstract

Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation

Abstract: WASp XLN mutation leads to abnormal cell division with reduced Ig switching and accelerated plasma cell generation MB IgA+ Prolifera on, Ig switching Plasma cells GC Abnormal cell division Pa ent B cells, n=6 Muta ons

Cited by 5 publications

References 51 publications

Understanding immunoactinopathies: A decade of research on WAS gene defects

Understanding immunoactinopathies: A decade of research on WAS gene defects

Controlled WASp activity regulates the proliferative response for Treg cell differentiation in the thymus

Not too little, not too much: the impact of mutation types in Wiskott-Aldrich syndrome and RAC2 patients

Contact Info

Product

Resources

About