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.

Regardless of their age, adult patients with Wiskott-Aldrich syndrome should be considered for hematopoietic stem cell transplantation if clinically indicated.

OBJECTIVE: To examine how the level of perceived work ability and its changes over time are associated with the risk of full disability pension (DP) among those receiving partial DP.
METHODS: We retrieved survey data on perceived work ability and covariates (sociodemographic factors and health behaviors) from a cohort study of Finnish public sector employees at two time points: 2008 and 2012 and linked them with register data on DP obtained from the Finnish Centre for Pensions up to the end of 2018. Participants had begun receiving partial DP in 2008 and responded to either the 2008 survey (n = 159) or both surveys (n = 80). We used Cox regression for the analyses.
RESULTS: During the follow-up, 61 (38%) of those receiving partial DP transitioned to full DP. Those with perceived poor work ability were at a higher risk of full DP (HR 1.93; 95% CI 1.11-3.38) than those with at least moderate work ability, after adjustment for covariates. During four years of receiving partial DP, perceived work ability decreased among 36% of the participants, and remained unchanged or improved among 64%. Change in work ability was not associated with a risk of full DP.
CONCLUSIONS: Among those receiving partial DP, perceived poor work ability was a risk factor for full DP. Our findings highlight the importance of monitoring the level of perceived work ability of those receiving partial DP to enable identifying individuals at an increased risk of full DP.

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.

There is a lack of data on post-HSCT non-osteopenic bone pathology specifically for children with inborn errors of immunity (IEI). We collected data on non-osteopenic bone pathology in children with IEI post-HSCT over two decades in a large tertiary pediatric immunology center.
Descriptive study with data analysis of bone pathology in allo-HSCT for IEI was performed between 1/1/2000 to 31/12/2018 including patients alive at follow-up to July 2022. Records were analyzed for bone pathology and risk factors. Exclusion criteria included isolated reduced bone density, fractures, and skeletal anomalies due to underlying IEI and short stature without other bone pathology. Bone pathologies were divided into 5 categories: bone tumors; skeletal dysplasia; avascular necrosis; evolving bone deformities; slipped upper femoral epiphysis.
A total of 429 children received HSCT between 2000 and 2018; 340 are alive at last assessment. Non-osteopenic bone pathology was observed post-HSCT in 9.4% of patients (32/340, mean 7.8 years post-HSCT). Eleven patients (34%) had > 1 category of bone pathology. Seventeen patients (17/32; 53%) presented with bilateral bone pathology. The majority of patients received treosulfan-based conditioning (26/32; 81.2%). Totally, 65.6% (21/32) of patients had a history of prolonged steroid use (> 6 months). Pain was the presenting symptom in 66% of patients, and surgical intervention was required in 43.7%. The highest incidence of bone pathologies was seen in Wiskott-Aldrich syndrome (WAS) (n = 8/34; 23.5%) followed by hemophagocytic lymphohistiocytosis patients (n = 3/16; 18.8%).
Non-osteopenic bone pathology in long-term survivors of allo-HSCT for IEI is not rare. Most patients did not present with complaints until at least 5 years post-HSCT highlighting the need for ongoing bone health assessment for patients with IEI. Children presenting with stunted growth and bone pathology post-HSCT should undergo skeletal survey to rule out development of post-HSCT skeletal dysplasia. Increased rates and complexity of bone pathology were seen amongst patients with Wiskott-Aldrich syndrome.

Patients with Wiskott-Aldrich syndrome (WAS) harbor mutations in the WAS gene and suffer from immunodeficiency, microthrombocytopenia, and eczema. T-cells play an important role in immune response in the skin and the γδT-cells have an important role in skin homeostasis. Since WAS patients often present with eczema, we wanted to examine whether the T-cell receptor gamma (TRG) repertoire of the γδT-cells is affected in these patients. In addition, the immunoglobulin heavy chain (IGH) repertoire from genomic DNA of WAS patients was not yet studied. Thus, we sought to determine the effects that specific WAS mutations from our patients have in shaping the TRG and IGH immune repertoires. We collected clinical and genetic data on four WAS patients, each harboring a different mutation in the WAS gene. Using next-generation sequencing (NGS), we analyzed their TRG and IGH repertoires using genomic DNA isolated from their peripheral blood. We analyzed the TRG and IGH repertoire sequences to show repertoire restriction, clonal expansions, preferential utilization of specific V genes, and unique characteristics of the antigen binding region in WAS patients with eczema compared to healthy controls. Both the TRG and IGH repertoire showed diverse repertoire comparable to healthy controls on one the hand, and on the other hand, the IGH repertoire showed increased diversity, more evenly distributed repertoire and immaturity of the antigen binding region. Thus, we demonstrate by analyzing the repertoire based on genomic DNA, the various effect that WAS mutations have in shaping the TRG and IGH adaptive immune repertoires.

Actin is an important cytoskeletal protein involved in signal transduction, cell structure and motility. Actin regulators include actin-monomer-binding proteins, Wiskott-Aldrich syndrome (WAS) family of proteins, nucleation proteins, actin filament polymerases and severing proteins. This group of proteins regulate the dynamic changes in actin assembly/disassembly, thus playing an important role in cell motility, intracellular transport, cell division and other basic cellular activities. Lymphocytes are important components of the human immune system, consisting of T-lymphocytes (T cells), B-lymphocytes (B cells) and natural killer cells (NK cells). Lymphocytes are indispensable for both innate and adaptive immunity and cannot function normally without various actin regulators. In this review, we first briefly introduce the structure and fundamental functions of a variety of well-known and newly discovered actin regulators, then we highlight the role of actin regulators in T cell, B cell and NK cell, and finally provide a landscape of various diseases associated with them. This review provides new directions in exploring actin regulators and promotes more precise and effective treatments for related diseases.

Wiskott-Aldrich Syndrome Protein (WASP) deficiency causes Wiskott-Aldrich Syndrome (WAS), a sex-linked disorder characterized by combined immunodeficiency, microthrombocytopenia, and eczema. Like WASP-deficient humans, WASP-deficient mice produce normal numbers of functionally defective T cells. Here, we report a WAS patient with a novel germline frameshifting WAS mutation encoding a truncated form of WASP lacking the C-terminal cofilin homology (C) and the acidic region (A) domains (WASPΔCA). Although stably overexpressed in embryonic kidney cell lines, WASPΔCA was undetectable in circulating patient leukocytes. Deep sequencing, transcript profiling, and protein degradation analyses demonstrated patient lymphocytes employ an array of genetic, epigenetic, and proteasomal strategies to avoid expressing WASPΔCA.

Refractory Maillard reaction products (MRPs) produced during thermal hydrolysis pretreatment (THP) of waste activated sludge (WAS) may negatively impact the performance of downstream anaerobic digestion (AD) and nitrogen removal processes. Operating THP at lower temperature can mitigate the production of MRPs and improve biodegradability of WAS, while solubilization of WAS is reduced. This study intends to develop a method to reduce the refractory MRPs of WAS without compromising on the solubilization. Fe3+ was introduced into THP process (165 °C, 30 min) to mitigate Maillard reaction. Effects of Fe3+ on solubilization of WAS, reduction of refractory residuals, accumulative methane production, and microbial community shift were studied. Results confirm that solubilization of WAS was improved and refractory residuals were reduced with the amendment of 10 mg-Fe/L FeCl3. MRPs mitigation mechanisms were investigated and mainly attributed to Fe3+-triggered Fenton-like reactions. Methane production was enhanced by 10.4 ± 0.8% and attributed to the improved biodegradability of THP liquor, as well as to the enrichment of protein degradation and methane production related microbial community. This work provides a simple, economical, and safe strategy to reduce refractory residuals discharged from THP-AD system and to enhance methane production for more energy recovery.

Production of MCFAs (Medium-chain fatty acids) from simple substrate (i.e., ethanol and acetate) and WAS with chain elongation microbiome was investigated in this study. The results showed that rapid production of MCFAs was observed when simple substrate was utilized. 1889 mg/L of caproate and 3434 mg/L of butyrate were achieved after 10 d\'s reaction. H2 proportion in the headspace could reach as high as 10.1% on day 8 and then declined quickly. However, when WAS was used, the bacterial consortia was not able to hydrolyze WAS efficiently, which resulted in poor MCFAs production performance. Presence of ethanol could improve the hydrolysis process to a limited degree, which resulted in solubilization of a small fraction of protein and carbohydrate. Around 33.8% and 36.9% of the total detected electrons on day 6 in the 50 mM and 100 mM tests were extracted from WAS respectively. Those results indicate that the chain elongation microbial consortia tended to receive electrons form ethanol directly other than the complex WAS.