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Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders. [ABSTRACT FROM AUTHOR]

Dysregulation of Abelson interactor 1 (ABI1) is associated with various states of disease including developmental defects, pathogen infections, and cancer. ABI1 is an adaptor protein predominantly known to regulate actin cytoskeleton organization processes such as those involved in cell adhesion, migration, and shape determination. Linked to cytoskeleton via vasodilator-stimulated phosphoprotein (VASP), Wiskott-Aldrich syndrome protein family (WAVE), and neural-Wiskott-Aldrich syndrome protein (N-WASP)-associated protein complexes, ABI1 coordinates regulation of various cytoplasmic protein signaling complexes dysregulated in disease states. The roles of ABI1 beyond actin cytoskeleton regulation are much less understood. This comprehensive, protein-centric review describes molecular roles of ABI1 as an adaptor molecule in the context of its dysregulation and associated disease outcomes to better understand disease state-specific protein signaling and affected interconnected biological processes. [ABSTRACT FROM AUTHOR]

The axon guidance cue netrin-1 signals through its receptor DCC (deleted in colorectal cancer) to attract commissural axons to the midline. Variants in DCC are frequently associated with congenital mirror movements (CMMs). A CMM-associated variant in the cytoplasmic tail of DCC is located in a conserved motif predicted to bind to a regulator of actin dynamics called the WAVE (Wiskott-Aldrich syndrome protein–family verprolin homologous protein) regulatory complex (WRC). Here, we explored how this variant affects DCC function and may contribute to CMM. We found that a conserved WRC-interacting receptor sequence (WIRS) motif in the cytoplasmic tail of DCC mediated the interaction between DCC and the WRC. This interaction was required for netrin-1–mediated axon guidance in cultured rodent commissural neurons. Furthermore, the WIRS motif of Fra, the Drosophila DCC ortholog, was required for attractive signaling in vivo at the Drosophila midline. The CMM-associated R1343H variant of DCC, which altered the WIRS motif, prevented the DCC-WRC interaction and impaired axon guidance in cultured commissural neurons and in Drosophila. The findings reveal the WRC as a pivotal component of netrin-1–DCC signaling and uncover a molecular mechanism explaining how a human genetic variant in the cytoplasmic tail of DCC may lead to CMM. Editor's summary: Mirror movements—when intentional movements on one side of the body are mirrored involuntarily on the other side—can occur during normal development and with aging but are also caused by a congenital disorder called CMM. Chaudhari et al. investigated a CMM-associated variant in the axon guidance receptor DCC. They found that the variant disrupted the binding between DCC and the intracellular WAVE regulatory complex, which regulates actin dynamics that are critical for axonal navigation. In flies, neurons expressing the variant or a mutant lacking the WAVE-binding region failed to extend axons properly to and across the body midline, demonstrating how the variant may underlie CMM. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]

Current gene therapy for inborn errors of immunity lia-ue involved the use of gene addition approaches with -viral delivery. This main strategy has had demonstrated sitccess maility in severe conibilied iminitile deficieng, Wiskott-Aldrich syndrome, and chronic gramiloniatous disease. Despite the increasing success of gene tlierapy, there are limitations of gene therapy, and, therefore, hematopoietic steni cell transplantation continues to be the preferred option. With improvements iii viral delivery through next-generation lentiuiral vectors aild the advent of getle editing zoith CRISPR-Cas9, the efficticy mid safety of gene therapy may soon surpass hematopoietic stem cell tronsplaiitation. Furthermore, these advances improve the viability of gene therapy for inborn errors of immunity primarily through decreased risk of transplantation-related complications. Therefore, despite current liinitations, gene therapy for inborn errors of inimunity is poised to continue to expand to more patients and indications. [ABSTRACT FROM AUTHOR]

Immunological dysfunction in multiple lineages of hematopoietic cells and mixed chimerism after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with an increased risk of autoimmunity in patients with Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). Here, we report the efficacy of rituximab against autoimmunity in five patients with WAS and XLT. One patient with systemic arthritis and vasculitis, and two patients with immune thrombocytopenia were successfully treated with rituximab before initiating reduced-intensity conditioning. Rituximab was also used in combination with conditioning to prevent autoimmunity by depleting the recipient B cells in the other two patients with XLT. None of the patients developed autoimmunity without delay in donor B cell reconstitution, even though two patients had stable mixed chimerism after HSCT. These results suggest that aberrant B cell-intrinsic mechanisms are a central cause of autoimmunity, and rituximab is an effective therapeutic option for autoimmunity in patients with WAS and XLT.

Endosomal membrane trafficking is mediated by specific protein coats and formation of actin-rich membrane domains. The Retromer complex coordinates with sorting nexin (SNX) cargo adaptors including SNX27, and the SNX27-Retromer assembly interacts with the Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex which nucleates actin filaments establishing the endosomal recycling domain. Crystal structures, modeling, biochemical, and cellular validation reveal how the FAM21 subunit of WASH interacts with both Retromer and SNX27. FAM21 binds the FERM domain of SNX27 using acidic-Asp-Leu-Phe (aDLF) motifs similar to those found in the SNX1 and SNX2 subunits of the ESCPE-1 complex. Overlapping FAM21 repeats and a specific Pro-Leu containing motif bind three distinct sites on Retromer involving both the VPS35 and VPS29 subunits. Mutation of the major VPS35-binding site does not prevent cargo recycling; however, it partially reduces endosomal WASH association indicating that a network of redundant interactions promote endosomal activity of the WASH complex. These studies establish the molecular basis for how SNX27-Retromer is coupled to the WASH complex via overlapping and multiplexed motif-based interactions required for the dynamic assembly of endosomal membrane recycling domains. [ABSTRACT FROM AUTHOR]

The inducible T-cell costimulator (ICOS) deficiency was first described in 2003. Autosomal re-cessive inherited ICOS deficiency is classified as combined immunodeficiency (CID) and has a wide clinical spectrum including hypogammaglobulinemia, recurrent infections, enteropathies, autoimmunity, lymphoproliferation, and malignancy. WAS/WASL Interacting Protein Family Member 1 (WIPF1) mutation causes WIP deficiency, characterized by thrombocytopenia, immu-nodeficiency, and eczema. Here, we aimed to present a patient with coexisting ICOS and WIP de-ficiency. [ABSTRACT FROM AUTHOR]

Neurite outgrowth is a critical step in neural development, leading to the generation of neurite branches that allow individual neurons to make contacts with multiple neurons within the target region. Polyglutamine-binding protein 1 (PQBP1) is a highly conserved protein with a key role in neural development. Our recent mass spectrometric analysis showed that PQBP1 associates with neural Wiskott-Aldrich syndrome protein (N-WASP), an important actin polymerizationpromoting factor involved in neurite outgrowth. Here, we report that the WW domain of PQBP1 directly interacts with the proline-rich domain of N-WASP. The disruption of this interaction leads to impaired neurite outgrowth and growth cone size. Furthermore, we demonstrate that PQBP1/N-WASP interaction is critical for the recruitment of N-WASP to the growth cone, but does not affect N-WASP protein levels or NWASP-induced actin polymerization. Our results indicated that PQBP1 regulates neurite outgrowth by recruiting NWASP to the growth cone, thus representing an alternative molecular mechanism via which PQBP1-mediates neurite outgrowth. [ABSTRACT FROM AUTHOR]

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies. A specific mechanism of its metastasis has not been established. In this study, we investigated whether Neural Wiskott-Aldrich syndrome protein (N-WASP) plays a role in distant metastasis of PDAC. We found that N-WASP is markedly expressed in clinical patients with PDAC. Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group. N-WASP was noted to be a novel mediator of epithelial-mesenchymal transition (EMT) via gene expression profile studies. Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion, migration, and EMT. We also observed positive association of lysyl oxidase-like 2 (LOXL2) and focal adhesion kinase (FAK) with the N-WASP-mediated response, wherein EMT and invadopodia function were modulated. Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer. These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function, with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis. These findings may aid in the development of therapeutic strategies against pancreatic cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Inborn errors of immunity (IEI) are a diverse group of inherited diseases that affect the innate and adaptive immune systems, leading to symptoms and signs related to infections, autoimmunity, and allergies. There is a remarkable correlation between IEI and endocrinopathies. Our study aimed to retrospectively analyze the clinical, immunological, and endocrine features of our IEI patient Materials and Methods: We retrospectively reviewed medical records of IEI patients from our clinic. Results: Our study included 40 patients (23 men, 17 women) with a median age of 37 years (range:24-66). The predominant clinical phenotype observed was primary antibody deficiencies (92.5%). Only two patients had a genetic diagnosis: one with a pathogenic variant in the nuclear factor-kappaB2 deficiency (NFKB2) and another in Wiskott-Aldrich Syndrome (WAS) genes. At diagnosis, only one patient had endocrinopathies, but during the last visit 13 patients (32.5%) developed at least one endocrine pathology, among which thyroid disease was the most common. Thyroid disease was present in 11 patients (four with thyroid nodules, three with primary hypothyroidism, two with primary hypothyroidism and thyroid nodules, one with secondary hypothyroidism, one with Graves' disease). Additionally, adrenal insufficiency was observed in five patients and primary hypoparathyroidism was found in one patient. The patient diagnosed with NFKB2 deficiency was investigated for potential endocrine disorders that could accompany the genetic defect, despite the absence of clinical symptoms. The patient was subsequently diagnosed with central adrenal insufficiency following these investigations. Another patient in our study had primary adrenal insufficiency, primary hypoparathyroidism, thyroid nodule, and chronic mucocutaneous candidiasis. No mutations in the autoimmune regulatory and forkhead box protein P3 genes were detected in the targeted genome sequencing. Further genetic examination was planned for this patient. Conclusion: In our study, endocrinopathy was a frequent comorbidity observed in our IEI patients. We believe that establishing appropriate screening programs for endocrinopathies in IEI patients is crucial to guiding healthcare professionals. [ABSTRACT FROM AUTHOR]

Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive genetic disease characterized by clinical symptoms such as eczema, thrombocytopenia with small platelets, immune deficiency, prone to autoimmune diseases, and malignant tumors. This disease is caused by mutations of the WAS gene encoding WASprotein (WASP). The locus and type of mutations of the WAS gene and the expression quantity of WASP were strongly correlated with the clinical manifestations of patients. We found a novel mutation in the WAS gene (c. 931 + 5 G > C), which affected splicing to produce three abnormal mRNA, resulting in an abnormally truncated WASP. This mutation led to a reduction but not the elimination of the normal WASP population, resulting in causes X-linked thrombocytopenia (XLT) with mild clinical manifestations. Our findings revealed the pathogenic mechanism of this mutation. [ABSTRACT FROM AUTHOR]

Platelet function at vascular injury sites is tightly regulated through the actin cytoskeleton. The Wiskott–Aldrich syndrome protein-family verprolin-homologous protein (WAVE)-regulatory complex (WRC) activates lamellipodia formation via ARP2/3, initiated by GTP-bound RAC1 interacting with the WRC subunit CYFIP1. The protein FAM49b (Family of Unknown Function 49b), also known as CYRI-B (CYFIP-Related RAC Interactor B), has been found to interact with activated RAC1, leading to the negative regulation of the WRC in mammalian cells. To investigate the role of FAM49b in platelet function, we studied platelet-specific Fam49b−/−-, Cyfip1−/−-, and Cyfip1/Fam49b−/−-mice. Platelet counts and activation of Fam49b−/− mice were comparable to those of control mice. On fully fibrinogen-coated surfaces, Fam49b−/−-platelets spread faster with an increased mean projected cell area than control platelets, whereas Cyfip1/Fam49b−/−-platelets did not form lamellipodia, phenocopying the Cyfip1−/−-platelets. However, Fam49b−/−-platelets often assumed a polarized shape and were more prone to migrate on fibrinogen-coated surfaces. On 2D structured micropatterns, however, Fam49b−/−-platelets displayed reduced spreading, whereas spreading of Cyfip1−/−- and Cyfip1/Fam49b−/−-platelets was enhanced. In summary, FAM49b contributes to the regulation of morphology and migration of spread platelets, but to exert its inhibitory effect on actin polymerization, the functional WAVE complex must be present. [ABSTRACT FROM AUTHOR]

The Bin–Amphiphysin–Rvs (BAR) domain of endophilin binds to the cell membrane and shapes it into a tubular shape for endocytosis. Endophilin has a Src-homology 3 (SH3) domain at their C-terminal. The SH3 domain interacts with the proline-rich motif (PRM) that is found in proteins such as neural Wiskott–Aldrich syndrome protein (N-WASP). Here, we re-examined the binding sites of the SH3 domain of endophilin in N-WASP by machine learning-based prediction and identified the previously unrecognized binding site. In addition to the well-recognized PRM at the central proline-rich region, we found a PRM in front of the N-terminal WASP homology 1 (WH1) domain of N-WASP (NtPRM) as a binding site of the endophilin SH3 domain. Furthermore, the diameter of the membrane tubules in the presence of NtPRM mutant was narrower and wider than that in the presence of N-WASP and in its absence, respectively. Importantly, the NtPRM of N-WASP was involved in the membrane localization of endophilin A2 in cells. Therefore, the NtPRM contributes to the binding of endophilin to N-WASP in membrane remodeling. [ABSTRACT FROM AUTHOR]

Skeletal myogenesis is an intricate process involving the differentiation of progenitor cells into myofibers, which is regulated by actin cytoskeletal dynamics and myogenic transcription factors. Although recent studies have demonstrated the pivotal roles of actin-binding proteins (ABPs) as mechanosensors and signal transducers, the biological significance of WAVE2 (Wiskott–Aldrich syndrome protein family member 2), an ABP essential for actin polymerization, in myogenic differentiation of progenitor cells has not been investigated. Our study provides important insights into the regulatory roles played by WAVE2 in the myocardin-related transcription factor A (MRTFA)–serum response factor (SRF) signaling axis and differentiation of myoblasts. We demonstrate that WAVE2 expression is induced during myogenic differentiation and plays a pivotal role in actin cytoskeletal remodeling in C2C12 myoblasts. Knockdown of WAVE2 in C2C12 cells reduced filamentous actin levels, increased globular actin accumulation, and impaired the nuclear translocation of MRTFA. Furthermore, WAVE2 depletion in myoblasts inhibited the expression and transcriptional activity of SRF and suppressed cell proliferation in myoblasts. Consequently, WAVE2 knockdown suppressed myogenic regulatory factors (i.e., MyoD, MyoG, and SMYD1) expressions, thereby hindering the differentiation of myoblasts. Thus, this study suggests that WAVE2 is essential for myogenic differentiation of progenitor cells by modulating the mechanosensitive MRTFA–SRF axis. [ABSTRACT FROM AUTHOR]

Long noncoding RNA MYLK antisense RNA 1 (MYLK‐AS1) is the crux in multiple diseases. Therefore, the purpose of this study was to investigate the possible mechanism of MYLK‐AS1. A total of 62 colon cancer (CC) specimens and paired adjacent normal tissues were collected, and the expression of MYLK‐AS1, microRNA (miR)‐101‐5p/cell division cycle 42 (CDC42) was detected. CC cell lines were transfected with MYLK‐AS1, miR‐101‐5p, CDC42‐related plasmids, and the biological functions and markers of epithelial‐mesenchymal transition (EMT) were analyzed. The binding relationship between MYLK‐AS1, miR‐101‐5p, and CDC42 was evaluated. In CC tissues and cell lines, MYLK‐AS1 and CDC42 were highly expressed, and miR‐101‐5p was lowly expressed. Inhibition of MYLK‐AS1 or upregulation of miR‐101‐5p can inhibit CC cell growth and EMT. miR‐101‐5p inhibited CDC42/N‐wasp axis activation in CC cells by targeting CDC42. Knockdown of CDC42 or upregulation of miR‐101‐5p partially reversed the effects caused by upregulation of MYLK‐AS1. MYLK‐AS1, which is significantly upregulated in CC, may be a molecular sponge for miR‐101‐5p, and MYLK‐AS1 promotes the activation of the CDC42/N‐wasp axis in CC cells by targeting CDC42 through miR‐101‐5p, which in turn promotes tumor development. MYLK‐AS1 may be a potential biomarker and target for CC therapy. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) with unknown etiology, characterized by sustained damage repair of epithelial cells and abnormal activation of fibroblasts, the underlying mechanism of the disease remains elusive. Methods: To evaluate the role of Tuftelin1 (TUFT1) in IPF and elucidate its molecular mechanism. We investigated the level of TUFT1 in the IPF and bleomycin-induced mouse models and explored the influence of TUFT1 deficiency on pulmonary fibrosis. Additionally, we explored the effect of TUFT1 on the cytoskeleton and illustrated the relationship between stress fiber and pulmonary fibrosis. Results: Our results demonstrated a significant upregulation of TUFT1 in IPF and the bleomycin (BLM)-induced fibrosis model. Disruption of TUFT1 exerted inhibitory effects on pulmonary fibrosis in both in vivo and in vitro. TUFT1 facilitated the assembly of microfilaments in A549 and MRC-5 cells, with a pronounced association between TUFT1 and Neuronal Wiskott-Aldrich syndrome protein (N-WASP) observed during microfilament formation. TUFT1 can promote the phosphorylation of tyrosine residue 256 (Y256) of the N-WASP (pY256N-WASP). Furthermore, TUFT1 promoted transforming growth factor-β1 (TGF-β1) induced fibroblast activation by increasing nuclear translocation of pY256N-WASP in fibroblasts, while wiskostatin (Wis), an N-WASP inhibitor, suppressed these processes. Conclusions: Our findings suggested that TUFT1 plays a critical role in pulmonary fibrosis via its influence on stress fiber, and blockade of TUFT1 effectively reduces pro-fibrotic phenotypes. Pharmacological targeting of the TUFT1-N-WASP axis may represent a promising therapeutic approach for pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Wiskott-Aldrich syndrome (WAS) is a severe X-linked primary immunodeficiency resulting from a diversity of mutations distributed across all 12 exons of the WAS gene. WAS encodes a hematopoietic-specific and developmentally regulated cytoplasmic protein (WASp). The objective of this study was to develop a gene correction strategy potentially applicable to most WAS patients by employing nuclease-mediated, site-specific integration of a corrective WAS gene sequence into the endogenous WAS chromosomal locus. In this study, we demonstrate the ability to target the integration of WAS2-12-containing constructs into intron 1 of the endogenous WAS gene of primary CD34+ hematopoietic stem and progenitor cells (HSPCs), as well as WASp-deficient B cell lines and WASp-deficient primary T cells. This intron 1 targeted integration (TI) approach proved to be quite efficient and restored WASp expression in treated cells. Furthermore, TI restored WASp-dependent function to WAS patient T cells. Edited CD34+ HSPCs exhibited the capacity for multipotent differentiation to various hematopoietic lineages in vitro and in transplanted immunodeficient mice. This methodology offers a potential editing approach for treatment of WAS using patient’s CD34+ cells.

The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. We generated three isogenic WAS models using patient induced pluripotent stem cells and genome editing. These models recapitulated WAS phenotypes and revealed that WASP deficiency causes an upregulation of numerous RNA splicing factors and widespread altered splicing. Loss of WASP binding to splicing factor gene promoters frequently leads to aberrant epigenetic activation. WASP interacts with dozens of nuclear speckle constituents and constrains SRSF2 mobility. Using an optogenetic system, we showed that WASP forms phase-separated condensates that encompasses SRSF2, nascent RNA and active Pol II. The role of WASP in gene body condensates is corroborated by ChIPseq and RIPseq. Together our data reveal that WASP is a nexus regulator of RNA splicing that controls the transcription of splicing factors epigenetically and the dynamics of the splicing machinery through liquid-liquid phase separation.

Abstract Background Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene that leads to increased susceptibility to infections, thrombocytopenia, eczema, malignancies, and autoimmunity. Central nervous system (CNS) autoimmune manifestations are uncommon. Case Presentation We describe the case of a five-year-old boy with refractory thrombocytopenia and iron deficiency anemia who developed relapsing bilateral optic neuritis. Myelin oligodendrocyte glycoprotein antibody (MOG-IgG) via serum fluorescence-activated cell sorting assay was positive (titer 1:100), confirming a diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). At age six, molecular panel testing for genes associated with primary immunodeficiency identified a missense WAS gene variant. He was subsequently found to have decreased WAS protein expression, consistent with a diagnosis of WAS. Conclusions This case expands the reported spectrum of CNS autoimmunity associated with WAS and may help to inform long-term therapeutic options.

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

We describe two young patients with Wiskott-Aldrich Syndrome (WAS) who were treated by T-replete hematopoietic stem cell transplantation (HSCT) from the HLA haploidentical father according to a modified Baltimore protocol. Whereas similar protocols have been successfully used in various malignant and non-malignant diseases, this is the first report for this particular disease. The data being presented pertains to the report about two successful haploidentical transplants with post transplant cyclophosphamide (PTCY) after busulfan-based conditioning. [ABSTRACT FROM AUTHOR]

Background and aims: Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder characterized by severe eczema, recurrent infections, and micro-thrombocytopenia. Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic option for patients with classic form. The risk of developing post-transplant tumors appears to be higher in patients with WAS than in other inborn errors of immunity (IEIs), but the actual incidence is not well defined, due to the scarcity of published data. Methods: Herein, we describe a 10-year-old patient diagnosed with WAS, treated with HSCT in the first year of life, who subsequently developed two rare solid tumors, kaposiform hemangioendothelioma and desmoid tumor. A review of the literature on post-HSCT tumors in WAS patients has been performed. Results: The patient received diagnosis of classic WAS at the age of 2 months (Zhu score = 3), confirmed by WAS gene sequencing, which detected the nonsense hemizygous c.37C>T (Arg13X) mutation. At 9 months, patient underwent HSCT from a matched unrelated donor with an adequate immune reconstitution, characterized by normal lymphocyte subpopulations and mitogen proliferation tests. Platelet count significantly increased, even though platelet count never reached reference values. A mixed chimerism was also detected, with a residual WASP-population on monocytes (27.3%). The patient developed a kaposiform hemangioendothelioma at the age of 5. A second abdominal tumor was identified, histologically classified as a desmoid tumor when he reached the age of 10 years. Both hematopoietic and solid tumors were identified in long-term WAS survivors after HSCT. Conclusion: Here, we describe the case of a patient with WAS who developed two rare solid tumors after HSCT. An active surveillance program for the risk of tumors is necessary in the long-term follow-up of post-HSCT WAS patients. [ABSTRACT FROM AUTHOR]

Wiskott-Aldrich Syndrome (WAS) is an immunodeficiency disorder resulting from genetic mutations in the WAS protein (WASP) gene in the X chromosome, characterized by thrombocytopenia, eczema, and infections. This case report focused on a 12-year-old Iranian male with WAS with a history of Crohn's disease, meningitis, and bilateral hernia. His WAS was diagnosed at age six with a hemizygous c.777+1 G>A mutation in the WASP gene. The patient was referred to our clinic with symptoms including fever, abdominal pain, thrombocytopenia, and elevated ESR. Clinical Imaging revealed a significant lung nodule align bronchiectasis, mild ascites, bilateral epididymitis, and lymphadenopathy. Nephrotic syndrome with proteinuria and low levels of albumin have been observed. After six months of receiving intravenous immunoglobulin (IVIG) therapy in addition to antibiotics and antivirals, the patient suffered from arthritis, edema, and fever. Our WAS patient presented the late comorbidity of renal involvement, which highlights the monitoring of this patient, such as those involved in chronic infections. Therefore, a precise treatment approach is needed to manage either the primary immunodeficiency or the late-discovered diseases. [ABSTRACT FROM AUTHOR]

This clinical correspondence discusses the case of a 19-year-old male with Wiskott-Aldrich syndrome (WAS) who developed acrodermatitis continua of Hallopeau (ACH), a rare pustular psoriasis variant. The patient underwent various treatments, including gene therapy, but experienced treatment resistance. Ultimately, guselkumab, an IL-23 inhibitor, was initiated and resulted in significant improvement with reduced inflammation and complete resolution of pustules. The case highlights the potential of guselkumab in treating ACH in WAS patients and emphasizes the need for a multidisciplinary approach to manage complex skin conditions. [Extracted from the article]

Gene therapy is an innovative treatment for Primary Immune Deficiencies (PIDs) that uses autologous hematopoietic stem cell transplantation to deliver stem cells with added or edited versions of the missing or malfunctioning gene that causes the PID. Initial studies of gene therapy for PIDs in the 1990-2000's used integrating murine gamma-retroviral vectors. While these studies showed clinical efficacy in many cases, especially with the administration of marrow cytoreductive conditioning before cell re-infusion, these vectors caused genotoxicity and development of leukoproliferative disorders in several patients. More recent studies used lentiviral vectors in which the enhancer elements of the long terminal repeats self-inactivate during reverse transcription ("SIN" vectors). These SIN vectors have excellent safety profiles and have not been reported to cause any clinically significant genotoxicity. Gene therapy has successfully treated several PIDs including Adenosine Deaminase Severe Combined Immunodeficiency (SCID), X-linked SCID, Artemis SCID, Wiskott-Aldrich Syndrome, X-linked Chronic Granulomatous Disease and Leukocyte Adhesion Deficiency-I. In all, gene therapy for PIDs has progressed over the recent decades to be equal or better than allogeneic HSCT in terms of efficacy and safety. Further improvements in methods should lead to more consistent and reliable efficacy from gene therapy for a growing list of PIDs.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies. We report that overexpression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress. Increased expression of WASF3 in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue. Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation. In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID. [ABSTRACT FROM AUTHOR]

Background: Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene that leads to increased susceptibility to infections, thrombocytopenia, eczema, malignancies, and autoimmunity. Central nervous system (CNS) autoimmune manifestations are uncommon. Case Presentation: We describe the case of a five-year-old boy with refractory thrombocytopenia and iron deficiency anemia who developed relapsing bilateral optic neuritis. Myelin oligodendrocyte glycoprotein antibody (MOG-IgG) via serum fluorescence-activated cell sorting assay was positive (titer 1:100), confirming a diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). At age six, molecular panel testing for genes associated with primary immunodeficiency identified a missense WAS gene variant. He was subsequently found to have decreased WAS protein expression, consistent with a diagnosis of WAS. Conclusions: This case expands the reported spectrum of CNS autoimmunity associated with WAS and may help to inform long-term therapeutic options. [ABSTRACT FROM AUTHOR]

Summary: Wiskott–Aldrich syndrome (WAS) is an X‐linked recessive disorder caused by WAS gene mutations resulting in haematopoietic/immune cell defects. Recent studies report accelerated death of WAS platelets and lymphocytes. Data on megakaryocyte (MK) maturation, viability and their possible role in thrombocytopenia development in WAS are limited. In this study we evaluate the MK viability and morphology in untreated, romiplostim‐treated WAS patients compared with normal controls. The study included 32 WAS patients and 17 healthy donors. MKs were captured from bone marrow aspirates by surface‐immobilized anti‐GPIIb‐IIIa antibody. Viability (by phosphatidylserine [PS] externalization), distribution by maturation stages and size of MK were determined by light microscopy. MK distribution by maturation stages in patients differed from controls. 40 ± 22% of WAS MKs versus 23 ± 11% of normal MKs were at maturation stage 3 (p = 0.02), whereas 24 ± 20% in WAS and 39 ± 14% in controls had megakaryoblast morphology (p = 0.05). Romiplostim treatment changed the MK maturation stages distribution close to normal. PS‐positive (PS+) MK in WAS was significantly higher (21 ± 21%) than in healthy controls (2 ± 4%, p < 0.01). WAS patients with more damaging truncating mutations and higher disease score had higher PS+ MK fraction (Spearman r = 0.6, p < 0.003). We conclude that WAS MKs have increased cell death tendency and changes in maturation pattern. Both could contribute to thrombocytopenia in WAS patients. [ABSTRACT FROM AUTHOR]

Background: Wiskott–Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia and eczema and is caused by a mutation in the WAS gene. WAS has heterogeneous clinical manifestations, and its clinically milder form is called X-linked thrombocytopenia (XLT). Patients with WAS/XLT sometimes have kidney complications, the most common of which is immunoglobulin (Ig)A nephropathy associated with aberrant glycosylation of IgA. Case diagnosis/treatment: The patient was a 6-year-old girl who was diagnosed with female XLT at the age of 4 years; she presented with microscopic hematuria and proteinuria at a school urinalysis. Her father had thrombocytopenia and IgA nephropathy while in his 20 s. The patient and her father had the same WAS gene mutations. A kidney biopsy was performed, and no abnormal findings were observed by light microscopy. Immunofluorescence analysis revealed a granular pattern of IgG staining along the capillary wall. Electron microscopy revealed small electron-dense deposits in subepithelial lesions. Consequently, we diagnosed her with membranous nephropathy (MN). Tissue PLA2R and THSD7A were negative, and she was judged unlikely to have secondary MN on the basis of blood test findings and IgG staining. We started the administration of angiotensin-converting enzyme inhibitors, and her proteinuria gradually decreased. Conclusion: To our knowledge, this is the first report of MN in a female WAS/XLT patient. WAS protein expression defects affect all immune system cells; however, the mechanisms underlying the occurrence of autoimmunity are not completely understood. In WAS/XLT patients, MN may develop as a result of increased autoantibody production, similar to other types of immunodeficiency. [ABSTRACT FROM AUTHOR]

Wiskott–Aldrich syndrome is an X-linked recessive primary immune-deficiency disorder very rarely reported from black African children. A 12-year old boy with recurrent sinopulmonary and diarrheal infections, eczema, thrombocytopenia, and low platelet volume was found by whole genome sequencing to harbor a predicted pathogenic c.1205dupC (p.Pro403Alafs*92) variant of a mutation in the WAS gene — confirming the diagnosis. This case report summarizes his presentation and management and provides a useful summary of the diagnosis and the responsible novel genetic mutation. [ABSTRACT FROM AUTHOR]

The exact etiopathogenesis of Kawasaki disease (KD), the most common childhood vasculitis, remains unknown; however, an aberrant immune response, possibly triggered by an infectious or environmental agent in genetically predisposed children, is believed to be the underlying pathogenetic mechanism. Patients with inborn errors of immunity (IEI) are predisposed to infections that trigger immune dysregulation due to an imbalance in various arms of the immune system. KD may develop as a complication in both primary and secondary immunodeficiencies. KD may occur either at disease presentation or have a later onset in IEIs. These include X-linked agammaglobulinemia (XLA), selective IgA deficiency, transient hypogammaglobulinemia of infancy; Wiskott–Aldrich syndrome (WAS), hyper IgE syndrome (HIES); chronic granulomatous disease (CGD), innate and intrinsic immunity defects, and autoinflammatory diseases, including PFAPA. Hitherto, the association between KD and IEI is confined to specific case reports and case series and, thus, requires extensive research for a comprehensive understanding of the underlying pathophysiological mechanisms. IEIs may serve as excellent disease models that would open new insights into the disease pathogenesis of children affected with KD. The current review highlights this critical association between KD and IEI supported by published literature. [ABSTRACT FROM AUTHOR]

Purpose: 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. Methods: 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. Results: 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%). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Objective: To investigate similarities and differences in immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). Method: We retrospectively analyzed the lymphocyte subpopulations and the serum level of various immune-related protein or peptide on Days 15, 30, 100, 180 and 360 post-transplantation in 70 children with WAS and 48 children with CGD who underwent allo-HSCT at the Transplantation Center of the Department of Hematology-Oncology, Children's Hospital of Chongqing Medical University from January 2007 to December 2020, and we analyzed the differences in the immune reconstitution process between the two groups. Results: ① The WAS group had higher lymphocyte subpopulation counts than the CGD group. ② Among children aged 1-3 years who underwent transplantation, the WAS group had higher lymphocyte subpopulation counts than the CGD group. ③ Further comparisons were performed between children with non-umbilical cord blood transplantation (non-UCBT) and children with umbilical cord blood transplantation (UCBT) in the WAS group. On Day 15 and 30 post-transplantation, the non-UCBT group had higher B-cell counts than the UCBT group. On the remaining time points post-transplantation, the UCBT group had higher lymphocyte subpopulation counts than the non-UCBT group. ④ Comparisons were performed between children with non-UCBT in the WAS group and in the CGD group, the lymphocyte subpopulation counts were higher in the WAS group compared to the CGD group. ⑤ On Day 100 posttransplantation, the CGD group had higher C3 levels than the WAS group. On Day 360 post-transplantation, the CGD group had higher IgA and C4 levels than the WAS group. Conclusion: ① The rate of immunity recovery was faster in children within the WAS group compared to those children within the CGD group, which may be attributed to the difference of percentage undergoing UCBT and primary diseases. ② In the WAS group, the non-UCBT group had higher B-cell counts than the UCBT group at Day 15 and 30 post-transplantation, however, the UCBT group had higher B-cell counts than the non-UCBT group at Day 100 and 180 post-transplantation, suggesting that cord blood has strong B-cell reconstitution potentiality after transplantation. [ABSTRACT FROM AUTHOR]