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Frontiers in Immunology 2023To investigate similarities and differences in immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with...
Differential analysis of immune reconstitution after allogeneic hematopoietic stem cell transplantation in children with Wiskott-Aldrich syndrome and chronic granulomatous disease.
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 post-transplantation, 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.
Topics: Humans; Child; Granulomatous Disease, Chronic; Immune Reconstitution; Retrospective Studies; Wiskott-Aldrich Syndrome; Hematopoietic Stem Cell Transplantation; Lymphocytosis
PubMed: 37388746
DOI: 10.3389/fimmu.2023.1202772 -
Immunological Reviews Nov 2013The importance of the cytoskeleton in mounting a successful immune response is evident from the wide range of defects that occur in actin-related primary... (Review)
Review
The importance of the cytoskeleton in mounting a successful immune response is evident from the wide range of defects that occur in actin-related primary immunodeficiencies (PIDs). Studies of these PIDs have revealed a pivotal role for the actin cytoskeleton in almost all stages of immune system function, from hematopoiesis and immune cell development, through to recruitment, migration, intercellular and intracellular signaling, and activation of both innate and adaptive immune responses. The major focus of this review is the immune defects that result from mutations in the Wiskott-Aldrich syndrome gene (WAS), which have a broad impact on many different processes and give rise to clinically heterogeneous immunodeficiencies. We also discuss other related genetic defects and the possibility of identifying new genetic causes of cytoskeletal immunodeficiency.
Topics: Actin Cytoskeleton; Actins; Animals; Humans; Immune System; Immunologic Deficiency Syndromes; Mutation; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein Family
PubMed: 24117828
DOI: 10.1111/imr.12114 -
Frontiers in Immunology 2023Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder characterized by severe eczema, recurrent infections, and... (Review)
Review
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 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.
Topics: Male; Humans; Infant; Child; Wiskott-Aldrich Syndrome; Fibromatosis, Aggressive; Sarcoma, Kaposi; Hematopoietic Stem Cell Transplantation
PubMed: 37781361
DOI: 10.3389/fimmu.2023.1229674 -
Scandinavian Journal of Immunology Jan 2020Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by a mutation in the WAS gene that encodes the WAS protein (WASp); up to 5-10% of...
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by a mutation in the WAS gene that encodes the WAS protein (WASp); up to 5-10% of these patients develop inflammatory bowel disease (IBD). The mechanisms by which WASp deficiency causes IBD are unclear. Intestinal microbial dysbiosis and imbalances in host immune responses play important roles in the pathogenesis of polygenetic IBD; however, few studies have conducted detailed examination of the microbial alterations and their relationship with IBD in WAS. Here, we collected faecal samples from 19 children (all less than 2 years old) with WAS and samples from WASp-KO mice with IBD and subjected them to 16S ribosomal RNA sequencing. We found that microbial community richness and structure in WAS children were different from those in controls; WAS children revealed reduced microbial community richness and diversity. Relative abundance of Bacteroidetes and Verrucomicrobiain in WAS children was significantly lower, while that of Proteobacteria was markedly higher. WASp-KO mice revealed a significantly decreased abundance of Firmicutes. Faecal microbial dysbiosis caused by WASp deficiency is similar to that observed for polygenetic IBD, suggesting that WASp may play crucial function in microbial homoeostasis and that microbial dysbiosis may contribute to IBD in WAS. These microbial alterations may be useful targets for monitoring and therapeutically managing intestinal inflammation in WAS.
Topics: Animals; Biodiversity; Biomarkers; Case-Control Studies; Child, Preschool; Disease Models, Animal; Dysbiosis; Feces; Female; Gastrointestinal Microbiome; Humans; Infant; Inflammatory Bowel Diseases; Male; Metagenome; Metagenomics; Mice; Mice, Knockout; Mutation; RNA, Ribosomal, 16S; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 31267543
DOI: 10.1111/sji.12805 -
Clinical Immunology (Orlando, Fla.) Sep 2022T cells following immunological synapse (IS) formation with antigen-presenting cells produce multiple cytokines through T cell receptor, integrin, and costimulatory...
T cells following immunological synapse (IS) formation with antigen-presenting cells produce multiple cytokines through T cell receptor, integrin, and costimulatory signaling. Here, we investigated the cytokine profiles following IS formation in response to staphylococcal superantigen exposure in three adolescent patients with classical Wiskott-Aldrich syndrome (WAS) and in one patient with leukocyte adhesion deficiency (LAD) type 1. All WAS patients showed lower Th1 and Th2-skewed cytokine production; similar results were observed in the flow cytometric analysis of IFNγ- and IL-4-producing T cells. The patient with LAD type 1 with somatic mosaicism in 2% of CD8+ T cells showed lower Th1 and Th2 cytokine production than healthy controls. The patients with WAS were susceptible to infections and atopic manifestations, and the patients with LAD type 1 showed cold abscess on their skin, our findings using patient samples provide clinical insights into the mechanisms underlying immunodeficiency related to the symptoms of each disease.
Topics: Adolescent; Cytokines; Humans; Immunological Synapses; Leukocyte-Adhesion Deficiency Syndrome; Lymphocyte Activation; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35973636
DOI: 10.1016/j.clim.2022.109098 -
Clinical and Experimental Immunology Apr 2000
Review
Topics: Animals; Humans; Wiskott-Aldrich Syndrome
PubMed: 10759756
DOI: 10.1046/j.1365-2249.2000.01193.x -
Current Biology : CB Jun 1996The gene responsible for Wiskott-Aldrich syndrome, a disease affecting platelets and lymphocytes, has been cloned and its protein product (WASp) found to interact with... (Review)
Review
The gene responsible for Wiskott-Aldrich syndrome, a disease affecting platelets and lymphocytes, has been cloned and its protein product (WASp) found to interact with the GTPase Cdc42. WASp seems to provide a link between Cdc42 and the actin cytoskeleton, perhaps explaining the cellular defects underlying the disease.
Topics: Cell Cycle Proteins; GTP-Binding Proteins; Humans; Proteins; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; cdc42 GTP-Binding Protein
PubMed: 8793292
DOI: 10.1016/s0960-9822(09)00447-3 -
Journal of Clinical Pathology Dec 1991
Review
Topics: Blood Platelet Disorders; Humans; Kidney Diseases; Wiskott-Aldrich Syndrome
PubMed: 1791213
DOI: 10.1136/jcp.44.12.979 -
British Journal of Haematology Jun 1998
Review
Topics: Blood Platelets; Cytoskeleton; Dendritic Cells; Humans; Mutation; Proteins; Signal Transduction; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 9674729
DOI: 10.1046/j.1365-2141.1998.00756.x -
Journal of Clinical Immunology Jan 2023Patients with Wiskott-Aldrich syndrome (WAS) harbor mutations in the WAS gene and suffer from immunodeficiency, microthrombocytopenia, and eczema. T-cells play an...
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.
Topics: Humans; Wiskott-Aldrich Syndrome; Immunoglobulin Heavy Chains; B-Lymphocytes; T-Lymphocytes; Eczema
PubMed: 36044170
DOI: 10.1007/s10875-022-01349-8