Wiscott-Aldrich Syndrome Research Articles

Aberrant expression of the major sialoglycoprotein (CD43) on the monocytes of patients with myelodysplastic syndromes.

CD43, a sialylated glycoprotein expressed on the surface of most hematopoietic cells, has been implicated in cell adhesion and signaling. The reduced expression of this antigen in patients with Wiscott-Aldrich syndrome, in which progressive immunodeficiency is a major problem, raised the question whether abnormal expression of this molecule could affect the susceptibility to infections in patients with myelodysplastic syndromes (MDS). We studied the expression of this antigen on the monocytes of ten patients with chronic myelomonocytic leukemia (CMML) and compared the results with 67 patients suffering from other MDS syndromes and with 18 healthy individuals. We chose this series as it plays an important role in MDS patients where in most cases the neutrophils are defective. We also examined the following antigens as indicative of activation and adhesion of the monocytes in these patients: CD11b, CD18, CD35, CD38, CD44, CD69. We found decreased expression of CD43 on the monocytes of the RA, RAS, RAEB, and RAEB-t patients compared with the CMML and controls. The other activation molecules studied were found to be upregulated, suggesting the existence of activated monocytes in these patients. The increased levels of soluble vascular cell adhesion molecule in these patients suggest vascular endothelial activation in the absence of infection. Further experiments are needed to investigate the significance of CD43 downregulation in these patients, its role in cell adherence and tissue migration, and the correlation of the phenomenon to the increased susceptibility to infections observed in these patients.

The p150-Spir protein provides a link between c-Jun N-terminal kinase function and actin reorganization.

The Jun N-terminal kinase (JNK) is a downstream effector of Rac and Cdc42 GTPases involved in actin reorganization [1-3]. A role of the Drosophila JNK homologue, Basket (DJNK/Bsk), in the regulation of cell shape changes and actin reorganization arises from its function in the process of dorsal closure [4-6]. One potential mechanism for induction of cytoskeletal changes by JNK is via transcriptional activation of the decapentaplegic gene (dpp, a member of the TGFbeta superfamily) [6]. A direct link between JNK signalling and actin organization has not yet been found, however. We have identified a novel DJNK-interacting protein, p150-Spir, that belongs to the Wiscott-Aldrich syndrome protein (WASP) homology domain 2 (WH2) family of proteins involved in actin reorganization [7] [8]. It is a multidomain protein with a cluster of four WH2 domains, a modified FYVE zinc-finger motif [9], and a DEJL motif, a docking site for JNK [10], at its carboxy-terminal end. In mouse fibroblasts, p150-Spir colocalized with F-actin and its overexpression induced clustering of filamentous actin around the nucleus. When coexpressed with p150-Spir in NIH 3T3 cells, JNK translocated to and colocalizes with p150-Spir at discrete spots around the nucleus. Carboxy-terminal sequences of p150-Spir were phosphorylated by JNK both in vitro and in vivo. We conclude that p150-Spir is a downstream target of JNK function and provides a direct link between JNK and actin organization.

Bone Marrow Transplantation for Non-Malignant Disease

AbstractThis article reviews the experience in hematopoietic stem cell transplantation (HSCT) for non-malignant disease. HSCT has long been applied as treatment of life-threatening congenital immunodeficiency and metabolic diseases. In Section I, Dr. Parkman reviews that experience for severe combined immunodeficiency, Wiscott-Aldrich syndrome, hyper IGM syndrome, Chédiak-Higashi disease and hereditary lymphohistiocytosis. The value of HSCT in genetic metabolic diseases such as osteopetrosis, osteogenesis imperfecta and the storage diseases are reviewed. In Section II, Dr. Walters reviews the experience over the last decade with allogeneic stem cell transplantation in patients with thalassemia major and sickle cell disease. In Section III, Dr. Sullivan reviews the more recent investigations using stem cell transplantation in patients with advanced autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, multiple sclerosis and juvenile rheumatoid arthritis. The pathogenesis and outcome with conventional care of these patients, the selection criteria and current results for HSCT, and the future directions in clinical research and patient care using this modality are addressed.

Bone Marrow Transplantation for Non-Malignant Disease

This article reviews the experience in hematopoietic stem cell transplantation (HSCT) for non-malignant disease. HSCT has long been applied as treatment of life-threatening congenital immunodeficiency and metabolic diseases. In Section I, Dr. Parkman reviews that experience for severe combined immunodeficiency, Wiscott-Aldrich syndrome, hyper IGM syndrome, Chédiak-Higashi disease and hereditary lymphohistiocytosis. The value of HSCT in genetic metabolic diseases such as osteopetrosis, osteogenesis imperfecta and the storage diseases are reviewed. In Section II, Dr. Walters reviews the experience over the last decade with allogeneic stem cell transplantation in patients with thalassemia major and sickle cell disease. In Section III, Dr. Sullivan reviews the more recent investigations using stem cell transplantation in patients with advanced autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, multiple sclerosis and juvenile rheumatoid arthritis. The pathogenesis and outcome with conventional care of these patients, the selection criteria and current results for HSCT, and the future directions in clinical research and patient care using this modality are addressed.

Bone Marrow Transplantation for Non-Malignant Disease.

This article reviews the experience in hematopoietic stem cell transplantation (HSCT) for non-malignant disease. HSCT has long been applied as treatment of life-threatening congenital immunodeficiency and metabolic diseases. In Section I, Dr. Parkman reviews that experience for severe combined immunodeficiency, Wiscott-Aldrich syndrome, hyper IGM syndrome, Chédiak-Higashi disease and hereditary lymphohistiocytosis. The value of HSCT in genetic metabolic diseases such as osteopetrosis, osteogenesis imperfecta and the storage diseases are reviewed. In Section II, Dr. Walters reviews the experience over the last decade with allogeneic stem cell transplantation in patients with thalassemia major and sickle cell disease. In Section III, Dr. Sullivan reviews the more recent investigations using stem cell transplantation in patients with advanced autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, multiple sclerosis and juvenile rheumatoid arthritis. The pathogenesis and outcome with conventional care of these patients, the selection criteria and current results for HSCT, and the future directions in clinical research and patient care using this modality are addressed.

Wiscott-Aldrich syndrome

Wiscott-Aldrich syndrome

Identification and characterization of small GTPase-associated kinases.

AbstractRho-family signal-transduction cascades, which appear to be conserved in all eukaryotes, probably coordinate cytoskeletal reorganization and transcriptional activation via a variety of protein and lipid kinases, and other as-yet-undefined target proteins. The dissection of these cascades has begun with the identification of a growing number of Rho-p21 interacting proteins, though for the most part it remains to be established which of these proteins represents bona fide targets. Here we describe a method that was developed to analyze p21-interacting proteins in total protein extracts after their separation on sodium dodecyl sulfate (SDS)-polyacrylamide gels. In fact, both guanosine 5′ triphosphatase (GTPase)-activating proteins and GTPase-inhibitory proteins can be detected in situ, and the latter class have been successfully identified in expression screens. Novel p21-targets have now been characterized by this method, including the Cdc42-binding tyrosine kinase (ACK) (1); the p21-activated kinase (PAK) (2,3); the p160 RhoA-associated kinase (ROK) (4,5); and the neutrophil Wiscott-Aldrich Syndrome protein (WASP) (6). Deletion analysis of a number of cDNAs encoding these proteins have shown the p2l-binding domains encompass less than 60 amino acid residues (1,2).KeywordsSodium Dodecyl SulfateExpression ScreeningAgarose PlateConserve Amino Acid MotifProtein OverlayThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Bee1, a yeast protein with homology to Wiscott-Aldrich syndrome protein, is critical for the assembly of cortical actin cytoskeleton.

Yeast protein, Bee1, exhibits sequence homology to Wiskott-Aldrich syndrome protein (WASP), a human protein that may link signaling pathways to the actin cytoskeleton. Mutations in WASP are the primary cause of Wiskott-Aldrich syndrome, characterized by immuno-deficiencies and defects in blood cell morphogenesis. This report describes the characterization of Bee1 protein function in budding yeast. Disruption of BEE1 causes a striking change in the organization of actin filaments, resulting in defects in budding and cytokinesis. Rather than assemble into cortically associated patches, actin filaments in the buds of delta bee1 cells form aberrant bundles that do not contain most of the cortical cytoskeletal components. It is significant that delta bee1 is the only mutation reported so far that abolishes cortical actin patches in the bud. Bee1 protein is localized to actin patches and interacts with Sla1p, a Src homology 3 domain-containing protein previously implicated in actin assembly and function. Thus, Bee1 protein may be a crucial component of a cytoskeletal complex that controls the assembly and organization of actin filaments at the cell cortex.

328 ATOPIC MANIFESTATIONS OF PRIMARY IMMUNE DEFICIENCIES

During screening of 367 children with primary immune deficiencies (PID) for allergic manifestations the most frequent atopic finding was dermatitis, established in all patients with Wiscott-Aldrich syndrome (n = 11) and hyper-IgE syndrome (n = 20), in 25 from 108 patients with selective IgA deficiency (sIgAd) and in 2 from 19 patients with chronic granulematous disease. Bronchial asthma or wheezing bronchitis were diagnosed in 26 patients with sIgAd. Among the patients with other PID, including 113 patients with hypogammaglobulinemia (congenital X-linked, common variable, with elevated IgM), 66 patients with ataxia-teleangiectasia and 30 patients with chronic mucocutaneous candidiasis atopy was absent, apparently due to inability of such patients to produce IgE-antibodies. The occurence of urticaria, predominantly based on non-specific phenomenon of histamine liberation, and non-atopic dermatitis was the same in different forms of PID.

Alterations of the p53 gene in Epstein-Barr virus-associated immunodeficiency-related lymphomas.

Mutations of the p53 tumor suppressor gene are among the most common genetic alterations found in many different human malignancies, including those of the colon, lung, and breast. Alterations in wild-type p53 lead to loss of the suppressor function and thus contribute to tumorigenesis. The potential role of p53 mutations in a sampling of B-cell lymphomas, the majority of which were associated with Epstein-Barr virus (EBV), was investigated. Twenty-six biopsy specimens from immunocompromised patients, including allograft recipients and patients with AIDS, Wiscott-Aldrich syndrome, and human T-cell leukemia virus type 1 infection, in comparison with three Burkitt lymphomas and four Burkitt lymphoma cell lines were analyzed. Mutation in p53 was detected in all four Burkitt lymphoma cell lines as well as the three Burkitt lymphoma biopsy specimens. In patients with AIDS, 5 of 10 lymphomas were EBV positive, and 1 had a mutation in p53. Mutation in p53 was not detected in 14 EBV-positive lymphomas which arose in transplant recipients. These data indicate that with the exception of Burkitt lymphomas, p53 mutations are not involved in the majority EBV-positive B-cell lymphomas which develop in immunocompromised patients.

CD43, a molecule defective in Wiskott-Aldrich syndrome, binds ICAM-1

THE protein CD43 (also known as sialophorin, leukosialin, large sialoglycoprotein or gp115) is expressed on the surface of T lymphocytes, monocytes, neutrophils, platelets and some B lymphocytes. Expression of CD43 is deficient and/or defective in the X-chromosome-linked immunodeficiency disorder Wiscott-Aldrich syndrome, suggesting that CD43 might have a role in T-cell activation. We have shown that expression of human CD43 in an HLA-DR-specific murine T-cell hybridoma enhances the antigen-specific response to stimulation by the human lymphoblastoid cell line Daudi, and that Daudi cells bind specifically to purified immobilized CD43. These data indicate that the specific interaction of CD43 with a ligand on the surface of Daudi cells might contribute to T-cell activation. Here we report evidence that intercellular adhesion molecule-1 (ICAM-1, or CD54), is a ligand for CD43.

Growth After Bone Marrow Transplantation in Children

Growth of the patients with hematological malignancies, aplastic anemia, Fanconi's anemia, and Wiscott-Aldrich syndrome who had been treated with bone marrow transplantation (BMT) was studied. Fourteen out of 21 patients showed suppression of linear growth after BMT. Recovery of the growth velocity after 1-2 years tended to occur if BMT was performed at younger age. Six of eight patients with chronic graft-versus-host-disease (CGVHD) had impaired growth after BMT, whereas eight of 13 (61%) without CGVHD did. Provocative tests for growth hormone (GH) performed 5-72 months after BMT revealed three boys who showed poor response to more than two different stimuli. Two of these three boys had prolonged suppression of growth. Neither the age at BMT, difference in disease, nor presence of posttransplant growth retardation gave significant difference in the response of GH to provocative tests. It was concluded that approximately two-thirds of marrow-grafted children experienced transient decrease in growth velocity after BMT.

Successful allogeneic cryopreserved marrow transplantation.

Cryopreservation has been used extensively in autologous marrow transplantation (BMT), but there has been limited use in allogeneic BMT. We describe here 6 cases of successful engraftment following allogeneic BMT with cryopreserved marrow. Patients suffered from Wiscott-Aldrich syndrome, osteopetrosis, aplastic anemia, and acute lymphocytic, acute non-lymphocytic, and chronic myelogenous leukemia, and ranged in age from 5 mos to 35 yrs. Marrow was collected using standard techniques. In one case T-cells were removed to prevent graft-vs-host disease. Marrow was frozen for a variety of reasons. Buffy coat cells were frozen at controlled rate in 10% DMSO, and stored in liquid nitrogen for 6 to 49 d. Engraftment (WBC greater than 1000/uL x 3 d) occurred from 13 to 37 d post BMT. In 4 of 4 cases in which data are available, donor origin of engraftment was documented, 1 with cytogenetics, 2 with red cell typing, and 4 with restriction fragment length polymorphisms. 3 patients are alive and well 21, 21, and 42 months post BMT. These results suggest frozen marrow can be successfully used for allogeneic BMT.

Computed Tomography in Opportunistic Lung Infections

Chest radiography in two teenage boys, one with Wiscott-Aldrich's syndrome and one with acute lymphatic leucemia in remission showed increased interstitial pattern. In both computed tomography (CT) of the lungs showed heavy interstitial pneumonia, rather different in appearance but in both cases equal to the CT findings in opportunistic lung infections known from immunoincompetent patients with for instance pneumocystis carinii and/or cytomegalo virus infections. In both patients the CT findings led to lung biopsy establishing the etiologic agent.

Indium 111 labeled white blood cell scintigraphy for the diagnosis of upper abdominal abscesses in a child with wiscott-Aldrich syndrome

We report on a case of multiple hepatic abscesses in an immunodeficient patient where initial radiologic evaluation by ultrasonography and computed tomography confused early management by failing to demonstrate the abscesses and by suggesting other diagnoses. Indium 111 (In-111) white blood cell (WBC) scanning with Tc-99 liver-spleen scan subtraction accurately demonstrated subcapsular hepatic abscesses in four out of four sequential studies, and later confirmed resolution of the abscesses. We suggest that In-111 WBC scanning may be used as a highly specific method of diagnosing suspected upper abdominal abscesses in children.

Bone Marrow Transplantation Symposium: Bone Marrow Transplantation for Immunodeficiency Diseases

Allogeneic bone marrow transplantation (BMT) was applied in 1968 to treat severe combined immunodeficiency disease (SCID). Almost simultaneously, marrow from an MHC-matched donor corrected the immunological deficiency of a patient with Wiscott-Aldrich Syndrome (WAS). In the first successful treatment of X-linked SCID the match was imperfect and, although SCID was cured, a graft vs. host reaction caused pancytopenia. A second BMT from the same donor successfully treated a complicating aplastic anemia. Subsequently, it has been possible to cure most patients with SCID who are in reasonably good condition at the time of BMT without other manipulation if a matched sibling donor is available. Successes are reported from Holland, France, Italy, England, Scandinavia, Japan, Germany, and from many centers in the United States. Similarly, BMT is used to correct SCID due to adenosine deaminase (ADA) deficiency or nucleoside phosphorylase (NP) deficiency, which underlie two forms of SCID. Bone marrow transplantation using HLA-matched sibling donors can now treat, successfully, at least eight genetically separable forms of SCID. Highly lethal defects of phagocytic function (including LFA-1, MO-1, CR-3 deficiencies, IL-2 and IL-1 receptor deficiencies), defects of killing after phagocytosis (as in chronic granulomatous disease, WAS, and Kostmann's Syndrome), and certain inborn errors of metabolism can be cured by BMT.(ABSTRACT TRUNCATED AT 250 WORDS)

FAVORABLE RESPONSE TO IVIgG IN A WISCOTT-ALDRICH SYNDROME INFANT WITH SEVERE THROMBOCYTOPENIA REFRACTORY TO SPLENECTOMY

Other than bone marrow transplantation, splenectomy is the only effective, long term therapy for the severe thrombocytopenia of Wiscott-Aldrich Syndrome (WAS). Occasional WAS patients demonstrate continued severe thrombocytopenia, either immediately postsplenectomy (p-s) or following an initial improvement in platelet count. These patients may respond to less satisfactory treatment modalities such as steroids or other immunosuppressive agents. We recently evaluated a WAS patient with persistent, severe thrombocytopenia p-s who demonstrated a favorable response to SandoglobulinR (IVIgG). The diagnosis of WAS was based on the following criteria: eczema noted at one month of age, thrombocytopenia and mucous membrane bleeding beginning at two months of age, tiny platelets on peripheral blood smear and a bone marrow aspirate demonstrating normal megakaryocyte numbers and morphology. Bleeding episodes were treated with platelet transfusions until 9 mos. of age at which time splenectomy was performed. Severe thrombocytopenia (platelet count (PC) < 20,000/mm3) persisted p-s requiring continued platelet transfusions. IVIgG, 1gm/kg/day for 3 consecutive days, was given 5 days, It wks, and 7 wks p-s. Post infusion, peak PCs (238,000, 171,000 and 36,000/mm3 respectively) were noted 1-3 days following each course of IVIgG; no platelet transfusions were required during the treatment period. The potential benefits of this modality justify its further investigation in the p-s, WAS patient with persistent thrombocytopenia.

The in vivo antibody responses to polymerized flagellin (POL) in man

The capacity of antibody response in man was evaluated by a single intradermal injection of polymerized flagellin (POL) from Salmonella adelaide. The antibody was titrated in sera (with or without treatment with 2-mercaptoethanol) by microhemaglutination using antigen-sensitized group O red blood cells (RBC). The naturally occurring antibody to POL was detected in 64% of 190 nonimmunized healthy subjects. Its frequency and titer gradually increased with age. In 10 healthy adult subjects and 15 patients with miscellaneous diseases, a good response with both IgM and IgG antibody was induced. The IgM to IgG switch-over was more clearly elucidated in subjects without the natural antibody. In 12 immunodeficient patients, the subjects with T- and/or B-cell dysfunction did not produce or poorly produced the antibody. Four subjects with Wiscott-Aldrich syndrome (WAS) revealed a comparatively high antibody response; two of them became significantly responsive to POL after administration of transfer factor and reimmunization with POL. POL is one of the best applicable test antigens and appears to act as a T-independent immunogen in man.