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4.
Curr Opin Allergy Clin Immunol ; 18(6): 453-458, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30299399

RESUMO

PURPOSE OF REVIEW: Conventional gene therapy has been a successful, curative treatment modality for many primary immune deficiencies with significant improvements in the last decade. However, the risk of leukemic transformation with viral-mediated gene addition still remains, and unregulated gene addition is not an option for certain diseases in which the target gene is closely controlled. The recent bloom in genome modification platforms has created the opportunity to site-specifically correct mutated DNA base pairs or insert a corrective cDNA minigene while maintaining gene expression under control of endogenous regulatory elements. RECENT FINDINGS: There is an abundance of ongoing research utilizing programmable nucleases to facilitate site-specific gene correction of many primary immune deficiencies including X-linked severe combined immune deficiency, X-linked chronic granulomatous disease, Wiskott-Aldrich syndrome, X-linked hyper-IgM syndrome, X-linked agammaglobulinemia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked. In all, these studies have demonstrated the ability to integrate corrective DNA sequences at a precise location in the genome at rates likely to either cure or ameliorate disease. SUMMARY: Gene editing for primary immune deficiency (PID) has advanced to the point to that translation to clinical trials is likely to occur in the next several years. At the current pace of research in DNA repair mechanisms, stem cell biology, and genome-editing technology, targeted genome modification represents the next chapter of gene therapy for PID.


Assuntos
Agamaglobulinemia , Edição de Genes/métodos , Doenças Genéticas Ligadas ao Cromossomo X , Terapia Genética/métodos , Síndrome de Wiskott-Aldrich , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Animais , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/imunologia , Síndrome de Wiskott-Aldrich/terapia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia
5.
Nat Commun ; 9(1): 1779, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29725003

RESUMO

Mutations in Wiskott-Aldrich syndrome protein (WASP) cause autoimmune sequelae including colitis. Yet, how WASP mediates mucosal homeostasis is not fully understood. Here we show that WASP-mediated regulation of anti-inflammatory macrophages is critical for mucosal homeostasis and immune tolerance. The generation and function of anti-inflammatory macrophages are defective in both human and mice in the absence of WASP. Expression of WASP specifically in macrophages, but not in dendritic cells, is critical for regulation of colitis development. Importantly, transfer of WT anti-inflammatory macrophages prevents the development of colitis. DOCK8-deficient macrophages phenocopy the altered macrophage properties associated with WASP deficiency. Mechanistically, we show that both WASP and DOCK8 regulates macrophage function by modulating IL-10-dependent STAT3 phosphorylation. Overall, our study indicates that anti-inflammatory macrophage function and mucosal immune tolerance require both WASP and DOCK8, and that IL-10 signalling modulates a WASP-DOCK8 complex.


Assuntos
Colite/imunologia , Homeostase , Inflamação/imunologia , Interleucina-10/fisiologia , Mucosa Intestinal/metabolismo , Macrófagos/imunologia , Proteína da Síndrome de Wiskott-Aldrich/fisiologia , Animais , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Colite/prevenção & controle , Deleção de Genes , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Imunidade nas Mucosas , Interleucina-10/metabolismo , Interleucina-1beta/fisiologia , Interleucina-23/fisiologia , Mucosa Intestinal/imunologia , Macrófagos/citologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais , Síndrome de Wiskott-Aldrich/imunologia , Proteína da Síndrome de Wiskott-Aldrich/genética , Proteína da Síndrome de Wiskott-Aldrich/metabolismo
8.
J Allergy Clin Immunol ; 142(5): 1605-1617.e4, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29447842

RESUMO

BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients experience autoimmunity caused by a breakdown in T- and B-cell tolerance. Moreover, excessive production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs) contributes to autoimmune signs; however, the factors that trigger excessive innate activation have not been defined. OBJECTIVE: Neutrophil extracellular traps (NETs) emerged as major initiating factors in patients with diseases such as systemic lupus erythematosus and rheumatoid arthritis. In this study we explored the possible involvement of aberrant neutrophil functions in patients with WAS. METHODS: We evaluated the expression of a set of granulocyte genes associated with NETs in a cohort of patients with WAS and the presence of NET inducers in sera. Using a mouse model of WAS, we analyzed NET release by WASp-null neutrophils and evaluated the composition and homeostasis of neutrophils in vivo. By using depletion experiments, we assessed the effect of neutrophils in promoting inflammation and reactivity against autoantigens. RESULTS: Transcripts of genes encoding neutrophil enzymes and antimicrobial peptides were increased in granulocytes of patients with WAS, and serum-soluble factors triggered NET release. WASp-null neutrophils showed increased spontaneous NETosis, induced IFN-I production by pDCs, and activated B cells through B-cell activating factor. Consistently, their depletion abolished constitutive pDC activation, normalized circulating IFN-I levels, and, importantly, abolished production of autoantibodies directed against double-stranded DNA, nucleosomes, and myeloperoxidase. CONCLUSIONS: These findings reveal that neutrophils are involved in the pathogenic loop that causes excessive activation of innate cells and autoreactive B cells, thus identifying novel mechanisms that contribute to the autoimmunity of WAS.


Assuntos
Interferon Tipo I/imunologia , Neutrófilos/imunologia , Síndrome de Wiskott-Aldrich/imunologia , Adolescente , Adulto , Animais , Autoanticorpos/imunologia , Linfócitos B/imunologia , Pré-Escolar , Células Dendríticas/imunologia , Armadilhas Extracelulares , Feminino , Expressão Gênica , Humanos , Lactente , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndrome de Wiskott-Aldrich/genética , Adulto Jovem
9.
J Allergy Clin Immunol ; 142(4): 1272-1284, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29421274

RESUMO

BACKGROUND: Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, infections, and susceptibility to autoimmunity and malignancies. Thrombocytopenia is a constant finding, but its pathogenesis remains elusive. OBJECTIVE: To dissect the basis of the WAS platelet defect, we used a novel conditional mouse model (CoWas) lacking Wiskott-Aldrich syndrome protein (WASp) only in the megakaryocytic lineage in the presence of a normal immunologic environment, and in parallel we analyzed samples obtained from patients with WAS. METHODS: Phenotypic and functional characterization of megakaryocytes and platelets in mutant CoWas mice and patients with WAS with and without autoantibodies was performed. Platelet antigen expression was examined through a protein expression profile and cluster proteomic interaction network. Platelet immunogenicity was tested by using ELISAs and B-cell and platelet cocultures. RESULTS: CoWas mice showed increased megakaryocyte numbers and normal thrombopoiesis in vitro, but WASp-deficient platelets had short lifespan and high expression of activation markers. Proteomic analysis identified signatures compatible with defects in cytoskeletal reorganization and metabolism yet surprisingly increased antigen-processing capabilities. In addition, WASp-deficient platelets expressed high levels of surface and soluble CD40 ligand and were capable of inducing B-cell activation in vitro. WASp-deficient platelets were highly immunostimulatory in mice and triggered the generation of antibodies specific for WASp-deficient platelets, even in the context of a normal immune system. Patients with WAS also showed platelet hyperactivation and increased plasma soluble CD40 ligand levels correlating with the presence of autoantibodies. CONCLUSION: Overall, these findings suggest that intrinsic defects in WASp-deficient platelets decrease their lifespan and dysregulate immune responses, corroborating the role of platelets as modulators of inflammation and immunity.


Assuntos
Plaquetas/imunologia , Síndrome de Wiskott-Aldrich/imunologia , Adolescente , Adulto , Animais , Autoimunidade , Ligante de CD40/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Inflamação/sangue , Inflamação/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contagem de Plaquetas , Síndrome de Wiskott-Aldrich/sangue , Proteína da Síndrome de Wiskott-Aldrich/genética , Proteína da Síndrome de Wiskott-Aldrich/imunologia , Adulto Jovem
11.
J Leukoc Biol ; 103(3): 577-590, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28851742

RESUMO

Microthrombocytopenia is the clinical hallmark of WAS, a rare X-linked immunodeficiency that is characterized by eczema, autoimmunity, and cancer susceptibility. This disease is caused by mutations in the WAS gene, which is expressed in hematopoietic cells and regulates actin cytoskeleton remodeling thereby modulating various cellular functions, including motility, immunologic synapse assembly, and signaling. Despite extensive studies that have provided great insight into the relevance of this molecule to innate and cellular immunity, the exact mechanisms of microthrombocytopenia in WAS are still unknown. This review focuses on the recent progress made in dissecting the pathogenesis of platelet defects in patients with WAS and their murine counterparts. In parallel, we will provide an overview of the state-of-the art platelets as immune modulators at the interface between hemostasis and the immune system, which suggests that these cells may have a direct role in the pathogenesis of immune dysregulation in WAS.


Assuntos
Autoimunidade , Plaquetas/imunologia , Síndrome de Wiskott-Aldrich/imunologia , Animais , Plaquetas/patologia , Humanos , Transdução de Sinais , Síndrome de Wiskott-Aldrich/patologia
12.
Nat Commun ; 8(1): 1576, 2017 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-29146903

RESUMO

Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott-Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells. In ex vivo models of enteropathogenic Escherichia coli and Shigella flexneri infection, WASp deficiency causes defective bacterial clearance, excessive inflammasome activation and host cell death that are associated with dysregulated septin cage-like formation, impaired autophagic p62/LC3 recruitment and defective formation of canonical autophagosomes. Taken together, we propose that dysregulation of autophagy and inflammasome activities contribute to the autoinflammatory manifestations of WAS, thereby identifying potential targets for therapeutic intervention.


Assuntos
Citoesqueleto de Actina/metabolismo , Autofagia/imunologia , Inflamassomos/imunologia , Proteína da Síndrome de Wiskott-Aldrich/genética , Proteína da Síndrome de Wiskott-Aldrich/metabolismo , Síndrome de Wiskott-Aldrich/imunologia , Animais , Autofagia/genética , Carga Bacteriana/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Escherichia coli Enteropatogênica/imunologia , Humanos , Imunidade Inata/imunologia , Interferon Tipo I/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Nigericina/farmacologia , Septinas/metabolismo , Shigella flexneri/imunologia , Células THP-1 , Receptor 4 Toll-Like/imunologia , Síndrome de Wiskott-Aldrich/metabolismo
14.
Eur J Immunol ; 47(11): 1857-1866, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28805251

RESUMO

The Wiskott-Aldrich syndrome protein (WASP) participates in innate and adaptive immunity through regulation of actin cytoskeleton-dependent cellular processes, including immune synapse formation, cell signaling, migration and cytokine release. There is also emerging evidence for a direct role in nuclear transcription programmes uncoupled from actin polymerization. A deeper understanding of some of the more complex features of Wiskott Aldrich syndrome (WAS) itself, such as the associated autoimmunity and inflammation, has come from identification of defects in the number and function of anti-inflammatory myeloid cells and regulatory T and B cells, as well as defects in positive and negative B-cell selection. In this review we outline the cellular defects that have been characterized in both human WAS patients and murine models of the disease. We will emphasize in particular recent discoveries that provide a mechanistic insight into disease pathology, including lymphoid and myeloid cell homeostasis, immune synapse assembly and immune cell signaling.


Assuntos
Proteína da Síndrome de Wiskott-Aldrich/imunologia , Animais , Humanos , Camundongos , Síndrome de Wiskott-Aldrich/imunologia
15.
Allergy ; 72(12): 1916-1924, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28600891

RESUMO

BACKGROUND: Food allergies are a growing health problem, and the development of therapies that prevent disease onset is limited by the lack of adjuvant-free experimental animal models. We compared allergic sensitization in patients with food allergy or Wiskott-Aldrich syndrome (WAS) and defined whether spontaneous disease in Was-/- mice recapitulates the pathology of a conventional disease model and/or human food allergy. METHODS: Comparative ImmunoCAP ISAC microarray was performed in patients with food allergy or WAS. Spontaneous food allergy in Was-/- mice was compared to an adjuvant-based model in wild-type mice (WT-OVA/alum). Intestinal and systemic anaphylaxis was assessed, and the role of the high-affinity IgE Fc receptor (FcεRI) in allergic sensitization was evaluated using Was-/- Fcer1a-/- mice. RESULTS: Polysensitization to food was detected in both WAS and food-allergic patients which was recapitulated in the Was-/- model. Oral administration of ovalbumin (OVA) in Was-/- mice induced low titers of OVA-specific IgE compared to the WT-OVA/alum model. Irrespectively, 79% of Was-/- mice developed allergic diarrhea following oral OVA challenge. Systemic anaphylaxis occurred in Was-/- mice (95%) with a mortality rate >50%. Spontaneous sensitization and intestinal allergy occurred independent of FcεRI expression on mast cells (MCs) and basophils. CONCLUSIONS: Was-/- mice provide a model of food allergy with the advantage of mimicking polysensitization and low food-antigen IgE titers as observed in humans with clinical food allergy. This model will facilitate studies on aberrant immune responses during spontaneous disease development. Our results imply that therapeutic targeting of the IgE/FcεRI activation cascade will not affect sensitization to food.


Assuntos
Hipersensibilidade Alimentar/etiologia , Hipersensibilidade Alimentar/metabolismo , Mastócitos/imunologia , Mastócitos/metabolismo , Receptores de IgE/metabolismo , Proteína da Síndrome de Wiskott-Aldrich/genética , Adulto , Alérgenos/imunologia , Anafilaxia , Animais , Modelos Animais de Doenças , Feminino , Hipersensibilidade Alimentar/diagnóstico , Expressão Gênica , Humanos , Imunização , Imunoglobulina E/imunologia , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Síndrome de Wiskott-Aldrich/diagnóstico , Síndrome de Wiskott-Aldrich/imunologia , Adulto Jovem
16.
Hum Immunol ; 78(9): 565-573, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28535968

RESUMO

Wiskott-Aldrich syndrome (WAS) is a severe and rare primary immunodeficiency. Several studies show that WAS protein (WASp) plays a key role in the function of certain lymphocyte subsets. So far, no study has described distinct immunophenotypic abnormalities associated with WAS; thus the prognostic significance of any such abnormalities is unclear. This study examined many differences in the percentage/absolute numbers of distinct lymphocyte subsets in 20 WAS patients and 20 age/sex-matched healthy controls, and analyzed the association between these abnormalities and clinical disease scores. The results showed that the numbers of CD4+ T cells, B cells, and CD8+ naïve T cells were significantly lower in WAS patients; furthermore, the numbers in WASp-negative patients were lower than those in WASp-positive patients. WAS patients showed a selective reduction in expression of CD19 by naïve and transitional B cells. There was a negative association between the number of B cells and the WAS clinical scores. Also, CD8+ naïve T cell numbers in patients with a score of 3-5A were lower than those in patients with a score of 2. The absence of WASp leads to a reduction in the population of specific lymphocyte subsets; therefore, these findings may help future management of patients with WAS.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Subpopulações de Linfócitos/imunologia , Síndrome de Wiskott-Aldrich/imunologia , Antígenos CD19/metabolismo , Células Cultivadas , Pré-Escolar , Humanos , Memória Imunológica , Imunofenotipagem , Lactente , Recém-Nascido , Contagem de Linfócitos , Síndrome de Wiskott-Aldrich/diagnóstico , Proteína da Síndrome de Wiskott-Aldrich/imunologia
17.
Clin Immunol ; 179: 47-53, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28232030

RESUMO

BACKGROUND: Low dose IL-2 can restore the function of T and NK cells from Wiskott-Aldrich (WAS) patients. However, the safety of in vivo IL-2 in WAS is unknown. OBJECTIVES: A phase-I study to assess safety of low dose IL-2 in WAS. METHODS: Patients received 5 daily subcutaneous IL-2 injections, every 2months, for three courses. A "3+3" dose escalation method was used. RESULTS: 6 patients received the 0.5millionunits/m2/day dose without serious adverse events. However, 2 of 3 patients receiving the 1millionunits/m2/day dose developed thrombocytopenia requiring platelet transfusions. A statistically significant platelet increase occurred in patients receiving the 0.5millionunits/m2/day dose. A trend toward higher T, B and NK cell numbers and higher T regulatory cell percentages was observed. CONCLUSION: We have identified a safe IL-2 dose for WAS patients. Additional trials are indicated to study the efficacy of this immunostimulant as a therapy for WAS.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Interleucina-2/administração & dosagem , Síndrome de Wiskott-Aldrich/tratamento farmacológico , Adjuvantes Imunológicos/efeitos adversos , Adjuvantes Imunológicos/uso terapêutico , Adolescente , Linfócitos B/imunologia , Criança , Pré-Escolar , Humanos , Interleucina-2/efeitos adversos , Interleucina-2/uso terapêutico , Células Matadoras Naturais/imunologia , Contagem de Leucócitos , Contagem de Plaquetas , Linfócitos T/imunologia , Síndrome de Wiskott-Aldrich/sangue , Síndrome de Wiskott-Aldrich/imunologia
19.
Allergol. immunopatol ; 44(5): 450-454, sept.-oct. 2016. graf
Artigo em Inglês | IBECS | ID: ibc-155858

RESUMO

Background: The Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive immunodeficiency disorder, caused by mutations in the WAS protein (WASP) gene and characterised by thrombocytopenia, small platelets, eczema, and recurrent infections associated with increased risk of autoimmunity and malignancy disorders. The gene for WAS has been mapped to the short arm of the X chromosome at Xp 11.22-23 and early detection of patients and diagnosis of new mutation might reduce related complications and increase their life expectancy. Method and result: We found a novel mutation by sequence analysis of genomic DNA coding of a 9-month old boy suffering from WAS. The mutation was insertion G in exon 10 of WASP gene. The consequence of the G insertion is a premature stop immediately at amino acid 335 (N335X or p.G334GfsX1) and truncated protein. Conclusion: The mutation analysis is helpful for the diagnosis of WAS patients and also expanding the spectrum of WASP mutations for carrier detection and prenatal diagnosis (AU)


No disponible


Assuntos
Humanos , Masculino , Lactente , Síndrome de Wiskott-Aldrich/complicações , Síndrome de Wiskott-Aldrich/imunologia , Eczema/complicações , Eczema/imunologia , Trombocitopenia/complicações , Trombocitopenia/imunologia , Genômica/métodos , Recidiva , Rinite/epidemiologia , Rinite/imunologia , Sinusite/epidemiologia , Sinusite/imunologia , Imunoglobulina G/análise
20.
Infez Med ; 24(3): 237-40, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27668906

RESUMO

A male newborn developed a post-natal cytomegalovirus (CMV) infection, arising in the clinical setting of congenital thrombocytopenia, which was diagnosed as being alloimmune. The evidence of active CMV infection in an infant showing slow-resolution lower airways infection, persistent neonatal and low platelet volume thrombocytopenia, and diffuse eczema (associated to very high levels of serum immunoglobulin E) led to the diagnosis of Wiskott-Aldrich syndrome (WAS) before the third month of life, despite the presence of several confounding clinical factors. The correct interpretation of all clinical features supported the precocious diagnosis of WAS.


Assuntos
Infecções por Citomegalovirus/etiologia , Hipergamaglobulinemia/etiologia , Imunoglobulina E/sangue , Trombocitopenia Neonatal Aloimune/etiologia , Síndrome de Wiskott-Aldrich/diagnóstico , Adulto , Infecções por Citomegalovirus/imunologia , Diagnóstico Precoce , Eczema/etiologia , Feminino , Glucuronidase/imunologia , Humanos , Imunidade Materno-Adquirida , Hospedeiro Imunocomprometido , Lactente , Masculino , Hipersensibilidade a Leite/complicações , Trombocitopenia Neonatal Aloimune/imunologia , Síndrome de Wiskott-Aldrich/complicações , Síndrome de Wiskott-Aldrich/imunologia
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