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3.
Cell Rep ; 24(3): 619-629, 2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-30021160

RESUMO

Wiskott-Aldrich syndrome protein (WASp) is a main cytoskeletal regulator in B cells. WASp-interacting protein (WIP) binds to and stabilizes WASp but also interacts with actin. Using mice with a mutated actin binding domain of WIP (WIPΔABD), we here investigated the role of WIP binding to actin during B cell activation. We found an altered differentiation of WIPΔABD B cells and diminished antibody affinity maturation after immunization. Mechanistically, WIPΔABD B cells showed impaired B cell receptor (BCR)-induced PI3K signaling and actin reorganization, likely caused by diminished CD81 expression and altered CD19 dynamics on the B cell surface. WIPΔABD B cells displayed reduced in vivo motility, concomitantly with impaired chemotaxis and defective F-actin polarization, HS1 phosphorylation, and polarization of HS1 to F-actin-rich structures after CXCL12 stimulation in vitro. We thus concluded that WIP binding to actin, independent of its binding to WASp, is critical for actin cytoskeleton plasticity in B cells.

4.
J Allergy Clin Immunol ; 141(3): 1060-1073.e3, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28629746

RESUMO

BACKGROUND: Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor κ light chain enhancer of activated B cells (NF-κB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IκBα have impaired noncanonical NF-κB activity and defective lymphorganogenesis. OBJECTIVE: We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. METHODS: A disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-κB signaling in skin-derived fibroblasts. RESULTS: Disease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB subunit 2/p100 and RELB proto-oncogene, NF-κB subunit (RelB) components of the noncanonical NF-κB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus α-lymphotoxin ß receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. CONCLUSIONS: IκBα point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-κB activity in patients with AD EDA-ID.

5.
Clin Immunol ; 187: 68-75, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29051008

RESUMO

Defects in DNA Recombination due to mutations in RAG1/2 or DCLRE1C result in combined immunodeficiency (CID) with a range of disease severity. We present the clinical, immunologic and molecular characteristics of 21 patients with defects in RAG1, RAG2 or DCLRE1C, who accounted for 24% of combined immune deficiency cases in the Kuwait National Primary Immunodeficiency Disorders Registry. The distribution of the patients was as follow: 8 with RAG1 deficiency, 6 with RAG2 deficiency and 7 with DCLRE1C deficiency. Nine patients presented with SCID, 6 with OS, 2 with leaky SCID and 4 with CID and granuloma and/or autoimmunity (CID-G/AI). Eight patients [(7 SCID and 1 OS) (38%)] received hematopoietic stem cell transplant (HSCT). The median age of HSCT was 11.5months and the median time from diagnosis to HSCT was 6months. Fifty percent of the transplanted patients are alive while only 23% of the untransplanted ones are alive.

6.
Front Immunol ; 9: 3146, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30697212

RESUMO

Objective: To present the genetic causes of patients with primary immune deficiencies (PIDs) in Kuwait between 2004 and 2017. Methods: The data was obtained from the Kuwait National Primary Immunodeficiency Disorders Registry. Genomic DNA from patients with clinical and immunological features of PID was sequenced using Sanger sequencing (SS), next generation sequencing (NGS) of targeted genes, whole exome sequencing (WES), and/or whole genome sequencing (WGS). Functional assays were utilized to assess the biologic effect of identified variants. Fluorescence in situ hybridization (FISH) for 22q11.2 deletion and genomic hybridizations arrays were performed when thymic defects were suspected. Results: A total of 264 patients were registered during the study period with predominance of patients with immunodeficiencies affecting cellular and humoral immunity (35.2%), followed by combined immunodeficiencies with associated syndromic features (24%). Parental consanguinity and family history suggestive of PID were reported in 213 (81%) and 145 patients (55%), respectively. Genetic testing of 206 patients resulted in a diagnostic yield of 70%. Mutations were identified in 46 different genes and more than 90% of the reported genetic defects were transmitted by in an autosomal recessive pattern. The majority of the mutations were missense mutations (57%) followed by deletions and frame shift mutations. Five novel disease-causing genes were discovered. Conclusions: Genetic testing should be an integral part in the management of primary immunodeficiency patients. This will help the delivery of precision medicine and facilitate proper genetic counseling. Studying inbred populations using sophisticated diagnostic methods can allow better understanding of the genetics of primary immunodeficiency disorders.


Assuntos
Consanguinidade , Estudos de Associação Genética , Predisposição Genética para Doença , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/genética , Alelos , Biomarcadores , Estudos de Coortes , Feminino , Estudos de Associação Genética/métodos , Genética Populacional , Humanos , Síndromes de Imunodeficiência/diagnóstico , Hibridização in Situ Fluorescente , Kuweit/epidemiologia , Masculino , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma
7.
J Clin Immunol ; 37(8): 811-819, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29058101

RESUMO

PURPOSE: The dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive-combined immunodeficiency whose clinical spectra include recurrent infections, autoimmunity, malignancies, elevated serum IgE, eczema, and food allergies. Here, we report on patients with loss of function DOCK8 mutations with profound immune dysregulation suggestive of an immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like disorder. METHODS: Immunophenotyping of lymphocyte subpopulations and analysis of DOCK8 protein expression were evaluated by flow cytometry. T regulatory (Treg) cells were isolated by cell sorting, and their suppressive activity was analyzed by flow cytometry. Gene mutational analysis was performed by whole-exome and Sanger sequencing. RESULTS: Patient 1 (P1) presented at 10 months of age with chronic severe diarrhea and active colitis in the absence of an infectious trigger, severe eczema with elevated serum IgE, and autoimmune hemolytic anemia, suggestive of an IPEX-related disorder. Whole-exome sequencing revealed a homozygous nonsense mutation in DOCK8 at the DOCK-homology region (DHR)-1 (c.1498C>T; p. R500X). Patient P2, a cousin of P1 who carries the same DOCK8 nonsense mutation, presented with eczema and recurrent ear infections in early infancy, and she developed persistent diarrhea by 3 years of age. Patient P3 presented with lymphoproliferation, severe eczema with allergic dysregulation, and chronic diarrhea with colitis. She harbored a homozygous loss of function DOCK8 mutation (c.2402 -1G→A). Treg cell function was severely compromised by both DOCK8 mutations. CONCLUSION: DOCK8 deficiency may present severe immune dysregulation with features that may overlap with those of IPEX and other IPEX-like disorders.


Assuntos
Transtornos Cromossômicos/diagnóstico , Diabetes Mellitus Tipo 1/congênito , Diarreia/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Fatores de Troca do Nucleotídeo Guanina/genética , Hipersensibilidade/diagnóstico , Doenças do Sistema Imunitário/congênito , Infecção/diagnóstico , Mutação/genética , Linfócitos T Reguladores/imunologia , Anemia Hemolítica , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Feminino , Genes Recessivos/genética , Humanos , Doenças do Sistema Imunitário/diagnóstico , Imunoglobulina E/metabolismo , Imunofenotipagem , Lactente
10.
Clin Immunol ; 183: 198-200, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28917720

RESUMO

JAK3 is a tyrosine kinase essential for signaling downstream of the common gamma chain subunit shared by multiple cytokine receptors. JAK3 deficiency results in T-B+NK- severe combined immune deficiency (SCID). We report a patient with SCID due to a novel mutation in the JAK3 JH4 domain. The function of the JH4 domain remains unknown. This is the first report of a missense mutation in the JAK3 JH4 domain, thereby demonstrating the importance of the JH4 domain of JAK3 in host immunity.


Assuntos
Janus Quinase 3/metabolismo , Osteomielite/genética , Imunodeficiência Combinada Severa/genética , Coluna Vertebral/patologia , Evolução Fatal , Feminino , Humanos , Lactente , Janus Quinase 3/genética , Mutação , Osteomielite/complicações , Domínios Proteicos , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/patologia
11.
Front Immunol ; 8: 798, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28769923

RESUMO

Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/- natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16-/int CD57- cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.

15.
Blood Adv ; 1(23): 2083-2087, 2017 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-29296855

RESUMO

CDH17 is expressed in human thymic epithelial cells.CDH17 mutations may be a rare cause of leaky severe combined immune deficiency that can be corrected by HSCT.

16.
J Clin Invest ; 126(11): 4219-4236, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27760045

RESUMO

Alterations in the apoptosis of immune cells have been associated with autoimmunity. Here, we have identified a homozygous missense mutation in the gene encoding the base excision repair enzyme Nei endonuclease VIII-like 3 (NEIL3) that abolished enzymatic activity in 3 siblings from a consanguineous family. The NEIL3 mutation was associated with fatal recurrent infections, severe autoimmunity, hypogammaglobulinemia, and impaired B cell function in these individuals. The same homozygous NEIL3 mutation was also identified in an asymptomatic individual who exhibited elevated levels of serum autoantibodies and defective peripheral B cell tolerance, but normal B cell function. Further analysis of the patients revealed an absence of LPS-responsive beige-like anchor (LRBA) protein expression, a known cause of immunodeficiency. We next examined the contribution of NEIL3 to the maintenance of self-tolerance in Neil3-/- mice. Although Neil3-/- mice displayed normal B cell function, they exhibited elevated serum levels of autoantibodies and developed nephritis following treatment with poly(I:C) to mimic microbial stimulation. In Neil3-/- mice, splenic T and B cells as well as germinal center B cells from Peyer's patches showed marked increases in apoptosis and cell death, indicating the potential release of self-antigens that favor autoimmunity. These findings demonstrate that deficiency in NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies, and predisposition to autoimmunity.


Assuntos
Doenças Autoimunes , Linfócitos B/imunologia , Endodesoxirribonucleases/deficiência , Predisposição Genética para Doença , N-Glicosil Hidrolases/deficiência , Linfócitos T/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/imunologia , Autoanticorpos/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos B/patologia , Endodesoxirribonucleases/imunologia , Feminino , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Knockout , N-Glicosil Hidrolases/imunologia , Poli I-C/farmacologia , Linfócitos T/patologia
17.
J Clin Invest ; 126(10): 3837-3851, 2016 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-27599296

RESUMO

Wiskott-Aldrich syndrome (WAS) is associated with mutations in the WAS protein (WASp), which plays a critical role in the initiation of T cell receptor-driven (TCR-driven) actin polymerization. The clinical phenotype of WAS includes susceptibility to infection, allergy, autoimmunity, and malignancy and overlaps with the symptoms of dedicator of cytokinesis 8 (DOCK8) deficiency, suggesting that the 2 syndromes share common pathogenic mechanisms. Here, we demonstrated that the WASp-interacting protein (WIP) bridges DOCK8 to WASp and actin in T cells. We determined that the guanine nucleotide exchange factor activity of DOCK8 is essential for the integrity of the subcortical actin cytoskeleton as well as for TCR-driven WASp activation, F-actin assembly, immune synapse formation, actin foci formation, mechanotransduction, T cell transendothelial migration, and homing to lymph nodes, all of which also depend on WASp. These results indicate that DOCK8 and WASp are in the same signaling pathway that links TCRs to the actin cytoskeleton in TCR-driven actin assembly. Further, they provide an explanation for similarities in the clinical phenotypes of WAS and DOCK8 deficiency.


Assuntos
Citoesqueleto de Actina/metabolismo , Proteínas de Transporte/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Proteína da Síndrome de Wiskott-Aldrich/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Movimento Celular , Células HEK293 , Humanos , Sinapses Imunológicas/metabolismo , Linfonodos/citologia , Mecanotransdução Celular , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , Mapas de Interação de Proteínas , Multimerização Proteica , Transporte Proteico , Linfócitos T/fisiologia
18.
Clin Immunol ; 171: 65-66, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27538774

RESUMO

Whole exome sequencing is increasingly used in the diagnosis of primary immunodeficiencies due to the overlapping and atypical presentations of these disorders. We report two patients who presented with recurrent infections and early onset colitis. They were investigated by whole exome sequencing due to suspicion of primary immunodeficiency and found to have mutations in pyrin known to cause familial Mediterranean fever.


Assuntos
Colite/genética , Febre Familiar do Mediterrâneo/genética , Síndromes de Imunodeficiência/genética , Pirina/genética , Pré-Escolar , Colite/diagnóstico , Consanguinidade , Diagnóstico Diferencial , Febre Familiar do Mediterrâneo/diagnóstico , Feminino , Humanos , Síndromes de Imunodeficiência/diagnóstico , Lactente , Masculino , Mutação
19.
J Allergy Clin Immunol ; 138(3): 852-859.e3, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27130861

RESUMO

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Reports of outcomes are still limited. OBJECTIVE: We sought to analyze the results of HSCT in patients with DOCK8 deficiency and report whether approaches resulting in mixed chimerism result in clinically relevant immune reconstitution. METHODS: We performed a retrospective chart review of 11 patients with DOCK8 deficiency and measured DOCK8 expression and cytokine production. RESULTS: Of 11 patients, 7 received HSCT from related and 4 from unrelated donors; 9 patients received busulfan-based conditioning regimens. Survival was excellent (10 [91%] of 11 patients alive), including a patient who had undergone liver transplantation. Patients showed significant improvements in the frequency and severity of infections. Although eczema resolved in all, food allergies and high IgE levels persisted in some patients. Lymphopenia, eosinophilia, low numbers of naive CD8(+) T cells and switched memory B cells, and TH1/TH2 cytokine imbalance improved in most patients. Although the 8 matched related or unrelated donor recipients had full donor chimerism, all 3 recipients of mismatched unrelated donor HSCT had high levels of donor T-cell chimerism and low B-cell and myeloid cell chimerism (0% to 46%). Almost all switched memory B cells were of donor origin. All patients, including those with mixed chimerism, mounted robust antibody responses to vaccination. CONCLUSION: Allogeneic HSCT ameliorated the infectious and atopic symptoms of patients with DOCK8 deficiency. In patients with mixed chimerism, selective advantage for donor-derived T cells and switched memory B cells promoted restoration of cellular and humoral immunity and protection against opportunistic infection.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/deficiência , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/imunologia , Linfócitos B/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Linfócitos T/imunologia , Resultado do Tratamento
20.
Clin Immunol ; 166-167: 100-2, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27063589

RESUMO

ORAI1 is the pore-forming subunit of the calcium release-activated calcium channel responsible for calcium influx into cells triggered by endoplasmic reticulum store depletion. We report here a patient with severe combined immunodeficiency and absent store-operated calcium entry due to a novel mutation in ORAI1 that results in the expression of a C-terminally truncated protein that abolishes ORAI1 binding to STIM1.


Assuntos
Mutação , Proteínas de Neoplasias/genética , Proteína ORAI1/genética , Imunodeficiência Combinada Severa/genética , Molécula 1 de Interação Estromal/genética , Sequência de Bases , Exoma/genética , Evolução Fatal , Feminino , Células HEK293 , Homozigoto , Humanos , Lactente , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/metabolismo , Ligação Proteica/genética , Análise de Sequência de DNA , Deleção de Sequência , Imunodeficiência Combinada Severa/metabolismo , Molécula 1 de Interação Estromal/metabolismo
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