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1.
Nat Immunol ; 20(2): 152-162, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643259

RESUMO

Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER-Golgi intermediate compartment. Here, we found that deficiency in the Ca2+ sensor stromal interaction molecule 1 (STIM1) caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient with combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and coexpression of full-length STIM1 or a STING-interacting fragment of STIM1 suppressed the function of dominant STING mutants that cause autoinflammatory diseases. Furthermore, deficiency in STIM1 strongly enhanced the expression of type I interferons after viral infection and prevented the lethality of infection with a DNA virus in vivo. This work delineates a STIM1-STING circuit that maintains the resting state of the STING pathway.


Assuntos
Interferon Tipo I/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Animais , Pré-Escolar , DNA Viral/imunologia , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Fibroblastos , Técnicas de Inativação de Genes , Células HEK293 , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Humanos , Imunidade Inata , Células Jurkat , Macrófagos , Masculino , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Células NIH 3T3 , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Cultura Primária de Células , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/imunologia , Células Vero
4.
Proc Natl Acad Sci U S A ; 116(3): 970-975, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30591564

RESUMO

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.


Assuntos
Diferenciação Celular , Imunidade nas Mucosas/genética , Doenças Inflamatórias Intestinais , Mucosa Intestinal , Proteína Serina-Treonina Quinases de Interação com Receptores , Imunodeficiência Combinada Severa , Linfócitos B/imunologia , Linfócitos B/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Células HCT116 , Células HEK293 , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Mutação , NF-kappa B/genética , NF-kappa B/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
6.
Front Immunol ; 9: 2078, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30283440

RESUMO

The caspase recruitment domain family member 11 (CARD11 or CARMA1)-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] signalosome complex serves as a molecular bridge between cell surface antigen receptor signaling and the activation of the NF-κB, JNK, and mTORC1 signaling axes. This positions the CBM complex as a critical regulator of lymphocyte activation, proliferation, survival, and metabolism. Inborn errors in each of the CBM components have now been linked to a diverse group of human primary immunodeficiency diseases termed "CBM-opathies." Clinical manifestations range from severe combined immunodeficiency to selective B cell lymphocytosis, atopic disease, and specific humoral defects. This surprisingly broad spectrum of phenotypes underscores the importance of "tuning" CBM signaling to preserve immune homeostasis. Here, we review the distinct clinical and immunological phenotypes associated with human CBM complex mutations and introduce new avenues for targeted therapeutic intervention.


Assuntos
Proteína 10 de Linfoma CCL de Células B/imunologia , Proteínas Adaptadoras de Sinalização CARD/imunologia , Guanilato Ciclase/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Imunodeficiência Combinada Severa/imunologia , Transdução de Sinais/imunologia , Proteína 10 de Linfoma CCL de Células B/genética , Proteína 10 de Linfoma CCL de Células B/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Guanilato Ciclase/genética , Guanilato Ciclase/metabolismo , Homeostase/genética , Homeostase/imunologia , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Mutação/imunologia , Ligação Proteica , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/metabolismo , Transdução de Sinais/genética
8.
J Clin Immunol ; 38(7): 778-786, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30251145

RESUMO

Severe combined immunodeficiency (SCID) is characterized by a major T cell deficiency. Infants with SCID are asymptomatic at birth but die from infections in the first year of life if not treated. Survival rates are better for early treatment. SCID therefore meets criteria for newborn screening (NBS). T cell receptor excision circle (TREC) quantification is a reliable marker of T cell deficiency and can be performed using Guthrie cards. The DEPISTREC project was designed to study the feasibility, clinical utility, and cost-effectiveness of generalized SCID screening in France. About 200,000 babies from all over the country were screened at birth with a commercial kit. We determined assay performance and proposed a cutoff for classification of results. Our findings suggest that, given clearly established validation rules and decision-making procedures, the TREC assay is a suitably specific and sensitive method for high-throughput SCID screening. Clinical Trials: NCT02244450.


Assuntos
Imunodeficiência Combinada Severa/diagnóstico , Bioensaio , Biomarcadores , Tomada de Decisão Clínica , Análise Custo-Benefício , Gerenciamento Clínico , França/epidemiologia , Humanos , Lactente , Recém-Nascido , Triagem Neonatal , Vigilância em Saúde Pública , Kit de Reagentes para Diagnóstico , Receptores de Antígenos de Linfócitos T/metabolismo , Reprodutibilidade dos Testes , Imunodeficiência Combinada Severa/epidemiologia , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
9.
Clin Exp Immunol ; 194(2): 166-179, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30251416

RESUMO

Dipeptidyl peptidase 4 (DPP4, CD26) is a serine protease that is expressed constitutively by many haematopoietic and non-haematopoietic tissues. It exists as a membrane-associated protein, as well as in an active, soluble form (herein called sDPP4), present at high concentrations in bodily fluids. Despite the proposed use of sDPP4 as a biomarker for multiple diseases, its cellular sources are not well defined. Here, we report that individuals with congenital lymphocyte immunodeficiency had markedly lower serum concentrations of sDPP4, which were restored upon successful treatment and restoration of lymphocyte haematopoiesis. Using irradiated lymphopenic mice and wild-type to Dpp4-/- reciprocal bone marrow chimeric animals, we found that haematopoietic cells were a major source of circulating sDPP4. Furthermore, activation of human and mouse T lymphocytes resulted in increased sDPP4, providing a mechanistic link between immune system activation and sDPP4 concentration. Finally, we observed that acute viral infection induced a transient increase in sDPP4, which correlated with the expansion of antigen-specific CD8+ T cell responses. Our study demonstrates that sDPP4 concentrations are determined by the frequency and activation state of lymphocyte populations. Insights from these studies will support the use of sDPP4 concentration as a biomarker for inflammatory and infectious diseases.


Assuntos
Biomarcadores/metabolismo , Dipeptidil Peptidase 4/metabolismo , Vírus da Influenza A/fisiologia , Proteínas de Membrana/metabolismo , Infecções por Orthomyxoviridae/imunologia , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Animais , Secreções Corporais , Dipeptidil Peptidase 4/genética , Modelos Animais de Doenças , Hematopoese/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Solubilidade , Quimeras de Transplante
10.
Clin Immunol ; 197: 1-5, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30121298

RESUMO

V(D)J recombination, during which recognition and repair of broken DNA chains are accomplished by non-homologous end joining pathway, is a critical process in B and T cell development.Null mutations of each enzyme or protein of this pathway result in T- B- NK+ severe combined immunodeficiency whereas hypomorphic mutations result in atypical(leaky)severe combined immunodeficiency forms. We present two siblings with PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide) mutation who presented with granulomatous skin lesions and recurrent lung infections. Primary immune deficiencies may initially present with skin findings. Disruption in central and peripheral B-cell tolerance and impaired intrathymic T-cell maturation,a central player in T-cell tolerance, have been identified as the mechanism of autoimmunity and granuloma seen in patients. The variation in clinical phenotypes of patients with PRKDC mutation suggests that additional factors such as modifying genes, epigenetic and environmental factors may affect the severity and clinical phenotype of the disease. Functional studies during the follow-up and evaluation before and after hematopoeitic stem cell transplantation will hopefully increase our knowledge about the autoimmune and inflammatory process of the disease spectrum.


Assuntos
Proteína Quinase Ativada por DNA/genética , Granuloma/genética , Histiocitose de Células não Langerhans/genética , Proteínas Nucleares/genética , Imunodeficiência Combinada Severa/genética , Dermatopatias/genética , Pré-Escolar , Feminino , Granuloma/imunologia , Granuloma/patologia , Transplante de Células-Tronco Hematopoéticas , Histiocitose de Células não Langerhans/imunologia , Histiocitose de Células não Langerhans/patologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , Recém-Nascido , Pneumonia Bacteriana/genética , Pneumonia Bacteriana/imunologia , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia , Irmãos , Dermatopatias/imunologia , Dermatopatias/patologia
11.
Blood Adv ; 2(15): 1828-1832, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30061307

RESUMO

DNA ligase 4 deficiency (LIG4-SCID) causes lymphopenia (T-B-NK+) and a radiosensitive SCID (RS-SCID) phenotype. We demonstrate, for the first time, flow cytometric-based kinetic analysis of phosphorylated H2AX (γH2AX) in lymphocyte subsets, especially NK cells, for the assessment of LIG4-SCID. Measurement of phosphorylated (p) ATM, SMC1, and H2AX (γH2AX) was performed by flow cytometry to assess DNA repair defects in a 3-year-old girl. Functional assessment (phosphorylation) was measured in T and NK cells (B cells were absent) before irradiation (background control) or after low-dose (2Gy) irradiation (1 and 24 hours). We observed maximal γH2AX at 1 hour postirradiation, with dephosphorylation at 24 hours postirradiation in healthy control patients. The patient showed normal frequencies (percentage) of T cells and NK cells for γH2AX, but increased levels of γH2AX compared with control patients at 1 hour postirradiation. At 24 hours postirradiation, there was a lack of dephosphorylation in a substantial proportion of lymphocytes (with differences observed between T and NK cells) compared with healthy control patients. Although there was dephosphorylation of γH2AX at 24 hours in patient lymphocytes compared with 1 hour, the amount remained elevated at 24 hours compared with in control patients. The data from pATM and pSMC1 were uninformative. Flow-based kinetic analysis of γH2AX is a useful marker for the diagnosis of LIG4-SCID.


Assuntos
DNA Ligase Dependente de ATP/deficiência , Raios gama , Histonas/imunologia , Células Matadoras Naturais , Imunodeficiência Combinada Severa , Linfócitos T , Biomarcadores , DNA Ligase Dependente de ATP/imunologia , Feminino , Citometria de Fluxo , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Fosforilação/imunologia , Tolerância a Radiação/genética , Tolerância a Radiação/imunologia , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
12.
Science ; 361(6404): 810-813, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30026316

RESUMO

RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.


Assuntos
Artrite/genética , Doenças Inflamatórias Intestinais/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Imunodeficiência Combinada Severa/genética , Alelos , Artrite/imunologia , Citocinas/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Linfopenia/genética , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Linhagem , Imunodeficiência Combinada Severa/imunologia
13.
J Clin Immunol ; 38(6): 646-655, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30046960

RESUMO

PURPOSE: To review the clinical and laboratory spectrum of RAG gene defects in humans, and discuss the mechanisms underlying phenotypic heterogeneity, the basis of immune dysregulation, and the current and perspective treatment modalities. METHODS: Literature review and analysis of medical records RESULTS: RAG gene defects in humans are associated with a surprisingly broad spectrum of clinical and immunological phenotypes. Correlation between in vitro recombination activity of the mutant RAG proteins and the clinical phenotype has been observed. Altered T and B cell development in this disease is associated with defects of immune tolerance. Hematopoietic cell transplantation is the treatment of choice for the most severe forms of the disease, but a high rate of graft failure has been observed. CONCLUSIONS: Phenotypic heterogeneity of RAG gene defects in humans may represent a diagnostic challenge. There is a need to improve treatment for severe, early-onset forms of the disease. Optimal treatment modalities for patients with delayed-onset disease presenting with autoimmunity and/or inflammation remain to be defined.


Assuntos
Proteínas de Ligação a DNA/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Proteínas Nucleares/genética , Animais , Autoimunidade , Variação Biológica da População , Proteínas de Ligação a DNA/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Imunidade , Mutação , Proteínas Nucleares/metabolismo , Fenótipo , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia
14.
Georgian Med News ; (279): 107-110, 2018 Jun.
Artigo em Russo | MEDLINE | ID: mdl-30035731

RESUMO

In connection with the urgency of early diagnosis of severe combined immune deficiency, the case from the clinical practice of the National Science Center for Maternity and Childhood, Astana, was considered. This clinical case indicates that it is difficult to verify the diagnosis of severe combined failure, as the child was hospitalized in city clinics with various infectious diseases before receiving the right treatment more than 10 times in 4 months of life. Also, this clinical example confirms that the most effective method of treating this disorder at the present stage is bone marrow transplantation. With all medical prescriptions and recommendations, a complete restoration of the immune system is possible.


Assuntos
Imunodeficiência Combinada Severa/diagnóstico , Teste em Amostras de Sangue Seco , Humanos , Lactente , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Transplante de Células-Tronco
15.
Orv Hetil ; 159(23): 948-956, 2018 Jun.
Artigo em Húngaro | MEDLINE | ID: mdl-29860883

RESUMO

Severe combined immunodeficiency is the first immune deficiency disorder which was included in the newborn screening program in the United States in 2010. In Hungary, newborn screening for severe combined immunodeficiencies is crucial because of the routine BCG vaccination, as in the case of an affected newborn with negative family history, the vaccine may lead to fatal BCG-itis. This paper analyzes the possibilities of introducing newborn screening for severe combined immunodeficiencies and summarizes current experiences and results. Orv Hetil. 2018; 159(23): 948-956.


Assuntos
Linfopenia/diagnóstico , Triagem Neonatal/métodos , Imunodeficiência Combinada Severa/diagnóstico , Linfócitos T/imunologia , Teste em Amostras de Sangue Seco , Diagnóstico Precoce , Feminino , Humanos , Hungria , Recém-Nascido , Linfopenia/imunologia , Masculino , Imunodeficiência Combinada Severa/imunologia
16.
Blood ; 131(26): 2967-2977, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29728406

RESUMO

Allogeneic hematopoietic stem cell transplant (HSCT) typically results in donor T-cell engraftment and function in patients with severe combined immunodeficiency (SCID), but humoral immunity, particularly when using donors other than matched siblings, is variable. B-cell function after HSCT for SCID depends on the genetic cause, the use of pre-HSCT conditioning, and whether donor B-cell chimerism is achieved. Patients with defects in IL2RG or JAK3 undergoing HSCT without conditioning often have poor B-cell function post-HSCT, perhaps as a result of impairment of IL-21 signaling in host-derived B cells. To investigate the effect of pre-HSCT conditioning on B-cell function, and the relationship of in vitro B-cell function to clinical humoral immune status, we analyzed 48 patients with IL2RG/JAK3 SCID who were older than 2 years after HSCT with donors other than matched siblings. T follicular helper cells (TFH) developed in these patients with kinetics similar to healthy young children; thus, poor B-cell function could not be attributed to a failure of TFH development. In vitro differentiation of B cells into plasmablasts and immunoglobulin secretion in response to IL-21 strongly correlated with the use of conditioning, donor B-cell engraftment, freedom from immunoglobulin replacement, and response to tetanus vaccine. Patients receiving immunoglobulin replacement who had normal serum immunoglobulin M showed poor response to IL-21 in vitro, similar to those with low serum IgM. In vitro response of B cells to IL-21 may predict clinically relevant humoral immune function in patients with IL2RG/JAK3 SCID after HSCT.


Assuntos
Linfócitos B/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Subunidade gama Comum de Receptores de Interleucina/imunologia , Interleucinas/imunologia , Janus Quinase 3/imunologia , Imunodeficiência Combinada Severa/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Linfócitos B/citologia , Diferenciação Celular , Criança , Pré-Escolar , Feminino , Humanos , Imunidade Humoral , Subunidade gama Comum de Receptores de Interleucina/genética , Janus Quinase 3/genética , Ativação Linfocitária , Masculino , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Transplante Homólogo , Adulto Jovem
17.
Antivir Ther ; 23(6): 505-511, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29790481

RESUMO

BACKGROUND: Cytomegalovirus (CMV) infection is a major risk factor for mortality in infants with severe combined immunodeficiency (SCID) and other profound immune defects. Specific antiviral therapy must be initiated early and aggressively because of the potential for antiviral resistance, rapid dissemination and poor transplant outcomes. Combination antiviral therapy is routinely administered for some viral infections, but the value of this approach for the treatment of CMV is unclear. Here we explore a strategy of initial combination therapy for high-risk infants with CMV infection. METHODS: We reviewed medical records of infants ≤6 months of age hospitalized between 2007-2015 who received ganciclovir (GCV) or foscarnet (FOS) monotherapy or initial combination GCV + FOS for CMV disease. The combination therapy group consisted of severely immunocompromised infants being considered for haematopoietic cell transplantation (HCT). RESULTS: Four patients received initial combination antiviral therapy and 26 patients received initial monotherapy during the study period. Combination antiviral recipients demonstrated initial improvement in viraemia and two of three who continued with this therapy survived the infection. Clinically significant resistance mutations did not emerge. Toxicity was common; neutropenia, thrombocytopenia and electrolyte abnormalities were the most frequent adverse events in both groups. Creatinine elevation was uncommon in both groups. CONCLUSIONS: Combination GCV + FOS therapy may be a safe alternative to monotherapy in high-risk infants, especially those who are pre-transplant with primary immune deficiency syndromes and high viral loads.


Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Foscarnet/uso terapêutico , Ganciclovir/uso terapêutico , Hospedeiro Imunocomprometido , Imunodeficiência Combinada Severa/imunologia , Viremia/tratamento farmacológico , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/imunologia , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/virologia , Quimioterapia Combinada , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/terapia , Imunodeficiência Combinada Severa/virologia , Análise de Sobrevida , Carga Viral/efeitos dos fármacos , Viremia/imunologia , Viremia/mortalidade , Viremia/virologia
18.
Expert Rev Clin Immunol ; 14(7): 549-556, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29806948

RESUMO

INTRODUCTION: Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune defect in adults. Within the broad spectrum of CVID, a proportion of patients present with a predominant T cell phenotype associated with increased mortality. These patients are termed late-onset combined immunodeficiency (LOCID) and are currently separated from patients suffering from CVID. Areas covered: We have recently codiscovered a new CVID-like disorder caused by mutations of the NFKB1 gene. Members of this non-consanguineous New Zealand kindred have a very diverse spectrum of phenotypes in spite of carrying the identical mutation. The proband appears to have the autoimmune variant. The proband's recently deceased sister best matched LOCID while other family members are less severely affected, including one asymptomatic adult brother, who has an affected daughter. Differences in genetics was one of the main arguments for separating these disorders in the past. Expert commentary: Given the recent advances in the understanding of the genetic basis of these conditions, we present the case that LOCID should now be considered a subset of CVID, rather than a separate disorder. At a clinical level, this distinction is less important but it is imperative these patients are carefully evaluated, the relevant complications are treated, and they are offered prognostic information.


Assuntos
Imunodeficiência de Variável Comum/genética , Genótipo , Mutação/genética , Subunidade p50 de NF-kappa B/genética , Imunodeficiência Combinada Severa/genética , Linfócitos T/fisiologia , Adolescente , Idade de Início , Idoso , Autoimunidade , Imunodeficiência de Variável Comum/imunologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Linhagem , Fenótipo , Imunodeficiência Combinada Severa/imunologia
20.
Sci Rep ; 8(1): 4726, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29549333

RESUMO

Bats are an important animal model with long lifespans, low incidences of tumorigenesis and an ability to asymptomatically harbour pathogens. Currently, in vivo studies of bats are hampered due to their low reproduction rates. To overcome this, we transplanted bat cells from bone marrow (BM) and spleen into an immunodeficient mouse strain NOD-scid IL-2R-/- (NSG), and have successfully established stable, long-term reconstitution of bat immune cells in mice (bat-mice). Immune functionality of our bat-mouse model was demonstrated through generation of antigen-specific antibody response by bat cells following immunization. Post-engraftment of total bat BM cells and splenocytes, bat immune cells survived, expanded and repopulated the mouse without any observable clinical abnormalities. Utilizing bat's remarkable immunological functions, this novel model has a potential to be transformed into a powerful platform for basic and translational research.


Assuntos
Transplante de Medula Óssea/métodos , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Linfócitos/imunologia , Imunodeficiência Combinada Severa/terapia , Quimeras de Transplante/imunologia , Animais , Quirópteros , Rejeição de Enxerto/prevenção & controle , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Imunodeficiência Combinada Severa/imunologia
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