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1.
Nat Rev Genet ; 20(7): 377-388, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30737492

RESUMO

The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery and more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human-rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.


Assuntos
Doenças Transmissíveis/terapia , Doenças Genéticas Inatas/terapia , Células-Tronco Pluripotentes Induzidas/citologia , Modelos Biológicos , Neoplasias/terapia , Engenharia Tecidual/métodos , Animais , Diferenciação Celular , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Quimera/genética , Quimera/imunologia , Doenças Transmissíveis/genética , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/patologia , Descoberta de Drogas/métodos , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/patologia , Terapia Genética/métodos , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Células-Tronco Pluripotentes Induzidas/transplante , Modelos Animais , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Organoides/citologia , Organoides/efeitos dos fármacos , Organoides/imunologia , Transplante de Tecidos/métodos , Transplante Heterólogo
2.
Exp Clin Transplant ; 17(Suppl 1): 31-37, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30777520

RESUMO

To avoid the ethical issues of embryonic stem cells, genome engineering has focused on inducible pluripotent stem cells, which can develop into all 3 germ layers. The ability to detect methylation patterns in these cells allows research into pluripotency markers. The recently developed CRISPR system has allowed widespread application of genome engineering techniques. The CRISPR-Cas9 system, a potent system for genome editing, can be used for gene knockout or knock-in genome manipulations through substitution of a target genetic sequence with a desired donor sequence. Two types of genome engineering can be initiated: homologous or nonhomologous DNA repair by the Cas9 nuclease. Delivery of the CRISPR-Cas9 and target donor vectors in human pluripotent stem cells can be accomplished via viral and nonviral delivery methods. Nonviral delivery includes lipid-mediated transfection and electroporation. It has become the most common and efficient in vitro delivery method for human pluripotent stem cells. The CRISPR-Cas9 system can be combined with inducible pluripotent stem cells to generate single or multiple gene knockouts, correct mutations, or insert reporter transgenes. Knockouts can also be utilized to investigate epigenetic roles and targets, such as investigation of DNA methylation. CRISPR could be combined with human pluripotent stem cells to explore genetic determinants of lineage choice, differentiation, and stem cell fate, allowing investigators to study how various genes or noncoding elements contribute to specific processes and pathways. The CRISPR-Cas9 system can also be used to create null or nucleasedead Cas9, which has no enzymatic activity but has been utilized through fusion with other functional protein domains. In conclusion, RNA-guided genome targeting will have broad implications for synthetic biology, direct perturbation of gene networks, and targeted ex vivo and in vivo gene therapy.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Doenças Genéticas Inatas/terapia , Genoma Humano , Células-Tronco Pluripotentes Induzidas/transplante , Transplante de Células-Tronco/métodos , Animais , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Predisposição Genética para Doença , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Fenótipo , Transplante de Células-Tronco/efeitos adversos , Resultado do Tratamento
3.
J Allergy Clin Immunol ; 143(1): 292-304.e8, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29775636

RESUMO

BACKGROUND: Mutations in tetratricopeptide repeat domain 7A (TTC7A) and its mouse orthologue, Ttc7, result in a multisystemic disease, mostly affecting the epithelial barriers and immune system. Despite successful hematopoietic stem cell transplantation, ongoing progression of gastrointestinal manifestations can be life-threatening in TTC7A-deficient patients. OBJECTIVE: We sought to identify whether TTC7A mutations dysregulate epithelial cells only or whether a cell-intrinsic defect in lymphocytes or other cells contributes to disease manifestations. METHODS: Ttc7-mutated (Ttc7fsn/fsn) mice were crossed to generate double-mutant (Rag2-/-Ttc7fsn/fsn) and triple-mutant (Rag2-/-IL2rg-/-Ttc7fsn/fsn) mice. These models, together with bone marrow chimeras, were used to explore the role of adaptive and innate lymphocytes in the flaky skin phenotype. The effect of the Ttc7fsn/fsn mutation on stromal cells was tested in a xenograft model in conjunction with transcriptomic analysis of Ttc7fsn/fsn fibroblasts. RESULTS: We observed that the severity of epithelial hyperproliferation was accentuated by lymphocytes, whereas the phenotype was not induced by transfer of Ttc7-mutated hematopoietic cells. Furthermore, mice completely lacking the lymphocytic compartment were not protected from epithelial hyperproliferation. Ttc7-mutated mouse fibroblasts expressed increased transcript levels of insulin-like growth factor 1 (Igf1) and the antimicrobial protein regenerating islet-derived protein 3γ (Reg3γ). In a xenograft model Ttc7-mutated fibroblasts markedly increased epithelial proliferation of keratinocytes. Thus Ttc7-mutated fibroblasts were identified as potent instigators of epithelial hyperproliferation. CONCLUSION: Our results reveal a previously unsuspected fundamental cell-extrinsic role of Ttc7. We have identified potential candidates for molecularly targeted treatment strategies that will need to be evaluated in future preclinical studies.


Assuntos
Proliferação de Células , Dermatite/imunologia , Células Epiteliais/imunologia , Fibroblastos/imunologia , Doenças Genéticas Inatas/imunologia , Linfócitos/imunologia , Mutação , Proteínas/imunologia , Animais , Células 3T3 BALB , Dermatite/genética , Dermatite/patologia , Células Epiteliais/patologia , Fibroblastos/patologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Linfócitos/patologia , Camundongos , Camundongos Knockout , Proteínas/genética
4.
J Allergy Clin Immunol ; 143(1): 276-291.e6, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29800648

RESUMO

BACKGROUND: Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), result in hyperactivation of the PI3K-AKT-mechanistic target of rapamycin pathway and underlie a novel inborn error of immunity. Affected subjects exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or cytomegalovirus infection, and increased incidence of B-cell lymphoproliferation, lymphoma, or both. Mechanisms underlying disease pathogenesis remain unknown. OBJECTIVE: Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in patients with PIK3CD GOF mutations, identify key molecules required for cell-mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this and other EBV-opathies. METHODS: We studied the consequences of PIK3CD GOF mutations on the generation, differentiation, and function of CD8+ T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV. RESULTS: PIK3CD GOF total and EBV-specific CD8+ T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70. CONCLUSIONS: PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8+ T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Classe I de Fosfatidilinositol 3-Quinases , Infecções por Vírus Epstein-Barr , Mutação com Ganho de Função , Doenças Genéticas Inatas/imunologia , Herpesvirus Humano 4/imunologia , Células Matadoras Naturais/imunologia , Adolescente , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/genética , Senescência Celular/genética , Senescência Celular/imunologia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/patologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Vigilância Imunológica/genética , Células Matadoras Naturais/patologia , Masculino , Pessoa de Meia-Idade
5.
J Exp Med ; 215(12): 3194-3212, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30463877

RESUMO

In contrast to the common role of histone deacetylases (HDACs) for gene repression, HDAC activity provides a required positive function for IFN-stimulated gene (ISG) expression. Here, we show that HDAC1/2 as components of the Sin3A complex are required for ISG transcriptional elongation but not for recruitment of RNA polymerase or transcriptional initiation. Transcriptional arrest by HDAC inhibition coincides with failure to recruit the epigenetic reader Brd4 and elongation factor P-TEFb due to sequestration of Brd4 on hyperacetylated chromatin. Brd4 availability is regulated by an equilibrium cycle between opposed acetyltransferase and deacetylase activities that maintains a steady-state pool of free Brd4 available for recruitment to inducible promoters. An ISG expression signature is a hallmark of interferonopathies and other autoimmune diseases. Combined inhibition of HDAC1/2 and Brd4 resolved the aberrant ISG expression detected in cells derived from patients with two inherited interferonopathies, ISG15 and USP18 deficiencies, defining a novel therapeutic approach to ISG-associated autoimmune diseases.


Assuntos
Doenças Autoimunes/imunologia , Regulação da Expressão Gênica/imunologia , Doenças Genéticas Inatas/imunologia , Histona Desacetilase 1/imunologia , Histona Desacetilase 2/imunologia , Proteínas Nucleares/imunologia , Regiões Promotoras Genéticas/imunologia , Fatores de Transcrição/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Proteínas de Ciclo Celular , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Células HEK293 , Células HeLa , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Humanos , Interferons/genética , Interferons/imunologia , Proteínas Nucleares/genética , Fator B de Elongação Transcricional Positiva/genética , Fator B de Elongação Transcricional Positiva/imunologia , Fatores de Transcrição/genética
6.
J Exp Med ; 215(10): 2485-2496, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30194267

RESUMO

Activated PI3K-delta syndrome (APDS) is an immunodeficiency caused by gain-of-function mutations in PIK3CD. This disease exhibits complex immune phenotypes including increased IgM, recurrent infection, and impaired vaccine responses. To better understand the impact of B cells in this disease, we generated an inducible model of the common APDS mutation (hPIK3CD-E1021K; referred to as aPIK3CD) and intercrossed these mice with B cell-specific Cre models. Mb1-aPIK3CD mice exhibited bone marrow B lymphopenia and, conversely, expansion of the peripheral innate B1a and MZ B cell compartments. aPIK3CD B cells manifest increased pS6 and increased survival at several stages, without alterations in cycling, and baseline increases in plasma cells, natural IgM, and IgG3. Finally, Mb1-aPIK3CD mice exhibited blunted T cell-independent immune responses, and both AID- and CD21-aPIK3CD mice displayed reduced class-switched antibodies following T cell-dependent immunization. Thus, aPIK3CD alters B cell development and function and is counter-productive during immune responses, providing insight into B cell-intrinsic contributions to the APDS phenotype.


Assuntos
Mutação com Ganho de Função , Doenças Genéticas Inatas/imunologia , Imunidade Inata , Síndromes de Imunodeficiência/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Plasmócitos/imunologia , Animais , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Ativação Enzimática/genética , Ativação Enzimática/imunologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/genética , Plasmócitos/patologia
7.
Front Immunol ; 9: 76, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29445374

RESUMO

The immunome (immune cell phenotype, gene expression, and serum cytokines profiling) in pulmonary fibrosis is incompletely defined. Studies focusing on inherited forms of pulmonary fibrosis provide insights into mechanisms of fibrotic lung disease in general. To define the cellular and molecular immunologic phenotype in peripheral blood, high-dimensional flow cytometry and large-scale gene expression of peripheral blood mononuclear cells and serum proteomic multiplex analyses were performed and compared in a cohort with familial pulmonary fibrosis (FPF), an autosomal dominant disorder with incomplete penetrance; Hermansky-Pudlak syndrome pulmonary fibrosis (HPSPF), a rare autosomal recessive disorder; and their unaffected relatives. Our results showed high peripheral blood concentrations of activated central memory helper cells in patients with FPF. Proportions of CD38+ memory CD27- B-cells, IgA+ memory CD27+ B-cells, IgM+ and IgD+ B-cells, and CD39+ T helper cells were increased whereas those of CD39- T helper cells were reduced in patients affected with either familial or HPSPF. Gene expression and serum proteomic analyses revealed enrichment of upregulated genes associated with mitosis and cell cycle control in circulating mononuclear cells as well as altered levels of several analytes, including leptin, cytokines, and growth factors. In conclusion, dysregulation of the extra-pulmonary immunome is a phenotypic feature of FPF or HPSPF. Further studies investigating the blood immunome are indicated to determine the role of immune system dysregulation in the pathogenesis of pulmonary fibrosis. Clinical Trial Registration: www.ClinicalTrials.gov, identifiers NCT00968084, NCT01200823, NCT00001456, and NCT00084305.


Assuntos
Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Fibrose Pulmonar/etiologia , Adulto , Idoso , Alelos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Células Sanguíneas/metabolismo , Suscetibilidade a Doenças , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/metabolismo , Síndrome de Hermanski-Pudlak/diagnóstico , Síndrome de Hermanski-Pudlak/genética , Síndrome de Hermanski-Pudlak/imunologia , Humanos , Imunofenotipagem , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Fibrose Pulmonar/diagnóstico , Fibrose Pulmonar/metabolismo , Testes de Função Respiratória , Linfócitos T/imunologia , Linfócitos T/metabolismo , Tomografia Computadorizada por Raios X
8.
Autoimmunity ; 51(1): 18-24, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29308663

RESUMO

Complement convertases are enzymatic complexes, which play a critical role in propagation and amplification of the complement cascade. Under physiological conditions, convertases decay shortly after being formed in either spontaneous or inhibitor-driven process. Prolongation of their half-life by C3NeF autoantibodies that prevent convertase dissociation results in pathogenic condition often manifested by renal diseases. However, the diagnosis of convertase abnormalities is difficult due to the labile nature of these enzymes and low credibility of existing methods. Only recently, two-step functional assays employing C5-depleted serum or C5 inhibitors were introduced. Their advantage is convertase formation in the physiological milieu of whole serum and the drawback is inter-assay variability due to variations in rabbit erythrocytes used for the haemolysis-based readout. Abovementioned problems demand the application of the internal standard in each experiment. Obtaining a defined preparation of autoantibodies is complicated due to ethical and practical considerations. We found that recombinant, his-tagged factor B (fB) variant K323E retains full hemolytic activity and possess the ability to form convertases with prolonged half-life either in fB-depleted serum or when mixed with normal human serum. Such dominant character of K323E mutation allows using recombinant protein as a reference in functional convertase assays, not limited to these using rabbit erythrocytes. Additionally, our results demonstrate that gain of function mutations in complement components mimic the phenotype of C3NeF. Hence, patients with such "genetic C3NeF" would not benefit from B-cell depletion (e.g. by rituximab) and therefore should be properly diagnosed in order to choose suitable therapeutic intervention.


Assuntos
Autoanticorpos/imunologia , Ativação do Complemento , Fator B do Complemento , Mutação com Ganho de Função , Animais , Ativação do Complemento/genética , Ativação do Complemento/imunologia , Fator B do Complemento/genética , Fator B do Complemento/imunologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/patologia , Humanos , Nefropatias/genética , Nefropatias/imunologia , Nefropatias/patologia , Coelhos
9.
Hepatology ; 67(5): 1943-1955, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29220536

RESUMO

The scavenger receptor CD36 recognizes a diverse set of ligands and has been implicated in a wide variety of normal and pathological processes, including lipid metabolism, angiogenesis, atherosclerosis, and phagocytosis. In particular, recent findings have demonstrated its crucial functions in sterile inflammation and tumor metastasis. However, the role of CD36 in immune-mediated hepatitis remains unclear. Concanavalin A (ConA)-induced liver injury is a well-established experimental T cell-mediated hepatitis. To understand the role of CD36 in hepatitis, we tested the susceptibility of CD36-deficient (CD36-/- ) mice to this model, evaluated by a liver enzyme test, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, histological analysis, mononuclear cell (MNC) infiltration, and hepatic proinflammatory factor production. CD36-/- mice were less sensitive to ConA-induced hepatitis and had a significantly lower number of liver MNCs (LMNCs), including CD4+ cells, CD8+ T cells, natural killer cells, natural killer T cells, infiltrating macrophages, and neutrophils, as well as reduced expression of inflammatory mediators (tumor necrosis factor α, CXC chemokine ligand (CXCL) 10, interleukin (IL)-1α, monocyte chemotactic protein 1, and IL-6) compared with controls. Notably, we used bone marrow chimeric mice to demonstrate that CD36 expression on nonhematopoietic cells was required to drive ConA-induced liver injury. Furthermore, our data show that the CD36 receptor was essential for CXCL10-induced hepatocyte apoptosis and activation of IκB kinase, Akt, and Jun N-terminal kinase. Moreover, treatment of wild-type mice with genistein, a tyrosine kinase inhibitor that blocks CD36-Lyn signaling, attenuated ConA-induced liver injury and reduced the number of MNCs. CONCLUSIONS: Our findings suggest that CD36 plays an important proinflammatory role in ConA-induced liver injury by promoting hepatic inflammation and mediating the proapoptotic effect of chemokine CXCL10, and therefore, may be a potential therapeutic target for immune-mediated hepatitis. (Hepatology 2018;67:1943-1955).


Assuntos
Transtornos Plaquetários/patologia , Antígenos CD36/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Quimiocina CXCL10/metabolismo , Doenças Genéticas Inatas/patologia , Hepatite/metabolismo , Animais , Apoptose/efeitos dos fármacos , Transtornos Plaquetários/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Doenças Genéticas Inatas/imunologia , Genisteína/farmacologia , Hepatite/imunologia , Hepatite/patologia , Hepatócitos/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
10.
Clin Endocrinol (Oxf) ; 88(3): 491-497, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29266367

RESUMO

OBJECTIVE: Idiopathic Isolated ATCH deficiency (IIAD) is a rare cause of secondary adrenal insufficiency. As the condition is rare, and the diagnostic criteria ill-defined, there are few good clinical descriptions in the literature. We have described presenting features, autoimmune associations, natural history and responses to CRF, in a large case series of patients presenting with IIAD. DESIGN: This is a retrospective case note analysis with data derived from the recently commenced National Pituitary Database of Ireland. PATIENTS: Twenty-three patients with isolated ACTH deficiency were identified. A thorough chart and biochemistry review was performed. RESULTS: Twenty-three patients were examined (18 women and 5 men). Age at presentation ranged from 17 to 88 years, (median 48 years). Most patients complained of fatigue; 9 patients presented with hyponatraemia, 13 had autoimmune illnesses (primary hypothyroidism, n = 9). CRF stimulation testing was available in 12 of the 23 patients, 5 of whom demonstrated a rise in plasma ACTH concentrations, indicating hypothalamic, rather than pituitary aetiology. Two patients recovered ACTH secretion, and 2 patients progressed to have other pituitary hormone deficiencies. CONCLUSIONS: IIAD typically presents with insidious symptoms. Euvolaemic hyponatraemia is common at diagnosis. It is associated with autoimmune diseases, particularly primary hypothyroidism. As two patients recovered ACTH secretion, and two progressed to other pituitary hormone deficits, repeat pituitary testing should be considered, to identify recovery of function, or progression to other hormone deficits.


Assuntos
Hormônio Adrenocorticotrópico/deficiência , Doenças do Sistema Endócrino/complicações , Doenças do Sistema Endócrino/patologia , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/patologia , Hipoglicemia/complicações , Hipoglicemia/patologia , Adolescente , Insuficiência Adrenal/etiologia , Hormônio Adrenocorticotrópico/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes , Autoimunidade , Doenças do Sistema Endócrino/imunologia , Feminino , Doenças Genéticas Inatas/imunologia , Humanos , Hipoglicemia/imunologia , Hiponatremia , Irlanda , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
11.
Curr Protein Pept Sci ; 19(10): 958-971, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28847291

RESUMO

Currently it is well known that all biological drugs, including those with a fully human structure, are capable of inducing a host immune response known as immunogenicity [1]. The presence of ADAs can condition the drug´s level and action, thus modifying the therapeutic effect and even the safety profile by its mechanism of action - neutralizing or non-neutralizing - and / or an increase in its clearance. Immunogenicity is a dynamic factor to be taken into account in biological therapy, especially in long-term treatments, and as a relevant aspect in the assessment of secondary response loss [2]. With the above, not only the knowledge but also the management of the immunogenicity of the different biological treatments, represent a useful instrument for optimization of the strategies of use for each drug, and in the design of predictive models of response, which finally permits a significant improvement in the efficacy and safety profile, aiming to a personalization of the therapies, especially in patients with autoimmune diseases, genetic disorders and cancer [3]. This review summarizes the events of immunogenicity that produce the biological drug, the factor that influence to immunogenicity and the assessment of immunogenicity.


Assuntos
Fatores Biológicos/imunologia , Proteínas/imunologia , Imunidade Adaptativa , Anticorpos/sangue , Anticorpos/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Fatores Biológicos/farmacologia , Fatores Biológicos/uso terapêutico , Medicamentos Biossimilares/farmacologia , Medicamentos Biossimilares/uso terapêutico , Doenças Genéticas Inatas/tratamento farmacológico , Doenças Genéticas Inatas/imunologia , Humanos , Imunidade Ativa , Imunidade Humoral , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Peptídeos/imunologia , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Proteínas/farmacologia , Proteínas/uso terapêutico
12.
Nat Rev Rheumatol ; 14(1): 7-18, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29255211

RESUMO

Autoimmunity and immunodeficiency were previously considered to be mutually exclusive conditions; however, increased understanding of the complex immune regulatory and signalling mechanisms involved, coupled with the application of genetic analysis, is revealing the complex relationships between primary immunodeficiency syndromes and autoimmune diseases. Single-gene defects can cause rare diseases that predominantly present with autoimmune symptoms. Such genetic defects also predispose individuals to recurrent infections (a hallmark of immunodeficiency) and can cause primary immunodeficiencies, which can also lead to immune dysregulation and autoimmunity. Moreover, risk factors for polygenic rheumatic diseases often exist in the same genes as the mutations that give rise to primary immunodeficiency syndromes. In this Review, various primary immunodeficiency syndromes are presented, along with their pathogenetic mechanisms and relationship to autoimmune diseases, in an effort to increase awareness of immunodeficiencies that occur concurrently with autoimmune diseases and to highlight the need to initiate appropriate genetic tests. The growing knowledge of various genetically determined pathologic mechanisms in patients with immunodeficiencies who have autoimmune symptoms opens up new avenues for personalized molecular therapies that could potentially treat immunodeficiency and autoimmunity at the same time, and that could be further explored in the context of autoimmune rheumatic diseases.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Síndromes de Imunodeficiência/imunologia , Doenças Reumáticas/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Doenças Autoimunes/terapia , Autoimunidade/genética , Diagnóstico Diferencial , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Terapia de Alvo Molecular/métodos , Mutação , Doenças Raras/genética , Doenças Reumáticas/genética , Doenças Reumáticas/terapia , Fatores de Risco
13.
J Clin Invest ; 127(12): 4415-4420, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29106381

RESUMO

Primary immunodeficiencies are often monogenic disorders characterized by vulnerability to specific infectious pathogens. Here, we performed whole-exome sequencing of a patient with disseminated Mycobacterium abscessus, Streptococcus viridians bacteremia, and cytomegalovirus (CMV) viremia and identified mutations in 2 genes that regulate distinct IFN pathways. The patient had a homozygous frameshift deletion in IFNGR2, which encodes the signal transducing chain of the IFN-γ receptor, that resulted in minimal protein expression and abolished downstream signaling. The patient also harbored a homozygous deletion in IFNAR1 (IFNAR1*557Gluext*46), which encodes the IFN-α receptor signaling subunit. The IFNAR1*557Gluext*46 resulted in replacement of the stop codon with 46 additional codons at the C-terminus. The level of IFNAR1*557Gluext*46 mutant protein expressed in patient fibroblasts was comparable to levels of WT IFNAR1 in control fibroblasts. IFN-α-induced signaling was impaired in the patient fibroblasts, as evidenced by decreased STAT1/STAT2 phosphorylation, nuclear translocation of STAT1, and expression of IFN-α-stimulated genes critical for CMV immunity. Pretreatment with IFN-α failed to suppress CMV protein expression in patient fibroblasts, whereas expression of WT IFNAR1 restored IFN-α-mediated suppression of CMV. This study identifies a human IFNAR1 mutation and describes a digenic immunodeficiency specific to type I and type II IFNs.


Assuntos
Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Mutação , Receptor de Interferon alfa e beta , Receptores de Interferon , Bacteriemia/genética , Bacteriemia/imunologia , Bacteriemia/microbiologia , Citomegalovirus/imunologia , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Feminino , Fibroblastos/imunologia , Fibroblastos/microbiologia , Fibroblastos/virologia , Doenças Genéticas Inatas/microbiologia , Doenças Genéticas Inatas/virologia , Humanos , Síndromes de Imunodeficiência/microbiologia , Síndromes de Imunodeficiência/virologia , Masculino , Infecções por Micobactéria não Tuberculosa/genética , Infecções por Micobactéria não Tuberculosa/imunologia , Mycobacterium abscessus/imunologia , Fosforilação/genética , Fosforilação/imunologia , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/imunologia , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT2/genética , Fator de Transcrição STAT2/imunologia , Infecções Estreptocócicas/genética , Infecções Estreptocócicas/imunologia , Viremia/genética , Viremia/imunologia , Viremia/virologia , Estreptococos Viridans/imunologia
14.
Curr Opin Microbiol ; 40: 46-57, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29128761

RESUMO

It has been estimated that there are at least 1.5 million fungal species, mostly present in the environment, but only a few of these fungi cause human disease. Most fungal diseases are self-healing and benign, but some are chronic or life-threatening. Acquired and inherited defects of immunity, including breaches of mucocutaneous barriers and circulating leukocyte deficiencies, account for most severe modern-day mycoses. Other types of infection typically accompany these fungal infections. More rarely, severe fungal diseases can strike otherwise healthy individuals. Historical reports of fungi causing chronic peripheral infections (e.g. affecting the nails, skin, hair), and invasive diseases (e.g. brain, lungs, liver), in otherwise healthy patients, can be traced back to the mid-20th century. These fungi typically cause endemic, but not epidemic diseases, are more likely to underlie sporadic than familial cases, and only threaten a small proportion of infected individuals. The basis of this 'idiosyncratic' susceptibility has long remained unexplained, but it has recently become apparent that 'idiopathic' fungal diseases, in children, teenagers, and even adults, may be caused by single-gene inborn errors of immunity. The study of these unusual primary immunodeficiencies (PIDs) has led to the identification of molecules and cells playing a crucial role in human host defenses against certain fungi at particular anatomic sites. A picture is emerging of inborn errors of IL-17 immunity selectively underlying chronic mucocutaneous candidiasis, with little inter-individual variability, and of inborn errors of CARD9 immunity underlying various life-threatening invasive fungal diseases, differing between patients.


Assuntos
Fungos/fisiologia , Doenças Genéticas Inatas/imunologia , Micoses/imunologia , Animais , Fungos/genética , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/microbiologia , Humanos , Imunidade , Micoses/genética , Micoses/microbiologia
16.
J Clin Invest ; 127(5): 1991-2006, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28414293

RESUMO

Inborn errors of DNA repair or replication underlie a variety of clinical phenotypes. We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency. Four of the 5 patients also had postnatal growth retardation. The association of neutropenia and NK cell deficiency, which is unusual among primary immunodeficiencies and bone marrow failures, was due to a blockade in the bone marrow and was mildly symptomatic. We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients. The GINS complex is essential for eukaryotic DNA replication, and homozygous null mutations of GINS component-encoding genes are embryonic lethal in mice. The patients' fibroblasts displayed impaired GINS complex assembly, basal replication stress, impaired checkpoint signaling, defective cell cycle control, and genomic instability, which was rescued by WT GINS1. The residual levels of GINS1 activity reached 3% to 16% in patients' cells, depending on their GINS1 genotype, and correlated with the severity of growth retardation and the in vitro cellular phenotype. The levels of GINS1 activity did not influence the immunological phenotype, which was uniform. Autosomal recessive, partial GINS1 deficiency impairs DNA replication and underlies intra-uterine (and postnatal) growth retardation, chronic neutropenia, and NK cell deficiency.


Assuntos
Proteínas de Ligação a DNA/deficiência , Doenças Genéticas Inatas , Transtornos do Crescimento , Síndromes de Imunodeficiência , Células Matadoras Naturais , Neutropenia , Animais , Proteínas de Ligação a DNA/imunologia , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/imunologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/imunologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Lactente , Masculino , Camundongos , Neutropenia/genética , Neutropenia/imunologia
17.
Jpn J Clin Oncol ; 47(5): 463-466, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28334791

RESUMO

Nivolumab, an anti-programmed death-1 antibody, is a breakthrough treatment for several malignancies. Its specific adverse effects caused by autoimmunity are termed immune-related adverse events, which involve several endocrine dysfunctions. Herein, we report two cases of isolated adrenocorticotropic hormone (ACTH) deficiency induced by nivolumab for the treatment of metastatic malignant melanoma. Case 1 was a 39-year-old man and Case 2 was a 50-year-old woman, both of whom presented with progressive melanoma. After 13 courses of nivolumab administration, both cases were diagnosed with adrenal insufficiency. Despite their basal serum ACTH and cortisol levels being low with little response to corticotropin-releasing hormone loading, other anterior pituitary hormone levels were preserved. Based on these endocrinological data, isolated ACTH deficiency was diagnosed. Magnetic resonance imaging showed normal pituitary glands, excluding hypophysitis. Finally, hydrocortisone replacement enabled the patients to continue nivolumab treatment. Therefore, it is important to consider isolated ACTH syndrome as a possible and potentially severe immune-related adverse event of nivolumab, even when head magnetic resonance imaging of affected cases does not show enlargement. We should not misdiagnose hidden immune-related adverse events behind general complaints of malignancies such as general malaise and appetite loss, to allow successful treatment using this beneficial immune checkpoint inhibitor.


Assuntos
Hormônio Adrenocorticotrópico/deficiência , Anticorpos Monoclonais/efeitos adversos , Autoimunidade , Doenças do Sistema Endócrino/induzido quimicamente , Doenças do Sistema Endócrino/imunologia , Doenças Genéticas Inatas/induzido quimicamente , Doenças Genéticas Inatas/imunologia , Hipoglicemia/induzido quimicamente , Hipoglicemia/imunologia , Hormônio Adrenocorticotrópico/imunologia , Adulto , Autoimunidade/efeitos dos fármacos , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Nivolumabe
18.
Sci Rep ; 7: 43469, 2017 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-28233860

RESUMO

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease in which the abnormalities in alveolar surfactant accumulation are caused by impairments of GM-CSF pathway attributing to defects in a variety of genes. However, hereditary PAP is extremely uncommon and a detailed understanding in the genetic inheritance of PAP in a family may provide timely diagnosis, treatment and proper intervention including genetic consultation. Here, we described a comprehensive analysis of genome and gene expression for a family containing one affected child with a diagnosis of PAP and two other healthy siblings. Family-based whole-genome analysis revealed a homozygous deletion that disrupts CSF2RA, CRLF2, and IL3RA gene in the pseudoautosomal region of the X chromosome in the affected child and one of asymptomatic siblings. Further functional pathway analysis of differentially expressed genes in IL-1ß-treated peripheral blood mononuclear cells highlighted the insufficiency of immune response in the child with PAP, especially the protection against bacterial infection. Collectively, our results reveal a novel allele as the genetic determinant of a family with PAP and provide insights into variable expressivity and incomplete penetrance of this rare disease, which will be helpful for proper genetic consultation and prompt treatment to avoid mortality and morbidity.


Assuntos
Cromossomos Humanos X/química , Doenças Genéticas Inatas/genética , Subunidade alfa de Receptor de Interleucina-3/deficiência , Proteinose Alveolar Pulmonar/genética , Receptores de Citocinas/deficiência , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/deficiência , Doenças Assintomáticas , Criança , Pré-Escolar , Feminino , Deleção de Genes , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/patologia , Homozigoto , Humanos , Interleucina-1beta/farmacologia , Subunidade alfa de Receptor de Interleucina-3/genética , Subunidade alfa de Receptor de Interleucina-3/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Masculino , Linhagem , Penetrância , Cultura Primária de Células , Proteinose Alveolar Pulmonar/diagnóstico , Proteinose Alveolar Pulmonar/imunologia , Proteinose Alveolar Pulmonar/patologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Índice de Gravidade de Doença , Irmãos , Sequenciamento Completo do Genoma
19.
Expert Rev Clin Immunol ; 13(6): 571-597, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28064547

RESUMO

INTRODUCTION: Hallmark of autoinflammatory syndromes (AIS) is the periodic recurrence of 'sterile' inflammatory attacks characterized by fever and organ- or tissue-specific inflammation. Basic research projects over the last two decades have boosted our understanding of pathological pathways, mainly involving interleukin (IL)-1 biosynthesis, and also revealed that their dysregulation results from genetically-heterogeneous inborn errors of innate immunity and leads to multiple inflammatory phenotypes. Starting from the evidence of poor response to IL-1 inhibitors of some patients with multi-organ inflammation, further research studies have disclosed a crucial role for nuclear factor (NF)-κB and type I interferon (IFN) in specific AIS. Presently, new genetically-defined AIS have been identified, following the in-depth analysis of molecular pathways which involve either constitutive NF-κB activation or IFN signaling. Areas covered: This review is intended as a spelling booklet to help clinicians approaching patients with AIS in a simple way, using the component of the innate immunity they mainly affect. AIS have been split into 4 groups: IL-1-mediated disorders, NF-κB-mediated disorders, IFN-mediated disorders, and syndromes with still unraveled pathogenetic mechanisms or without any dominating cytokine involved. This classification has mere scholastic purposes and does not reflect the intimate complexity of each disorder discussed herein. Expert commentary: The understanding of dysregulated molecular pathways driving specific phenotypes in most AIS has prompted numerous projects to discover therapies targeting directly cytokine-mediated manifestations in such problematic patients, hopefully aimed to decrease or cancel inflammation and lead to a drastic change in patients' lives. The future has only begun.


Assuntos
Doenças Autoimunes/imunologia , Doenças Genéticas Inatas/imunologia , Imunoterapia/métodos , Inflamação/imunologia , Interleucina-1/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/terapia , Criança , Testes Genéticos , Humanos , Imunidade Inata , Recém-Nascido , Interferon Tipo I/metabolismo , Interleucina-1/genética , NF-kappa B/metabolismo , Fenótipo , Guias de Prática Clínica como Assunto , Transdução de Sinais
20.
Curr Stem Cell Res Ther ; 12(2): 124-133, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-26496888

RESUMO

Stem cell-based therapies are recognized as a new way to treat various diseases and injuries, with a wide range of health benefits. The goal is to heal or replace diseased or destroyed organs or body parts with healthy new cells provided by stem cell transplantation. The current practical form of stem cell therapy is the hematopoietic stem cells transplant applied for the treatment of hematological disorders. There are over 2100 clinical studies in progress concerning hematopoietic stem cell therapies. All of them are using hematopoietic stem cells to treat various diseases like: cancers, leukemia, lymphoma, cardiac failure, neural disorders, auto-immune diseases, immunodeficiency, metabolic or genetic disorders. Several challenges are to be addressed prior to developing and applying large scale cell therapies: 1) to explain and control the mechanisms of differentiation and development toward a specific cell type needed to treat the disease, 2) to obtain a sufficient number of desired cell type for transplantation, 3) to overcome the immune rejection and 4) to show that transplanted cells fulfill their normal functions in vivo after transplants.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Terapia de Alvo Molecular/métodos , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Doenças Autoimunes/terapia , Diferenciação Celular , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/terapia , Sobrevivência de Enxerto , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/terapia , Células-Tronco Hematopoéticas/imunologia , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/terapia , Leucemia/imunologia , Leucemia/patologia , Leucemia/terapia , Linfoma/imunologia , Linfoma/patologia , Linfoma/terapia , Doenças Metabólicas/imunologia , Doenças Metabólicas/patologia , Doenças Metabólicas/terapia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/terapia
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