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1.
Nat Immunol ; 25(2): 282-293, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38172257

RESUMEN

Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.


Asunto(s)
Ceramidas , Proteínas de Unión al GTP , Animales , Humanos , Longevidad/genética , Células Endoteliales/metabolismo , Mamíferos/metabolismo
2.
Nat Immunol ; 22(2): 128-139, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33398182

RESUMEN

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Activación de Complemento/efectos de los fármacos , Complemento C5/antagonistas & inhibidores , Inactivadores del Complemento/uso terapéutico , Metabolismo Energético/efectos de los fármacos , Hipoproteinemia/tratamiento farmacológico , Inmunidad Innata/efectos de los fármacos , Enteropatías Perdedoras de Proteínas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Biomarcadores/sangre , Antígenos CD55/deficiencia , Antígenos CD55/genética , Complemento C5/metabolismo , Inactivadores del Complemento/efectos adversos , Inactivadores del Complemento/farmacocinética , Predisposición Genética a la Enfermedad , Humanos , Hipoproteinemia/genética , Hipoproteinemia/inmunología , Hipoproteinemia/metabolismo , Mutación , Fenotipo , Enteropatías Perdedoras de Proteínas/genética , Enteropatías Perdedoras de Proteínas/inmunología , Enteropatías Perdedoras de Proteínas/metabolismo , Resultado del Tratamiento
4.
J Biol Chem ; 299(7): 104866, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37247757

RESUMEN

Stimulator of interferon genes (STING) is a sensor of cyclic dinucleotides including cyclic GMP-AMP, which is produced by cyclic GMP-AMP synthase (cGAS) in response to cytosolic DNA. The cGAS-STING signaling pathway regulates both innate and adaptive immune responses, as well as fundamental cellular functions such as autophagy, senescence, and apoptosis. Mutations leading to constitutive activation of STING cause devastating human diseases. Thus, the cGAS-STING pathway is of great interest because of its role in diverse cellular processes and because of the potential therapeutic implications of targeting cGAS and STING. Here, we review molecular and cellular mechanisms of STING signaling, and we propose a framework for understanding the immunological and other cellular functions of STING in the context of disease.


Asunto(s)
Nucleotidiltransferasas , Transducción de Señal , Humanos , Transducción de Señal/fisiología , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Inflamación/metabolismo , ADN/metabolismo , Citosol/metabolismo , Inmunidad Innata
5.
J Clin Immunol ; 42(1): 108-118, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34655400

RESUMEN

X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus (EBV) infection and N-linked glycosylation defect (XMEN) disease is an inborn error of immunity caused by loss-of-function mutations in the magnesium transporter 1 (MAGT1) gene. The original studies of XMEN patients focused on impaired magnesium regulation, leading to decreased EBV-cytotoxicity and the loss of surface expression of the activating receptor "natural killer group 2D" (NKG2D) on CD8+ T cells and NK cells. In vitro studies showed that supraphysiological supplementation of magnesium rescued these defects. Observational studies in 2 patients suggested oral magnesium supplementation could decrease EBV viremia. Hence, we performed a randomized, double-blind, placebo-controlled, crossover study in 2 parts. In part 1, patients received either oral magnesium L-threonate (MLT) or placebo for 12 weeks followed by 12 weeks of the other treatment. Part 2 began with 3 days of high-dose intravenous (IV) magnesium sulfate (MgSO4) followed by open-label MLT for 24 weeks. One EBV-infected and 3 EBV-naïve patients completed part 1. One EBV-naïve patient was removed from part 2 of the study due to asymptomatic elevation of liver enzymes during IV MgSO4. No change in EBV or NKG2D status was observed. In vitro magnesium supplementation experiments in cells from 14 XMEN patients failed to significantly rescue NKG2D expression and the clinical trial was stopped. Although small, this study indicates magnesium supplementation is unlikely to be an effective therapeutic option in XMEN disease.


Asunto(s)
Proteínas de Transporte de Catión , Infecciones por Virus de Epstein-Barr , Neoplasias , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X , Linfocitos T CD8-positivos , Proteínas de Transporte de Catión/genética , Estudios Cruzados , Suplementos Dietéticos , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4/fisiología , Humanos , Magnesio/metabolismo , Magnesio/uso terapéutico , Neoplasias/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética
6.
J Clin Immunol ; 40(5): 671-681, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32451662

RESUMEN

"X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia" (XMEN) disease is an inborn error of glycosylation and immunity caused by loss of function mutations in the magnesium transporter 1 (MAGT1) gene. It is a multisystem disease that strongly affects certain immune cells. MAGT1 is now confirmed as a non-catalytic subunit of the oligosaccharyltransferase complex and facilitates Asparagine (N)-linked glycosylation of specific substrates, making XMEN a congenital disorder of glycosylation manifesting as a combined immune deficiency. The clinical disease has variable expressivity, and impaired glycosylation of key MAGT1-dependent glycoproteins in addition to Mg2+ abnormalities can explain some of the immune manifestations. NKG2D, an activating receptor critical for cytotoxic function against EBV, is poorly glycosylated and invariably decreased on CD8+ T cells and natural killer (NK) cells from XMEN patients. It is the best biomarker of the disease. The characterization of EBV-naïve XMEN patients has clarified features of the genetic disease that were previously attributed to EBV infection. Extra-immune manifestations, including hepatic and neurological abnormalities, have recently been reported. EBV-associated lymphomas remain the main cause of severe morbidity. Unfortunately, treatment options to address the underlying mechanism of disease remain limited and Mg2+ supplementation has not proven successful. Here, we review the expanding clinical phenotype and recent advances in glycobiology that have increased our understanding of XMEN disease. We also propose updating XMEN to "X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation defect" in light of these novel findings.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Proteínas de Transporte de Catión/genética , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/fisiología , Células Asesinas Naturales/inmunología , Mutación/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética , Animales , Citotoxicidad Inmunológica , Proteínas de Drosophila/genética , Glicosilación , Humanos , Deficiencia de Magnesio , Neoplasias , Fenotipo
7.
Nat Commun ; 15(1): 4696, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38824133

RESUMEN

Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3'-5' DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of radiation injury, we reasoned that nuclear TREX1 would cause DNA damage. Here, we show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.


Asunto(s)
Daño del ADN , Exodesoxirribonucleasas , Fosfoproteínas , Animales , Exodesoxirribonucleasas/genética , Exodesoxirribonucleasas/metabolismo , Humanos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Ratones , Reparación del ADN por Recombinación , Fenotipo , Mutación , Drosophila/genética , Envejecimiento/genética , Envejecimiento/metabolismo , Femenino , Drosophila melanogaster/genética , Masculino , Enfermedades de la Retina , Enfermedades Vasculares , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias
8.
J Exp Med ; 219(6)2022 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-35551368

RESUMEN

Inborn errors of immunity (IEIs) unveil regulatory pathways of human immunity. We describe a new IEI caused by mutations in the GTPase of the immune-associated protein 6 (GIMAP6) gene in patients with infections, lymphoproliferation, autoimmunity, and multiorgan vasculitis. Patients and Gimap6-/- mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipids. We find that GIMAP6 complexes with GABARAPL2 and GIMAP7 to regulate GTPase activity. Also, GIMAP6 is induced by IFN-γ and plays a critical role in antibacterial immunity. Finally, we observed that Gimap6-/- mice died prematurely from microangiopathic glomerulosclerosis most likely due to GIMAP6 deficiency in kidney endothelial cells.


Asunto(s)
GTP Fosfohidrolasas , Síndromes de Inmunodeficiencia , Animales , Autofagia , Células Endoteliales/metabolismo , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Humanos , Inflamación , Ratones
9.
Front Immunol ; 12: 726406, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35069520

RESUMEN

X-linked moesin associated immunodeficiency (X-MAID) is a primary immunodeficiency disease in which patients suffer from profound lymphopenia leading to recurrent infections. The disease is caused by a single point mutation leading to a R171W amino acid change in the protein moesin (moesinR171W). Moesin is a member of the ERM family of proteins, which reversibly link the cortical actin cytoskeleton to the plasma membrane. Here, we describe a novel mouse model with global expression of moesinR171W that recapitulates multiple facets of patient disease, including severe lymphopenia. Further analysis reveals that these mice have diminished numbers of thymocytes and bone marrow precursors. X-MAID mice also exhibit systemic inflammation that is ameliorated by elimination of mature lymphocytes through breeding to a Rag1-deficient background. The few T cells in the periphery of X-MAID mice are highly activated and have mostly lost moesinR171W expression. In contrast, single-positive (SP) thymocytes do not appear activated and retain high expression levels of moesinR171W. Analysis of ex vivo CD4 SP thymocytes reveals defects in chemotactic responses and reduced migration on integrin ligands. While chemokine signaling appears intact, CD4 SP thymocytes from X-MAID mice are unable to polarize and rearrange cytoskeletal elements. This mouse model will be a valuable tool for teasing apart the complexity of the immunodeficiency caused by moesinR171W, and will provide new insights into how the actin cortex regulates lymphocyte function.


Asunto(s)
Movimiento Celular/inmunología , Proteínas de Microfilamentos/deficiencia , Linfocitos T/inmunología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/inmunología , Animales , Movimiento Celular/genética , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Proteínas de Microfilamentos/inmunología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética
10.
J Clin Invest ; 130(1): 507-522, 2020 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-31714901

RESUMEN

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαß+ T cells (αßDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.


Asunto(s)
Síndrome Linfoproliferativo Autoinmune/inmunología , Deficiencia de Magnesio/inmunología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/inmunología , Antígenos CD/genética , Antígenos CD/inmunología , Síndrome Linfoproliferativo Autoinmune/genética , Síndrome Linfoproliferativo Autoinmune/patología , Relación CD4-CD8 , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/inmunología , Femenino , Glicosilación , Humanos , Deficiencia de Magnesio/genética , Deficiencia de Magnesio/patología , Masculino , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/patología
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