RESUMEN

Natural killer (NK) cells often become dysfunctional during tumor progression, but the molecular mechanisms underlying this phenotype remain unclear. To explore this phenomenon, we set up mouse lymphoma models activating or not activating NK cells. Both tumor types elicited type I interferon production, leading to the expression of a T cell exhaustion-like signature in NK cells, which included immune checkpoint proteins (ICPs). However, NK cell dysfunction occurred exclusively in the tumor model that triggered NK cell activation. Moreover, ICP-positive NK cells demonstrated heightened reactivity compared to negative ones. Furthermore, the onset of NK cell dysfunction was swift and temporally dissociated from ICPs induction, which occurred as a later event during tumor growth. Last, NK cell responsiveness was restored when stimulation was discontinued, and interleukin-15 had a positive impact on this reversion. Therefore, our data demonstrate that the reactivity of NK cells is dynamically controlled and that NK cell dysfunction is a reversible process uncoupled from the expression of ICPs.

Asunto(s)

Células Asesinas Naturales , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Animales , Ratones , Proteínas de Punto de Control Inmunitario/metabolismo , Proteínas de Punto de Control Inmunitario/genética , Activación de Linfocitos/inmunología , Línea Celular Tumoral , Interleucina-15/metabolismo , Linfoma/inmunología , Linfoma/patología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Humanos

RESUMEN

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients' blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.

Asunto(s)

Anemia Hemolítica Autoinmune , Autoinmunidad , Haploinsuficiencia , Lupus Eritematoso Sistémico , Proteína Tirosina Fosfatasa no Receptora Tipo 2 , Humanos , Haploinsuficiencia/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Anemia Hemolítica Autoinmune/genética , Anemia Hemolítica Autoinmune/inmunología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Femenino , Masculino , Niño , Autoinmunidad/genética , Adolescente , Mutación , Trombocitosis/genética , Trombocitosis/inmunología , Proteína 1 Supresora de la Señalización de Citocinas/genética , Autoanticuerpos/inmunología , Citocinas/metabolismo , Preescolar , Linfocitos T/inmunología , Trombocitopenia

RESUMEN

BACKGROUND: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has an essential role in the non-homologous end-joining pathway that repairs DNA double-strand breaks in V(D)J recombination involved in the expression of T- and B-cell receptors. Whereas homozygous mutations in Prkdc define the Scid mouse, a model that has been widely used in biology, human mutations in PRKDC are extremely rare and the disease spectrum has not been described so far. OBJECTIVES: To provide an update on the genetics, clinical spectrum, immunological profile, and therapy of DNA-PKcs deficiency in human. METHODS: The clinical, biological, and treatment data from the 6 cases published to date and from 1 new patient were obtained and analyzed. Rubella PCR was performed on available granuloma material. RESULTS: We report on 7 patients; 6 patients displayed the autosomal recessive p.L3062R mutation in PRKDC-encoding DNA-PKcs. Atypical severe combined immunodeficiency with inflammatory lesions, granulomas, and autoimmunity was the predominant clinical manifestation (n = 5 of 7). Rubella viral strain was detected in the granuloma of 1 patient over the 2 tested. T-cell counts, including naive CD4+CD45RA+ T cells and T-cell function were low at diagnosis for 6 patients. For most patients with available values, naive CD4+CD45RA+ T cells decreased over time (n = 5 of 6). Hematopoietic stem cell transplantation was performed in 5 patients, of whom 4 are still alive without transplant-related morbidity. Sustained T- and B-cell reconstitution was observed, respectively, for 4 and 3 patients, after a median follow-up of 8 years (range 3-16 years). CONCLUSIONS: DNA-PKcs deficiency mainly manifests as an inflammatory disease with granuloma and autoimmune features, along with severe infections.

RESUMEN

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by its large heterogeneity in terms of clinical presentation and severity. The pathophysiology of SLE involves an aberrant autoimmune response against various tissues, an excess of apoptotic bodies, and an overproduction of type-I interferon. The genetic contribution to the disease is supported by studies of monozygotic twins, familial clustering, and genome-wide association studies (GWAS) that have identified numerous risk loci. In the early 70s, complement deficiencies led to the description of familial forms of SLE caused by a single gene defect. High-throughput sequencing has recently identified an increasing number of monogenic defects associated with lupus, shaping the concept of monogenic lupus and enhancing our insights into immune tolerance mechanisms. Monogenic lupus (moSLE) should be suspected in patients with either early-onset lupus or syndromic lupus, in male, or in familial cases of lupus. This review discusses the genetic basis of monogenic SLE and proposes its classification based on disrupted pathways. These pathways include defects in the clearance of apoptotic cells or immune complexes, interferonopathies, JAK-STATopathies, TLRopathies, and T and B cell dysregulations.

Asunto(s)

Autoinmunidad , Lupus Eritematoso Sistémico , Humanos , Masculino , Complejo Antígeno-Anticuerpo , Autoinmunidad/genética , Estudio de Asociación del Genoma Completo , Lupus Eritematoso Sistémico/genética , Fenotipo , Femenino , Estudios en Gemelos como Asunto

RESUMEN

PURPOSE: Protein kinase C δ (PKCδ) deficiency is a rare genetic disorder identified as a monogenic cause of systemic lupus erythematosus in 2013. Since the first cases were described, the phenotype has expanded to include children presenting with autoimmune lymphoproliferative syndrome-related syndromes and infection susceptibility similar to chronic granulomatous disease or combined immunodeficiency. We review the current published data regarding the pathophysiology, clinical presentation, investigation and management of PKCδ deficiency. METHODS: Literature review was performed using MEDLINE. RESULTS: Twenty cases have been described in the literature with significant heterogeneity. CONCLUSION: The variation in clinical presentation delineates the broad and critical role of PKCδ in immune tolerance and effector functions against pathogens.

Asunto(s)

Síndrome Linfoproliferativo Autoinmune , Lupus Eritematoso Sistémico , Niño , Humanos , Proteína Quinasa C-delta/genética , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/genética , Síndrome Linfoproliferativo Autoinmune/genética , Tolerancia Inmunológica , Variación Biológica Poblacional

RESUMEN

Autosomal recessive PRKCD deficiency has previously been associated with the development of systemic lupus erythematosus in human patients, but the mechanisms underlying autoimmunity remain poorly understood. We introduced the Prkcd G510S mutation that we previously associated to a Mendelian cause of systemic lupus erythematosus in the mouse genome, using CRISPR-Cas9 gene editing. PrkcdG510S/G510S mice recapitulated the human phenotype and had reduced lifespan. We demonstrate that this phenotype is linked to a B cell-autonomous role of Prkcd. A detailed analysis of B cell activation in PrkcdG510S/G510S mice shows an upregulation of the PI3K/mTOR pathway after the engagement of the BCR in these cells, leading to lymphoproliferation. Treatment of mice with rapamycin, an mTORC1 inhibitor, significantly improves autoimmune symptoms, demonstrating in vivo the deleterious effect of mTOR pathway activation in PrkcdG510S/G510S mice. Additional defects in PrkcdG510S/G510S mice include a decrease in peripheral mature NK cells that might contribute to the known susceptibility to viral infections of patients with PRKCD mutations.

Asunto(s)

Autoinmunidad , Lupus Eritematoso Sistémico , Humanos , Animales , Ratones , Serina-Treonina Quinasas TOR/metabolismo , Linfocitos B , Proliferación Celular

RESUMEN

BACKGROUND: Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans. OBJECTIVES: To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human. METHODS: We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24th 2022. RESULTS: We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients. CONCLUSIONS: DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI).

Asunto(s)

Endodesoxirribonucleasas , Enfermedades Inflamatorias del Intestino , Interferón Tipo I , Lupus Eritematoso Sistémico , Nefritis Lúpica , Vasculitis , Anticuerpos Anticitoplasma de Neutrófilos/genética , Cromatina , ADN , Endodesoxirribonucleasas/genética , Endodesoxirribonucleasas/metabolismo , Humanos , Interferón Tipo I/genética , Interferones , Lupus Eritematoso Sistémico/genética , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/genética , Fenotipo , Vasculitis/diagnóstico

Asunto(s)

Artritis Juvenil , Artritis Juvenil/complicaciones , Humanos , Péptidos y Proteínas de Señalización Intracelular , Macrófagos

RESUMEN

EOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions. By contrast, T-BET is dominant in mature NK cells, where it induces responsiveness to IL-12 and represses the cell cycle, likely through transcriptional repressors. Regardless, many genes with distinct functions are co-regulated by the two transcription factors. By generating two gene-modified mice facilitating chromatin immunoprecipitation of endogenous EOMES and T-BET, we show a strong overlap in their DNA binding targets, as well as extensive epigenetic changes during NK cell differentiation. Our data thus suggest that EOMES and T-BET may distinctly govern, via differential expression and co-factors recruitment, NK cell maturation by inserting partially overlapping epigenetic regulations.

Asunto(s)

Ciclo Celular/genética , Linaje de la Célula/genética , Células Asesinas Naturales/inmunología , Proteínas de Dominio T Box/genética , Animales , Secuencia de Bases , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Antígeno CD11b/genética , Antígeno CD11b/inmunología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/inmunología , Diferenciación Celular , Linaje de la Célula/efectos de los fármacos , Linaje de la Célula/inmunología , Epigénesis Genética/inmunología , Interleucina-12/farmacología , Células Asesinas Naturales/citología , Células Asesinas Naturales/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Regiones Promotoras Genéticas , Unión Proteica , Bazo/citología , Bazo/inmunología , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/inmunología , Transcripción Genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología

RESUMEN

The ability of operational atmospheric transport models to simulate the soil contamination caused by deposition processes is important in the response to a nuclear crisis. The Fukushima accident was characterized by wet deposition of Cs-137, which is difficult to simulate accurately based on observations. A sensitivity study investigated seven wet deposition schemes integrated into operational atmospheric transport models. Deposition maps produced from the multiple simulations are compared with each other and with the observed deposition. Similarities and discrepancies in average behavior are presented for a number of modeling cases on the basis of criteria representing soil contamination crisis management needs. This study confirms the importance of the wet deposition scheme in a crisis management context. None of the schemes used in the study are the best option to satisfy all the comparison criteria. This study suggests that crisis managers must not exclusively trust a single model for selecting responses. At the current time, it is preferable to use several wet deposition schemes in the modelling tools for emergency responses.

Asunto(s)

Accidente Nuclear de Fukushima , Monitoreo de Radiación , Radioisótopos de Cesio/análisis , Japón , Modelos Teóricos

RESUMEN

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vß21.3 T cell receptor ß chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vß21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vß21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.

Asunto(s)

Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19/inmunología , COVID-19/patología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/patología , Adulto , Niño , Preescolar , Citocinas/sangre , Antígenos HLA-DR/inmunología , Humanos , Activación de Linfocitos/inmunología , SARS-CoV-2/inmunología

RESUMEN

Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages.

Asunto(s)

Artritis Juvenil/metabolismo , Artritis Juvenil/patología , Autofagia , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Macrófagos/metabolismo , Adenilato Quinasa/metabolismo , Adolescente , Secuencia de Aminoácidos , Apoptosis/efectos de los fármacos , Artritis Juvenil/genética , Autofagia/efectos de los fármacos , Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Bacterias/metabolismo , Diferenciación Celular/efectos de los fármacos , Niño , Exoma/genética , Femenino , Homocigoto , Humanos , Inflamasomas/metabolismo , Inflamación/complicaciones , Inflamación/patología , Interferones/metabolismo , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/genética , Gotas Lipídicas/efectos de los fármacos , Gotas Lipídicas/metabolismo , Mutación con Pérdida de Función/genética , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Factor Estimulante de Colonias de Macrófagos/farmacología , Macrófagos/efectos de los fármacos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Monocitos/efectos de los fármacos , Monocitos/patología , FN-kappa B/metabolismo , Linaje , Proteómica , Receptores de Cinasa C Activada/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Adulto Joven

Asunto(s)

Enfermedades Autoinmunes/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Infecciones por Virus de Epstein-Barr/genética , Factores de Intercambio de Guanina Nucleótido/deficiencia , Factores de Intercambio de Guanina Nucleótido/genética , Linfoma/genética , Adolescente , Enfermedades Autoinmunes/inmunología , Autoinmunidad/genética , Autoinmunidad/inmunología , Niño , Proteínas de Unión al ADN/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Femenino , Factores de Intercambio de Guanina Nucleótido/inmunología , Humanos , Lactante , Linfoma/inmunología , Masculino , Linaje , Mutación Puntual

RESUMEN

T cell development proceeds under the influence of a network of transcription factors (TFs). The precise role of Zeb1, a member of this network, remains unclear. Here, we report that Zeb1 expression is induced early during T cell development in CD4-CD8- double-negative (DN) stage 2 (DN2). Zeb1 expression was further increased in the CD4+CD8+ double-positive (DP) stage before decreasing in more mature T cell subsets. We performed an exhaustive characterization of T cells in Cellophane mice that bear Zeb1 hypomorphic mutations. The Zeb1 mutation profoundly affected all thymic subsets, especially DN2 and DP cells. Zeb1 promoted the survival and proliferation of both cell populations in a cell-intrinsic manner. In the periphery of Cellophane mice, the number of conventional T cells was near normal, but invariant NKT cells, NK1.1+ γδ T cells and Ly49+ CD8 T cells were virtually absent. This suggested that Zeb1 regulates the development of unconventional T cell types from DP progenitors. A transcriptomic analysis of WT and Cellophane DP cells revealed that Zeb1 regulated the expression of multiple genes involved in the cell cycle and TCR signaling, which possibly occurred in cooperation with Tcf1 and Heb. Indeed, Cellophane DP cells displayed stronger signaling than WT DP cells upon TCR engagement in terms of the calcium response, phosphorylation events, and expression of early genes. Thus, Zeb1 is a key regulator of the cell cycle and TCR signaling during thymic T cell development. We propose that thymocyte selection is perturbed in Zeb1-mutated mice in a way that does not allow the survival of unconventional T cell subsets.

Asunto(s)

Receptores de Antígenos de Linfocitos T alfa-beta , Subgrupos de Linfocitos T , Animales , Diferenciación Celular , Proliferación Celular , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Transducción de Señal/genética , Timo

RESUMEN

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.

Asunto(s)

Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Autoinmunidad/genética , Proteína 1 Supresora de la Señalización de Citocinas/deficiencia , Proteína 1 Supresora de la Señalización de Citocinas/genética , Adolescente , Adulto , Edad de Inicio , Enfermedades Autoinmunes/metabolismo , Niño , Preescolar , Citocinas/metabolismo , Femenino , Haploinsuficiencia , Humanos , Masculino , Modelos Moleculares , Mutación , Linaje , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas/química , Linfocitos T/inmunología

RESUMEN

Root chicory (Cichorium intybus var. sativum) is a biennial plant that requires vernalization for flowering initiation. However, we previously showed that heat can induce root chicory flowering independently of vernalization. To deepen our understanding of the temperature control of flowering in this species, we investigated the impact of heat, vernalization and their interaction on flowering induction and reproductive development. Heat increased the flowering percentage of non-vernalized plants by 25% but decreased that of vernalized plants by 65%. After bolting, heat negatively affected inflorescence development, decreasing the proportion of sessile capitula on the floral stem by 40% and the floral stem dry weight by 42% compared to control conditions, although it did not affect the number of flowers per capitulum. Heat also decreased flower fertility: pollen production, pollen viability and stigma receptivity were respectively 25%, 3% and 82% lower in heat-treated plants than in untreated control plants. To investigate the genetic control of flowering by temperature in root chicory, we studied the expression of the FLC-LIKE1 (CiFL1) gene in response to heat; CiFL1 was previously shown to be repressed by vernalization in chicory and to repress flowering when over-expressed in Arabidopsis. Heat treatment increased CiFL1 expression, as well as the percentage of bolting and flowering shoot apices. Heat thus has a dual impact on flowering initiation in root chicory since it appears to both induce flowering and counteract vernalization. However, after floral transition, heat has a primarily negative impact on root chicory reproduction.

Asunto(s)

Cichorium intybus/crecimiento & desarrollo , Flores/crecimiento & desarrollo , Cichorium intybus/fisiología , Frío , Fertilidad , Calor

RESUMEN

The effectiveness of adjunctive photodynamic treatment (PDT) to non-surgical periodontal therapy has been shown to depend on initial periodontal status. As molar furcation involvement impairs healing response to non-surgical periodontal therapy, the aim of this study was to evaluate the impact of furcation involvement on PDT outcomes. Thirty-six patients suffering from severe chronic periodontitis were included in a 6-month split-mouth randomized clinical trial. PDT applications used the toluidine blue O and a light-emitting diode (LED) with a red spectrum. Repeated PDT applications were performed in addition to non-surgical periodontal treatment at baseline and at 3-months. Pocket probing depth (PPD), plaque index, bleeding on probing, and clinical attachment level were recorded at baseline, and again at 3- and 6-months. Furcation sites of molars were compared to other sites of molars and non-molars. Multilevel analysis showed no PDT effect in molar furcation sites while an additional significant reduction (odds ratio = 0.67) of pockets with PPD > 5 mm in other sites at 3-months was measured. PPD reduction appeared delayed in molar furcation sites treated with PDT. There is no additional apparent benefit to use PDT in molar furcation sites for the reduction of pockets with PPD > 5 mm contrary to other sites.

Asunto(s)

Periodontitis Crónica , Diente Molar , Fotoquimioterapia , Terapia Combinada , Femenino , Humanos , Bolsa Periodontal , Resultado del Tratamiento

RESUMEN

BACKGROUND: Systemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are considered important in its causation. Monogenic lupus has been associated with around 30 genotypes in humans and 60 in mice, while genome-wide association studies have identified more than 90 risk loci. We aimed to analyse the contribution of rare and predicted pathogenic gene variants in a population of unselected cases of childhood-onset SLE. METHODS: For this genetic panel analysis we designed a next-generation sequencing panel comprising 147 genes, including all known lupus-causing genes in humans, and potentially lupus-causing genes identified through GWAS and animal models. We screened 117 probands fulfilling American College of Rheumatology (ACR) criteria for SLE, ascertained through British and French cohorts of childhood-onset SLE, and compared these data with those of 791 ethnically matched controls from the 1000 Genomes Project and 574 controls from the FREX Consortium. FINDINGS: After filtering, mendelian genotypes were confirmed in eight probands, involving variants in C1QA, C1QC, C2, DNASE1L3, and IKZF1. Seven additional patients carried heterozygous variants in complement or type I interferon-associated autosomal recessive genes, with decreased concentrations of the encoded proteins C3 and C9 recorded in two patients. Rare variants that were predicted to be damaging were significantly enriched in the childhood-onset SLE cohort compared with controls; 25% of SLE probands versus 5% of controls were identified to harbour at least one rare, predicted damaging variant (p=2·98 × 10-11). Inborn errors of immunity were estimated to account for 7% of cases of childhood-onset SLE, with defects in innate immunity representing the main monogenic contribution. INTERPRETATION: An accumulation of rare variants that are predicted to be damaging in SLE-associated genes might contribute to disease expression and clinical heterogeneity. FUNDING: European Research Council.

Asunto(s)

Trastorno del Espectro Autista/rehabilitación , Terapia Cognitivo-Conductual/métodos , Remediación Cognitiva/métodos , Integración a la Comunidad , Adulto , Factores de Edad , Síndrome de Asperger/psicología , Síndrome de Asperger/rehabilitación , Atención , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/psicología , Remediación Cognitiva/organización & administración , Función Ejecutiva , Expresión Facial , Estudios de Factibilidad , Humanos , Masculino , Memoria , Pruebas Neuropsicológicas , Proyectos Piloto , Guías de Práctica Clínica como Asunto , Evaluación de Programas y Proyectos de Salud , Esquizofrenia/rehabilitación , Adulto Joven

RESUMEN

Systemic lupus erythematosus (SLE) is a severe lifelong multisystem autoimmune disease characterized by the presence of autoantibodies targeting nuclear autoantigens, increased production of type I interferon and B cell abnormalities. Clinical presentation of SLE is extremely heterogeneous and different groups of disease are likely to exist. Recently, childhood-onset SLE (cSLE) cases have been linked to single gene mutations, defining the concept of monogenic or Mendelian lupus. Genes associated with Mendelian lupus can be grouped in at least three functional categories. First, complement deficiencies represent the main cause of monogenic lupus and its components are involved in the clearance of dying cells, a mechanism also called efferocytosis. Mutations in extracellular DNASE have been also identified in cSLE patients and represent additional causes leading to defective clearance of nucleic acids and apoptotic bodies. Second, the study of Aicardi-Goutières syndromes has introduced the concept of type-I interferonopathies. Bona fide lupus syndromes have been associated to this genetic condition, driven by defective nucleic acids metabolism or innate sensors overactivity. Interferon signalling anomalies can be detected and monitored during therapies, such as Janus-kinase (JAK) inhibitors. Third, tolerance breakdown can occur following genetic mutations in B and/or T cell expressing key immunoregulatory molecules. Biallelic mutations in PRKCD are associated to lupus and lymphoproliferative diseases as PKC-δ displays proapoptotic activity and is crucial to eliminate self-reactive transitional B cells. Here we review the literature of the emerging field of Mendelian lupus and discuss the physiopathological learning from these inborn errors of immunity. In addition, clinical and biological features are highlighted as well as specific therapies that have been tested in these genetic contexts.

Asunto(s)

Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/clasificación , Lupus Eritematoso Sistémico/genética , Polimorfismo Genético , Humanos , Lupus Eritematoso Sistémico/inmunología