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2.
Clin Exp Rheumatol ; 41(12): 2448-2457, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-38019154

RESUMEN

OBJECTIVES: To analyse how the potential exposure to air pollutants can influence the key components at the time of diagnosis of Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease). METHODS: For the present study, the following variables were selected for harmonization and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Air pollution indexes per country were defined according to the OECD (1990-2021), including emission data of nitrogen and sulphur oxides (NO/SO), particulate matter (PM2.5 and 1.0), carbon monoxide (CO) and volatile organic compounds (VOC) calculated per unit of GDP, Kg per 1000 USD. RESULTS: The results of the chi-square tests of independence for each air pollutant with the frequency of dry eyes at diagnosis showed that, except for one, all variables exhibited p-values <0.0001. The most pronounced disparities emerged in the dry eye prevalence among individuals inhabiting countries with the highest NO/SO exposure, a surge of 4.61 percentage points compared to other countries, followed by CO (3.59 points), non-methane (3.32 points), PM2.5 (3.30 points), and PM1.0 (1.60 points) exposures. Concerning dry mouth, individuals residing in countries with worse NO/SO exposures exhibited a heightened frequency of dry mouth by 2.05 percentage points (p<0.0001), followed by non-methane exposure (1.21 percentage points increase, p=0.007). Individuals inhabiting countries with the worst NO/SO, CO, and PM2.5 pollution levels had a higher mean global ESSDAI score than those in lower-risk nations (all p-values <0.0001). When systemic disease was stratified according to DAS into low, moderate, and high systemic activity levels, a heightened proportion of individuals manifesting moderate/severe systemic activity was observed in countries with worse exposures to NO/SO, CO, and PM2.5 pollutant levels. CONCLUSIONS: For the first time, we suggest that pollution levels could influence how SjD appears at diagnosis in a large international cohort of patients. The most notable relationships were found between symptoms (dryness and general body symptoms) and NO/SO, CO, and PM2.5 levels.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Síndrome de Sjögren , Xerostomía , Humanos , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Material Particulado/efectos adversos , Material Particulado/análisis , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/epidemiología , Síndrome de Sjögren/etiología , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis
3.
Clin Exp Rheumatol ; 41(12): 2437-2447, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-38019164

RESUMEN

OBJECTIVES: To analyse how the key components at the time of diagnosis of the Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease) can be influenced by the potential exposure to climate-related natural hazards. METHODS: For the present study, the following variables were selected for harmonisation and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Climate-related hazards per country were defined according to the OECD and included seven climate-related hazard types: extreme temperature, extreme precipitation, drought, wildfire, wind threats, river flooding, and coastal flooding. Climatic variables were defined as dichotomous variables according to whether each country is ranked among the ten countries with the most significant exposure. RESULTS: After applying data-cleaning techniques and excluding people from countries not included in the OECD climate rankings, the database study analysed 16,042 patients from 23 countries. The disease was diagnosed between 1 and 3 years earlier in people living in countries included among the top 10 worst exposed to extreme precipitation, wildfire, wind threats, river flooding, and coastal flooding. A lower frequency of dry eyes was observed in people living in countries exposed to wind threats, river flooding, and coastal flooding, with a level of statistical association being classified as strong (p<0.0001 for the three variables). The frequency of dry mouth was significantly lower in people living in countries exposed to river flooding (p<0.0001) and coastal flooding (p<0.0001). People living in countries included in the worse climate scenarios for extreme temperature (p<0.0001) and river flooding (p<0.0001) showed a higher mean ESSDAI score in comparison with people living in no-risk countries. In contrast, those living in countries exposed to worse climate scenarios for wind threats (p<0.0001) and coastal flooding (p<0.0001) showed a lower mean ESSDAI score in comparison with people living in no-risk countries. CONCLUSIONS: Local exposure to extreme climate-related hazards plays a role in modulating the presentation of Sjögren across countries concerning the age at which the disease is diagnosed, the frequency of dryness, and the degree of systemic activity.


Asunto(s)
Síndromes de Ojo Seco , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/epidemiología , Síndrome de Sjögren/complicaciones , Fenotipo
4.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-34575873

RESUMEN

Sjögren's syndrome (SjS) is a chronic autoimmune disease primarily involving the exocrine glands in which the involvement of the innate immune system is largely uncharacterized. Mer signaling has been found to be protective in several autoimmune diseases but remains unstudied in SjS. Here, we investigated the role of Mer signaling in SjS. Mer knockout (MerKO) mice were examined for SjS disease criteria. SjS-susceptible (SjSS) C57BL/6.NOD-Aec1Aec2 mice were assessed for defective Mer signaling outcomes, soluble Mer (sMer) levels, A disintegrin and metalloprotease 17 (ADAM17) activity, and Rac1 activation. In addition, SjS patient plasma samples were evaluated for sMer levels via ELISA, and sMer levels were correlated to disease manifestations. MerKO mice developed submandibular gland (SMG) lymphocytic infiltrates, SMG apoptotic cells, anti-nuclear autoantibodies (ANA), and reduced saliva flow. Mer signaling outcomes were observed to be diminished in SjSS mice, as evidenced by reduced Rac1 activation in SjSS mice macrophages in response to apoptotic cells and impaired efferocytosis. Increased sMer was also detected in SjSS mouse sera, coinciding with higher ADAM17 activity, the enzyme responsible for cleavage and inactivation of Mer. sMer levels were elevated in patient plasma and positively correlated with focus scores, ocular staining scores, rheumatoid factors, and anti-Ro60 levels. Our data indicate that Mer plays a protective role in SjS, similar to other autoimmune diseases. Furthermore, we suggest a series of events where enhanced ADAM17 activity increases Mer inactivation and depresses Mer signaling, thus removing protection against the loss of self-tolerance and the onset of autoimmune disease in SjSS mice.


Asunto(s)
Regulación Enzimológica de la Expresión Génica , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/metabolismo , Tirosina Quinasa c-Mer/genética , Proteína ADAM17/metabolismo , Animales , Anticuerpos Antinucleares/química , Apoptosis , Autoanticuerpos/metabolismo , Autoinmunidad , Modelos Animales de Enfermedad , Femenino , Humanos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Fenotipo , Saliva/metabolismo , Transducción de Señal , Timocitos/metabolismo
5.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-34575862

RESUMEN

Decades ago, we and many other groups showed a nucleo-cytoplasmic translocation of La protein in cultured cells. This shuttling of La protein was seen after UV irradiation, virus infections, hydrogen peroxide exposure and the Fenton reaction based on iron or copper ions. All of these conditions are somehow related to oxidative stress. Unfortunately, these harsh conditions could also cause an artificial release of La protein. Even until today, the shuttling and the cytoplasmic function of La/SS-B is controversially discussed. Moreover, the driving mechanism for the shuttling of La protein remains unclear. Recently, we showed that La protein undergoes redox-dependent conformational changes. Moreover, we developed anti-La monoclonal antibodies (anti-La mAbs), which are specific for either the reduced form of La protein or the oxidized form. Using these tools, here we show that redox-dependent conformational changes are the driving force for the shuttling of La protein. Moreover, we show that translocation of La protein to the cytoplasm can be triggered in a ligand/receptor-dependent manner under physiological conditions. We show that ligands of toll-like receptors lead to a redox-dependent shuttling of La protein. The shuttling of La protein depends on the redox status of the respective cell type. Endothelial cells are usually resistant to the shuttling of La protein, while dendritic cells are highly sensitive. However, the deprivation of intracellular reducing agents in endothelial cells makes endothelial cells sensitive to a redox-dependent shuttling of La protein.


Asunto(s)
Transporte Activo de Núcleo Celular , Autoantígenos/química , Núcleo Celular/metabolismo , Oxígeno/química , Ribonucleoproteínas/química , Anticuerpos Monoclonales/química , Citoplasma/metabolismo , Epítopos/química , Proteínas Fluorescentes Verdes/metabolismo , Células HEK293 , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Óxido Nítrico/metabolismo , Oxidación-Reducción , Conformación Proteica , Transducción de Señal , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/metabolismo , Rayos Ultravioleta , Antígeno SS-B
6.
Int J Mol Sci ; 22(3)2021 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-33530489

RESUMEN

Since the first description of nuclear autoantigens in the late 1960s and early 1970s, researchers, including ourselves, have found it difficult to establish monoclonal antibodies (mabs) against nuclear antigens, including the La/SS-B (Sjögrens' syndrome associated antigen B) autoantigen. To date, only a few anti-La mabs have been derived by conventional hybridoma technology; however, those anti-La mabs were not bona fide autoantibodies as they recognize either human La specific, cryptic, or post-translationally modified epitopes which are not accessible on native mouse La protein. Herein, we present a series of novel murine anti-La mabs including truly autoreactive ones. These mabs were elicited from a human La transgenic animal through adoptive transfer of T cells from non-transgenic mice immunized with human La antigen. Detailed epitope and paratope analyses experimentally confirm the hypothesis that somatic hypermutations that occur during T cell dependent maturation can lead to autoreactivity to the nuclear La/SS-B autoantigen.


Asunto(s)
Autoantígenos/inmunología , Autoinmunidad/genética , Linfocitos B/inmunología , Linfocitos B/metabolismo , Comunicación Celular/inmunología , Ribonucleoproteínas/inmunología , Hipermutación Somática de Inmunoglobulina , Linfocitos T/inmunología , Células 3T3 , Traslado Adoptivo , Secuencia de Aminoácidos , Animales , Especificidad de Anticuerpos/genética , Autoanticuerpos/química , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Autoantígenos/química , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Modelos Animales de Enfermedad , Mapeo Epitopo , Epítopos/química , Epítopos/inmunología , Técnica del Anticuerpo Fluorescente , Células Germinativas/metabolismo , Humanos , Inmunización , Ratones , Ratones Transgénicos , Modelos Moleculares , Conformación Proteica , Ribonucleoproteínas/química , Linfocitos T/metabolismo , Antígeno SS-B
7.
Int J Mol Sci ; 22(7)2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33806091

RESUMEN

According to the literature, the autoantigen La is involved in Cap-independent translation. It was proposed that one prerequisite for this function is the formation of a protein dimer. However, structural analyses argue against La protein dimers. Noteworthy to mention, these structural analyses were performed under reducing conditions. Here we describe that La protein can undergo redox-dependent structural changes. The oxidized form of La protein can form dimers, oligomers and even polymers stabilized by disulfide bridges. The primary sequence of La protein contains three cysteine residues. Only after mutation of all three cysteine residues to alanine La protein becomes insensitive to oxidation, indicating that all three cysteines are involved in redox-dependent structural changes. Biophysical analyses of the secondary structure of La protein support the redox-dependent conformational changes. Moreover, we identified monoclonal anti-La antibodies (anti-La mAbs) that react with either the reduced or oxidized form of La protein. Differential reactivities to the reduced and oxidized form of La protein were also found in anti-La sera of autoimmune patients.


Asunto(s)
Autoantígenos/química , Oxidación-Reducción , Ribonucleoproteínas/química , Síndrome de Sjögren/inmunología , Anticuerpos Antinucleares , Autoanticuerpos/inmunología , Autoinmunidad , Citocinas/metabolismo , Disulfuros/química , Epítopos/química , Humanos , Lupus Eritematoso Sistémico/inmunología , Oxígeno/química , Polímeros/química , Multimerización de Proteína , Estructura Secundaria de Proteína , ARN/química , Proteínas de Unión al ARN/inmunología , Proteínas Recombinantes/química , Temperatura , Antígeno SS-B
8.
PLoS Genet ; 13(6): e1006820, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28640813

RESUMEN

Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.


Asunto(s)
2',5'-Oligoadenilato Sintetasa/genética , Interferón Tipo I/genética , Sitios de Carácter Cuantitativo/genética , Síndrome de Sjögren/genética , 2',5'-Oligoadenilato Sintetasa/biosíntesis , Alelos , Empalme Alternativo/genética , Femenino , Regulación de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Interferón Tipo I/metabolismo , Masculino , Síndrome de Sjögren/metabolismo , Síndrome de Sjögren/patología , Virosis/genética , Virosis/virología
9.
Int J Mol Sci ; 20(5)2019 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-30866434

RESUMEN

The Bacillus anthracis Edema Toxin (ET), composed of a Protective Antigen (PA) and the Edema Factor (EF), is a cellular adenylate cyclase that alters host responses by elevating cyclic adenosine monophosphate (cAMP) to supraphysiologic levels. However, the role of ET in systemic anthrax is unclear. Efferocytosis is a cAMP-sensitive, anti-inflammatory process of apoptotic cell engulfment, the inhibition of which may promote sepsis in systemic anthrax. Here, we tested the hypothesis that ET inhibits efferocytosis by primary human macrophages and evaluated the mechanisms of altered efferocytic signaling. ET, but not PA or EF alone, inhibited the efferocytosis of early apoptotic neutrophils (PMN) by primary human M2 macrophages (polarized with IL-4, IL-10, and/or dexamethasone) at concentrations relevant to those encountered in systemic infection. ET inhibited Protein S- and MFGE8-dependent efferocytosis initiated by signaling through MerTK and αVß5 receptors, respectively. ET inhibited Rac1 activation as well as the phosphorylation of Rac1 and key activating sites of calcium calmodulin-dependent kinases CamK1α, CamK4, and vasodilator-stimulated phosphoprotein, that were induced by the exposure of M2(Dex) macrophages to Protein S-opsonized apoptotic PMN. These results show that ET impairs macrophage efferocytosis and alters efferocytic receptor signaling.


Asunto(s)
Antígenos Bacterianos/farmacología , Bacillus anthracis/metabolismo , Toxinas Bacterianas/farmacología , Macrófagos/citología , Neutrófilos/citología , Fagocitosis/efectos de los fármacos , Antígenos de Superficie/metabolismo , Polaridad Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , AMP Cíclico/metabolismo , Dexametasona/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Proteínas de la Leche/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Proteína S/metabolismo , Receptores de Vitronectina/metabolismo , Transducción de Señal/efectos de los fármacos , Tirosina Quinasa c-Mer/metabolismo
10.
Clin Exp Rheumatol ; 36 Suppl 112(3): 80-88, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29148407

RESUMEN

OBJECTIVES: Evaluate the presence of minor salivary gland (SG) fibrosis in primary Sjögren's syndrome (pSS) as a function of disease pathology or a consequence of ageing. METHODS: Subjects with sicca symptoms attending a Sjögren's research clinic were classified by American European Consensus Group (AECG) criteria as either pSS or non-SS (nSS). Discovery (n=34 pSS, n=28 nSS) and replication (n=35 pSS, n=31 nSS) datasets were evaluated. Minor SG cross-sections from haematoxylin and eosin stained slides were imaged, digitally reconstructed and analysed for percent area fibrosis. Relationships between SG fibrosis, age, and clinical measures were evaluated using Spearman correlations. Association with SS was assessed by: ROC curve, Variable Selection Using Random Forests (VSURF) and uni- and bi-variate regression analyses. RESULTS: SS subjects had significantly more fibrotic tissue in their minor labial salivary glands (median 24.39%, range 5.12-51.67%) than nSS participants (median 16.7%, range 5.97-38.65%, p<0.0001); age did not differ between groups (average ± SD pSS 50.2 ±13.9 years, nSS 53.8±12.4 years). In both the discovery and replication data sets, multiple regression models showed that the area of minor salivary gland fibrosis predicted pSS significantly better than age alone. Age-corrected linear regression revealed that the area of minor salivary gland fibrosis positively associated with vanBijsterveld score (p=0.042) and biopsy focus score (p=0.002). ROC curve and VSURF analyses ranked fibrosis as a significantly more important variable for subject discrimination than age. CONCLUSIONS: SG fibrosis is an element of pSS pathology that is related to focus score and is not solely attributable to age.


Asunto(s)
Glándulas Salivales Menores/patología , Síndrome de Sjögren/patología , Adulto , Factores de Edad , Anciano , Área Bajo la Curva , Biopsia , Estudios de Casos y Controles , Femenino , Fibrosis , Humanos , Modelos Lineales , Modelos Logísticos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Glándulas Salivales Menores/inmunología , Índice de Severidad de la Enfermedad , Síndrome de Sjögren/inmunología
11.
J Immunol ; 194(4): 1514-22, 2015 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-25582858

RESUMEN

A human La/Sjögren's syndrome-B (hLa)-specific TCR/hLa neo-self-Ag double-transgenic (Tg) mouse model was developed and used to investigate cellular tolerance and autoimmunity to the ubiquitous RNA-binding La Ag often targeted in systemic lupus erythematosus and Sjögren's syndrome. Extensive thymic clonal deletion of CD4(+) T cells occurred in H-2(k/k) double-Tg mice presenting high levels of the I-E(k)-restricted hLa T cell epitope. In contrast, deletion was less extensive in H-2(k/b) double-Tg mice presenting lower levels of the epitope, and some surviving thymocytes were positively selected as thymic regulatory T cells (tTreg). These mice remained serologically tolerant to hLa and healthy. H-2(k/b) double-Tg mice deficient of all endogenous Tcra genes, a deficiency known to impair Treg development and function, produced IgG anti-hLa autoantibodies and displayed defective tTreg development. These autoimmune mice had interstitial lung disease characterized by lymphocytic aggregates containing Tg T cells with an activated, effector memory phenotype. Salivary gland infiltrates were notably absent. Thus, expression of nuclear hLa Ag induces thymic clonal deletion and tTreg selection, and lymphocytic infiltration of the lung is a consequence of La-specific CD4(+) T cell autoimmunity.


Asunto(s)
Autoantígenos/inmunología , Autoinmunidad/inmunología , Enfermedades Pulmonares Intersticiales/inmunología , Ribonucleoproteínas/inmunología , Linfocitos T Reguladores/inmunología , Animales , Presentación de Antígeno/inmunología , Autoanticuerpos/inmunología , Ensayo de Inmunoadsorción Enzimática , Epítopos de Linfocito T/inmunología , Citometría de Flujo , Genes Codificadores de la Cadena alfa de los Receptores de Linfocito T/inmunología , Humanos , Tolerancia Inmunológica/inmunología , Inmunohistoquímica , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Reacción en Cadena de la Polimerasa , Receptores de Antígenos de Linfocitos T , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/inmunología , Timo/citología , Timo/inmunología , Antígeno SS-B
12.
Ann Rheum Dis ; 73(1): 31-8, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23968620

RESUMEN

OBJECTIVE: To compare the performance of the American-European Consensus Group (AECG) and the newly proposed American College of Rheumatology (ACR) classification criteria for Sjögren's Syndrome (SS) in a well-characterised sicca cohort, given ongoing efforts to resolve discrepancies and weaknesses in the systems. METHODS: In a multidisciplinary clinic for the evaluation of sicca, we assessed features of salivary and lacrimal gland dysfunction and autoimmunity as defined by tests of both AECG and ACR criteria in 646 participants. Global gene expression profiles were compared in a subset of 180 participants. RESULTS: Application of the AECG and ACR criteria resulted in classification of 279 and 268 participants with SS, respectively. Both criteria were met by 244 participants (81%). In 26 of the 35 AECG+/ACR participants, the minor salivary gland biopsy focal score was ≥1 (74%), while nine had positive anti-Ro/La (26%). There were 24 AECG-/ACR+ who met ACR criteria mainly due to differences in the scoring of corneal staining. All patients with SS, regardless of classification, had similar gene expression profiles, which were distinct from the healthy controls. CONCLUSIONS: The two sets of classification criteria yield concordant results in the majority of cases and gene expression profiling suggests that patients meeting either set of criteria are more similar to other SS participants than to healthy controls. Thus, there is no clear evidence for increased value of the new ACR criteria over the old AECG criteria from the clinical or biological perspective. It is our contention, supported by this report, that improvements in diagnostic acumen will require a more fundamental understanding of the pathogenic mechanisms than is at present available.


Asunto(s)
Síndrome de Sjögren/clasificación , Transcriptoma , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Consenso , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/genética , Estados Unidos , Adulto Joven
13.
Immunohorizons ; 8(3): 269-280, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38517345

RESUMEN

Bacillus anthracis peptidoglycan (PGN) is a major component of the bacterial cell wall and a key pathogen-associated molecular pattern contributing to anthrax pathology, including organ dysfunction and coagulopathy. Increases in apoptotic leukocytes are a late-stage feature of anthrax and sepsis, suggesting there is a defect in apoptotic clearance. In this study, we tested the hypothesis that B. anthracis PGN inhibits the capacity of human monocyte-derived macrophages (MΦ) to efferocytose apoptotic cells. Exposure of CD163+CD206+ MΦ to PGN for 24 h impaired efferocytosis in a manner dependent on human serum opsonins but independent of complement component C3. PGN treatment reduced cell surface expression of the proefferocytic signaling receptors MERTK, TYRO3, AXL, integrin αVß5, CD36, and TIM-3, whereas TIM-1, αVß3, CD300b, CD300f, STABILIN-1, and STABILIN-2 were unaffected. ADAM17 is a major membrane-bound protease implicated in mediating efferocytotic receptor cleavage. We found multiple ADAM17-mediated substrates increased in PGN-treated supernatant, suggesting involvement of membrane-bound proteases. ADAM17 inhibitors TAPI-0 and Marimastat prevented TNF release, indicating effective protease inhibition, and modestly increased cell-surface levels of MerTK and TIM-3 but only partially restored efferocytic capacity by PGN-treated MΦ. We conclude that human serum factors are required for optimal recognition of PGN by human MΦ and that B. anthracis PGN inhibits efferocytosis in part by reducing cell surface expression of MERTK and TIM-3.


Asunto(s)
Carbunco , Bacillus anthracis , Humanos , Tirosina Quinasa c-Mer/metabolismo , Peptidoglicano/farmacología , Peptidoglicano/metabolismo , Carbunco/metabolismo , Carbunco/patología , Eferocitosis , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Macrófagos/metabolismo , Pared Celular/metabolismo , Pared Celular/patología
14.
Res Sq ; 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38196575

RESUMEN

Sjögren's Disease (SjD) is a systemic autoimmune disease without a clear etiology or effective therapy. Utilizing unbiased single-cell and spatial transcriptomics to analyze human minor salivary glands in health and disease we developed a comprehensive understanding of the cellular landscape of healthy salivary glands and how that landscape changes in SjD patients. We identified novel seromucous acinar cell types and identified a population of PRR4+CST3+WFDC2- seromucous acinar cells that are particularly targeted in SjD. Notably, GZMK+CD8 T cells, enriched in SjD, exhibited a cytotoxic phenotype and were physically associated with immune-engaged epithelial cells in disease. These findings shed light on the immune response's impact on transitioning acinar cells with high levels of secretion and explain the loss of this specific cell population in SjD. This study explores the complex interplay of varied cell types in the salivary glands and their role in the pathology of Sjögren's Disease.

15.
bioRxiv ; 2023 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-37066181

RESUMEN

Bacillus anthracis peptidoglycan (PGN) is a major component of the bacterial cell wall and a key pathogen-associated molecular pattern (PAMP) contributing to anthrax pathology, including organ dysfunction and coagulopathy. Increases in apoptotic lymphocytes are a late-stage feature of anthrax and sepsis, suggesting there is a defect in apoptotic clearance. Here, we tested the hypothesis that B. anthracis PGN inhibits the capacity of human monocyte-derived macrophages (MΦ) to efferocytose apoptotic cells. Exposure of CD163+CD206+ MΦ to PGN for 24h impaired efferocytosis in a manner dependent on human serum opsonins but independent of complement component C3. PGN treatment reduced cell surface expression of the pro-efferocytic signaling receptors MERTK, TYRO3, AXL, integrin αVß5, CD36 and TIM-3, whereas TIM-1, αVß3, CD300b, CD300f, STABILIN-1 and STABILIN-2 were unaffected. ADAM17 is a major membrane-bound protease implicated in mediating efferocytotic receptor cleavage. We found multiple ADAM17-mediated substrates increased in PGN-treated supernatant suggesting involvement of membrane-bound proteases. ADAM17 inhibitors TAPI-0 and Marimastat prevented TNF release, indicating effective protease inhibition, and modestly increased cell-surface levels of MerTK and TIM-3 but only partially restored efferocytic capacity by PGN-treated MΦ. We conclude that human serum factors are required for optimal recognition of PGN by human MΦ and that B. anthracis PGN inhibits efferocytosis in part by reducing cell surface expression of MERTK and TIM-3.

16.
EClinicalMedicine ; 61: 102062, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37457113

RESUMEN

Background: What baseline predictors would be involved in mortality in people with primary Sjögren syndrome (SjS) remains uncertain. This study aimed to investigate the baseline characteristics collected at the time of diagnosis of SjS associated with mortality and to identify mortality risk factors for all-cause death and deaths related to systemic SjS activity measured by the ESSDAI score. Methods: In this international, real-world, retrospective, cohort study, we retrospectively collected data from 27 countries on mortality and causes of death from the Big Data Sjögren Registry. Inclusion criteria consisted of fulfilling 2002/2016 SjS classification criteria, and exclusion criteria included chronic HCV/HIV infections and associated systemic autoimmune diseases. A statistical approach based on a directed acyclic graph was used, with all-cause and Sjögren-related mortality as primary endpoints. The key determinants that defined the disease phenotype at diagnosis (glandular, systemic, and immunological) were analysed as independent variables. Findings: Between January 1st, 2014 and December 31, 2023, data from 11,372 patients with primary SjS (93.5% women, 78.4% classified as White, mean age at diagnosis of 51.1 years) included in the Registry were analysed. 876 (7.7%) deaths were recorded after a mean follow-up of 8.6 years (SD 7.12). Univariate analysis of prognostic factors for all-cause death identified eight Sjögren-related variables (ocular and oral tests, salivary biopsy, ESSDAI, ANA, anti-Ro, anti-La, and cryoglobulins). The multivariate CPH model adjusted for these variables and the epidemiological features showed that DAS-ESSDAI (high vs no high: HR = 1.68; 95% CI, 1.27-2.22) and cryoglobulins (positive vs negative: HR = 1.72; 95% CI, 1.22-2.42) were independent predictors of all-cause death. Of the 640 deaths with available information detailing the specific cause of death, 14% were due to systemic SjS. Univariate analysis of prognostic factors for Sjögren-cause death identified five Sjögren-related variables (oral tests, clinESSDAI, DAS-ESSDAI, ANA, and cryoglobulins). The multivariate competing risks CPH model adjusted for these variables and the epidemiological features showed that oral tests (abnormal vs normal results: HR = 1.38; 95% CI, 1.01-1.87), DAS-ESSDAI (high vs no high: HR = 1.55; 95% CI, 1.22-1.96) and cryoglobulins (positive vs negative: HR = 1.52; 95% CI, 1.16-2) were independent predictors of SjS-related death. Interpretation: The key mortality risk factors at the time of SjS diagnosis were positive cryoglobulins and a high systemic activity scored using the ESSDAI, conferring a 2-times increased risk of all-cause and SjS-related death. ESSDAI measurement and cryoglobulin testing should be considered mandatory when an individual is diagnosed with SjS. Funding: Novartis.

17.
Curr Allergy Asthma Rep ; 12(1): 1-7, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22086298

RESUMEN

Toll-like receptors (TLRs) have attracted increased attention in recent years, not only for their role in sensing conserved microbial components, but also in the realm of autoimmunity. Although TLRs are most widely known for their capacity to detect conserved motifs of infectious agents, mounting evidence indicates that these innate receptors also promote autoimmune conditions by causing uncontrolled autoinflammation as a result of chronic recognition of self. In response to the need for modern approaches to treatment of autoimmune diseases, several groups have begun investigating ways to target TLRs as new therapeutic options for autoimmune conditions. Here we discuss recent data describing advances in TLRs as therapeutic targets for treatment of autoimmune diseases, with a focus on systemic lupus erythematosus.


Asunto(s)
Lupus Eritematoso Sistémico/tratamiento farmacológico , Receptores Toll-Like/antagonistas & inhibidores , Animales , Autoinmunidad/efectos de los fármacos , Autoinmunidad/inmunología , ADN/metabolismo , Humanos , Inmunosupresores/farmacología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Ácidos Nucleicos/metabolismo , Receptores Toll-Like/agonistas , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo
18.
RMD Open ; 8(2)2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36456101

RESUMEN

OBJECTIVE: Sjögren's disease (SjD) is an autoimmune disease characterised by inflammatory destruction of exocrine glands. Patients with autoantibodies to Ro/SSA (SjDRo+) exhibit more severe disease. Long non-coding RNAs (lncRNAs) are a functionally diverse class of non-protein-coding RNAs whose role in autoimmune disease pathology has not been well characterised. METHODS: Whole blood RNA-sequencing (RNA-seq) was performed on SjD cases (n=23 Ro/SSA negative (SjDRo-); n=27 Ro/SSA positive (SjDRo+) and healthy controls (HCs; n=27). Bioinformatics and pathway analyses of differentially expressed (DE) transcripts (log2 fold change ≥2 or ≤0.5; padj<0.05) were used to predict lncRNA function. LINC01871 was characterised by RNA-seq analyses of HSB-2 cells with CRISPR-targeted LINC01871 deletion (LINC01871-/ -) and in vitro stimulation assays. RESULTS: Whole blood RNA-seq revealed autoantibody-specific transcription profiles and disproportionate downregulation of DE transcripts in SjD cases relative to HCs. Sixteen DE lncRNAs exhibited correlated expression with the interferon (IFN)-regulated gene, RSAD2, in SjDRo+ (r≥0.65 or ≤-0.6); four antisense lncRNAs exhibited IFN-regulated expression in immune cell lines. LINC01871 was upregulated in all SjD cases. RNA-seq and pathway analyses of LINC01871-/ - cells implicated roles in cytotoxic function, differentiation and IFNγ induction. LINC01871 was induced by IFNγ in a myeloid cell line and regulated by calcineurin/NFAT pathway and T cell receptor (TCR) signalling in primary human T cells. CONCLUSION: LINC01871 influences expression of many immune cell genes and growth factors, is IFNγ inducible, and regulated by calcineurin signalling and TCR ligand engagement. Altered LINC01871 expression may influence the dysregulated T cell inflammatory pathways implicated in SjD.


Asunto(s)
Enfermedades Autoinmunes , ARN Largo no Codificante , Síndrome de Sjögren , Humanos , Interferones , ARN Largo no Codificante/genética , Calcineurina , Antivirales , Síndrome de Sjögren/genética , Autoanticuerpos , Inmunidad , Receptores de Antígenos de Linfocitos T
19.
Blood ; 113(19): 4534-40, 2009 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-19224760

RESUMEN

We previously reported the inhibitory action of interleukin-6 (IL-6) on B lymphopoiesis with SHIP(-/-) mice and showed that IL-6 biases lineage commitment toward myeloid cell fates in vitro and in vivo. Because elevated IL-6 is a feature of chronic inflammatory diseases, we applied an animal model of systemic lupus erythematosus (SLE) to determine whether IL-6 has similar effects on hematopoiesis. We found that IL-6 levels were elevated in the B6.Sle1.Yaa mice, and the increase was accompanied by losses of CD19(+) B cells and more primitive B-lymphoid progenitors in bone marrow. Both the CD19(+) B-cell population and their progenitors recovered in an IL-6(-/-) background. The uncommitted progenitors, containing precursors for both lymphoid and myeloid fates, expressed IL-6 receptor-alpha chain and responded to IL-6 by phosphorylation of STAT3. IL-6 stimulation caused uncommitted progenitors to express the Id1 transcription factor, which is known to inhibit lymphopoiesis and elevate myelopoiesis, and its expression was MAPK dependent. We conclude that chronic inflammatory conditions accompanied by increased IL-6 production bias uncommitted progenitors to a myeloid fate by inducing Id1 expression.


Asunto(s)
Modelos Animales de Enfermedad , Interleucina-6/fisiología , Lupus Eritematoso Sistémico/patología , Linfopoyesis/fisiología , Células Mieloides/patología , Animales , Antígenos CD19/metabolismo , Linfocitos B/metabolismo , Linfocitos B/patología , Diferenciación Celular , Células Cultivadas , Medio de Cultivo Libre de Suero , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Lupus Eritematoso Sistémico/etiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
20.
J Infect Dis ; 202(2): 251-60, 2010 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-20533877

RESUMEN

Bacillus anthracis remains a serious bioterrorism concern, and the currently licensed vaccine remains an incomplete solution for population protection from inhalation anthrax and has been associated with concerns regarding efficacy and safety. Thus, understanding how to generate long-lasting protective immunity with reduced immunizations or provide protection through postexposure immunotherapeutics are long-sought goals. Through evaluation of a large military cohort, we characterized the levels of antibodies against protective antigen and found that over half of anthrax vaccinees had low serum levels of in vitro toxin neutralization capacity. Using solid-phase epitope mapping and confirmatory assays, we identified several neutralization-associated humoral epitopes and demonstrated that select antipeptide responses mediated protection in vitro. Finally, passively transferred antibodies specific for select epitopes provided protection in an in vivo lethal toxin mouse model. Identification of these antigenic regions has important implications for vaccine design and the development of directed immunotherapeutics.


Asunto(s)
Carbunco/inmunología , Anticuerpos Antibacterianos/inmunología , Bacillus anthracis/inmunología , Adulto , Secuencia de Aminoácidos , Animales , Carbunco/epidemiología , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/química , Anticuerpos Antibacterianos/genética , Antígenos Bacterianos/toxicidad , Toxinas Bacterianas/toxicidad , Bioterrorismo , Línea Celular , Ensayo de Inmunoadsorción Enzimática , Epítopos/inmunología , Femenino , Humanos , Inmunización/métodos , Inmunoglobulina G/sangre , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Oklahoma , Péptidos/análisis , Péptidos/química , Grupos Raciales , Vacunación/métodos
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