RESUMEN
Anti-aquaporin-4 antibody (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and Sjögren syndrome (SS) are likely comorbidities. However, the exact effects of age and disease duration on the positivity rates of serum anti-Ro/SSA and anti-La/SSB (anti-SSA/SSB) antibodies and the presence of sicca symptoms in patients with AQP4-IgG remain unknown. In the present study, we evaluated the data from patients with suspected NMOSD who had neurological episodes and tested for serum AQP4-IgG. Associations between the presence of serum AQP4-IgG and SS-related findings were evaluated. The presence of anti-SSA/SSB antibodies [odds ratio (OR), 7.34; 95% confidence interval (CI), 5.71-9.43; p < 0.0001] and that of sicca symptoms (OR, 2.08; 95% CI, 1.67-2.58; p < 0.0001) were both higher in patients with AQP4-IgG (n = 1,651) than in those without AQP4-IgG (n = 2,796). Meanwhile, neither age nor the elapsed time from neurological onset was linked to the prevalence of anti-SSA/SSB antibodies or sicca symptoms, and the prevalence rates of the SS-related factors were elevated since the onset of neurological episodes in those with AQP4-IgG. The frequency of sicca symptoms among those with anti-SSA/SSB antibodies was irrespective of AQP4-IgG (OR, 1.11; 95% CI, 0.67-1.85; p = 0.6892). The measured AQP4-IgG titers did not differ significantly according to the presence of anti-SSA/SSB antibodies (p = 0.2386; Mann-Whitney U test). In summary, age and duration of NMOSD were not the factors producing an elevated prevalence of anti-SSA/SSB antibodies and sicca symptoms in patients with AQP4-IgG, implying that the occurrence of comorbid SS is likely to temporarily precede or synchronize with the onset of AQP4-IgG-positive NMOSD.
Asunto(s)
Neuromielitis Óptica , Síndrome de Sjögren , Humanos , Neuromielitis Óptica/epidemiología , Acuaporina 4 , Anticuerpos Antinucleares , Inmunoglobulina G , AutoanticuerposRESUMEN
AIMS: Anti-Ro/La autoantibodies are especially prevalent in autoimmune diseases but are also relatively frequent in healthy adults. Their arrhythmogenic effect on the immature cardiac conductive system is well established, with substantial evidence demonstrating an increased risk for congenital atrioventricular block in neonates of seropositive mothers. Despite their wide distribution and their arrhythmogenic potential effect, there are no large population studies conducted in seropositive adults. Thus, this is the first large population-based study to examine the association of anti-Ro/La seropositivity with cardiac rhythm and conduction disturbances. METHODS AND RESULTS: This cross-sectional designed study involved the electronic health records of the largest health maintenance organization in Israel. All subjects that were tested positive for anti-Ro/anti-La antibodies between the years 2002 and 2019 were included and were matched by age, gender, and place of residence, with controls. Rates of different cardiac rhythm and conduction disturbances were compared between groups. Sensitivity analyses were performed using propensity score matching. The study population included 17 231 anti-Ro/La seropositive subjects and 84 368 controls. Anti-Ro seropositive patients had higher rates of conduction disturbances (3.0 vs. 1.7%, P < 0.001) and rhythm disturbances (10.5 vs. 7.0%, P < 0.001). Patients who tested positive for anti-La alone did not demonstrate a significant association with arrhythmias. Multivariate logistic regression analysis, controlling for possible confounders, showed an increased risk for cardiac conduction disturbances [odds ratio (OR) 1.44, 95% confidence interval (CI) 1.25-1.66, P < 0.001], as well as for cardiac rhythm disturbances (OR 1.21, 95% CI 1.11-1.31, P < 0.001) among anti-Ro seropositive patients. However, the association with rhythm disturbances was more robust in certain subgroup analyses. CONCLUSIONS: Anti-Ro seropositivity is positively associated with adult cardiac conduction disturbances and, to a lesser extent, cardiac rhythm disturbances, regardless of the presence of concurrent autoimmune disease.
Asunto(s)
Enfermedades Autoinmunes , Sistema de Conducción Cardíaco , Recién Nacido , Adulto , Humanos , Estudios Transversales , Arritmias Cardíacas/epidemiología , Fenómenos Fisiológicos Cardiovasculares , AutoanticuerposRESUMEN
OBJECTIVES: To identify the prenatal predisposing factors related to neonatal lupus erythematosus (NLE). MATERIALS AND METHODS: A retrospective case-control study was made of 131 pregnant women with positive anti-Ro or anti-La autoantibodies and known neonatal outcomes between January 2002 and December 2019 at Siriraj Hospital, Bangkok, Thailand. There were 101 unaffected neonates and 30 NLE cases confirmed postnatally. Demographic and clinical data of the mothers and neonates with and without NLE were statistically compared. RESULTS: NLE was diagnosed in 30 out of 131 cases. A multivariate analysis identified the following significant factors for NLE: maternal anti-La antibodies (odds ratio (OR), 3.591; p = 0.030); and maternal treatment with either hydroxychloroquine (OR, 0.082; p = 0.001) or prednisolone (OR, 0.136; p = 0.017). Of the significant variables examined in the multivariate analysis models, high levels of maternal anti-La antibodies were found to be the strongest predictor of noncardiac NLE (OR, 4.558; p = 0.032), while a female baby was significantly higher in pregnancies complicated by cardiac NLE (OR, 5.374; p = 0.046). Hydroxychloroquine still provided a protective effect for both cardiac and noncardiac NLE (p = 0.039 and 0.032, respectively). CONCLUSIONS: The maternal anti-La antibodies were a beneficial predictor for NLE, especially as their high titers were influentially associated with noncardiac features. A female fetus seemed to present an increased risk for developing a congenital heart block. Nevertheless, the treatment with hydroxychloroquine during the pregnancies demonstrated a potentially protective factor against both cardiac and noncardiac manifestations.
Asunto(s)
Lupus Eritematoso Sistémico , Anticuerpos Antinucleares/inmunología , Estudios de Casos y Controles , Causalidad , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Lactante , Recién Nacido , Lupus Eritematoso Sistémico/congénito , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/epidemiología , Embarazo , Estudios Retrospectivos , TailandiaRESUMEN
Neonatal lupus erythematosus (NLE) is a congenital autoimmune condition in which the transplacental passage of immunoglobulin G (IgG) directed against auto-antigens causes clinical symptoms in the foetus or neonate. Anti-Ro/SS-A, anti-La/SS-B, and to a lesser extent, anti-U1RNP autoantibodies (aAbs) have the strongest association with NLE. However, ~ 50% of affected mothers are asymptomatic despite carrying those aAbs. The clinical picture of the disease is very diverse. Cardiac manifestations are the most severe, including congenital heart block (CHB), with a mortality rate of ~18%. Preventative therapy with hydroxychloroquine (HCQ) reduces the recurrence rate of CHB in subsequent pregnancies by ~50%.
RESUMEN
The anti-La mab 312B, which was established by hybridoma technology from human-La transgenic mice after adoptive transfer of anti-human La T cells, immunoprecipitates both native eukaryotic human and murine La protein. Therefore, it represents a true anti-La autoantibody. During maturation, the anti-La mab 312B acquired somatic hypermutations (SHMs) which resulted in the replacement of four aa in the complementarity determining regions (CDR) and seven aa in the framework regions. The recombinant derivative of the anti-La mab 312B in which all the SHMs were corrected to the germline sequence failed to recognize the La antigen. We therefore wanted to learn which SHM(s) is (are) responsible for anti-La autoreactivity. Humanization of the 312B ab by grafting its CDR regions to a human Ig backbone confirms that the CDR sequences are mainly responsible for anti-La autoreactivity. Finally, we identified that a single amino acid replacement (D > Y) in the germline sequence of the CDR3 region of the heavy chain of the anti-La mab 312B is sufficient for anti-La autoreactivity.
Asunto(s)
Anticuerpos Antinucleares/genética , Autoanticuerpos/genética , Hipermutación Somática de Inmunoglobulina/genética , Secuencia de Aminoácidos , Aminoácidos/genética , Aminoácidos/metabolismo , Anticuerpos Antinucleares/inmunología , Anticuerpos Antinucleares/metabolismo , Autoanticuerpos/química , Autoanticuerpos/inmunología , Autoanticuerpos/metabolismo , Autoinmunidad/genética , Regiones Determinantes de Complementariedad/genética , Regiones Determinantes de Complementariedad/inmunología , Regiones Determinantes de Complementariedad/metabolismo , Epítopos/genética , Epítopos/inmunología , Células HeLa , Humanos , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismo , Análisis de Secuencia de ProteínaRESUMEN
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-BRESUMEN
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-BRESUMEN
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-BRESUMEN
Sjogren's disease (BS) is a systemic autoimmune disease, the main symptoms of which are associated with dry eyes, mouth, skin, respiratory and gastrointestinal tract, etc., but there are a large number of extra-vascular symptoms that can accompany this disease: weakness, swelling of the lymph nodes, respiratory failure, pain and swelling of the joints, rash, dysphagia, gastro-esophageal reflux, lymphoma, etc. In addition, the etiology of this disease remains unknown, and the pathogenesis is partially studied. The diagnosis of Sjogren's disease is complicated by a variety of clinical manifestations, as well as subacute and chronic variants of the course of the disease, in addition, the diagnostic criteria are periodically changed. It is recommended to adhere to the domestic diagnostic criteria considering the presence of laboratory signs of an autoimmune disease. The article presents a clinical observation of a patient with the development of the main symptoms and signs of BS and autoimmune hepatitis for 20 years. Recurrent mumps or chronic bilateral enlargement of the parotid salivary glands may be the first symptom of Sjogren's disease, which is recommended to extend the examination in order to identify other, sometimes latent signs of the disease.
Asunto(s)
Síndrome de Sjögren , Humanos , Hígado , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/diagnósticoRESUMEN
BACKGROUND: Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in systemic lupus erythematosus (SLE). METHODS: We retrospectively analyzed cases of proliferative and membranous LN patients who underwent a renal biopsy at our hospital in 1993-2016. We analyzed the association between complete renal response (CR) rates at 12 months after induction therapy and predictive factors for CR and their association with renal flares. RESULTS: Of the 95 cases analyzed, we were able to track the therapeutic responses of 81 patients at 12 months after their induction therapy. The median follow-up duration after renal biopsy was 51 months (interquartile range: 16.5-154.5 months). The Cox proportional hazards model showed that, compared to not attaining CR at 12 months, the attainment of CR at 12 months was correlated with being free from renal flares. The multivariate logistic analysis revealed that the predictive factors for CR at 12 months were the anti-La/SSB antibodies (U/ml) (odds ratio (OR) 1.22, 95% confidence interval (CI) 1.01-1.63, p = 0.0220), blood urea nitrogen (BUN) (OR 0.68, 95% CI 0.44-0.90, p = 0.00048) and serum ß2 microglobulin (MG) (OR 0.26, 95% CI 0.06-0.74, p = 0.00098) levels. CONCLUSIONS: Among LN patients, being free from renal flares was associated with attaining CR at 12 months after induction therapy. Anti-La/SSB antibodies were a positive predictive factor, and BUN and serum ß2MG levels were negative predictive factors of CR at 12 months.
Asunto(s)
Hospitales Universitarios , Inmunosupresores/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/etiología , Adulto , Autoantígenos/sangre , Nitrógeno de la Urea Sanguínea , Femenino , Estudios de Seguimiento , Humanos , Japón , Estimación de Kaplan-Meier , Riñón/patología , Modelos Logísticos , Nefritis Lúpica/sangre , Nefritis Lúpica/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Fragmentos de Péptidos/sangre , Modelos de Riesgos Proporcionales , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Microglobulina beta-2/sangreRESUMEN
Fetal atrioventricular (AV) block is a rare and potentially devastating condition. Most commonly fetal AV block is mediated by maternal lupus antibodies which cause irreversible damage to the AV node. For many fetuses, the only potential intervention is premature delivery and highly invasive pacemaker implantation. However, there exists a small subset of fetuses with non-immune mediated AV block who appear to have far better outcomes, with potential for spontaneous resolution and a return to sinus rhythm. Despite this, it is not clear that prenatal counseling takes this fact into account. We describe a series of three patients with non-immune fetal second-degree AV block with spontaneous resolution prior to delivery, underscoring the need for appropriate prenatal counseling in this scenario.
Asunto(s)
Bloqueo Atrioventricular/diagnóstico por imagen , Ecocardiografía , Diagnóstico Prenatal , Adolescente , Bloqueo Atrioventricular/fisiopatología , Femenino , Edad Gestacional , Humanos , Embarazo , Remisión Espontánea , Síndrome de Turner/diagnósticoRESUMEN
New 2016 ACR/EULAR classification criteria for primary Sjogren's syndrome (SS) have been developed and endorsed by the ACR. The newly proposed criteria include simple-to-perform items.Two important points of the new criteria should be considered. Firstly, they indicate that either salivary gland biopsy or anti-Ro must be positive in order to corroborate the inflammatory and autoimmune nature of the disease. Secondly, the criteria recognize the systemic nature of SS, namely that patients without salivary or ocular glandular symptoms, but with extraglandular manifestations and B cell activation markers were also included in the SS classification. Additionally, the new criteria modified some technical points. The ocular staining score threshold was increased to 5 due to the higher specificity. The immunological profile includes only anti-Ro antibodies, while positivity for antinuclear antibodies and rheumatoid factor or isolated anti-La was excluded due to a lack of specificity.The 2016 ACR/EULAR criteria are suitable for early identification of SS, providing patients with the opportunity of enrollment in clinical trials for new specific treatment. Although validation has been successful, the real life application of these criteria will test their performance.
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Síndrome de Sjögren/clasificación , Síndrome de Sjögren/diagnóstico , Anticuerpos Antinucleares/sangre , Biomarcadores/sangre , Femenino , Humanos , Masculino , Factor Reumatoide/sangre , Factores de Riesgo , Síndrome de Sjögren/sangreRESUMEN
OBJECTIVE: MCTD is a chronic, immune-mediated disorder defined by the combined presence of serum anti-RNP antibodies and distinct clinical features, including progressive lung fibrosis. The aim of the study was to evaluate the potential impact of anti-SSA (i.e. Ro52 and Ro60) and anti-SSB autoantibodies as markers for disease outcomes in MCTD. METHODS: Stored serum samples from 113 patients included in the cross-sectional, nationwide Norwegian MCTD cohort were screened for the presence of anti-Ro52, anti-Ro60 and anti-SSB by a commercial line immunoassay. Correlation analyses were carried out with clinical parameters, including quantitative lung fibrosis scores by high-resolution CT. Lung fibrosis was defined by reticular pattern changes according to the Fleischner Society CT criteria for interstitial lung disease. RESULTS: Anti-Ro52 antibodies were present in 29%, anti-Ro60 in 19% and anti-SSB in 6% of the MCTD sera. High-resolution CT scoring identified lung fibrosis in 38 of 113 (34%) MCTD patients. Anti-Ro52 antibodies were detected in 50% (19 of 38) of the MCTD patients with lung fibrosis and in 19% (14 of 75) without lung fibrosis (P < 0.001). The odds ratio for the presence of anti-Ro52 antibodies in lung fibrosis was 4.4 (95% CI 1.8, 10.3). Anti-Ro52 antibodies were equally frequent in patients with mild to moderate (eight of 17; 44%) and severe fibrosis (11 of 21; 52%). Anti-Ro52 was not associated with any of the other clinical parameters assessed, nor was anti-Ro60 or anti-SSB. CONCLUSION: Our cross-sectional data suggest that anti-Ro52 antibodies may serve as a potential marker for lung fibrosis in MCTD.
Asunto(s)
Anticuerpos Antinucleares/inmunología , Enfermedad Mixta del Tejido Conjuntivo/inmunología , Fibrosis Pulmonar/inmunología , Ribonucleoproteínas/inmunología , Adulto , Anticuerpos Antinucleares/sangre , Enfermedad Crónica , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Mixta del Tejido Conjuntivo/sangre , Enfermedad Mixta del Tejido Conjuntivo/complicaciones , Fibrosis Pulmonar/sangre , Fibrosis Pulmonar/etiología , Estudios RetrospectivosRESUMEN
Sjogren's syndrome (SS) has been associated with the expression of anti-Ro and anti-La antibodies. Anti-salivary gland protein 1 (SP1) antibodies have recently been identified in patients with SS. The current work involved a cross sectional study to determine whether anti-SP1 antibodies were identified in particular subgroups of patients with SS. The results of this study revealed that anti-SP1 antibodies were present in the sera of 52% of SS patients while anti-Ro/anti-La was present in 63% of patients. 19% of patients had anti-SP1 without anti-Ro/anti-La. Patients with SS and lymphoma expressed anti-Ro, anti-La and anti-SP1 together. In SS associated with RA, 50% had antibodies anti-SP1 while 40% had anti-Ro/anti-La. In conclusion, anti-SP1 antibodies are commonly seen in both primary and secondary SS and rarely in normal controls. Future studies are needed to determine the roles and timing of expression of anti-SP1 antibodies in Sjogren's syndrome.
Asunto(s)
Proteínas y Péptidos Salivales/inmunología , Síndrome de Sjögren/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/inmunología , Autoanticuerpos , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Sjögren/metabolismo , Adulto JovenRESUMEN
Kikuchi disease is a self-limited disorder of unknown etiology characterized by focal painful lymphadenitis, fever, and weight loss that can be mistaken for malignancy. Diagnosis is established by node biopsy. Kikuchi disease is endemic in Asia; 10 cases have been reported in the US to date. We report 3 cases and review other US cases.
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Linfadenitis Necrotizante Histiocítica/diagnóstico , Ganglios Linfáticos/patología , Adolescente , Biopsia , Niño , Connecticut , Diagnóstico Diferencial , Femenino , Humanos , MasculinoRESUMEN
Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by periepithelial lymphocytic infiltrates in affected tissues and the production of plethora of autoantibodies. Among them autoimmune responses against Ro/SSA and La/SSB are of major importance since their detection is routinely used for disease diagnosis and clinical characterization. Although the exact mechanisms underlying disease pathogenesis are not fully understood, the important role of salivary gland epithelial cells (SGEC) in the initiation and development of the local immune responses is well-established. SGECs are also capable to mediate the exposure of the Ro/SSA and La/SSB autoantigens to the immune system by elevated apoptosis and autoantigen release in apoptotic bodies and/or by the secretion of autoantigen-containing exosomes. The expression of these autoantigens in epithelial cells appears to be tightly regulated. Up-to-date, signaling of certain innate immunity receptors, such as TLR3, appear to be implicated in the regulation of Ro/SSA and La/SSB expression by SGECs, whereas the deregulated expression of certain miRNAs that are predicted to target them in SS patients suggests a regulatory feedback at the post-transcriptional level. In the periphery, the humoral autoimmune responses are further regulated by the development of an active network of idiotypic-antiidiotypic antibodies. The plethora of mechanisms suggests that autoimmune humoral responses in SS are tightly regulated. In this review, the major humoral autoimmune responses, recent advances on the role of epithelial cells in their development, as well as possible regulatory mechanisms will be discussed.
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Autoanticuerpos/inmunología , Inmunomodulación , Fenotipo , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/inmunología , Animales , Autoanticuerpos/sangre , Autoinmunidad/genética , Autoinmunidad/inmunología , Humanos , Glándulas Salivales/inmunología , Glándulas Salivales/patología , Síndrome de Sjögren/genética , Síndrome de Sjögren/metabolismoRESUMEN
Sjögren's Syndrome (SS) is a chronic, inflammatory autoimmune disease characterized by lacrimal gland lymphocytic infiltration and epithelial cell death, as well as by the presence of serum autoantibodies. Although the symptoms of this syndrome are well characterized, patients are not diagnosed until 5-10 years into disease progression; furthermore, the early series of events leading to the initiation of SS are not well understood. In order to better understand the early events of the disease, we have been using ovariectomized (OVX) NOD.B10.H2(b) mice as a genetically predisposed model of SS. Previously, we have shown that removal of ovarian hormones through ovariectomy accelerated the symptoms of this disease, and in early events of SS in the lacrimal glands, lymphocytic infiltration preceded acinar cell apoptosis. To further elucidate the earlier events of this disease in the SS animal model, we investigated the expression and concentration of pro-inflammatory cytokines in the lacrimal glands as well as the presence of autoantibodies in both lacrimal glands and serum. Six weeks old NOD.B10.H2(b) and C57BL/10 control mice were either sham-operated, OVX, OVX and treated with 17ß-estradiol (E2), or OVX and treated with dihydrotestosterone (DHT). Lacrimal glands were collected at 3, 7, 21, and 30 days after surgery and analyzed for cytokines IL-1ß, TNF-α, IFN-γ, IL-10, and IL-4 gene expression by using quantitative RT-PCR and for cytokine levels using ELISA. Furthermore, anti-Ro/SSA and anti-La/SSB autoantibodies were measured in the serum and lacrimal glands supernatants using ELISA. The results of this study showed that OVX caused a significant increase in the expression and levels of the cytokines IL-1ß, TNF-α, and IL-4 in the lacrimal glands of the NOD.B10.H2(b) mice starting at 3 days after OVX, while a significant increase of IL-10 gene expression and levels was observed only at later experimental time points. A small but significant increase in the expression of IL-1ß and IL-4 was observed only at later experimental time points in the lacrimal glands of OVX C57BL/10 mice, while no significant changes in the expression of TNF-α and IL-10 were seen at any experimental times in this group. No significant differences were observed in the levels of the cytokines IL-1ß, TNF-α, IL-4, and IL-10 in the lacrimal glands of the OVX C57BL/10 mice at any of the experimental times studied compared to the sham-operated group. IFN-γ was not detected in either mouse strains at the level of mRNA and protein. OVX in the NOD.B10.H2(b) mice also caused an increase in the levels of anti-Ro/SSA autoantibodies in the serum only, while no anti-La/SSB autoantibodies were found in the serum or lacrimal gland supernatants. Physiological doses of E2 or DHT at time of OVX prevented the upregulation of cytokines and the presence of anti-Ro/SSA autoantibodies in these animals. These results showed that a decrease in the concentrations of ovarian hormones in the genetically predisposed mice accelerated the onset of the disease by upregulating various pro-inflammatory cytokines at different time points and promoting the formation of anti-Ro/SSA serum autoantibodies, creating an environment favorable for the initiation of SS.
Asunto(s)
Autoanticuerpos/sangre , Citocinas/genética , Dihidrotestosterona/farmacología , Modelos Animales de Enfermedad , Estradiol/farmacología , Aparato Lagrimal/metabolismo , Síndrome de Sjögren/genética , Animales , Anticuerpos Antinucleares/sangre , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Análisis de Secuencia por Matrices de Oligonucleótidos , Ovariectomía , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Síndrome de Sjögren/inmunología , Factores de Tiempo , Regulación hacia Arriba/fisiologíaRESUMEN
BACKGROUND AND AIMS: Emerging evidence suggests an arrhythmogenic effect of Anti-Ro/SSA (anti-Ro) and anti-La/SSB (anti-La) antibodies in adults, potentially involving a subclinical intracardiac inflammatory process. Despite the established association between inflammation and ischemic heart disease (IHD), it is noteworthy that as of now no study has delved into the potential link between these antibodies and IHD. This population-based study aimed to examine the association between anti-Ro/La seropositivity and IHD in the general adult population. METHODS: We conducted a retrospective study using electronic medical records from the largest health maintenance organization in Israel. Patients with positive serology for either or both anti-Ro and anti-La antibodies were included, along with matched controls. Multivariate logistic regression models were utilized to assess the odds of IHD in seropositive patients compared to controls. RESULTS: Among 17,231 seropositive patients and 84,368 controls, the rate of IHD was significantly higher in the seropositive group (9.7 % vs. 8.1 %,OR = 1.23; 95%CI 1.14-1.31; p<0.001). The association was more pronounced in younger patients [<40 years old (OR = 3.36; 95%CI 1.66-6.82; p<0.001), 40-49 years old (OR = 1.85; 95%CI 1.26-2.73; p<0.01), 50-59 years old (OR = 1.87; 95%CI 1.55-2.26; p<0.001), 60-69 years old (OR = 1.26; 95%CI 1.11-1.42; p<0.001), ≥70 years old (OR = 1.11; 95%CI 1.03-1.20; p<0.01)], as well as in patients with fewer traditional cardiovascular risk-factors (none:OR = 1.29; 95 % CI 1.09 to 1.77; p<0.01, 1-2:OR = 1.30; 95 % CI 1.19 to 1.41; p<0.001, ≥3:OR = 1.09; 95 % CI 0.99 to 1.21; p=0.076). CONCLUSIONS: Our study demonstrates for the first time a positive association between anti-Ro/La seropositivity and IHD in the general adult population, especially among younger individuals with fewer traditional cardiovascular risk factors.
Asunto(s)
Anticuerpos Antinucleares , Isquemia Miocárdica , Humanos , Isquemia Miocárdica/epidemiología , Isquemia Miocárdica/sangre , Isquemia Miocárdica/inmunología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Israel/epidemiología , Anciano , Factores de Riesgo , Anticuerpos Antinucleares/sangre , Modelos Logísticos , Oportunidad Relativa , Análisis Multivariante , Biomarcadores/sangre , Factores de EdadRESUMEN
Background: Autoimmune diseases encompass a diverse array of disorders that disturb the optimal functioning of the immune system, which is to eliminate the 'foreign or/and dangerous' to mistakenly target the body's own tissues. Objective: The aim of this research is to evaluate the most effective approach to managing autoimmune diseases within the framework of pregnancy. Methods: The exact causes and etiologies of these diseases are multifactorial and mostly still unclear. Ro/SSA autoantibodies and La/SSB, could be found in Sjögren's disease (SJ), systemic lupus (SLE) and other autoimmune disorders. Smoking, stress, UV exposure, vitamin D deficiency, and other genetic and environmental factors have been identified as risk factors for rheumatic diseases. Results: Over the years, an ever-increasing incidence of these diseases has been observed in the general population, with the female sex being at increased risk for their occurrence. This fact raises the question of what should be the management of these pathological entities during pregnancy. Taking into account the very significant impact on the quality of paitients'daily life and the seemingly augmented prevalence of autoimmune diseases, as well as their preference in the female population, the reasonable question arises as to what should be the optimal management of these diseases in the context of pregnancy. Conclusion: Given the limited data of the global medical community regarding the etiological factors and mechanisms that trigger the onset of rheumatic diseases, the management of pregnant women is a complex conundrum that health professionals are challenged to face and solve.