RESUMO
For many decades, the clinical unmet needs of primary Sjögren's Syndrome (pSS) have been left unresolved due to the rareness of the disease and the complexity of the underlying pathogenic mechanisms, including the pSS-associated lymphomagenesis process. Here, we present the HarmonicSS cloud-computing exemplar which offers beyond the state-of-the-art data analytics services to address the pSS clinical unmet needs, including the development of lymphoma classification models and the identification of biomarkers for lymphomagenesis. The users of the platform have been able to successfully interlink, curate, and harmonize 21 regional, national, and international European cohorts of 7,551 pSS patients with respect to the ethical and legal issues for data sharing. Federated AI algorithms were trained across the harmonized databases, with reduced execution time complexity, yielding robust lymphoma classification models with 85% accuracy, 81.25% sensitivity, 85.4% specificity along with 5 biomarkers for lymphoma development. To our knowledge, this is the first GDPR compliant platform that provides federated AI services to address the pSS clinical unmet needs.
RESUMO
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.
Assuntos
Regulação Enzimológica da Expressão Gênica , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , c-Mer Tirosina Quinase/genética , Proteína ADAM17/metabolismo , Animais , Anticorpos Antinucleares/química , Apoptose , Autoanticorpos/metabolismo , Autoimunidade , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Fenótipo , Saliva/metabolismo , Transdução de Sinais , Timócitos/metabolismoRESUMO
Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized primarily by immune-mediated destruction of exocrine tissues, such as those of the salivary and lacrimal glands, resulting in the loss of saliva and tear production, respectively. This disease predominantly affects middle-aged women, often in an insidious manner with the accumulation of subtle changes in glandular function occurring over many years. Patients commonly suffer from pSS symptoms for years before receiving a diagnosis. Currently, there is no effective cure for pSS and treatment options and targeted therapy approaches are limited due to a lack of our overall understanding of the disease etiology and its underlying pathology. To better elucidate the underlying molecular nature of this disease, we have performed RNA-sequencing to generate a comprehensive global gene expression profile of minor salivary glands from an ethnically diverse cohort of patients with pSS. Gene expression analysis has identified a number of pathways and networks that are relevant in pSS pathogenesis. Moreover, our detailed integrative analysis has revealed a primary Sjögren's syndrome molecular signature that may represent important players acting as potential drivers of this disease. Finally, we have established that the global transcriptomic changes in pSS are likely to be attributed not only to various immune cell types within the salivary gland but also epithelial cells which are likely playing a contributing role. Overall, our comprehensive studies provide a database-enriched framework and resource for the identification and examination of key pathways, mediators, and new biomarkers important in the pathogenesis of this disease with the long-term goals of facilitating earlier diagnosis of pSS and to mitigate or abrogate the progression of this debilitating disease.
Assuntos
Células Epiteliais/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Glândulas Salivares Menores/metabolismo , Síndrome de Sjogren/genética , Transcriptoma , Estudos de Casos e Controles , Biologia Computacional , Células Epiteliais/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Glândulas Salivares Menores/imunologia , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologiaRESUMO
OBJECTIVE: Primary Sjögren syndrome (SS) is characterized by a focal lymphocytic infiltrate in exocrine glands. We describe patients who lacked this key feature. METHODS: We evaluated patients with sicca in a comprehensive clinic at which medical, dental, and ophthalmological examinations were performed. All subjects underwent a minor salivary gland biopsy with focus score calculation. Extraglandular manifestations were also determined. We categorized subjects as high, intermediate, or low in terms of expression of interferon (IFN)-regulated genes. RESULTS: About 20% (51 of 229, 22%) of those classified as having primary SS had a focus score of zero. Compared to those with anti-Ro positivity and a focus score > 1.0, the patients with focus score of zero (who by classification criteria must be anti-Ro-positive) were statistically less likely to have anti-La (or SSB) and elevated immunoglobulin, as well as less severe corneal staining. The focus score zero patients were less likely to have elevated expression of IFN-regulated genes in peripheral blood mononuclear cells than anti-Ro-positive SS patients with a focal salivary infiltrate. CONCLUSION: There are only a few clinical differences between patients with primary SS with focus score zero and those with both anti-Ro and a focus score > 1.0. The small subset of focus score zero patients tested did not have elevated expression of IFN-regulated genes, but did have systemic disease. Thus, extraglandular manifestations are perhaps more related to the presence of anti-Ro than increased IFN. This may have relevance to pathogenesis of SS.
Assuntos
Movimento Celular/imunologia , Ceratoconjuntivite Seca/imunologia , Linfócitos/imunologia , Glândulas Salivares/imunologia , Síndrome de Sjogren/imunologia , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Autoantígenos/imunologia , Biópsia , Regulação da Expressão Gênica , Técnicas Histológicas , Humanos , Interferons/genética , Interferons/metabolismo , Ceratoconjuntivite Seca/sangue , Ceratoconjuntivite Seca/patologia , Linfócitos/patologia , RNA Citoplasmático Pequeno/imunologia , Fator Reumatoide/sangue , Ribonucleoproteínas/imunologia , Glândulas Salivares/patologia , Síndrome de Sjogren/sangue , Síndrome de Sjogren/patologia , Antígeno SS-BRESUMO
OBJECTIVE: To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes. METHODS: pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200. RESULTS: Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell-attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters. CONCLUSION: Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.
Assuntos
Expressão Gênica , Síndrome de Sjogren/genética , Adulto , Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Fator Ativador de Células B/genética , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Quimiocina CXCL13/genética , Quimiocina CXCL13/imunologia , Quimiocina CXCL13/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Quimiocina CXCL9/metabolismo , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Redes Reguladoras de Genes , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Interferons/genética , Interferons/imunologia , Interferons/metabolismo , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Interleucina-1alfa/metabolismo , Interleucinas/genética , Interleucinas/imunologia , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Fenótipo , Síndrome de Sjogren/classificação , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
OBJECTIVE: To describe the clinical and serologic manifestations of Sjögren's syndrome (SS) in ethnic groups of the US. METHODS: This was a cross-sectional study of 648 patients with primary SS: 20 African American (AA), 164 American Indian (AI), 426 European American (EA), and 38 patients of other races evaluated in a multidisciplinary Sjögren's International Collaborative Clinical Alliance research clinic. RESULTS: AA subjects comprised 3.1% of the SS cohort, much lower than the percentage of AA in the state of Oklahoma (P = 3.01 × E - 05), the US (P = 2.24E - 13), or a systemic lupus erythematosus (SLE) cohort at the same institution (P = 4.26 × 10E - 27). In contrast, the percentage of AI in the SS cohort (25.3%) was much higher than expected (P = 3.17E - 09 versus SLE cohort, P = 6.36 - 26 versus Oklahoma, and P = 8.14E - 96 versus US population). The SS classification criteria were similar between AA and EA, but subjects of AI ancestry had lower rates of abnormal tear and salivary flow, as well as anti-Ro/SSA and anti-La/SSB antibodies. Paradoxically, AI had higher levels of disease activity (mean ± SD European League Against Rheumatism Sjögren's Syndrome Disease Activity Index score 3.77 ± 4.78) in comparison to EA (2.90 ± 4.12; P = 0.011) and more extraglandular manifestations affecting mainly the articular and glandular domains. Meanwhile, AA patients were characterized by higher rates of hypergammaglobulinemia (odds ratio [OR] 1.39 [95% confidence interval (95% CI) 1.39-8.65]; P = 0.01), elevated erythrocyte sedimentation rate (ESR) (OR 3.95 [95% CI 1.46-9.95]; P = 0.009), and parotid enlargement (OR 4.40 [95% CI 1.49-13.07]; P = 0.02). CONCLUSION: AI are affected at high rates with SS but present with few classical features, potentially preventing timely diagnosis. In contrast to SLE, SS is infrequent and not more severe among AA, but the triad of hypergammaglobulinemia, increased ESR, and parotid enlargement warrants extra vigilance for lymphomagenesis.
Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Indígenas Norte-Americanos/estatística & dados numéricos , Síndrome de Sjogren/etnologia , Síndrome de Sjogren/epidemiologia , População Branca/estatística & dados numéricos , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oklahoma/epidemiologia , Fatores de RiscoRESUMO
OBJECTIVES: To analyse the frequency and characterise the systemic presentation of primary Sjögren's syndrome (SS) out of the ESSDAI classification in a large international, multi-ethnic cohort of patients. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry based on world-wide data-sharing and cooperative merging of pre-existing clinical SS databases from leading centres in clinical research in SS from the five continents. A list of 26 organ-by-organ systemic features not currently included in the ESSDAI classification was defined according to previous studies; these features were retrospectively recorded. RESULTS: Information about non-ESSDAI features was available in 6331 patients [5,917 female, mean age at diagnosis 52 years, mainly White (86.3%)]. A total of 1641 (26%) patients had at least one of the ESSDAI systemic features. Cardiovascular manifestations were the most frequent organ-specific group of non-ESSDAI features reported in our patients (17% of the total cohort), with Raynaud's phenomenon being reported in 15%. Patients with systemic disease due to non-ESSDAI features had a lower frequency of dry mouth (90.7% vs. 94.1%, p<0.001) and positive minor salivary gland biopsy (86.7% vs. 89%, p=0.033), a higher frequency of anti-Ro/SSA (74.7% vs. 68.7%, p<0.001), anti-La/SSB antibodies (44.5% vs. 40.4%, p=0.004), ANA (82.7% vs. 79.5%, p=0.006), low C3 levels (17.4% vs. 9.7%, p<0.001), low C4 levels (14.4% vs. 9.6%, p<0.001), and positive serum cryoglobulins (8.6% vs. 5.5%, p=0.001). Systemic activity measured by the ESSDAI, clinESSDAI and DAS was higher in patients with systemic disease out of the ESSDAI in comparison with those without these features (p<0.001 for all comparisons). CONCLUSIONS: More than a quarter of patients with primary SS may have systemic manifestations not currently included in the ESSDAI classification, with a wide variety of cardiovascular, digestive, pulmonary, neurological, ocular, ENT (ear, nose, and throat), cutaneous and urological features that increase the scope of the systemic phenotype of the disease. However, the individual frequency of each of these non-ESSDAI features was very low, except for Raynaud's phenomenon.
Assuntos
Síndrome de Sjogren , Estudos de Coortes , Etnicidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Estudos Retrospectivos , Índice de Gravidade de Doença , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/fisiopatologiaAssuntos
Glândulas Exócrinas/fisiologia , Olho/patologia , Síndrome de Sjogren/diagnóstico , Corticosteroides/uso terapêutico , Animais , Antirreumáticos/uso terapêutico , Transtornos de Deglutição , Diagnóstico Diferencial , Epistaxe , Fibromialgia , Humanos , Ictiose , Terapia de Imunossupressão , Qualidade de Vida , Sialografia , Síndrome de Sjogren/terapiaRESUMO
OBJECTIVES: To evaluate the influence of the main immunological markers on the disease phenotype at diagnosis in a large international cohort of patients with primary Sjögren's syndrome (SjS). METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. As a first step, baseline clinical information from leading centres on clinical research in SjS of the 5 continents was collected. The centres shared a harmonised data architecture and conducted cooperative online efforts in order to refine collected data under the coordination of a big data statistical team. Inclusion criteria were the fulfillment of the 2002 classification criteria. Immunological tests were carried out using standard commercial assays. RESULTS: By January 2018, the participant centres had included 10,500 valid patients from 22 countries. The cohort included 9,806 (93%) women and 694 (7%) men, with a mean age at diagnosis of primary SjS of 53 years, mainly White (78%) and included from European countries (71%). The frequency of positive immunological markers at diagnosis was 79.3% for ANA, 73.2% for anti-Ro, 48.6% for RF, 45.1% for anti- La, 13.4% for low C3 levels, 14.5% for low C4 levels and 7.3% for cryoglobulins. Positive autoantibodies (ANA, Ro, La) correlated with a positive result in salivary gland biopsy, while hypocomplementaemia and especially cryoglo-bulinaemia correlated with systemic activity (mean ESSDAI score of 17.7 for cryoglobulins, 11.3 for low C3 and 9.2 for low C4, in comparison with 3.8 for negative markers). The immunological markers with a great number of statistically-significant associations (p<0.001) in the organ-by-organ ESS- DAI evaluation were cryoglobulins (9 domains), low C3 (8 domains), anti-La (7 domains) and low C4 (6 domains). CONCLUSIONS: We confirm the strong influence of immunological markers on the phenotype of primary SjS at diagnosis in the largest multi-ethnic international cohort ever analysed, with a greater influence for cryoglobulinaemic-related markers in comparison with Ro/La autoantibodies and ANA. Immunological patterns play a central role in the phenotypic expression of the disease already at the time of diagnosis, and may guide physicians to design a specific personalised management during the follow-up of patients with primary SjS.
Assuntos
Autoanticorpos/sangue , Complemento C3/análise , Complemento C4/análise , Crioglobulinas/análise , Síndrome de Sjogren/imunologia , Adulto , Idoso , Anticorpos Antinucleares/sangue , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Sistema de Registros , Fator Reumatoide/sangue , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/epidemiologiaRESUMO
OBJECTIVE: Patients with Sjögren's syndrome (SS) are prone to develop malignant lymphomas, and a correlation has been established between the lymphoproliferations occurring in these disorders and the presence in patients' blood of an unusual B cell population that down-regulates complement receptor 2/CD21. This study was undertaken to identify the B cell compartment from which these lymphoproliferations emerge and determine the mechanisms that promote clonal B cell expansion in patients with SS. METHODS: The reactivity of antibodies expressed by CD19+CD10-CD27-IgM+CD21-/low cells isolated from the blood of patients with SS was tested using a polymerase chain reaction-based approach that allows us to clone and express, in vitro, recombinant antibodies produced by single B cells. RESULTS: Clonal expansions were identified in CD21-/low B cells isolated from the peripheral blood of 3 patients with SS. These lymphoproliferations expressed B cell receptors (BCRs) that displayed somatic hypermutation lineage trees characteristic of a strong selection by antigens; one of these antigens was identified as a ribosomal self antigen. When the mutated BCR sequences expressed by the expanded CD21-/low B cell clones from patients with SS were reverted in vitro to their germline counterparts, one clone remained autoreactive. CONCLUSION: Clonal lymphoproliferations in patients with SS preferentially accumulate in the autoreactive CD21-/low B cell compartment often expanded in these subjects, and recognition of self antigens may drive the clonal B cell expansion while further refining BCR self-reactivity.
Assuntos
Linfócitos B/imunologia , Transtornos Linfoproliferativos/etiologia , Síndrome de Sjogren/imunologia , Adulto , Idoso , Autoanticorpos/genética , Autoanticorpos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Imunoprecipitação , Transtornos Linfoproliferativos/imunologia , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Complemento 3d/imunologia , Receptores de Complemento 3d/metabolismo , Síndrome de Sjogren/complicaçõesRESUMO
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.
Assuntos
Glândulas Salivares Menores/patologia , Síndrome de Sjogren/patologia , Adulto , Fatores Etários , Idoso , Área Sob a Curva , Biópsia , Estudos de Casos e Controles , Feminino , Fibrose , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Glândulas Salivares Menores/imunologia , Índice de Gravidade de Doença , Síndrome de Sjogren/imunologiaRESUMO
OBJECTIVE: Determine the presence and assess the extent of fatty infiltration of the minor salivary glands (SG) of primary SS patients (pSS) as compared to those with non-SS sicca (nSS). METHODS: Minor SG biopsy samples from 134 subjects with pSS (n = 72) or nSS (n = 62) were imaged. Total area and fatty replacement area for each glandular cross-section (n = 4-6 cross-sections per subject) were measured using Image J (National Institutes of Health, Bethesda, MD). The observer was blinded to subject classification status. The average area of fatty infiltration calculated per subject was evaluated by logistic regression and general linearized models (GLM) to assess relationships between fatty infiltration and clinical exam results, extent of fibrosis and age. RESULTS: The average area of fatty infiltration for subjects with pSS (median% (range) 4.97 (0.05-30.2)) was not significantly different from that of those with nSS (3.75 (0.087-41.9). Infiltration severity varied widely, and subjects with fatty replacement greater than 6% were equivalently distributed between pSS and nSS participants (χ2 p = .50). Age accounted for all apparent relationships between fatty infiltration and fibrosis or reduced saliva flow. The all-inclusive GLM for prediction of pSS versus non-SS classification including fibrosis, age, fatty replacement, and focus score was not significantly different from any desaturated model. In no iteration of the model did fatty replacement exert a significant effect on the capacity to predict pSS classification. CONCLUSIONS: Fatty infiltration is an age-associated phenomenon and not a selective feature of Sjögren's syndrome. Sicca patients who do not fulfil pSS criteria have similar rates of fatty infiltration of the minor SG.
Assuntos
Tecido Adiposo/patologia , Envelhecimento/imunologia , Envelhecimento/patologia , Glândulas Salivares Menores/imunologia , Glândulas Salivares Menores/patologia , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia , Adulto , Idoso , Autoanticorpos/imunologia , Biomarcadores , Biópsia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Síndrome de Sjogren/metabolismoRESUMO
The association of primary Sjögren's syndrome (pSS) with Major Histocompatibility Complex (MHC) alleles is quintessential of MHC-disease associations. Indeed, although disease associations with classical HLA class I and II alleles/haplotypes are amply documented, further dissection is often prevented by the strong linkage disequilibrium across the entire MHC complex. Here we study the association of pSS, not with HLA genes, but with the non-conventional MHC encoded class I gene, MICA (MHC class I chain-related gene A). MICA is selectively expressed within epithelia, and is the major ligand for the activatory receptor, NKG2D, both attributes relevant to pSS' etiology. MICA-pSS association was studied in two independent (French and UK) cohorts representing a total of 959 cases and 1,043 controls. MICA*008 allele was shown to be significantly associated with pSS (pcor=2.61 × 10-35). A multivariate logistic regression showed that this association was independent of all major known MHC-linked risk loci/alleles, as well as other relevant candidate loci that are in linkage disequilibrium with MICA*008 i.e. HLA-B*08:01, rs3131619 (T), MICB*008, TNF308A, HLA-DRB1*03:01 and HLA-DRB1*15:01 (P = 1.84 × 10-04). Furthermore, independently of the MICA*008 allele, higher levels of soluble MICA proteins were detected in sera of pSS patients compared to healthy controls. This study hence defines MICA as a new, MHC-linked, yet HLA-independent, pSS risk locus and opens a new front in our understanding of the still enigmatic pathophysiology of this disease. The fact that the soluble MICA protein is further amplified in MICA*008 carrying individuals, might also be relevant in other auto-immune diseases and cancer.
Assuntos
Antígenos de Histocompatibilidade Classe I/genética , Síndrome de Sjogren/genética , Adulto , Alelos , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Antígenos HLA-B/genética , Cadeias HLA-DRB1/genética , Haplótipos , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Desequilíbrio de Ligação , Complexo Principal de Histocompatibilidade/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , População Branca/genéticaRESUMO
OBJECTIVES: To assess the association of smoking habits with the clinical, serological, and histopathological manifestations of Sjögren's syndrome (SS) and non-Sjögren's sicca (non-SS sicca). METHODS: Cross-sectional case-control study of 1288 patients with sicca symptoms (587 SS and 701 non-SS sicca) evaluated in a multi-disciplinary research clinic. Smoking patterns were obtained from questionnaire data and disease-related clinical and laboratory data were compared between current, past, ever, and never smokers. RESULTS: Current smoking rates were 4.6% for SS patients compared to 14.1% in non-SS sicca (p = 5.17x10E-09), 18% in a local lupus cohort (p = 1.13x10E-14) and 16.8% in the community (p = 4.12x10E-15). Current smoking was protective against SS classification (OR 0.35, 95%CI 0.22-0.56, FDR q = 1.9E10-05), focal lymphocytic sialadenitis (OR 0.26, 95%CI 0.15-0.44, FDR q = 1.52x10E-06), focus score ≥1 (OR 0.22, 95%CI 0.13-0.39, FDR q = 1.43x10E-07), and anti-Ro/SSA(+) (OR 0.36, 95%CI 0.2-0.64, FDR q = 0.0009); ever smoking was protective against the same features and against anti-La/SSB(+) (OR 0.52, 95%CI 0.39-0.70, FDR q = 5.82x10E-05). Duration of smoking was inversely correlated with SS even after controlling for socioeconomic status, BMI, alcohol and caffeine consumption. CONCLUSIONS: Current tobacco smoking is negatively and independently associated with SS, protecting against disease-associated humoral and cellular autoimmunity. The overall smoking rate amongst SS patients is significantly lower than in matched populations and the effects of smoking are proportional to exposure duration. In spite of the protective effects of tobacco on SS manifestations, it is associated with other serious comorbidities such as lung disease, cardiovascular risk and malignancy, and should thus be strongly discouraged in patients with sicca.
Assuntos
Síndrome de Sjogren/sangue , Síndrome de Sjogren/patologia , Fumar , Adulto , Idoso , Autoanticorpos/sangue , Biomarcadores , Biópsia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Síndrome de Sjogren/diagnóstico , Fumar/efeitos adversosRESUMO
OBJECTIVE: Incomplete lupus erythematosus (ILE) involves clinical and/or serologic manifestations consistent with but insufficient for systemic lupus erythematosus (SLE) classification. Because the nature of ILE is poorly understood and no treatment recommendations exist, we examined the clinical manifestations, medication history, and immunologic features in a diverse collection of ILE and SLE patients. METHODS: Medical records of subjects enrolled in the Lupus Family Registry and Repository were reviewed for medication history and American College of Rheumatology (ACR) classification criteria to identify ILE patients (3 ACR criteria; n = 440) and SLE patients (≥4 ACR criteria; n = 3,397). Participants completed the Connective Tissue Disease Screening Questionnaire. Anticardiolipin and plasma B lymphocyte stimulator (BLyS) were measured by enzyme-linked immunosorbent assay, antinuclear antibodies (ANAs) by indirect immunofluorescence, and 13 autoantibodies by bead-based assays. RESULTS: On average, ILE patients were older than SLE patients (46.2 years versus 42.0 years; P < 0.0001), and fewer ILE patients were African American (23.9% versus 32.2%; P < 0.001). ILE patients exhibited fewer autoantibody specificities than SLE patients (1.3 versus 2.6; P < 0.0001) and were less likely to have ANA titers ≥1:1,080 (10.5% versus 19.5%; P < 0.0001). BLyS levels were intermediate in ILE patients (controls < ILE; P = 0.016; ILE < SLE; P = 0.008). Pericarditis, renal, or neurologic manifestations occurred in 12.5% of ILE patients and were associated with non-European American race/ethnicity (P = 0.012). Hydroxychloroquine use increased over time, but was less frequent in ILE than SLE patients (65.2% versus 83.1%; P < 0.0001). CONCLUSION: Although usually characterized by milder symptoms, ILE manifestations may require immunomodulatory treatments. Longitudinal studies are necessary to understand how ILE affects organ damage and future SLE risk, and to delineate molecular pathways unique to ILE.
Assuntos
Anticorpos Anticardiolipina/sangue , Fator Ativador de Células B/imunologia , Lúpus Eritematoso Sistêmico/classificação , Lúpus Eritematoso Sistêmico/diagnóstico , Testes Sorológicos , Terminologia como Assunto , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Biomarcadores/sangue , Ilhas Virgens Britânicas , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Etnicidade , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Hidroxicloroquina/uso terapêutico , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Porto Rico , Grupos Raciais , Sistema de Registros , Índice de Gravidade de Doença , Inquéritos e Questionários , Estados Unidos , Ilhas Virgens AmericanasRESUMO
OBJECTIVES: To analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry designed in 2014. By January 2016, 20 centres from five continents were participating. Multivariable logistic regression analyses were performed. RESULTS: We included 7748 women (93%) and 562 men (7%), with a mean age at diagnosis of primary SjS of 53â years. Ethnicity data were available for 7884 patients (95%): 6174 patients (78%) were white, 1066 patients (14%) were Asian, 393 patients (5%) were Hispanic, 104 patients (1%) were black/African-American and 147 patients (2%) were of other ethnicities. SjS was diagnosed a mean of 7â years earlier in black/African-American compared with white patients; the female-to-male ratio was highest in Asian patients (27:1) and lowest in black/African-American patients (7:1); the prevalence of sicca symptoms was lowest in Asian patients; a higher frequency of positive salivary biopsy was found in Hispanic and white patients. A north-south gradient was found with respect to a lower frequency of ocular involvement in northern countries for dry eyes and abnormal ocular tests in Europe (OR 0.46 and 0.44, respectively) and Asia (OR 0.18 and 0.49, respectively) compared with southern countries. Higher frequencies of antinuclear antibodies (ANAs) were reported in northern countries in America (OR=1.48) and Asia (OR=3.80) while, in Europe, northern countries had lowest frequencies of ANAs (OR=0.67) and Ro/La (OR=0.69). CONCLUSIONS: This study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis.
Assuntos
Povo Asiático/estatística & dados numéricos , Negro ou Afro-Americano/estatística & dados numéricos , Hispânico ou Latino/estatística & dados numéricos , Sistema de Registros , Síndrome de Sjogren/etnologia , População Branca/estatística & dados numéricos , Adulto , Idoso , Anticorpos Antinucleares/sangue , Estudos Transversais , Oftalmopatias/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prevalência , Síndrome de Sjogren/sangue , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Análise EspacialRESUMO
Sjögren syndrome (SjS) is a systemic autoimmune disease that primarily affects the exocrine glands (mainly the salivary and lacrimal glands) and results in the severe dryness of mucosal surfaces, principally in the mouth and eyes. This disease predominantly affects middle-aged women, but can also be observed in children, men and the elderly. The clinical presentation of SjS is heterogeneous and can vary from sicca symptoms to systemic disease (characterized by peri-epithelial lymphocytic infiltration of the affected tissue or the deposition of the immune complex) and lymphoma. The mechanism underlying the development of SjS is the destruction of the epithelium of the exocrine glands, as a consequence of abnormal B cell and T cell responses to the autoantigens Ro/SSA and La/SSB, among others. Diagnostic criteria for SjS include the detection of autoantibodies in patient serum and histological analysis of biopsied salivary gland tissue. Therapeutic approaches for SjS include both topical and systemic treatments to manage the sicca and systemic symptoms of disease. SjS is a serious disease with excess mortality, mainly related to the systemic involvement of disease and the development of lymphomas in some patients. Knowledge of SjS has progressed substantially, but this disease is still characterized by sicca symptoms, the systemic involvement of disease, lymphocytic infiltration to exocrine glands, the presence of anti-Ro/SSA and anti-La/SSB autoantibodies and the increased risk of lymphoma in patients with SjS.
Assuntos
Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/fisiopatologia , Síndrome de Sjogren/terapia , Anticorpos/análise , Anticorpos/sangue , Diagnóstico Diferencial , Humanos , Imunoglobulinas/análise , Imunoglobulinas/sangue , Linfoma/etiologia , Glândulas Salivares/patologiaRESUMO
The genes associated with Sjögren syndrome (SS) can be assigned to the NF-kB pathway, the IFN signaling pathway, lymphocyte signaling, and antigen presentation. The frequencies of risk variants show they are common with modest genetic effects. The strongest genetic association outside the human leukocyte antigen region is in IRF5, a gene relevant in the IFN signaling pathway and for B cell differentiation. Although no association has been found with the NF-kB gene itself, associations in TNFAIP3 and TNIP1 (both genome-wide significant), VCAM1 and IRAK1BP (both suggestive), point to genetic explanations for dysregulation of the NF-kB pathway in SS.
Assuntos
Síndrome de Sjogren/genética , Apresentação de Antígeno/genética , Linfócitos B , Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Antígenos HLA/genética , Humanos , Fatores Reguladores de Interferon/genética , Interferons/genética , Interleucinas/genética , Linfócitos , NF-kappa B , Receptores CXCR5/genética , Fator de Transcrição STAT4/genética , Transdução de Sinais/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Molécula 1 de Adesão de Célula Vascular/genética , Quinases da Família src/genéticaRESUMO
BACKGROUND AND OBJECTIVE: A germline and coding polymorphism (rs2230926) of TNFAIP3 (A20), a central gatekeeper of nuclear factor-kappa B (NF-kB) activation, was recently found associated with primary Sjögren's syndrome (pSS)-associated lymphoma in a French cohort. We aimed to replicate this association. PATIENTS AND METHODS: The rs2230926 polymorphism was genotyped in cases and controls of European ancestry from two independent cohorts from UK and France. Case control association tests were performed (Fisher's test) in the two cohorts, followed by a meta-analysis of the two cohorts. RESULTS: The UK cohort included 308 controls and 590 patients with pSS including 31 with a history of lymphoma. The French cohort consisted of 448 controls and 589 patients with pSS including 47 with lymphoma. In both cohorts, the rs2230926 missense polymorphism was not associated with pSS. However, in the UK cohort, the rs2230926G variant was significantly associated with pSS-associated lymphoma (OR=2.74, 95% CI (1.07 to 7.03), p=0.0423, compared with patients with pSS without lymphoma, and OR=3.12, 95% CI (1.16 to 8.41), p=0.0314, compared with healthy controls) as observed in the French cohort. The meta-analysis of the two cohorts confirmed these results (OR=2.48, 95% CI (1.87 to 3.28) p=0.0037 and OR=2.60, 95% CI (1.91 to 3.53) p=0.0031, respectively). CONCLUSIONS: This study confirms the role of A20 impairment in pSS-associated lymphoma. Subtle germline abnormalities of genes leading to impaired control of NF-kB activation in B cells continuously stimulated by autoimmunity enhance the risk of lymphoma.
Assuntos
Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfoma/genética , Proteínas Nucleares/genética , Síndrome de Sjogren/genética , Estudos de Casos e Controles , Estudos de Coortes , França , Doença de Hodgkin/genética , Humanos , Modelos Logísticos , Linfoma/complicações , Linfoma de Células B/genética , Análise Multivariada , Micose Fungoide/genética , Polimorfismo de Nucleotídeo Único , Síndrome de Sjogren/complicações , Neoplasias Cutâneas/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Reino Unido , População Branca/genéticaRESUMO
OBJECTIVES: Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association. METHODS: Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR. RESULTS: The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10(-4), OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10(-7), OR 0.71; case-only pmeta=1.9×10(-4), OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR. CONCLUSIONS: These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.