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1.
Artigo em Inglês | MEDLINE | ID: mdl-31445906

RESUMO

INTRODUCTION: Spinocerebellar ataxia type 10 (SCA10) is a hereditary neurodegenerative disorder caused by repeat expansions in the ATXN10 gene. Patients present with cerebellar ataxia frequently accompanied by seizures. Even though loss of cerebellar Purkinje neurons has been described, its brain degeneration pattern is unknown. Our aim was to characterize the gray and white matter degeneration patterns in SCA10 patients and the association with clinical features. METHODS: We enrolled 18 patients with molecular diagnosis of SCA10 and 18 healthy individuals matched for age and sex. All participants underwent brain MRI including high-resolution anatomical and diffusion images. Whole-brain Tract-Based Spatial Statistics (TBSS) and Voxel-Based Morphometry (VBM) were performed to identify white and grey matter degeneration respectively. A second analysis in the cerebellum identified the unbiased pattern of degeneration. Motor impairment was assessed using the SARA Scale. RESULTS: TBSS analysis in the patient group revealed white matter atrophy exclusively in the cerebellum. VBM analysis showed extensive grey matter degeneration in the cerebellum, brainstem, thalamus, and putamen. Significant associations between cerebellar degeneration and SARA scores were found. Additionally, degeneration in thalamic GM and WM in the cerebellar lobule VI were significantly associated with the presence of seizures. CONCLUSION: The results show that besides cerebellum and brainstem, brain degeneration in SCA10 includes predominantly the putamen and thalamus; involvement of the latter is strongly associated with seizures. Analysis of the unbiased degeneration pattern in the cerebellum suggests lobules VIIIb, IX, and X as the primary cerebellar targets of the disease, which expands to the anterior lobe in later stages.

2.
Clin Exp Rheumatol ; 37 Suppl 118(3): 97-106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31464664

RESUMO

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.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31199565

RESUMO

OBJECTIVE: To describe the clinical and serological manifestations of Sjögren's syndrome (SS) in ethnic groups of the United States. METHODS: Cross-sectional study of 648 patients with primary SS: 20 African-American (AA), 164 American Indian (AI), 426 European-American (EA) and 38 of other races evaluated in a multi-disciplinary sicca 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=3.01xE-05), the United States (p=2.24E-13) or a lupus cohort at the same institution (p=4.26x10E-27). In contrast, the percentage of AI in the SS cohort (25.3%) was much higher than expected (p=3.17E-09 vs. SLE; p=6.36-26 vs. Oklahoma and p=8.14E-96 vs. USA 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 ESSDAI 3.77±4.78) in comparison to whites (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 (OR 1.39, 95%CI 1.39-8.65, p=0.01), elevated 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). CONCLUSIONS: American Indians 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 amongst AA, but the triad of hypergammaglobulinemia, increased ESR and parotid enlargement warrants extra vigilance for lymphomagenesis. This article is protected by copyright. All rights reserved.

4.
J Rheumatol ; 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092717

RESUMO

OBJECTIVE: Primary Sjögren's syndrome (SS) is characterized by a focal lymphocytic infiltrate in exocrine glands. We undertook this study to describe patients that lacked this key feature. METHODS: We evaluated subjects 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. Extra-glandular manifestations were also determined. We categorized subjects as high, intermediate, or low in terms of the expression of interferon-regulated genes. RESULTS: About 20% (51 of 229, 22%) of those classified as primary Sjögren's syndrome had a focus score of zero. Compared to those with anti-Ro positivity and a focus score >1.0, the focus score zero patients (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. In addition, the focus score zero patients were less likely to have elevated expression of interferon-regulated genes in peripheral blood mononuclear cells than anti-Ro positive SS subjects with a focal salivary infiltrate. CONCLUSION: There are only a few clinical differences between primary Sjögren's syndrome patients with focus score zero and those with both anti-Ro and a focus score >1.0. Nonetheless, the small subset of focus score zero patients tested did not have elevated expression of interferon-regulated genes, but did have systemic disease. Thus, extra-glandular manifestations are perhaps more related to the presence of anti-Ro than increased interferon. This may have relevance to Sjögren's syndrome pathogenesis.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30770922

RESUMO

Primary Sjögren's syndrome (pSS) is considered to be a multifactorial disease, where underlying genetic predisposition, epigenetic mechanisms and environmental factors contribute to disease development. In the last 5 years, the first genome-wide association studies in pSS have been completed. The strongest signal of association lies within the HLA genes, whereas the non-HLA genes IRF5 and STAT4 show consistent associations in multiple ethnicities but with a smaller effect size. The majority of the genetic risk variants are found at intergenic regions and their functional impact has in most cases not been elucidated. Epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNAs play a role in the pathogenesis of pSS by their modulating effects on gene expression and may constitute a dynamic link between the genome and phenotypic manifestations. This article reviews the hitherto published genetic studies and our current understanding of epigenetic mechanisms in pSS.

7.
Clin Exp Rheumatol ; 36 Suppl 112(3): 102-112, 2018 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30156539

RESUMO

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/epidemiologia
8.
Clin Exp Rheumatol ; 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29998833

RESUMO

OBJECTIVES: Microbial infections and mucosal dysbiosis influence morbidity in patients with systemic lupus erythematosus (SLE). In the oral cavity, periodontal bacteria and subgingival plaque dysbiosis provide persistent inflammatory stimuli at the mucosal surface. This study was undertaken to evaluate whether exposure to periodontal bacteria influences disease parameters in SLE patients. METHODS: Circulating antibodies to specific periodontal bacteria have been used as surrogate markers to determine an ongoing bacterial burden, or as indicators of past exposure to the bacteria. Banked serum samples from SLE patients in the Oklahoma Lupus Cohort were used to measure antibody titres against periodontal pathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Treponema denticola) and commensals (Capnocytophaga ochracea, and Streptococcus gordonii) by ELISA. Correlations between anti-bacterial antibodies and different clinicalparameters of SLE including, autoantibodies (anti-dsDNA, anti-SmRNP, anti-SSA/Ro and anti-SSB/La), complement, and disease activity (SLEDAI and BILAG) were studied. RESULTS: SLE patients had varying amounts of antibodies to different oral bacteria. The antibody titres against A. actinomycetemcomitans, P. gingivalis, T. denticola, and C. ochracea were higher in patients positive for anti-dsDNA antibodies, and they showed significant correlations with anti-dsDNA titres and reduced levels of complement. Among the periodontal pathogens, only antibodies to A. actinomycetemcomitans were associated with higher disease activity. CONCLUSIONS: Our results suggest that exposure to specific pathogenic periodontal bacteria influences disease activity in SLE patients. These findings provide a rationale for assessing and improving periodontal health in SLE patients, as an adjunct to lupus therapies.

9.
Lupus Sci Med ; 5(1): e000247, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29531773

RESUMO

Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with varied morbidity and mortality. We assessed clinical presentations, autoantibody specificities and therapeutic interventions in Native American (NA) patients with SLE. Methods: Patients with SLE meeting 1997 American College of Rheumatology classification criteria (n=3148) were enrolled between 1992 and 2010 in the multiethnic, cross-sectional Lupus Family Registry and Repository. Clinical, demographic and therapeutic information were extracted from medical records using a standardised form and formalised training. Autoantibodies were assessed by indirect immunofluorescence (antinuclear antibodies (ANA) and antidouble-stranded DNA), precipitin (ENA) and ELISA (IgG and IgM anticardiolipins). Results: NA patients met SLE classification at a younger age (29.89±12.3 years) than European Americans (EA; 32.02±12.87, P=0.0157) and a similar age to African-Americans (AAs) and Hispanics (HIS). More NA patients had concurrent rheumatic diseases or symptoms, such as Raynaud's phenomenon, interstitial lung disease, SjÓ§gren's syndrome and systemic sclerosis. Compared with EAs, NAs were more likely to have high-titre ANA (≥1:3240; P<0.0001) and had more SLE-associated autoantibodies. Autoantibodies with unknown specificities were more common in NAs (41%) compared with other racial/ethnic groups in this collection (AA: 24%, P=0.0006; EA: 17%, P<0.0001; HIS: 23%, P=0.0050). Fewer NA patients used hydroxychloroquine (68%) compared with others (AA: 74%, P=0.0308; EA: 79%, P=0.0001, HIS: 77%, P=0.0173); this was influenced by lower hydroxychloroquine use in NA patients from Latin America (32%). NA patients had higher rates of methotrexate use (28%) compared with AA (18%, P=0.0006) and HIS patients (14%, P=0.0003), higher azathioprine use (38%) compared with EA patients (30%, P=0.0105) and higher mycophenolate mofetil use (26%) compared with EA (17%, P=0.0012) and HIS patients (11%, P<0.0001). Conclusions: NA patients are diagnosed with SLE earlier in life and present worse concurrent rheumatic disease symptoms than EA patients. NA patients also are more likely to have expanded autoantibody profiles and precipitins of unknown specificities.

10.
Arthritis Rheumatol ; 70(7): 1102-1113, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29457375

RESUMO

OBJECTIVE: To better understand the role of B cells, the potential mechanisms responsible for their aberrant activation, and the production of autoantibodies in the pathogenesis of Sjögren's syndrome (SS), this study explored patterns of selection pressure and sites of N-glycosylation acquired by somatic mutation (acN-glyc) in the IgG variable (V) regions of antibody-secreting cells (ASCs) isolated from the minor salivary glands of patients with SS and non-SS control patients with sicca symptoms. METHODS: A novel method to produce and characterize recombinant monoclonal antibodies (mAb) from single cell-sorted ASC infiltrates was applied to concurrently probe expressed genes (all heavy- and light-chain isotypes as well as any other gene of interest not related to immunoglobulin) in the labial salivary glands of patients with SS and non-SS controls. V regions were amplified by reverse transcription-polymerase chain reaction, sequenced, and analyzed for the incidence of N-glycosylation and selection pressure. For specificity testing, the amplified regions were expressed as either the native mAb or mutant mAb lacking the acN-glyc motif. Protein modeling was used to demonstrate how even an acN-glyc site outside of the complementarity-determining region could participate in, or inhibit, antigen binding. RESULTS: V-region sequence analyses revealed clonal expansions and evidence of secondary light-chain editing and allelic inclusion, of which neither of the latter two have previously been reported in patients with SS. Increased frequencies of acN-glyc were found in the sequences from patients with SS, and these acN-glyc regions were associated with an increased number of replacement mutations and lowered selection pressure. A clonal set of polyreactive mAb with differential framework region 1 acN-glyc motifs was also identified, and removal of the acN-glyc could nearly abolish binding to autoantigens. CONCLUSION: These findings support the notion of an alternative mechanism for the selection and proliferation of some autoreactive B cells, involving V-region N-glycosylation, in patients with SS.

11.
Clin Exp Rheumatol ; 36 Suppl 112(3): 80-88, 2018 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29148407

RESUMO

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/imunologia
13.
Autoimmunity ; 50(8): 451-457, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28988489

RESUMO

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/metabolismo
14.
Arthritis Rheumatol ; 69(11): 2187-2192, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28692793

RESUMO

OBJECTIVE: Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) are related by clinical and serologic manifestations as well as genetic risks. Both diseases are more commonly found in women than in men, at a ratio of ~10 to 1. Common X chromosome aneuploidies, 47,XXY and 47,XXX, are enriched among men and women, respectively, in either disease, suggesting a dose effect on the X chromosome. METHODS: We examined cohorts of SS and SLE patients by constructing intensity plots of X chromosome single-nucleotide polymorphism alleles, along with determining the karyotype of selected patients. RESULTS: Among ~2,500 women with SLE, we found 3 patients with a triple mosaic, consisting of 45,X/46,XX/47,XXX. Among ~2,100 women with SS, 1 patient had 45,X/46,XX/47,XXX, with a triplication of the distal p arm of the X chromosome in the 47,XXX cells. Neither the triple mosaic nor the partial triplication was found among the controls. In another SS cohort, we found a mother/daughter pair with partial triplication of this same region of the X chromosome. The triple mosaic occurs in ~1 in 25,000-50,000 live female births, while partial triplications are even rarer. CONCLUSION: Very rare X chromosome abnormalities are present among patients with either SS or SLE and may inform the location of a gene(s) that mediates an X dose effect, as well as critical cell types in which such an effect is operative.


Assuntos
Cromossomos Humanos X/genética , Lúpus Eritematoso Sistêmico/genética , Mosaicismo/estatística & dados numéricos , Aberrações dos Cromossomos Sexuais/estatística & dados numéricos , Síndrome de Sjogren/genética , Alelos , Teorema de Bayes , Feminino , Dosagem de Genes , Humanos , Cariótipo , Lúpus Eritematoso Sistêmico/epidemiologia , Polimorfismo de Nucleotídeo Único , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/epidemiologia , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Síndrome de Sjogren/epidemiologia , Trissomia/genética , Síndrome de Turner/epidemiologia , Síndrome de Turner/genética
15.
PLoS Genet ; 13(6): e1006820, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28640813

RESUMO

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.


Assuntos
2',5'-Oligoadenilato Sintetase/genética , Interferon Tipo I/genética , Locos de Características Quantitativas/genética , Síndrome de Sjogren/genética , 2',5'-Oligoadenilato Sintetase/biossíntese , Alelos , Processamento Alternativo/genética , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Interferon Tipo I/metabolismo , Masculino , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Viroses/genética , Viroses/virologia
16.
PLoS One ; 12(4): e0175958, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28423040

RESUMO

Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant cerebellar ataxia disorder, is caused by a non-coding ATTCT microsatellite repeat expansion in the ataxin 10 gene. In a subset of SCA10 families, the 5'-end of the repeat expansion contains a complex sequence of penta- and heptanucleotide interruption motifs which is followed by a pure tract of tandem ATCCT repeats of unknown length at its 3'-end. Intriguingly, expansions that carry these interruption motifs correlate with an epileptic seizure phenotype and are unstable despite the theory that interruptions are expected to stabilize expanded repeats. To examine the apparent contradiction of unstable, interruption-positive SCA10 expansion alleles and to determine whether the instability originates outside of the interrupted region, we sequenced approximately 1 kb of the 5'-end of SCA10 expansions using the ATCCT-PCR product in individuals across multiple generations from four SCA10 families. We found that the greatest instability within this region occurred in paternal transmissions of the allele in stretches of pure ATTCT motifs while the intervening interrupted sequences were stable. Overall, the ATCCT interruption changes by only one to three repeat units and therefore cannot account for the instability across the length of the disease allele. We conclude that the AT-rich interruptions locally stabilize the SCA10 expansion at the 5'-end but do not completely abolish instability across the entire span of the expansion. In addition, analysis of the interruption alleles across these families support a parsimonious single origin of the mutation with a shared distant ancestor.


Assuntos
Ataxina-10/genética , Epilepsia/genética , Padrões de Herança , Repetições de Microssatélites , Mutação , Ataxias Espinocerebelares/genética , Alelos , Sequência de Bases , Epilepsia/patologia , Feminino , Expressão Gênica , Variação Genética , Humanos , Masculino , Linhagem , Fenótipo , Ataxias Espinocerebelares/patologia
17.
Lupus Sci Med ; 4(1): e000176, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28409015

RESUMO

OBJECTIVE: SLE is traditionally classified using the American College of Rheumatology (ACR) criteria. The Systemic Lupus International Collaborating Clinics (SLICC) recently validated an alternative system. This study examined large cohorts of subjects with SLE and incomplete lupus erythematosus (ILE) to compare the impact of ACR and SLICC criteria. METHODS: Medical records of subjects in the Lupus Family Registry and Repository were reviewed for documentation of 1997 ACR classification criteria, SLICC classification criteria and medication usage. Autoantibodies were assessed by indirect immunofluorescence (ANA, antidouble-stranded DNA), precipitin (Sm) and ELISA (anticardiolipin). Other relevant autoantibodies were detected by precipitin and with a bead-based multiplex assay. RESULTS: Of 3575 subjects classified with SLE under at least one system, 3312 (92.6%) were classified as SLE by both systems (SLEboth), 85 only by ACR criteria (SLEACR-only) and 178 only by SLICC criteria (SLESLICC-only). Of 440 subjects meeting 3 ACR criteria, 33.9% (149/440) were SLESLICC-only, while 66.1% (n=291, designated ILE) did not meet the SLICC classification criteria. Under the SLICC system, the complement criterion and the individual autoantibody criteria enabled SLE classification of SLESLICC-only subjects, while SLEACR-only subjects failed to meet SLICC classification due to the combined acute/subacute cutaneous criterion. The SLICC criteria classified more African-American subjects by the leucopenia/lymphopenia criterion than did ACR criteria. Compared with SLEACR-only subjects, SLESLICC-only subjects exhibited similar numbers of affected organ systems, rates of major organ system involvement (∼30%: pulmonary, cardiovascular, renal, neurological) and medication history. CONCLUSIONS: The SLICC criteria classify more subjects with SLE than ACR criteria; however, individuals with incomplete lupus still exist under SLICC criteria. Subjects who gain SLE classification through SLICC criteria exhibit heterogeneous disease, including potential major organ involvement. These results provide supportive evidence that SLICC criteria may be more inclusive of SLE subjects for clinical studies.

19.
PLoS One ; 12(2): e0170249, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28166540

RESUMO

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 adversos
20.
Clin Exp Rheumatol ; 35(3): 438-444, 2017 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28229827

RESUMO

OBJECTIVES: To characterise the serological and clinical findings in primary Sjögren's syndrome in which anti-La was found without anti-Ro. We hypothesised that a significant portion of these are falsely negative for anti-Ro60. METHODS: Twenty-nine sera from primary Sjögren's syndrome patients were tested for antibodies directed against La and Ro. Anti-La was detected using bovine La treated with or without DNAase and RNAase to identify potential false positivity. Anti-Ro60 antibodies were detected using HEp-2000 substrate (in which cells are transfected with human Ro60) and HEp-2 substrate. Anti-Ro60 and Ro-52 were also tested by in vitro transcription/translation followed by immunoprecipitation assay. RESULTS: All 29 sera bound La, even after treatment with DNAase and RNAase. Of the 29 sera, 25 were unequivocally negative on HEp-2000 (1:40 dilution). Four samples were anti-Ro60 positive with a speckled pattern, three of the four at 1:320 dilution. Thus, false negative anti-Ro60 exists in a small fraction (14%) of the Ro-negative/La-positive primary Sjögren's patients. However, all the samples were negative for Ro60 and Ro52 by in vitro immunoprecipitation assay. Clinically these patients tended not to have salivary gland pathology characteristic of Sjögren's syndrome. CONCLUSIONS: We found only a small fraction of Ro negative/La positive sera to show positive HEp-2000 pattern. These subjects did not have characteristic findings on pathological examination of minor salivary glands, suggesting these subjects have a process distinct from Sjögren's syndrome.


Assuntos
Anticorpos Antinucleares/sangue , Autoimunidade , Síndrome de Sjogren/sangue , Adulto , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Reações Falso-Negativas , Humanos , Imunoprecipitação , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Testes Sorológicos , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia
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