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2.
Lupus Sci Med ; 8(1)2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34728555

RESUMO

OBJECTIVE: We have investigated the molecular function of SCAMP5, a candidate risk gene for SLE exclusively expressed in plasmacytoid dendritic cells (pDCs) among peripheral leucocytes. METHODS: We tested the independence of the association in SCAMP5 with SLE by performing conditional analyses. We profiled the expression pattern of SCAMP5 among circulating leucocytes at the transcript and protein levels. Using lentiviral vectors, we localised the subcellular distribution of SCAMP5 alongside the interferon secretory pathway. We analysed pDCs for the expression of SCAMP5 and interferon production capacity by SCAMP5 genotype. Finally, we examined pDC-specific SCAMP5 isoforms by total RNAseq analysis and examined for genotype-associated quantitative differences therein. RESULTS: A conditional analysis revealed evidence of an independent genetic association of SCAMP5 with SLE. Among circulating leucocytes, SCAMP5 is uniquely expressed in pDCs at the transcript and protein levels, with main presence in the Golgi apparatus and minor presence at the cell periphery. In live cells, SCAMP5 displayed dynamic Golgi-cell surface trafficking and localised with the interferon secretory pathway. SCAMP5 did not differ in expression levels in pDCs between genotyped donors; however, a transient interferon secretory defect was noted in pDCs from donors carrying the risk genotype. CONCLUSIONS: SCAMP5 constitutes a novel SLE risk gene on the basis of genomic data and expression in a cell type widely implicated in SLE pathogenesis. While we could not find evidence of quantitative expression differences in SCAMP5 between genotyped donors, SCAMP5 remains an attractive gene to explore given its highly restricted expression pattern and colocalisation with interferon secretion.

3.
Nat Genet ; 53(10): 1504-1516, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34611364

RESUMO

Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance.


Assuntos
Variação Genética , Genética Populacional , Infecções por HIV/genética , Antígenos HLA/genética , Interações Hospedeiro-Patógeno/genética , Mapeamento Físico do Cromossomo , Alelos , Aminoácidos/genética , Frequência do Gene/genética , HIV-1/genética , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Padrões de Referência , Seleção Genética , Carga Viral
4.
BMJ Open ; 11(9): e050883, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521672

RESUMO

OBJECTIVE: Physical activity (PA) in preclinical rheumatoid arthritis (RA) is associated with lower RA risk and disease severity. As joint signs and symptoms of inflammatory arthritis serve as a barrier to PA in RA, it is important to consider whether they affect PA in the time prior to RA. Therefore, we investigated whether joint swelling, stiffness or pain were associated with PA in first-degree relatives (FDRs) of patients with RA, a population at higher risk for future RA. DESIGN: Prospective study design. SETTING: We recruited FDRs of patients with RA from academic centres, Veterans' hospitals and rheumatology clinics or through responses to advertising from six sites across the USA. PARTICIPANTS: We evaluated associations of joint stiffness, joint swelling and joint pain with PA time in 268 FDRs with ≥2 visits over an average 1.2 years. Clinicians confirmed joint swelling. Participants self-reported joint stiffness and/or pain. PRIMARY OUTCOME MEASURES: PA during a typical 24-hour day was quantified via questionnaire, weighted to reflect metabolic expenditure, where 24 hours was the minimum PA time. Linear mixed models evaluated associations between symptoms and change in PA over time, adjusting for age, sex, race, body mass index, smoking and RA-related autoantibodies. RESULTS: Average weighted PA time was 37±7 hours. In the cross-sectional analysis, PA time was 1.3±0.9 hours higher in FDRs reporting joint pain (p=0.15); and 0.8±1.6 and 0.4±1 hours lower in FDRs with joint swelling (p=0.60) and stiffness (p=0.69), respectively. Longitudinally, adjusting for baseline PA time, baseline symptoms were not significantly associated with changes in PA time. However, on average over time, joint stiffness and pain were associated with lower PA time (pinteraction=0.0002, pinteraction=0.002), and joint swelling was associated with higher PA time (pinteraction <0.0001). CONCLUSION: Baseline symptoms did not predict future PA time, but on average over time, joint symptoms influenced PA time.


Assuntos
Artrite Reumatoide , Artralgia/etiologia , Estudos Transversais , Exercício Físico , Humanos , Estudos Prospectivos
6.
Nat Genet ; 53(7): 962-971, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34127860

RESUMO

We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10-8) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4+ effector T cells. Using chromatin-accessibility profiling of CD4+ T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.


Assuntos
Alelos , Mapeamento Cromossômico , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Variação Genética , Genômica , Autoimunidade/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Descoberta de Drogas , Expressão Gênica , Genômica/métodos , Humanos , Terapia de Alvo Molecular , Mapeamento de Interação de Proteínas
7.
Ann Rheum Dis ; 2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33455918

RESUMO

OBJECTIVES: To determine if the polymorphism encoding the Arg206Cys substitution in DNASE1L3 explains the association of the DNASE1L3/PXK gene locus with systemic lupus erythematosus (SLE) and to examine the effect of the Arg206Cys sequence change on DNASE1L3 protein function. METHODS: Conditional analysis for rs35677470 was performed on cases and controls with European ancestry from the SLE Immunochip study, and genotype and haplotype frequencies were compared. DNASE1L3 protein levels were measured in cells and supernatants of HEK293 cells and monocyte-derived dendritic cells expressing recombinant and endogenous 206Arg and 206Cys protein variants. RESULTS: Conditional analysis on rs35677470 eliminated the SLE risk association signal for lead single-nucleotide polymorphisms (SNPs) rs180977001 and rs73081554, which are found to tag the same risk haplotype as rs35677470. The modest effect sizes of the SLE risk genotypes (heterozygous risk OR=1.14 and homozygous risk allele OR=1.68) suggest some DNASE1L3 endonuclease enzyme function is retained. An SLE protective signal in PXK (lead SNP rs11130643) remained following conditioning on rs35677470. The DNASE1L3 206Cys risk variant maintained enzymatic activity, but secretion of the artificial and endogenous DNASE1L3 206Cys protein was substantially reduced. CONCLUSIONS: SLE risk association in the DNASE1L3 locus is dependent on the missense SNP rs35677470, which confers a reduction in DNASE1L3 protein secretion but does not eliminate its DNase enzyme function.

8.
PLoS One ; 16(1): e0244187, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33444321

RESUMO

Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response.


Assuntos
Artrite Reumatoide/patologia , Interferon-alfa/farmacologia , Interleucina-10/farmacologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Abatacepte/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Fosforilação , Índice de Gravidade de Doença
9.
Ann Rheum Dis ; 80(2): 154-161, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32928740

RESUMO

OBJECTIVES: Little is known about the likelihood of developing inflammatory arthritis (IA) in individuals who screen autoantibody positive (aAb+) in a non-clinical research setting. METHODS: We screened for serum cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor isotype aAbs in subjects who were at increased risk for rheumatoid arthritis (RA) because they are a first-degree relative of an individual with classified RA (n=1780). We evaluated combinations of aAbs and high titre aAbs, as defined by 2-times (2 x) the standard cut-off and an optimal cut-off, as predictors of our two outcomes, aAb+ persistence and incident IA. RESULTS: 304 subjects (17.1%) tested aAb+; of those, 131 were IA-free and had at least one follow-up visit. Sixty-four per cent of these tested aAb+ again on their next visit. Anti-CCP+ at levels ≥2 x the standard cut-off was associated with 13-fold higher likelihood of aAb +persistence. During a median of 4.4 years (IQR: 2.2-7.2), 20 subjects (15.3%) developed IA. Among subjects that screened anti-CCP+ at ≥ 2 x or ≥an optimal cut-off, 32% and 26% had developed IA within 5 years, respectively. Both anti-CCP cut-offs conferred an approximate fourfold increased risk of future IA (HR 4.09 and HR 3.95, p<0.01). CONCLUSIONS: These findings support that aAb screening in a non-clinical setting can identify RA-related aAb+ individuals, as well as levels and combinations of aAbs that are associated with higher risk for future IA. Monitoring for the development of IA in aAb+ individuals and similar aAb testing approaches in at-risk populations may identify candidates for prevention studies in RA.


Assuntos
Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide/genética , Autoanticorpos/sangue , Programas de Rastreamento/estatística & dados numéricos , Fator Reumatoide/sangue , Adulto , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Progressão da Doença , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Estudos Prospectivos , Fatores de Risco
10.
Arthritis Rheumatol ; 73(6): 955-962, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33381911

RESUMO

OBJECTIVE: To determine the association of polyunsaturated fatty acid (PUFA)-derived lipid mediators with progression from rheumatoid arthritis (RA)-related autoimmunity to inflammatory arthritis (IA). METHODS: We conducted a prospective cohort study using data from the Studies of the Etiology of Rheumatoid Arthritis (SERA). SERA enrolled first-degree relatives (FDRs) of individuals with RA (FDR cohort) and individuals who screened positive for RA-related autoantibodies at health fairs (screened cohort). We followed up 133 anti-cyclic citrullinated peptide 3.1 (anti-CCP3.1)-positive participants, 29 of whom developed IA. Lipid mediators selected a priori were quantified from stored plasma samples using liquid chromatography tandem mass spectrometry. We fit multivariable Cox proportional hazards models for each lipid mediator as a time-varying variable. For lipid mediators found to be significantly associated with IA, we then examined interleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor (TNF) as potential statistical mediators. RESULTS: For every 1 natural log pg/ml increase in the circulating plasma levels of proinflammatory 5-HETE, the risk of developing IA increased by 241% (hazard ratio 2.41 [95% confidence interval 1.43-4.07]) after adjusting for age at baseline, cohort (FDR or screened), and shared epitope status. The models examining 15-HETE and 17-HDHA had the same trend but did not reach significance. We did not find evidence that the association between 5-HETE and IA risk was influenced by the proinflammatory cytokines tested. CONCLUSION: In a prospective cohort of anti-CCP-positive individuals, higher levels of 5-HETE, an important precursor to proinflammatory leukotrienes, is associated with subsequent IA. Our findings highlight the potential significance of these PUFA metabolites in pre-RA populations.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Autoimunidade/imunologia , Ácidos Graxos Insaturados/metabolismo , Adulto , Idoso , Artrite Reumatoide/epidemiologia , Estudos de Coortes , Progressão da Doença , Ácidos Docosa-Hexaenoicos/metabolismo , Família , Feminino , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Incidência , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Masculino , Análise de Mediação , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fator de Necrose Tumoral alfa/imunologia
11.
Genome Biol ; 21(1): 281, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213505

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further. RESULTS: We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody. CONCLUSIONS: We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis.

12.
Am J Obstet Gynecol ; 223(5): 624-664, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32707266

RESUMO

Women's health concerns are generally underrepresented in basic and translational research, but reproductive health in particular has been hampered by a lack of understanding of basic uterine and menstrual physiology. Menstrual health is an integral part of overall health because between menarche and menopause, most women menstruate. Yet for tens of millions of women around the world, menstruation regularly and often catastrophically disrupts their physical, mental, and social well-being. Enhancing our understanding of the underlying phenomena involved in menstruation, abnormal uterine bleeding, and other menstruation-related disorders will move us closer to the goal of personalized care. Furthermore, a deeper mechanistic understanding of menstruation-a fast, scarless healing process in healthy individuals-will likely yield insights into a myriad of other diseases involving regulation of vascular function locally and systemically. We also recognize that many women now delay pregnancy and that there is an increasing desire for fertility and uterine preservation. In September 2018, the Gynecologic Health and Disease Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development convened a 2-day meeting, "Menstruation: Science and Society" with an aim to "identify gaps and opportunities in menstruation science and to raise awareness of the need for more research in this field." Experts in fields ranging from the evolutionary role of menstruation to basic endometrial biology (including omic analysis of the endometrium, stem cells and tissue engineering of the endometrium, endometrial microbiome, and abnormal uterine bleeding and fibroids) and translational medicine (imaging and sampling modalities, patient-focused analysis of menstrual disorders including abnormal uterine bleeding, smart technologies or applications and mobile health platforms) to societal challenges in health literacy and dissemination frameworks across different economic and cultural landscapes shared current state-of-the-art and future vision, incorporating the patient voice at the launch of the meeting. Here, we provide an enhanced meeting report with extensive up-to-date (as of submission) context, capturing the spectrum from how the basic processes of menstruation commence in response to progesterone withdrawal, through the role of tissue-resident and circulating stem and progenitor cells in monthly regeneration-and current gaps in knowledge on how dysregulation leads to abnormal uterine bleeding and other menstruation-related disorders such as adenomyosis, endometriosis, and fibroids-to the clinical challenges in diagnostics, treatment, and patient and societal education. We conclude with an overview of how the global agenda concerning menstruation, and specifically menstrual health and hygiene, are gaining momentum, ranging from increasing investment in addressing menstruation-related barriers facing girls in schools in low- to middle-income countries to the more recent "menstrual equity" and "period poverty" movements spreading across high-income countries.


Assuntos
Saúde Global , Letramento em Saúde , Produtos de Higiene Menstrual , Menstruação , Hemorragia Uterina , Saúde da Mulher , Adenomiose/fisiopatologia , Atitude , Evolução Biológica , Pesquisa Biomédica , Congressos como Assunto , Países em Desenvolvimento , Educação , Endometriose/fisiopatologia , Endométrio/citologia , Endométrio/microbiologia , Endométrio/fisiologia , Feminino , Humanos , Leiomioma/fisiopatologia , Distúrbios Menstruais/fisiopatologia , Células-Tronco Mesenquimais , Microbiota , Técnicas Analíticas Microfluídicas , National Institute of Child Health and Human Development (U.S.) , Regeneração/fisiologia , Células-Tronco/fisiologia , Terminologia como Assunto , Engenharia Tecidual , Estados Unidos , Neoplasias Uterinas/fisiopatologia , Útero/citologia , Útero/diagnóstico por imagem , Útero/microbiologia , Útero/fisiologia
13.
Nat Genet ; 52(3): 247-253, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32066938

RESUMO

Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4+ T cell regulatory elements1-3. Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity4,5. Here, we characterized the dynamics of genetic regulatory effects at eight time points during memory CD4+ T cell activation with high-depth RNA-seq in healthy individuals. We discovered widespread, dynamic allele-specific expression across the genome, where the balance of alleles changes over time. These genes were enriched fourfold within autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes. HLA-DQB1 alleles had one of three distinct transcriptional regulatory programs. Using CRISPR-Cas9 genomic editing we demonstrated that a promoter variant is causal for T cell-specific control of HLA-DQB1 expression. Our study shows that genetic variation in cis-regulatory elements affects gene expression in a manner dependent on lymphocyte activation status, contributing to the interindividual complexity of immune responses.


Assuntos
Autoimunidade/genética , Variação Genética , Antígenos HLA/genética , Cadeias beta de HLA-DQ/genética , Ativação Linfocitária/genética , Regiões Promotoras Genéticas/genética , Alelos , Linfócitos T CD4-Positivos , Sistemas CRISPR-Cas , Linhagem Celular , Regulação da Expressão Gênica , Loci Gênicos , Técnicas de Genotipagem , Antígenos HLA/metabolismo , Cadeias beta de HLA-DQ/metabolismo , Humanos , Imunidade Celular , Linfócitos T Reguladores
14.
Arthritis Care Res (Hoboken) ; 72(12): 1766-1771, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31600025

RESUMO

OBJECTIVE: The aim of this study was to determine the association of perceived stress with incident inflammatory arthritis (IA) defined as having at least 1 joint consistent with rheumatoid arthritis (RA)-like synovitis based on examination. METHODS: We conducted a prospective cohort study in the Studies of the Etiologies of Rheumatoid Arthritis cohort. Participants without IA were recruited if they were a first-degree relative of an RA proband or screened positive for anti-citrullinated protein antibody. Perceived stress was measured using the Perceived Stress Scale-14 (PSS-14), in which scores can range from 0 to 56, and a higher score indicates greater perceived stress. The total PSS-14 score, as well as 2 subscores indicative of perceived distress and self-efficacy, were averaged across all study visits until development of IA or the last follow-up. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) of IA associated with average PSS-14 scores were obtained using Cox proportional hazards models. RESULTS: The mean total PSS-14 score was 20.4. We found that a 1-point increase in the perceived distress score was significantly associated with a 10-percent increase in the risk of IA (adjusted HR 1.10 [95% CI 1.02-1.19]). Total PSS-14 and self-efficacy were not associated with IA risk (adjusted HR 1.05 [95% CI 0.99-1.10] and 1.04 [95% CI 0.91-1.18], respectively). CONCLUSION: An association between perceived distress and incident IA was observed in this at-risk cohort. Replication of this finding in other preclinical and at-risk RA populations is needed.


Assuntos
Artrite Reumatoide/epidemiologia , Estresse Psicológico/epidemiologia , Adulto , Idoso , Artrite Reumatoide/diagnóstico , Colorado/epidemiologia , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Estresse Psicológico/diagnóstico
15.
JCI Insight ; 5(2)2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-31877114

RESUMO

Genetic variants within or near the interferon regulatory factor 5 (IRF5) locus associate with systemic lupus erythematosus (SLE) across ancestral groups. The major IRF5-SLE risk haplotype is common across populations, yet immune functions for the risk haplotype are undefined. We characterized the global immune phenotype of healthy donors homozygous for the major risk and nonrisk haplotypes and identified cell lineage-specific alterations that mimic presymptomatic SLE. Contrary to previous studies in B lymphoblastoid cell lines and SLE immune cells, IRF5 genetic variants had little effect on IRF5 protein levels in healthy donors. Instead, we detected basal IRF5 hyperactivation in the myeloid compartment of risk donors that drives the SLE immune phenotype. Risk donors were anti-nuclear antibody positive with anti-Ro and -MPO specificity, had increased circulating plasma cells and plasmacytoid dendritic cells, and had enhanced spontaneous NETosis. The IRF5-SLE immune phenotype was conserved over time and probed mechanistically by ex vivo coculture, indicating that risk neutrophils are drivers of the global immune phenotype. RNA-Seq of risk neutrophils revealed increased IRF5 transcript expression, IFN pathway enrichment, and decreased expression of ROS pathway genes. Altogether, the data support that individuals carrying the IRF5-SLE risk haplotype are more susceptible to environmental/stochastic influences that trigger chronic immune activation, predisposing to the development of clinical SLE.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Linhagem Celular , Feminino , Genótipo , Haplótipos , Humanos , Linfócitos/imunologia , Masculino , Neutrófilos/imunologia , Fatores de Risco
17.
Am J Hum Genet ; 105(3): 616-624, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474319

RESUMO

Rheumatoid arthritis (RA) is the most common immune-mediated arthritis. Anti-citrullinated peptide antibodies (ACPA) are highly specific to RA and assayed with the commercial CCP2 assay. Genetic drivers of RA within the MHC are different for CCP2-positive and -negative subsets of RA, particularly at HLA-DRB1. However, aspartic acid at amino acid position 9 in HLA-B (Bpos-9) increases risk to both RA subsets. Here we explore how individual serologies associated with RA drive associations within the MHC. To define MHC differences for specific ACPA serologies, we quantified a total of 19 separate ACPAs in RA-affected case subjects from four cohorts (n = 6,805). We found a cluster of tightly co-occurring antibodies (canonical serologies, containing CCP2), along with several independently expressed antibodies (non-canonical serologies). After imputing HLA variants into 6,805 case subjects and 13,467 control subjects, we tested associations between the HLA region and RA subgroups based on the presence of canonical and/or non-canonical serologies. We examined CCP2(+) and CCP2(-) RA-affected case subjects separately. In CCP2(-) RA, we observed that the association between CCP2(-) RA and Bpos-9 was derived from individuals who were positive for non-canonical serologies (omnibus_p = 9.2 × 10-17). Similarly, we observed in CCP2(+) RA that associations between subsets of CCP2(+) RA and Bpos-9 were negatively correlated with the number of positive canonical serologies (p = 0.0096). These findings suggest unique genetic characteristics underlying fine-specific ACPAs, suggesting that RA may be further subdivided beyond simply seropositive and seronegative.


Assuntos
Artrite Reumatoide/imunologia , Antígenos HLA/imunologia , Fenótipo , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos
18.
Nat Immunol ; 20(7): 928-942, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31061532

RESUMO

To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Perfilação da Expressão Gênica , Membrana Sinovial/metabolismo , Transcriptoma , Artrite Reumatoide/patologia , Autoimunidade/genética , Biomarcadores , Biologia Computacional/métodos , Estudos Transversais , Citocinas/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Transdução de Sinais , Análise de Célula Única/métodos , Membrana Sinovial/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fluxo de Trabalho
19.
Ann Rheum Dis ; 78(7): 996-1002, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31138531

RESUMO

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. METHODS: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. RESULTS: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10-5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10-53 and HLA-DRB1*03:01, p=3.25×10-9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10-26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10-11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10-13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10-6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10-64) and position 9 of HLA-B (p=7.03×10-11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. CONCLUSIONS: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.


Assuntos
Autoanticorpos/genética , Grupo com Ancestrais do Continente Europeu/genética , Cadeias HLA-DRB1/genética , Miosite/genética , Miosite/imunologia , Adulto , Alelos , Autoanticorpos/imunologia , Feminino , Genótipo , Cadeias HLA-DRB1/imunologia , Haplótipos , Humanos , Complexo Principal de Histocompatibilidade/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
20.
J Rheumatol ; 46(12): 1556-1559, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30988128

RESUMO

OBJECTIVE: We investigated the association of age and anticyclic citrullinated peptide antibodies (anti-CCP) in subjects without rheumatoid arthritis (RA). METHODS: Serum was tested for anti-CCP3.1 (IgG/IgA) in 678 first-degree relatives (FDR) of patients with RA and 330 patients with osteoarthritis (OA). Individual isotypes (anti-CCP-IgA and anti-CCP-IgG) were also tested in all FDR. RESULTS: In FDR, increasing age was significantly associated with positivity for anti-CCP3.1 (per year, OR 1.03) and anti-CCP-IgA (per year, OR 1.05) but not anti-CCP-IgG. In FDR and OA subjects, anti-CCP3.1 prevalence was significantly increased after age 50 years. CONCLUSION: Increasing age in individuals without RA should be considered in the interpretation of anti-CCP3.1 positivity.


Assuntos
Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide/sangue , Autoanticorpos/sangue , Imunoglobulina A/sangue , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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