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OBJECTIVES: To investigate the prognostic utility of 28 serum biomarkers in systemic sclerosis (SSc), SSc-associated interstitial lung disease (SSc-ILD) and clinically relevant disease subgroups. METHODS: Participants with sera, high-resolution computed tomography, and lung function within 12 months of baseline were identified from the Australian Scleroderma Cohort Study. Baseline was the time of serum collection. 27 of the prespecified 28 serum biomarkers were analysed and biomarker associations with mortality and ILD progression were investigated in univariable and multivariable analyses, including within disease subgroups and combined with established risk factors for poorer prognosis in SSc. RESULTS: 407 participants were identified, 252 (61.9%) with SSc-ILD. The median follow up after biomarker measurement was 6.31 (3.11-9.22) years. 16 biomarkers were associated with increased mortality. High levels of VCAM-1 were most strongly associated with mortality (HR 3.55; 95%CI 2.37-5.33; p< 0.001). Five additional biomarkers had a HR > 2: SP-D (2.28, 1.57-3.31; p< 0.001), E-selectin (2.19; 1.53-3.14; p< 0.001), IL-6 (2.15 1.50-3.09; p< 0.001), MMP3 (1.42-2.95; p< 0.001) and ET-1 (2.03, 1.40-2.92; p< 0.001). 11 biomarkers were independently associated with mortality following adjustment for sex, age and baseline forced vital capacity (FVC%predicted). Three biomarkers were associated with ILD progression at one year follow up: CXCL4 (OR 2.67, 1.46-4.88; p= 0.001), MMP-1 (2.56, 1.43-4.59; p= 0.002) and ET-1 (2.18, 1.24-3.83; p= 0.007). CONCLUSION: Multiple biomarkers, especially VCAM-1, E-Selectin, SP-D and CXCL4, provide prognostic utility beyond that of established risk factors for patients with SSc.
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The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.
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Síndrome de Behçet , Espondilartrite , Uveíte , Humanos , Predisposição Genética para Doença , Síndrome de Behçet/genética , Antígenos de Histocompatibilidade Classe I/genética , Aminopeptidases/genética , Antígenos de Histocompatibilidade Menor/genéticaRESUMO
The killer immunoglobulin-like receptors (KIRs), found predominantly on the surface of natural killer (NK) cells and some T-cells, are a collection of highly polymorphic activating and inhibitory receptors with variable specificity for class I human leukocyte antigen (HLA) ligands. Fifteen KIR genes are inherited in haplotypes of diverse gene content across the human population, and the repertoire of independently inherited KIR and HLA alleles is known to alter risk for immune-mediated and infectious disease by shifting the threshold of lymphocyte activation. We have conducted the largest disease-association study of KIR-HLA epistasis to date, enabled by the imputation of KIR gene and HLA allele dosages from genotype data for 12,214 healthy controls and 8,107 individuals with the HLA-B*27-associated immune-mediated arthritis, ankylosing spondylitis (AS). We identified epistatic interactions between KIR genes and their ligands (at both HLA subtype and allele resolution) that increase risk of disease, replicating analyses in a semi-independent cohort of 3,497 cases and 14,844 controls. We further confirmed that the strong AS-association with a pathogenic variant in the endoplasmic reticulum aminopeptidase gene ERAP1, known to alter the HLA-B*27 presented peptidome, is not modified by carriage of the canonical HLA-B receptor KIR3DL1/S1. Overall, our data suggests that AS risk is modified by the complement of KIRs and HLA ligands inherited, beyond the influence of HLA-B*27 alone, which collectively alter the proinflammatory capacity of KIR-expressing lymphocytes to contribute to disease immunopathogenesis.
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Epistasia Genética , Antígenos HLA/genética , Receptores KIR/genética , Espondilite Anquilosante/genética , Alelos , Aminopeptidases/genética , Humanos , Antígenos de Histocompatibilidade Menor/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis common in Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease most common in people of Mediterranean origin. MEFV, an FMF-associated gene, is also a candidate gene for AS. We aimed to identify AS susceptibility loci and also examine the association between MEFV and AS in Turkish and Iranian cohorts. We performed genome-wide association studies in 1001 Turkish AS patients and 1011 Turkish controls, and 479 Iranian AS patients and 830 Iranian controls. Serum IL-1ß, IL-17 and IL-23 cytokine levels were quantified in Turkish samples. An association of major effect was observed with a novel rare coding variant in MEFV in the Turkish cohort (rs61752717, M694V, OR = 5.3, P = 7.63×10(-12)), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65×10(-13)). 99.6% of Turkish AS cases, and 96% of those carrying MEFV rs61752717 variants, did not have FMF. In Turkish subjects, the association of rs61752717 was particularly strong in HLA-B27-negative cases (OR = 7.8, P = 8.93×10(-15)), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69×10(-8)). Serum IL-1ß, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1ß and IL-23 levels were increased in MEFV 694V carriers compared with non-carriers. Our data suggest that FMF and AS have overlapping aetiopathogenic mechanisms. Functionally important MEFV mutations, such as M694V, lead to dysregulated inflammasome function and excessive IL-1ß function. As IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy.
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Febre Familiar do Mediterrâneo/genética , Pirina/genética , Espondilite Anquilosante/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Febre Familiar do Mediterrâneo/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígeno HLA-B27/genética , Antígeno HLA-B51/genética , Humanos , Interleucina-1beta/sangue , Interleucina-23/sangue , Irã (Geográfico) , Masculino , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/imunologia , TurquiaRESUMO
OBJECTIVES: Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthropathy. Inflammation in AS is poorly understood. TBX21 encodes T-bet, a transcription factor, lying within a locus with genome-wide significant association with AS. T-bet is implicated in innate and adaptive immunity. However, the role of T-bet in AS pathogenesis is unclear. METHODS: We assessed the importance of T-bet in disease development and progression in peripheral blood mononuclear cells from 172 AS cases and 83 healthy controls carrying either risk or protective alleles of the peak AS-associated TBX21 single nucleotide polymorphism. Kinetics and localisation of T-bet expression in the SKG mouse model of spondyloarthropathy was examined, along with the impact of Tbx21 knockout on arthritis development in SKG mice. RESULTS: Patients with AS had higher T-bet expression than healthy individuals, driven predominantly by natural killer and CD8+ T cells, with expression levels in CD8+ T cells completely distinguishing AS cases from healthy controls. T-bet expression was increased in AS cases carrying risk compared with protective alleles of rs11657479. In curdlan-treated SKG mice, T-bet expression increased early after disease initiation and persisted throughout the course of disease. There was marked reduction in gut and peripheral joint inflammation, and less IFNγ-producing and IL-17-producing CD8+ T cells, in Tbx21-/- compared with wild-type SKG mice. CONCLUSIONS: AS-associated variants in TBX21 influence T-bet expression. T-bet+ innate and adaptive immune cells have altered IL-17 and IFNγ, and early activation marker CD69 expression than T-bet cells. This indicates that T-bet is a major component of inflammatory pathways of spondyloarthropathy in humans and mice.
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Artrite Experimental/genética , Citocinas/biossíntese , Espondilite Anquilosante/genética , Proteínas com Domínio T/genética , Adulto , Idoso , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica/fisiologia , Predisposição Genética para Doença , Genótipo , Humanos , Mediadores da Inflamação/metabolismo , Células Matadoras Naturais/imunologia , Linfonodos/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia , Proteínas com Domínio T/biossíntese , Adulto JovemRESUMO
BACKGROUND: Acromelic dysplasias are a group of disorders characterised by short stature, brachydactyly, limited joint extension and thickened skin and comprises acromicric dysplasia (AD), geleophysic dysplasia (GD), Myhre syndrome and Weill-Marchesani syndrome. Mutations in several genes have been identified for these disorders (including latent transforming growth factor ß (TGF-ß)-binding protein-2 (LTBP2), ADAMTS10, ADAMSTS17 and fibrillin-1 (FBN1) for Weill-Marchesani syndrome, ADAMTSL2 for recessive GD and FBN1 for AD and dominant GD), encoding proteins involved in the microfibrillar network. However, not all cases have mutations in these genes. METHODS: Individuals negative for mutations in known acromelic dysplasia genes underwent whole exome sequencing. RESULTS: A heterozygous missense mutation (exon 14: c.2087C>G: p.Ser696Cys) in latent transforming growth factor ß (TGF-ß)-binding protein-3 (LTBP3) was identified in a dominant AD family. Two distinct de novo heterozygous LTPB3 mutations were also identified in two unrelated GD individuals who had died in early childhood from respiratory failure-a donor splice site mutation (exon 12 c.1846+5G>A) and a stop-loss mutation (exon 28: c.3912A>T: p.1304*Cysext*12). CONCLUSIONS: The constellation of features in these AD and GD cases, including postnatal growth retardation of long bones and lung involvement, is reminiscent of the null ltbp3 mice phenotype. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum.
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Doenças do Desenvolvimento Ósseo/genética , Proteínas de Ligação a TGF-beta Latente/genética , Deformidades Congênitas dos Membros/genética , Mutação de Sentido Incorreto/genética , Exoma/genética , Éxons/genética , Fibrilina-1/genética , Heterozigoto , Humanos , Proteínas dos Microfilamentos/genética , Mutação , Fenótipo , Fator de Crescimento Transformador beta/genética , Síndrome de Weill-Marchesani/genéticaRESUMO
BACKGROUND: Ankylosing spondylitis (AS) is characterised by immune-mediated arthritis and osteoproliferation, ultimately leading to joint ankylosis. Whether inflammation is necessary for osteoproliferation is controversial, fuelled by the unclear efficacy of anti-inflammatory treatments on radiographic progression. In proteoglycan-induced spondylitis (PGISp), a mouse model of AS, inflammation is the prerequisite for osteoproliferation as osteoproliferation was only observed following inflammation-driven intervertebral disc (IVD) destruction. We hypothesised that early intervention with a potent anti-inflammatory therapy would protect IVD integrity and consequently alter disease progression. METHODS: PGISp mice received vehicle or a combination of etanercept (ETN) plus prednisolone (PRD) therapy for 2 or 6 weeks initiated at an early disease stage. Peripheral arthritis was scored longitudinally. Spinal disease was assessed using a semi-quantitative histological scoring regimen including inflammation, joint destruction and excessive tissue formation. RESULTS: ETN + PRD therapy significantly delayed the onset of peripheral arthritis. IVD integrity was significantly protected when treatment was commenced in early disease. Six-weeks of treatment resulted in trends towards reductions in intervertebral joint damage and excessive tissue formation. IVD score distribution was dichotomized, likely reflecting the extent of axial disease at initiation of therapy. In the sub-group of mice with high IVD destruction scores, ETN + PRD treatment significantly reduced IVD destruction severity, inflammation and bone erosion and reduced cartilage damage and excessive tissue formation. CONCLUSIONS: Early intervention with anti-inflammatory treatment not only improved inflammatory symptoms but also ameliorated structural damage of spine in PGISp mice. This preclinical observation suggests that early anti-inflammatory intervention may slow radiographic progression in AS patients.
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Anti-Inflamatórios/administração & dosagem , Modelos Animais de Doenças , Proteoglicanas/toxicidade , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/tratamento farmacológico , Animais , Esquema de Medicação , Quimioterapia Combinada , Etanercepte/administração & dosagem , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Prednisolona/administração & dosagem , Espondilite Anquilosante/patologiaRESUMO
Ankylosing spondylitis (AS) is a highly heritable disease for which there is a great unmet need for improved therapies. Genetics research has identified several major pathways involved in the disease, from which treatments have either now entered clinical practice or are in development. In particular, therapies targeting the IL-23 pathway were repositioned for use in AS following the discovery of multiple genes in the pathway as determinants of AS risk. Discovery of the association of aminopeptidase genes with AS, and subsequently with psoriasis, inflammatory bowel disease and other conditions, has triggered research into therapies targeting this pathway. The AS-genetic associations point to involvement of gut mucosal immunity in driving disease, and metagenomic studies have provided strong support that AS is a disease driven by interaction between the gut microbiome and host immune system, providing a rationale for the exploration of gut-targeted therapies for the disease.
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Alelos , Loci Gênicos , Predisposição Genética para Doença , Espondilite Anquilosante/genética , Genômica , HumanosRESUMO
INTRODUCTION: Single nucleotide polymorphisms in ERAP2 are strongly associated with ankylosing spondylitis (AS). One AS-associated single nucleotide polymorphism, rs2248374, causes a truncated ERAP2 protein that is degraded by nonsense-mediated decay. Approximately 25% of the populations of European ancestry are therefore natural ERAP2 knockouts. We investigated the effect of this associated variant on HLA class I allele presentation, surface heavy chains, endoplasmic reticulum (ER) stress markers and cytokine gene transcription in AS. METHODS: Patients with AS and healthy controls with either AA or GG homozygous status for rs2248374 were studied. Antibodies to CD14, CD19-ECD, HLA-A-B-C, Valpha7.2, CD161, anti-HC10 and anti-HLA-B27 were used to analyse peripheral blood mononuclear cells. Expression levels of ER stress markers (GRP78 and CHOP) and proinflammatory genes (tumour necrosis factor (TNF), IL6, IL17 and IL22) were assessed by qPCR. RESULTS: There was no significant difference in HLA-class I allele presentation or major histocompatibility class I heavy chains or ER stress markers GRP78 and CHOP or proinflammatory gene expression between genotypes for rs2248374 either between cases, between cases and controls, and between controls. DISCUSSION: Large differences were not seen in HLA-B27 expression or cytokine levels between subjects with and without ERAP2 in AS cases and controls. This suggests that ERAP2 is more likely to influence AS risk through other mechanisms.
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Aminopeptidases/genética , Citocinas/genética , Estresse do Retículo Endoplasmático/genética , Antígeno HLA-B27/genética , Leucócitos Mononucleares/imunologia , RNA Mensageiro/metabolismo , Espondilite Anquilosante/genética , Aminopeptidases/imunologia , Estudos de Casos e Controles , Citocinas/imunologia , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/imunologia , Expressão Gênica , Antígeno HLA-B27/imunologia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucinas/genética , Interleucinas/imunologia , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Espondilite Anquilosante/imunologia , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Interleucina 22RESUMO
There has been significant progress in our understanding of the pathogenesis of AS. The advent of genome-wide association studies has increased the known loci associated with AS to more than 40. The endoplasmic reticulum resident aminopeptidases (ERAP) 1 and 2 were identified in this manner and are of particular interest. There appears to be a genetic as well as a functional interaction of ERAP1 and 2 with HLA-B27 based on the known functions of these molecules. Recent studies on the structure, immunological effects and the peptide-trimming properties of ERAP 1 and 2 have helped to provide insight into their pathogenic potential in AS. In this review, we explore the role of ERAP 1 and 2 in the pathogenesis of AS.
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Aminopeptidases/fisiologia , Retículo Endoplasmático/enzimologia , Espondilite Anquilosante/etiologia , Espondilite Anquilosante/fisiopatologia , Aminopeptidases/genética , Estresse do Retículo Endoplasmático/fisiologia , Antígeno HLA-B27/genética , Antígeno HLA-B27/fisiologia , Humanos , Antígenos de Histocompatibilidade Menor , Espondilite Anquilosante/genéticaRESUMO
Adoptive T cell therapy uses the specificity of the adaptive immune system to target cancer and virally infected cells. Yet the mechanism and means by which to enhance T cell function are incompletely described, especially in the skin. In this study, we use a murine model of immunotherapy to optimize cell-mediated immunity in the skin. We show that in vitro-derived central but not effector memory-like T cells bring about rapid regression of skin-expressing cognate Ag as a transgene in keratinocytes. Local inflammation induced by the TLR7 receptor agonist imiquimod subtly yet reproducibly decreases time to skin graft rejection elicited by central but not effector memory T cells in an immunodeficient mouse model. Local CCL4, a chemokine liberated by TLR7 agonism, similarly enhances central memory T cell function. In this model, IL-2 facilitates the development in vivo of effector function from central memory but not effector memory T cells. In a model of T cell tolerogenesis, we further show that adoptively transferred central but not effector memory T cells can give rise to successful cutaneous immunity, which is dependent on a local inflammatory cue in the target tissue at the time of adoptive T cell transfer. Thus, adoptive T cell therapy efficacy can be enhanced if CD8(+) T cells with a central memory T cell phenotype are transferred, and IL-2 is present with contemporaneous local inflammation.
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Memória Imunológica/imunologia , Pele/imunologia , Pele/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Transferência Adotiva/métodos , Animais , Comunicação Celular/imunologia , Células Cultivadas , Células Epidérmicas , Epiderme/imunologia , Epiderme/transplante , Tolerância Imunológica , Imunidade Celular , Inflamação/imunologia , Inflamação/cirurgia , Inflamação/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Pele/citologia , Transplante de Pele/imunologia , Transplante de Pele/métodos , Transplante de Pele/patologia , Subpopulações de Linfócitos T/transplanteRESUMO
Recent advances in DNA sequencing have enabled mapping of genes for monogenic traits in families with small pedigrees and even in unrelated cases. We report the identification of disease-causing mutations in a rare, severe, skeletal dysplasia, studying a family of two healthy unrelated parents and two affected children using whole-exome sequencing. The two affected daughters have clinical and radiographic features suggestive of anauxetic dysplasia (OMIM 607095), a rare form of dwarfism caused by mutations of RMRP. However, mutations of RMRP were excluded in this family by direct sequencing. Our studies identified two novel compound heterozygous loss-of-function mutations in POP1, which encodes a core component of the RNase mitochondrial RNA processing (RNase MRP) complex that directly interacts with the RMRP RNA domains that are affected in anauxetic dysplasia. We demonstrate that these mutations impair the integrity and activity of this complex and that they impair cell proliferation, providing likely molecular and cellular mechanisms by which POP1 mutations cause this severe skeletal dysplasia.
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Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Doenças do Desenvolvimento Ósseo/genética , Mutação , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Análise de Sequência de DNA , Doenças do Desenvolvimento Ósseo/patologia , Proliferação de Células , Éxons/genética , Feminino , Humanos , Lactente , Leucócitos Mononucleares/metabolismo , Masculino , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único/genética , RNA Ribossômico 5,8S/genéticaRESUMO
OBJECTIVE: Ankylosing spondylitis (AS) is a common inflammatory arthritis affecting primarily the axial skeleton. IL23R is genetically associated with AS. This study was undertaken to investigate and characterize the role of interleukin-23 (IL-23) signaling in AS pathogenesis. METHODS: The study population consisted of patients with active AS (n = 17), patients with psoriatic arthritis (n = 8), patients with rheumatoid arthritis, (n = 9), and healthy subjects (n = 20). IL-23 receptor (IL-23R) expression in T cells was determined in each subject group, and expression levels were compared. RESULTS: The proportion of IL-23R-expressing T cells in the periphery was 2-fold higher in AS patients than in healthy controls, specifically driven by a 3-fold increase in IL-23R-positive γ/δ T cells in AS patients. The proportions of CD4+ and CD8+ cells that were positive for IL-17 were unchanged. This increased IL-23R expression on γ/δ T cells was also associated with enhanced IL-17 secretion, with no observable IL-17 production from IL-23R-negative γ/δ T cells in AS patients. Furthermore, γ/δ T cells from AS patients were heavily skewed toward IL-17 production in response to stimulation with IL-23 and/or anti-CD3/CD28. CONCLUSION: Recently, mouse models have shown IL-17-secreting γ/δ T cells to be pathogenic in infection and autoimmunity. Our data provide the first description of a potentially pathogenic role of these cells in a human autoimmune disease. Since IL-23 is a maturation and growth factor for IL-17-producing cells, increased IL-23R expression may regulate the function of this putative pathogenic γ/δ T cell population.
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Interleucina-17/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Interleucina/metabolismo , Espondilite Anquilosante/metabolismo , Adulto , Idoso , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/imunologia , Artrite Psoriásica/metabolismo , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/imunologia , Adulto JovemRESUMO
Memory T cells develop early during the preclinical stages of autoimmune diseases and have traditionally been considered resistant to tolerance induction. As such, they may represent a potent barrier to the successful immunotherapy of established autoimmune diseases. It was recently shown that memory CD8+ T cell responses are terminated when Ag is genetically targeted to steady-state dendritic cells. However, under these conditions, inactivation of memory CD8+ T cells is slow, allowing transiently expanded memory CD8+ T cells to exert tissue-destructive effector function. In this study, we compared different Ag-targeting strategies and show, using an MHC class II promoter to drive Ag expression in a diverse range of APCs, that CD8+ memory T cells can be rapidly inactivated by MHC class II+ hematopoietic APCs through a mechanism that involves a rapid and sustained downregulation of TCR, in which the effector response of CD8+ memory cells is rapidly truncated and Ag-expressing target tissue destruction is prevented. Our data provide the first demonstration that genetically targeting Ag to a broad range of MHC class II+ APC types is a highly efficient way to terminate memory CD8+ T cell responses to prevent tissue-destructive effector function and potentially established autoimmune diseases.
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Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Animais , Apresentação de Antígeno , Doenças Autoimunes/prevenção & controle , Antígenos de Histocompatibilidade Classe II/genética , Camundongos , Regiões Promotoras GenéticasRESUMO
Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of HLA inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual's underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.
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The complexity of the cellular and acellular players within the tumor microenvironment (TME) allows for significant variation in TME constitution and role in anticancer treatment response. Spatial alterations in populations of tumor cells and adjacent non-malignant cells, including endothelial cells, fibroblasts and tissue-infiltrating immune cells, often have a major role in determining disease progression and treatment response in cancer. Many current standard systemic antineoplastic treatments target the cancer cells and could be further refined to directly target commonly dysregulated cell populations of the TME. Recent developments in immuno-oncology and bioengineering have created an attractive potential to model these complexities at the level of the individual patient. These developments, along with the increasing momentum in precision medicine research and application, have catalysed exciting new discoveries in understanding drug-TME interactions, target identification, and improved efficacy of therapies. While rapid progress has been made, there are still many challenges to overcome in the development of accurate in vitro, in vivo and ex vivo models incorporating the cellular interactions that take place in the TME. In this review, we describe how advances in immuno-oncology and patient-derived models, such as patient-derived organoids and explant cultures, have enhanced the landscape of personalised immunotherapy prediction and treatment of solid organ malignancies. We describe and compare different immunological targets and perspectives on two-dimensional and three-dimensional modelling approaches that may be used to better rationalise immunotherapy use, ultimately providing a knowledge base for the integration of the autologous TME into these predictive models.
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Dengue, chikungunya and Zika viruses share similar disease features, rendering them difficult to distinguish clinically. Incapacitating arthralgia/arthritis is a specific manifestation associated with chikungunya virus infection. However, the profile of arthralgia/arthritis in Zika virus (ZIKV) cases has not been well characterized. Articles were extracted from PubMed and Scopus databases reporting original data from patients with arthralgia/arthritis, according to the Cochrane Collaboration. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 137 articles reporting ZIKV-associated joint symptoms were reviewed. Arthralgia was more frequently reported (n = 124 from case studies, n = 1779 from population-based studies) than arthritis (n = 7 and n = 121, respectively). Arthralgia was resolved in <1 week in 54%, and within 1-2 weeks in 40% of cases. The meta-analysis of cases in population-based studies identified a pooled prevalence of 53.55% for arthralgia. The pooled prevalence of arthralgia/arthritis during outbreaks depended on the geographic location, with a higher joint symptom burden observed in the Americas compared to South East Asia (Brazil: 60.79%; Puerto Rico: 68.89% and South East Asia: 26.46%). We conclude that non-specific constitutional arthralgia is the most common joint manifestation during ZIKV infection, being present in nearly half of cases but resolving by two weeks in >90% of these. We found no evidence of chronic rheumatic manifestations following ZIKV infection.
Assuntos
Artralgia/epidemiologia , Artrite/epidemiologia , Infecção por Zika virus/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artralgia/virologia , Artrite/virologia , Brasil/epidemiologia , Surtos de Doenças , Feminino , Humanos , Articulações/patologia , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem , Zika virus , Infecção por Zika virus/patologiaRESUMO
OBJECTIVE: Ankylosing spondylitis (AS) is a common spondyloarthropathy primarily affecting the axial skeleton and strongly associated with HLA-B*27 carriage. Genetic evidence implicates both autoinflammatory processes and autoimmunity against an HLA-B*27-restricted autoantigen in immunopathology. In addition to articular symptoms, up to 70% of AS patients present with concurrent bowel inflammation, suggesting that adverse interactions between a genetically primed host immune system and the gut microbiome contribute to the disease. Accordingly, this study aimed to characterize adaptive immune responses to antigenic stimuli in AS. METHODS: The peripheral CD4 and CD8 T cell receptor (TCR) repertoire was profiled in AS patients (n = 47) and HLA-B*27-matched healthy controls (n = 38). Repertoire diversity was estimated using the Normalized Shannon Diversity Entropy (NSDE) index, and univariate and multivariate statistical analyses were performed to characterize AS-associated clonal signatures. Furthermore, T cell proliferation and cytokine production in response to immunogenic antigen exposure were investigated in vitro in peripheral blood mononuclear cells from AS patients (n = 19) and HLA-B*27-matched healthy controls (n = 14). RESULTS: Based on the NSDE measure of sample diversity across CD4 and CD8 T cell repertoires, AS patients showed increased TCR diversity compared to healthy controls (for CD4 T cells, P = 7.8 × 10-6 ; for CD8 T cells, P = 9.3 × 10-4 ), which was attributed to a significant reduction in the magnitude of peripheral T cell expansions globally. Upon in vitro stimulation, fewer T cells from AS patients than from healthy controls expressed interferon-γ (for CD8 T cells, P = 0.03) and tumor necrosis factor (for CD4 T cells, P = 0.01; for CD8 T cells, P = 0.002). In addition, the CD8 TCR signature was altered in HLA-B*27+ AS patients compared to healthy controls, with significantly expanded Epstein-Barr virus-specific clonotypes (P = 0.03) and cytomegalovirus-specific clonotypes (P = 0.02). HLA-B*27+ AS patients also showed an increased incidence of "public" CD8 TCRs, representing identical clonotypes emerging in response to common antigen encounters, including homologous clonotypes matching those previously isolated from individuals with bacterial-induced reactive arthritis. CONCLUSION: The dynamics of peripheral T cell responses in AS patients are altered, suggesting that differential antigen exposure and disrupted adaptive immunity are underlying features of the disease.
Assuntos
Imunidade Adaptativa/genética , Variação Antigênica/genética , Receptores de Antígenos de Linfócitos T/imunologia , Espondilite Anquilosante/genética , Espondilite Anquilosante/imunologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , Entropia , Feminino , Antígeno HLA-B27/genética , Antígeno HLA-B27/imunologia , Humanos , Leucócitos Mononucleares , MasculinoRESUMO
The oxytocinase subfamily of M1 aminopeptidases plays an important role in processing and trimming of peptides for presentation on major histocompatibility (MHC) Class I molecules. Several large-scale genomic studies have identified association of members of this family of enzymes, most notably ERAP1 and ERAP2, with immune-mediated diseases including ankylosing spondylitis, psoriasis and birdshot chorioretinopathy. Much is now known about the genetics of these enzymes and how genetic variants alter their function, but how these variants contribute to disease remains largely unresolved. Here we discuss what is known about their structure and function and highlight some of the knowledge gaps that affect development of drugs targeting these enzymes.
Assuntos
Aminopeptidases/genética , Aminopeptidases/metabolismo , Doenças do Sistema Imunitário/etiologia , Doenças do Sistema Imunitário/metabolismo , Aminopeptidases/antagonistas & inibidores , Aminopeptidases/química , Apresentação de Antígeno , Autoimunidade , Biomarcadores , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Predisposição Genética para Doença , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/tratamento farmacológico , Inflamação/diagnóstico , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/terapia , Modelos Moleculares , Terapia de Alvo Molecular , Família Multigênica , Polimorfismo de Nucleotídeo Único , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Advances in genomic technology have enabled a greater understanding of the genetics of common immune-mediated diseases such as ankylosing spondylitis (AS), inflammatory bowel disease (IBD) and psoriasis. The substantial overlap in genetically identified pathogenic pathways has been demonstrated between these diseases. However, to date, gene discovery approaches have only mapped a minority of the heritability of these common diseases, and most disease-associated variants have been found to be non-coding, suggesting mechanisms of disease-association through transcriptional regulatory effects.Epigenetics is a major interface between genetic and environmental modifiers of disease and strongly influence transcription. DNA methylation is a well-characterised epigenetic mechanism, and a highly stable epigenetic marker, that is implicated in disease pathogenesis. DNA methylation is an under-investigated area in immune-mediated diseases, and many studies in the field are affected by experimental design limitations, related to study design, technical limitations of the methylation typing methods employed, and statistical issues. This has resulted in both sparsity of investigations into disease-related changes in DNA methylation, a paucity of robust findings, and difficulties comparing studies in the same disease.In this review, we cover the basics of DNA methylation establishment and control, and the methods used to examine it. We examine the current state of DNA methylation studies in AS, IBD and psoriasis; the limitations of previous studies; and the best practices for DNA methylation studies. The purpose of this review is to assist with proper experimental design and consistency of approach in future studies to enable a better understanding of the functional role of DNA methylation in immune-mediated disease.