RESUMO
In psoriatic arthritis (PsA), predisposing class I HLA alleles, the presence of synovial clonally proliferated CD8 + T cells and autoantibodies all point towards the loss of immune tolerance. However, the key mechanisms that lead to immune dysregulation are not fully understood. In other types of inflammatory arthritis, T regulatory cell (Treg) dysfunction and plasticity at sites of inflammation were suggested to negatively affect peripheral tolerance. We here addressed if Treg variances associate with psoriatic disease. We collected clinical data, sera and peripheral blood mononuclear cells from 13 healthy controls, 21 psoriasis and 21 PsA patients. In addition, we obtained synovial fluid mononuclear cells from 6 PsA patients. We studied characteristics of CD4 + CD25 + CD127loFoxp3 + Tregs by flow cytometry and used ELISA to quantify antibodies against ADAMTSL5, a recently discovered autoantigen in psoriatic disease. In comparison with their circulating counterparts, Tregs from inflamed joints express increased levels of ICOS, CTLA-4 and TIGIT. Furthermore, synovial fluid-derived Tregs have a distinct phenotype, characterized by IL-17A production and upregulation of CD161 and RORγt. We identified a subset of Tregs with intermediate Foxp3 expression as the major cytokine producer. Furthermore, ICOS + Tregs associate with PsA disease activity as measured by PASDAS. Lastly, we observed that presence of the Foxp3int Tregs associates with an increased abundance of anti-ADAMTSL5 autoantibodies. Tregs derived from the inflammatory environment of inflamed PsA joints exhibit a distinct phenotype, which associates with loss of peripheral immune tolerance in psoriatic disease.
Assuntos
Artrite Psoriásica , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Humanos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Interleucina-17 , Linfócitos T Reguladores , Autoanticorpos , Leucócitos Mononucleares , Fenótipo , Fatores de Transcrição , Fatores de Transcrição Forkhead , Proteína Coestimuladora de Linfócitos T Induzíveis , Proteínas ADAMTSRESUMO
INTRODUCTION: Psoriatic arthritis (PsA) is a chronic, inflammatory, musculoskeletal disease that affects up to 30% of patients with psoriasis. Current challenges in clinical care and research include personalised treatment, understanding the divergence of therapy response and unravelling the multifactorial pathophysiology of this complex disease. Moreover, there is an urgent clinical need to predict, assess and understand the cellular and molecular pathways underlying the response to disease-modifying antirheumatic drugs (DMARDs). The TOFA-PREDICT clinical trial addresses this need. Our primary objective is to determine key immunological factors predicting tofacitinib efficacy and drug-free remission in PsA. METHODS AND ANALYSIS: In this investigator-initiated, phase III, multicentre, open-label, four-arm randomised controlled trial, we plan to integrate clinical, molecular and imaging parameters of 160 patients with PsA. DMARD-naïve patients are randomised to methotrexate or tofacitinib. Additionally, patients who are non-responsive to conventional synthetic (cs)DMARDs continue their current csDMARD and are randomised to etanercept or tofacitinib. This results in four arms each with 40 patients. Patients are followed for 1 year. Treatment response is defined as minimal disease activity at week 16. Clinical data, biosamples and images are collected at baseline, 4 weeks and 16 weeks; at treatment failure (treatment switch) and 52 weeks. For the first 80 patients, we will use a systems medicine approach to assess multiomics biomarkers and develop a prediction model for treatment response. Subsequently, data from the second 80 patients will be used for validation. ETHICS AND DISSEMINATION: The study was approved by the Medical Research Ethics Committee in Utrecht, Netherlands, is registered in the European Clinical Trials Database and is carried out in accordance with the Declaration of Helsinki. The study's progress is monitored by Julius Clinical, a science-driven contract research organisation. TRIAL REGISTRATION NUMBER: EudraCT: 2017-003900-28.
Assuntos
Antirreumáticos , Artrite Psoriásica , Piperidinas , Pirimidinas , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Biomarcadores , Ensaios Clínicos Fase III como Assunto , Etanercepte/uso terapêutico , Furanos , Humanos , Fatores Imunológicos/uso terapêutico , Metotrexato/uso terapêutico , Estudos Multicêntricos como Assunto , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: Early identification of patients at risk of psoriatic arthritis (PsA) is essential to facilitate early diagnosis and improve clinical outcomes. Severe cutaneous psoriasis has been proposed to be associated with PsA, but a recent assessment of the evidence is lacking. Therefore, in this systematic review, we address the association of psoriasis skin severity with the presence and development of PsA. SUMMARY: We included articles from a review published in 2014 and supplemented these with recent literature by performing an additional systematic search to identify studies published between 1 January 2013 and 11 February 2021. A meta-analysis was performed when sufficient comparable evidence was available. Of 2,000 screened articles, we included 29 in the analysis, of which 16 were identified by our updated search. Nineteen studies reported psoriasis severity as psoriasis area and severity index (PASI), ten studies as body surface area (BSA), and two studies as "number of affected sites." Most studies show that more extensive skin disease is associated with the presence of PsA. The quantitative pooled analyses demonstrate higher PASI (mean difference [Δ] 1.59; 95% confidence interval [CI] 0.29-2.89) and higher BSA (Δ 5.31; 95% CI 1.78-8.83) in patients with PsA as compared to psoriasis patients without PsA. Results from prospective studies - that assess the risk of future development of PsA in psoriasis patients - were inconclusive. KEY MESSAGES: In patients with psoriasis, more severe skin involvement is associated with the presence of PsA, underpinning the importance of optimal dermatology-rheumatology collaboration in clinical care. There are insufficient data to support the use of psoriasis skin severity to predict the future development of PsA in psoriasis patients.
Assuntos
Artrite Psoriásica , Psoríase , Reumatologia , Humanos , Artrite Psoriásica/complicações , Artrite Psoriásica/diagnóstico , Estudos Prospectivos , Psoríase/complicações , Psoríase/diagnóstico , Pele , Índice de Gravidade de DoençaRESUMO
Interleukin (IL)-12 and IL-23 are pro-inflammatory cytokines produced by dendritic cells (DCs) and associated with Psoriasis (Pso) and Psoriatic Arthritis (PsA) pathogenesis. Tofacitinib, a Janus kinase inhibitor, effectively suppresses inflammatory cascades downstream the IL-12/IL-23 axis in Pso and PsA patients. Here, we investigated whether Tofacitinib directly regulates IL-12/IL-23 production in DCs, and how this regulation reflects responses to Tofacitinib in Pso patients. We treated monocyte-derived dendritic cells and myeloid dendritic cells with Tofacitinib and stimulated cells with either lipopolysaccharide (LPS) or a combination of LPS and IFN-γ. We assessed gene expression by qPCR, obtained skin microarray and blood Olink data and clinical parameters of Pso patients treated with Tofacitinib from public data sets. Our results indicate that in DCs co-stimulated with LPS and IFN-γ, but not with LPS alone, Tofacitinib leads to the decreased expression of IL-23/IL-12 shared subunit IL12B (p40). In Tofacitinib-treated Pso patients, IL-12 expression and psoriasis area and severity index (PASI) are significantly reduced in patients with higher IFN-γ at baseline. These findings demonstrate for the first time that Tofacitinib suppresses IL-23/IL-12 shared subunit IL12B in DCs upon active IFN-γ signaling, and that Pso patients with higher IFN-γ baseline levels display improved clinical response after Tofacitinib treatment.
Assuntos
Interferon gama , Subunidade p40 da Interleucina-12 , Inibidores de Janus Quinases , Piperidinas , Psoríase , Pirimidinas , Pele , Artrite Psoriásica/tratamento farmacológico , Células Dendríticas/imunologia , Humanos , Interferon gama/metabolismo , Subunidade p40 da Interleucina-12/antagonistas & inibidores , Subunidade p40 da Interleucina-12/sangue , Subunidade p40 da Interleucina-12/metabolismo , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Lipopolissacarídeos/imunologia , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Psoríase/tratamento farmacológico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pele/efeitos dos fármacos , Pele/imunologiaRESUMO
Dermal fibroblasts are strategically positioned underneath the basal epidermis layer to support keratinocyte proliferation and extracellular matrix production. In inflammatory conditions, these fibroblasts produce cytokines and chemokines that promote the chemoattraction of immune cells into the dermis and the hyperplasia of the epidermis, two characteristic hallmarks of psoriasis. However, how dermal fibroblasts specifically contribute to psoriasis development remains largely uncharacterized. In this study, we investigated through which cytokines and signaling pathways dermal fibroblasts contribute to the inflammatory features of psoriatic skin. We show that dermal fibroblasts from lesional psoriatic skin are important producers of inflammatory mediators, including IL-6, CXCL8, and CXCL2. This increased cytokine production was found to be regulated by ZFP36 family members ZFP36, ZFP36L1, and ZFP36L2, RNA-binding proteins with mRNA-degrading properties. In addition, the expression of ZFP36 family proteins was found to be reduced in chronic inflammatory conditions that mimic psoriatic lesional skin. Collectively, these results indicate that dermal fibroblasts are important producers of cytokines in psoriatic skin and that reduced expression of ZFP36 members in psoriasis dermal fibroblasts contributes to their inflammatory phenotype.
Assuntos
Fator 1 de Resposta a Butirato/metabolismo , Fibroblastos/metabolismo , Psoríase/imunologia , Fatores de Transcrição/metabolismo , Tristetraprolina/metabolismo , Biópsia , Fator 1 de Resposta a Butirato/genética , Estudos de Casos e Controles , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologia , Técnicas de Silenciamento de Genes , Voluntários Saudáveis , Humanos , Mediadores da Inflamação/metabolismo , Queratinócitos/imunologia , Queratinócitos/metabolismo , Psoríase/patologia , Fatores de Transcrição/genética , Tristetraprolina/genéticaRESUMO
OBJECTIVE: To compare immune cell phenotype and function in psoriatic arthritis (PsA) versus psoriasis in order to better understand the pathogenesis of PsA. METHODS: In-depth immunophenotyping of different T cell and dendritic cell subsets was performed in patients with PsA, psoriasis, or axial spondyloarthritis and healthy controls. Subsequently, we analyzed cells from peripheral blood, synovial fluid (SF), and skin biopsy specimens using flow cytometry, along with high-throughput transcriptome analyses and functional assays on the specific cell populations that appeared to differentiate PsA from psoriasis. RESULTS: Compared to healthy controls, the peripheral blood of patients with PsA was characterized by an increase in regulatory CD4+ T cells and interleukin-17A (IL-17A) and IL-22 coproducing CD8+ T cells. One population specifically differentiated PsA from psoriasis: i.e., CD8+CCR10+ T cells were enriched in PsA. CD8+CCR10+ T cells expressed high levels of DNAX accessory molecule 1 and were effector memory cells that coexpressed skin-homing receptors CCR4 and cutaneous lymphocyte antigen. CD8+CCR10+ T cells were detected under inflammatory and homeostatic conditions in skin, but were not enriched in SF. Gene profiling further revealed that CD8+CCR10+ T cells expressed GATA3, FOXP3, and core transcriptional signature of tissue-resident memory T cells, including CD103. Specific genes, including RORC, IFNAR1, and ERAP1, were up-regulated in PsA compared to psoriasis. CD8+CCR10+ T cells were endowed with a Tc2/22-like cytokine profile, lacked cytotoxic potential, and displayed overall regulatory function. CONCLUSION: Tissue-resident memory CD8+ T cells derived from the skin are enhanced in the circulation of patients with PsA compared to patients with psoriasis alone. This may indicate that aberrances in cutaneous tissue homeostasis contribute to arthritis development.
Assuntos
Artrite Psoriásica/imunologia , Linfócitos T CD8-Positivos/imunologia , Psoríase/imunologia , Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Aminopeptidases/genética , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Artrite Psoriásica/genética , Artrite Psoriásica/patologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Feminino , Fatores de Transcrição Forkhead/genética , Fator de Transcrição GATA3/genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Memória Imunológica/imunologia , Imunofenotipagem , Cadeias alfa de Integrinas/genética , Interleucina-17/imunologia , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Oligossacarídeos/metabolismo , Psoríase/genética , Psoríase/patologia , Receptor de Interferon alfa e beta/genética , Receptores CCR10/metabolismo , Receptores CCR4/metabolismo , Antígeno Sialil Lewis X/análogos & derivados , Antígeno Sialil Lewis X/metabolismo , Pele/patologia , Espondiloartropatias/genética , Espondiloartropatias/imunologia , Espondiloartropatias/patologia , Líquido Sinovial/citologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/metabolismo , Interleucina 22RESUMO
Objectives: Signals at the contact site of antigen-presenting cells (APCs) and T cells help orchestrate the adaptive immune response. CD155 on APCs can interact with the stimulatory receptor DNAM1 or inhibitory receptor TIGIT on T cells. The CD155/DNAM1/TIGIT axis is under extensive investigation as immunotherapy target in inflammatory diseases including cancer, chronic infection and autoimmune diseases. We investigated a possible role for CD155/DNAM1/TIGIT signaling in psoriatic disease. Methods: By flow cytometry, we analyzed peripheral blood mononuclear cells of patients with psoriasis (n = 20) or psoriatic arthritis (n = 21), and healthy individuals (n = 7). We measured CD155, TIGIT, and DNAM1 expression on leukocyte subsets and compared activation-induced cytokine production between CD155-positive and CD155-negative APCs. We assessed the effects of TIGIT and DNAM1 blockade on T cell activation, and related the expression of CD155/DNAM1/TIGIT axis molecules to measures of disease activity. Results: High CD155 expression associates with tumor necrosis factor (TNF) production in myeloid and plasmacytoid dendritic cells (DC). In CD1c+ myeloid DC, activation-induced CD155 expression associates with increased HLA-DR expression. CD8 T cells - but not CD4 T cells - express high levels of TIGIT. DNAM1 blockade decreases T cell pro-inflammatory cytokine production, while TIGIT blockade increased T cell proliferation. Finally, T cell TIGIT expression shows an inverse correlation with inflammation biomarkers in psoriatic disease. Conclusion: CD155 is increased on pro-inflammatory APCs, while the receptors DNAM1 and TIGIT expressed on T cells balance the inflammatory response by T cells. In psoriatic disease, low TIGIT expression on T cells is associated with systemic inflammation.
RESUMO
OBJECTIVES: Conventional synthetic DMARDs (csDMARDs) are the first-line treatment for PsA, but there is conflicting data regarding their efficacy and scarce reports describing the duration of use (drug retention) of csDMARD in this population. Their position in treatment recommendations is a matter of growing debate due to the availability of alternative treatment options with higher levels of evidence. We aimed to study drug retention and predictors for drug retention among PsA patients receiving first-line csDMARD monotherapy. METHODS: Retrospective cohort study in DMARD-naïve adult PsA patients in whom a first csDMARD was prescribed as monotherapy primarily to treat PsA-related symptoms. The main outcome was time to failure of the csDMARD (i.e. stopping the csDMARD or adding another DMARD). RESULTS: A total of 187 patients were included, who were mainly prescribed MTX (n = 163) or SSZ (n = 21). The pooled median drug retention time was 31.8 months (interquartile range 9.04-110). Drug retention was significantly higher in MTX (median 34.5 months; interquartile range 9.60-123) as compared with SSZ-treated patients (median 12.0 months; interquartile range 4.80- 55.7) (P =0.016, log-rank test). In multivariable Cox regression, the use of MTX and older age were associated with increased retention. The main reasons for treatment failure were inefficacy (52%) and side effects (28%). Upon failure, MTX treated patients were more commonly, subsequently treated with a biologic DMARD compared with SSZ (P < 0.05). CONCLUSION: MTX outperforms SSZ as a first-line csDMARD in DMARD-naïve PsA patients with respect to monotherapy drug retention in daily clinical practice.
Assuntos
Artrite Psoriásica/tratamento farmacológico , Metotrexato/uso terapêutico , Sulfassalazina/uso terapêutico , Antirreumáticos/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Falha de Tratamento , Resultado do TratamentoRESUMO
OBJECTIVE: To compare the Heel Enthesitis MRI Scoring model (HEMRIS) with clinical and PET/CT outcomes in patients with cutaneous psoriasis (Pso), psoriatic arthritis (PsA) or ankylosing spondylitis (AS). METHODS: This prospective, observational study included 38 patients with Pso, PsA and AS. Patients were included regardless of presence or absence of clinical heel enthesitis. MRI-scans of both ankles and a whole-body 18F-FDG PET/CT were acquired. MRIs were assessed for enthesitis by two independent and blinded observers according to the HEMRIS. A physician, blinded for imaging results, performed clinical evaluations of enthesitis at the Achilles tendon and plantar fascia. RESULTS: In total, 146 entheses were scored according to the HEMRIS and clinically assessed for enthesitis (6 entheses were clinically affected). In Achilles tendons with clinical enthesitis, the HEMRIS structural damage score was significantly higher, compared to Achilles tendons without clinical enthesitis (respective median scores 1.0 and 0.5; p=0.04). In clinically unaffected entheses, HEMRIS abnormalities occurred in 44/70 (63%) of Achilles tendons and in 23/70 (33%) of plantar fascia. At the Achilles tendon, local metabolic activity measured on PET/CT was weakly associated with the structural (rs=0.25, p=0.03) and total HEMRIS (rs=0.26, p=0.03). CONCLUSION: This study revealed a high prevalence of subclinical HEMRIS abnormalities and discrepancy between HEMRIS and clinical and PET/CT findings. This may suggest that the HEMRIS is a sensitive method for detection of inflammatory and structural disease of enthesitis at the Achilles tendon and plantar fascia, although the clinical significance of these MRI findings remains to be determined in longitudinal studies.
Assuntos
Entesopatia , Calcanhar , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adulto , Feminino , Calcanhar/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Non-Hodgkin orbital lymphoma (NHOL) and idiopathic orbital inflammation (IOI) are common orbital conditions with largely unknown pathophysiology that can be difficult to diagnose. In this study we aim to identify serum miRNAs associated with NHOL and IOI. We performed OpenArray® miRNA profiling in 33 patients and controls. Differentially expressed miRNAs were technically validated across technology platforms and replicated in an additional cohort of 32 patients and controls. We identified and independently validated a serum miRNA profile of NHOL that was remarkably similar to IOI and characterized by an increased expression of a cluster of eight miRNAs. Pathway enrichment analysis indicated that the miRNA-cluster is associated with immune-mediated pathways, which we supported by demonstrating the elevated expression of this cluster in serum of patients with other inflammatory conditions. The cluster contained miR-148a, a key driver of B-cell tolerance, and miR-365 that correlated with serum IgG and IgM concentrations. In addition, miR-29a and miR-223 were associated with blood lymphocyte and neutrophil populations, respectively. NHOL and IOI are characterized by an abnormal serum miRNA-cluster associated with immune pathway activation and linked to B cell and neutrophil dysfunction.
Assuntos
Inflamação/imunologia , Linfoma não Hodgkin/imunologia , MicroRNAs/imunologia , Doenças Orbitárias/imunologia , Neoplasias Orbitárias/imunologia , Adulto , Idoso , Feminino , Humanos , Inflamação/genética , Linfoma não Hodgkin/genética , Masculino , Pessoa de Meia-Idade , Doenças Orbitárias/genética , Neoplasias Orbitárias/genéticaRESUMO
Psoriasis is a common immune-mediated inflammatory condition that primarily affects skin and nails. 6-41% of psoriasis patients develop psoriatic arthritis (PsA). The ways in which PsA can manifest itself include peripheral arthritis, axial spondyloarthritis, dactylitis and enthesitis. This heterogeneous clinical picture makes it sometimes difficult to recognise PsA,potentially resulting in permanent joint damage and functional impairments. Some people see psoriasis and PsA as 2 manifestations of a single disease because the multifactorial origins of psoriasis and PsA are largely overlapping. Psoriatic conditions are associated with a high burden of disease, reduced quality of life and comorbidities, including psychiatric and cardiovascular conditions. In recent years, several immunological pathways, immune cells and cytokines have been identified as important factors in pathophysiology and as new therapeutic targets. For many PsA patients treatment with disease modifying anti-rheumatic drugs leads to significant improvement of symptoms and quality of life.
Assuntos
Artrite Psoriásica/fisiopatologia , Artrite Psoriásica/psicologia , Qualidade de Vida , Antirreumáticos/uso terapêutico , Artrite Psoriásica/terapia , Comorbidade , Humanos , Unhas Malformadas/etiologia , Unhas Malformadas/psicologia , Psoríase/fisiopatologia , Psoríase/psicologiaRESUMO
OBJECTIVE: The role of innate lymphoid cells (ILCs) in the pathophysiology of rheumatic diseases is emerging. Evidence from animal studies implicate type I IFN, produced by plasmacytoid dendritic cells, to be involved in regulating the survival of group 2 and group 3 ILCs (ILC2s and ILC3s) via the upregulation of Fas (CD95) expression. For the first time, we explored the frequency and phenotype of circulating ILCs in SLE and primary Sjögren's syndrome (pSS) in relationship to the IFN signature. METHODS: Frequencies and phenotypes of ILC subsets and plasmacytoid dendritic cells were assessed by flow cytometry in peripheral blood of patients with SLE (n = 20), pSS (n = 20) and healthy controls (n = 17). Patients were stratified by the presence or absence of an IFN signature as assessed by RT-qPCR on circulating mononuclear cells. RESULTS: ILC1 frequencies were increased in peripheral blood of patients with SLE as compared with healthy controls and correlate with disease activity in pSS patients. Overall, the frequencies of ILC2s or ILC3s did not differ between patients with SLE, pSS and healthy controls. However, patients with a high type I IFN signature expressed elevated levels of Fas on ILC2s and ILC3s, which coincided with decreased frequencies of these cells in blood. CONCLUSION: The presence of a type I IFN signature is related to Fas expression and frequencies of circulating ILC2s and ILC3s in patients with SLE and pSS, potentially altering the homeostatic balance of ILCs.
Assuntos
Interferons/sangue , Lúpus Eritematoso Sistêmico/sangue , Linfócitos/metabolismo , Síndrome de Sjogren/sangue , Receptor fas/metabolismo , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Citometria de Fluxo , Humanos , Imunidade Inata , Interferons/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Síndrome de Sjogren/imunologiaRESUMO
CXCL4 regulates multiple facets of the immune response and is highly upregulated in various Th17-associated rheumatic diseases. However, whether CXCL4 plays a direct role in the induction of IL-17 production by human CD4+ T cells is currently unclear. Here, we demonstrated that CXCL4 induced human CD4+ T cells to secrete IL-17 that co-expressed IFN-γ and IL-22, and differentiated naïve CD4+ T cells to become Th17-cytokine producing cells. In a co-culture system of human CD4+ T cells with monocytes or myeloid dendritic cells, CXCL4 induced IL-17 production upon triggering by superantigen. Moreover, when monocyte-derived dendritic cells were differentiated in the presence of CXCL4, they orchestrated increased levels of IL-17, IFN-γ, and proliferation by CD4+ T cells. Furthermore, the CXCL4 levels in synovial fluid from psoriatic arthritis patients strongly correlated with IL-17 and IL-22 levels. A similar response to CXCL4 of enhanced IL-17 production by CD4+ T cells was also observed in patients with psoriatic arthritis. Altogether, we demonstrate that CXCL4 boosts pro-inflammatory cytokine production especially IL-17 by human CD4+ T cells, either by acting directly or indirectly via myeloid antigen presenting cells, implicating a role for CXCL4 in PsA pathology.
Assuntos
Artrite Psoriásica/imunologia , Interleucina-17/biossíntese , Interleucinas/metabolismo , Fator Plaquetário 4/imunologia , Células Th17/imunologia , Células Apresentadoras de Antígenos/imunologia , Estudos de Casos e Controles , Diferenciação Celular/imunologia , Técnicas de Cocultura , Células Dendríticas/imunologia , Humanos , Ativação Linfocitária , Monócitos/imunologia , Interleucina 22RESUMO
OBJECTIVE: Innate lymphoid cells (ILCs) are a recently discovered group of cells that are essential to epithelial homeostasis and are implicated in psoriasis pathogenesis, yet they have never been reported in psoriatic arthritis (PsA). METHODS: ILC classes and subsets were characterized in the peripheral blood (PB) of healthy controls, patients with psoriasis, and patients with PsA and in the synovial fluid (SF) of patients with PsA and patients with rheumatoid arthritis (RA). Cell surface marker expression and intracellular cytokine production following stimulation were analyzed using flow cytometry. RESULTS: ILCs were identified in the SF and were 4-fold more abundant in PsA SF than in PsA PB. Fewer CCR6+ ILCs were found in PsA PB than in healthy control PB, while PsA SF was enriched for CCR6+ ILCs compared to PsA PB and RA SF. Natural cytotoxicity receptor NKp44+ group 3 ILCs were rare in PB and RA SF, but abundant in PsA SF. Increased numbers of interleukin-17A (IL-17A)-producing ILCs were present in PsA SF compared to RA SF. CCR6, NKp44, and melanoma cell adhesion molecule (MCAM) were expressed on the cell surface of SF ILCs that produced IL-17A. The number of circulating NKp44+, CCR6+, and MCAM+ ILCs in blood was inversely correlated with PsA disease activity. CONCLUSION: Our findings indicate that PsA SF is enriched for group 3 ILCs that express CCR6 and NKp44, which distinguishes the synovial compartment from RA. The increased IL-17A production by SF ILCs indicates a novel role for ILCs in PsA.
Assuntos
Artrite Psoriásica/patologia , Imunidade Inata/fisiologia , Linfócitos/patologia , Líquido Sinovial/citologia , Adulto , Artrite Psoriásica/metabolismo , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Antígeno CD146/metabolismo , Estudos de Casos e Controles , Humanos , Interleucina-17/metabolismo , Linfócitos/metabolismo , Pessoa de Meia-Idade , Receptor 2 Desencadeador da Citotoxicidade Natural/metabolismo , Receptores CCR6/metabolismo , Líquido Sinovial/metabolismoRESUMO
Rheumatic diseases can be divided in two groups, autoinflammatory and autoimmune disorders. The clinical presentation of both types of diseases overlap, but the pathological pathways underlying rheumatic autoinflammation and autoimmunity are distinct and are the subject of ongoing research. There are a number of ways in which these groups of diseases differ in terms of disease mechanisms and therapeutic responses. First, autoinflammatory diseases are driven by endogenous danger signals, metabolic mediators and cytokines, whereas autoimmunity involves the activation of T and B cells, the latter requiring V-(D)-J recombination of receptor-chain gene segments for maturation. Second, the efficacy of biologic agents directed against proinflammatory cytokines (for example IL-1ß and TNF) also highlights differences between autoinflammatory and autoimmune processes. Finally, whereas autoinflammatory diseases are mostly driven by inflammasome-induced IL-1ß and IL-18 production, autoimmune diseases are associated with type I interferon (IFN) signatures in blood. In this Review, we provide an overview of the monocyte intracellular pathways that drive autoinflammation and autoimmunity. We convey recent findings on how the type I IFN pathway can modulate IL-1ß signalling (and vice versa), and discuss why IL-1ß-mediated autoinflammatory diseases do not perpetuate into autoimmunity. The origins of intracellular autoantigens in autoimmune disorders are also discussed. Finally, we suggest how new mechanistic knowledge of autoinflammatory and autoimmune diseases might help improve treatment strategies to benefit patient care.