RESUMO
Rheumatic musculoskeletal diseases or RMD [rheumatoid arthritis (RA) and spondyloarthritis (SpA)] are systemic inflammatory diseases for which there are no biomarkers capable of predicting treatments with a higher likelihood of response in naive patients. In addition, the expiration of the anti-TNF blocking drugs' patents has resulted in the availability of anti-TNF biosimilar drugs with the same efficacy and safety than originators but at significantly reduced prices. To guarantee a personalized therapeutic approach to RMD treatment, a board of rheumatologists and stakeholders from the Campania region, Italy, developed a clinically applicable arthritis therapeutic algorithm to guide rheumatologists (DATA project). The general methodology relied on a Delphi technique forecast to produce a set of statements that summarized the experts' consensus. Selected clinical scenarios were discussed in light of the available evidence, and there were two rounds of voting on the therapeutic approaches. Separate discussions were held regarding rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The decision-making factors for each disease were clinical presentation, demographics, and comorbidities. In this paper, we describe a virtuous process between rheumatologists and healthcare system stakeholders that resulted in the development of a shared therapeutic algorithm for RMD patients naive to bDMARDs.
Assuntos
Antirreumáticos , Artrite Psoriásica , Artrite Reumatoide , Espondilartrite , Espondilite Anquilosante , Humanos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/tratamento farmacológico , Atenção à Saúde , Algoritmos , Antirreumáticos/uso terapêuticoRESUMO
BACKGROUND: Multiple studies have confirmed dysbiosis in ankylosing spondylitis (AS) and inflammatory bowel disease (IBD); however, due to methodological differences across studies, it has not been possible to determine if these diseases have similar or different gut microbiomes. RESULTS: In this study, faecal and intestinal biopsies were obtained from 33 Australian AS patients (including 5 with concomitant IBD, 'AS-IBD'), 59 IBD patients and 105 healthy controls. Stool samples were also obtained from 16 Italian AS patients and 136 Swedish AS patients. Focusing on the Australian cohort, AS, AS-IBD and IBD patients differed from one another and from healthy controls in both alpha and beta diversity. AS patients with and without clinical IBD could be distinguished from one another with moderate accuracy using stool microbiome (AUC=0.754). Stool microbiome also accurately distinguished IBD patients from healthy controls (AUC=0.757). Microbiome composition was correlated with disease activity measured by BASDAI and faecal calprotectin (FCP) levels. Enrichment of potentially pathogenic Streptococcus was noted in AS, AS-IBD and IBD patients. Furthermore, enrichment of another potentially pathogenic genus, Haemophilus, was observed in AS, AS-IBD, IBD, AS patients with increased BASDAI, and IBD patients with faecal calprotectin >100 µg/mg. Apart from these genera, no other taxa were shared between AS and IBD patients. CONCLUSIONS: In conclusion, the distinct gut microbiome of AS and AS-IBD patients compared to IBD patients and healthy controls is consistent with immunological and genetic evidence suggesting that the gut plays a different role in driving AS compared with IBD. However, enrichment of two potentially pathogenic genera in both diseases suggests that the presence of a shared/common microbial trigger of disease cannot be discounted.
Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Espondilite Anquilosante , Austrália , Doença Crônica , Microbioma Gastrointestinal/genética , Humanos , Complexo Antígeno L1 LeucocitárioRESUMO
The gastrointestinal tract regulates the trafficking of macromolecules between the environment and the host through an epithelial barrier mechanism and is an important part of the immune system controlling the equilibrium between tolerance and immunity to non-self-antigens. Various evidence indicates that intestinal inflammation occurs in patients with rheumatic diseases. In many rheumatic diseases intestinal inflammation appears to be linked to dysbiosis and possibly represents the common denominator in the pathogenesis of different rheumatic diseases. The continuative interaction between dysbiosis and the intestinal immune system may lead to the aberrant activation of immune cells that can re-circulate from the gut to the sites of extraintestinal inflammation as observed in patients with ankylosing spondylitis. The exact contribution of genetic factors in the development of intestinal inflammation in rheumatic diseases needs to be clarified.
Assuntos
Doenças do Tecido Conjuntivo/patologia , Intestinos/patologia , Artrite Psoriásica/complicações , Artrite Psoriásica/patologia , Síndrome de Behçet/complicações , Síndrome de Behçet/patologia , Doenças do Tecido Conjuntivo/complicações , Disbiose/etiologia , Humanos , Inflamação , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Intestinos/imunologia , Intestinos/microbiologia , Músculo Liso/patologia , Doenças Reumáticas/complicações , Doenças Reumáticas/patologia , Espondilartrite/complicações , Espondilartrite/patologia , Espondilite Anquilosante/complicações , Espondilite Anquilosante/patologiaRESUMO
Polymyalgia rheumatica (PMR) is a chronic, inflammatory disorder of unknown cause, almost exclusively occurring in people aged over 50 and often associated with giant cell arteritis. The evidence that PMR occurs almost exclusively in individuals aged over 50 may indicate that age-related immune alterations in genetically predisposed subjects contribute to development of the disease. Several infectious agents have been investigated as possible triggers of PMR even though the results are inconclusive. Activation of the innate and adaptive immune systems has been proved in PMR patients as demonstrated by the activation of dendritic cells and monocytes/macrophages and the altered balance between Th17 and Treg cells. Disturbed B cell distribution and function have been also demonstrated in PMR patients suggesting a pathogenesis more complex than previously imagined. In this review we will discuss the recent findings regarding the pathogenesis of PMR.
Assuntos
Polimialgia Reumática/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Imunidade Adaptativa/imunologia , Idoso , Linfócitos B/imunologia , Biomarcadores/sangue , Diferenciação Celular/imunologia , Medicina Baseada em Evidências , Arterite de Células Gigantes/imunologia , Humanos , Imunidade Inata/imunologia , Polimialgia Reumática/complicaçõesRESUMO
Macrophage activation syndrome (MAS) is hyperinflammatory life-threatening syndrome, associated typically with high levels of serum ferritin. This is an iron storage protein including heavy (H) and light (L) subunits, categorized on their molecular weight. The H-/L subunits ratio may be different in tissues, depending on the specific tissue and pathophysiological status. In this study, we analysed the bone marrow (BM) biopsies of adult MAS patients to assess the presence of: (i) H-ferritin and L-ferritin; (ii) CD68+ /H-ferritin+ and CD68+ /L-ferritin+ ; and (iii) interleukin (IL)-1ß, tumour necrosis factor (TNF) and interferon (IFN)-γ. We also explored possible correlations of these results with clinical data. H-ferritin, IL-1ß, TNF and IFN-γ were increased significantly in MAS. Furthermore, an increased number of CD68+ /H-ferritin+ cells and an infiltrate of cells co-expressing H-ferritin and IL-12, suggesting an infiltrate of M1 macrophages, were observed. H-ferritin levels and CD68+ /H-ferritin+ cells were correlated with haematological involvement of the disease, serum ferritin and C-reactive protein. L-ferritin and CD68+ /L-ferritin+ cells did not correlate with these parameters. In conclusion, during MAS, H-ferritin, CD68+ /H-ferritin+ cells and proinflammatory cytokines were increased significantly in the BM inflammatory infiltrate, pointing out a possible vicious pathogenic loop. To date, H-ferritin and CD68+ /H-ferritin+ were associated significantly with haematological involvement of the disease, suggesting biomarkers assessing severity of clinical picture.
Assuntos
Apoferritinas/metabolismo , Proteínas Sanguíneas/metabolismo , Medula Óssea/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Adulto , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biópsia , Proteína C-Reativa/metabolismo , Humanos , Inflamação , Pessoa de Meia-Idade , Estudos Retrospectivos , SíndromeRESUMO
T helper 9 (Th9) cells and interleukin (IL)-9 are involved in the pathogenesis of several autoimmune diseases. The exact role of IL-9 and Th9 cells in patients with systemic sclerosis (SSc) have not yet been studied adequately. IL-9, IL-9R, transcription factor PU.1 (PU.1), IL-4, thymic stromal lymphopoietin (TSLP) and transforming growth factor (TGF)-ß expression were assessed in skin and kidney biopsies of SSc patients and healthy controls (HC) by immunohistochemistry (IHC). The cellular source of IL-9 was also analysed by confocal microscopy analysis. Peripheral IL-9-producing cells were also studied by flow cytometry. The functional relevance of IL-9 increased expression in SSc was also investigated. Our results demonstrated a strong expression of IL-9, IL-9R, IL-4, TSLP and TGF-ß in skin tissues of patients with both limited and diffuse SSc. IL-9 expression was observed mainly in the context of skin infiltrating mononuclear cells and keratinizing squamous epithelium. IL-9 over-expression was also observed in renal biopsies of patients with SSc. IL-9 producing cells in the skin were identified as Th9 cells. Similarly, Th9 cells were expanded and were the major source of IL-9 among SSc peripheral blood mononuclear cells (PBMC), their percentage being correlated directly with the modified Rodnan skin score. Infiltrating mononuclear cells, mast cells and neutrophils expressed IL-9R. In in-vitro studies stimulation with rIL-9 significantly induced NET (neutrophil extracellular traps) release by dying cells (NETosis) in neutrophils, expansion of mast cells and increase of anti-systemic scleroderma 70 (Scl70) production by B cells. Our findings suggest that Th9 cells and IL-9 could be implicated in the pathogenesis of SSc.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-9/metabolismo , Escleroderma Sistêmico/imunologia , Adulto , Autoanticorpos/sangue , Linfócitos B/efeitos dos fármacos , Linfócitos T CD4-Positivos/classificação , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Citocinas/genética , Citocinas/metabolismo , Armadilhas Extracelulares/metabolismo , Feminino , Humanos , Interleucina-4/genética , Interleucina-4/metabolismo , Interleucina-9/sangue , Interleucina-9/genética , Interleucina-9/imunologia , Masculino , Mastócitos/imunologia , Mastócitos/metabolismo , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores de Interleucina-9/genética , Receptores de Interleucina-9/metabolismo , Escleroderma Sistêmico/fisiopatologia , Pele/imunologia , Pele/metabolismo , Pele/patologia , Transativadores/genética , Transativadores/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Linfopoietina do Estroma do TimoRESUMO
Cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-12, interferon (IFN)-γ, IL-23 and, more recently, IL-9, have been implicated in the initiation/maintenance of inflammation in psoriasis and psoriatic arthritis (PsA). In the present study we aimed to characterize the role of γδ T cells in peripheral blood and synovial fluid of PsA patients and to investigate their response to in-vitro stimulation with antigen or cytokines (IL-9 and IL-23). γδ T cells isolated from peripheral blood mononuclear cells and synovial fluid were analysed by flow cytometry to evaluate the phenotype and cytokine production. IL-23R and IL-9R gene expression were also evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Peripheral blood mononuclear cells (PBMC), sorted γδ T cells and γδ cell lines were also stimulated in vitro with isopentenyl pyrophosphate (IPP), recombinant IL-9 or recombinant IL-23. Our results show an expansion of γδ T cells with a predominant effector memory phenotype in peripheral blood and synovium of untreated PsA patients, which reverses significantly after treatment with anti-TNF-α or anti-IL-12/IL-23R monoclonal antibodies (mAbs). Moreover, in PsA patients γδ T cells activation is driven prevalently by IL-9/IL-9R interaction, and not only by IL-23/IL-23R. Together these findings indicate γδ T cells and IL-9 as new players in the pathogenesis of PsA.
Assuntos
Artrite Psoriásica/imunologia , Artrite Psoriásica/metabolismo , Interleucina-9/metabolismo , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Interleucina-9/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto , Idoso , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/tratamento farmacológico , Biomarcadores , Feminino , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Índice de Gravidade de Doença , Líquido Sinovial/imunologia , Adulto JovemRESUMO
Adult-onset Still's disease (AOSD) patients may show an evanescent salmon-pink erythema appearing during febrile attacks and reducing without fever. Some patients may experience this eruption for many weeks. During AOSD, exceptionally high serum levels of ferritin may be observed; it is an iron storage protein composed of 24 subunits, heavy (H) subunits and light (L) subunits. The ferritin enriched in L subunits (L-ferritin) and the ferritin enriched in H subunits (H-ferritin) may be observed in different tissues. In this work, we aimed to investigate the skin expression of both H-and L-ferritin and the number of macrophages expressing these molecules from AOSD patients with persistent cutaneous lesions. We observed an increased expression of H-ferritin in the skin, associated with an infiltrate in the biopsies obtained from persistent cutaneous lesions of AOSD patients. Furthermore, a positive correlation between H-ferritin skin levels as well as the number of CD68(+) /H-ferritin(+) cells and the multi-visceral involvement of the disease was observed. Our data showed an increased expression of H-ferritin in the skin of AOSD patients, associated with a strong infiltrate of CD68(+) /H-ferritin(+) cells. Furthermore, a correlation between the levels of H-ferritin as well as of the number of CD68(+) /H-ferritin(+) cells and the multi-visceral involvement of the disease was observed.
Assuntos
Apoferritinas/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Pele/imunologia , Pele/metabolismo , Doença de Still de Início Tardio/imunologia , Doença de Still de Início Tardio/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Apoferritinas/genética , Biomarcadores , Biópsia , Citocinas/metabolismo , Feminino , Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Macrófagos/imunologia , Masculino , Monócitos/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pele/patologia , Doença de Still de Início Tardio/diagnósticoRESUMO
Interleukin (IL)-9 is a 28-30 kDa monomeric glycosylated polypeptide belonging to the IL-7/IL-9 family of proteins that bind to a composite receptor consisting of the private receptor IL-9R and the IL-2 receptor, gamma (IL-2RG), a common gamma subunit shared by the receptors of many different cytokines. The IL-9R is expressed widely and IL-9 impacts a number of effector cells, such as effector T cells, B cells, innate lymphoid cells, mast cells, polymorphonuclear cells, epithelial cells and smooth muscle cells, playing an important role in regulating inflammatory immunity. The critical role of IL-9 in promoting cellular and humoral immune responses makes it an important focus of potential therapeutic interventions. Recently, a defined subset of T helper type cells, Th9 cells, has been identified by the potent production of IL-9. The involvement of the Th9 cell subset has been described in many types of inflammatory diseases, namely atopic diseases, helminth infections, experimental autoimmune encephalomyelitis and ulcerative colitis. In this review, we summarize the IL-9 biological activities, highlighting roles for IL-9 and Th9 cells in rheumatoid and psoriatic arthritis, systemic vasculitis, systemic lupus erythematosus and systemic sclerosis.
Assuntos
Interleucina-9/imunologia , Doenças Reumáticas/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Artrite Psoriásica/imunologia , Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Linfócitos B , Humanos , Imunidade Humoral , Interleucina-17/imunologia , Interleucina-9/biossíntese , Lúpus Eritematoso Sistêmico/imunologia , Escleroderma Sistêmico/imunologia , Transdução de Sinais , Subpopulações de Linfócitos T/classificaçãoRESUMO
In this work, we aimed to evaluate the levels of ferritin enriched in H subunits (H-ferritin) and ferritin enriched in L subunits (L-ferritin) and the cells expressing these two molecules in the lymph node (LN) biopsies obtained from adult-onset Still's disease (AOSD) patients, and the possible correlation among these data and the severity of the disease. Ten patients with AOSD underwent LN biopsy. All the samples were stained by immunofluorescence. A statistical analysis was performed to estimate the possible correlation among both H-ferritin and L-ferritin tissue expression and the clinical picture of the disease. Furthermore, the same analysis was performed to evaluate the possible correlation among the number of CD68(+)/H-ferritin(+) or CD68(+)/L-ferritin(+) cells and the clinical picture. Immunofluorescence analysis demonstrated an increased tissue H-ferritin expression in the LNs of AOSD patients. This increased expression correlated with the severity of the disease. An increased number of CD68 macrophages expressing H-ferritin was observed in the LN samples of our patients. Furthermore, we observed that the number of CD68(+)/H-ferritin(+) cells correlated significantly with the severity of the clinical picture. Our data showed an imbalance between the levels of H- and L-ferritin in LNs of AOSD patients and the evidence of an increased number of CD68(+)/H-ferritin(+) cells in the same organs. Furthermore, a correlation among both the tissue H-ferritin levels and the CD68(+)/H-ferritin(+) cells and the clinical picture was observed.
Assuntos
Linfonodos/citologia , Doença de Still de Início Tardio/imunologia , Doença de Still de Início Tardio/fisiopatologia , Adulto , Idoso , Antígenos CD/análise , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/análise , Antígenos de Diferenciação Mielomonocítica/imunologia , Apoferritinas/genética , Apoferritinas/imunologia , Biópsia , Feminino , Ferritinas/sangue , Imunofluorescência , Humanos , Linfonodos/química , Linfonodos/imunologia , Linfonodos/ultraestrutura , Macrófagos/química , Macrófagos/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The aim of this study was to investigate the relationship between immunoinflammatory markers and indexes of arterial stiffness in patients with seronegative spondyloarthritis (SpA). METHOD: We enrolled consecutive patients with inflammatory seronegative SpA referred to a rheumatology outpatient clinic. Control subjects were patients admitted in the same period for any cause other than chronic inflammatory disease or acute cardiovascular and cerebrovascular events. Carotid-femoral pulse wave velocity (PWV) was measured and the aortic pressure waveform was used to calculate the augmentation index (Aix). We also evaluated plasma levels of C-reactive protein (CRP), interleukin (IL)-1ß, tumour necrosis factor (TNF)-α, and interleukin (IL)-6 as markers of immunoinflammatory activation. RESULTS: This study enrolled 53 patients with SpA and 55 control subjects. After adjustment for blood glucose, cholesterol, and triglyceride levels, and systolic (SBP) and diastolic blood pressure (DBP), patients with seronegative SpA showed higher mean PWV and Aix compared to controls. Moreover, in patients with seronegative SpA, we observed higher mean plasma levels of IL-6, IL-1ß, and TNF-α in subjects with mean PWV > 8 m/s in comparison with those with PWV < 8 m/s. Multivariate analysis revealed a significant association between PWV > 8 m/s and male gender, age, diabetes, hypertension, low density lipoprotein cholesterol (LDL-C) > 120 mg/dL, total cholesterol (TC) > 200 mg/dL, coronary artery disease (CAD), microalbuminuria, carotid plaque, and plasma levels of IL-6, IL-1ß, and TNF-α. CONCLUSIONS: These findings emphasize the role of inflammatory variables and metabolic factors in indexes of high arterial stiffness. Thus, an inflammatory-metabolic background may influence the pathogenesis of increased arterial stiffness in seronegative inflammatory arthritis.
Assuntos
Citocinas/sangue , Índice de Gravidade de Doença , Espondilartrite/sangue , Espondilartrite/fisiopatologia , Rigidez Vascular/fisiologia , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Onda de Pulso , Fator de Necrose Tumoral alfa/sangueRESUMO
A better understanding about the mechanisms involved in the pathogenesis of type 2 diabetes mellitus (T2D) showed that inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin (IL)-1ß play a pivotal role, mirroring data largely reported in rheumatoid arthritis (RA). IL-1ß is produced mainly by monocytes (MO), and hyperglycaemia may be able to modulate, in the cytoplasm of these cells, the assembly of a nucleotide-binding domain and leucine-rich repeat containing family pyrin (NLRP3)-inflammosome, a cytosolic multi-protein platform where the inactive pro-IL-1ß is cleaved into active form, via caspase-1 activity. In this paper, we evaluated the production of IL-1 ß and TNF, in peripheral blood MO of patients affected by RA or T2D or both diseases, in order to understand if an alteration of the glucose metabolism may influence their proinflammatory status. Our data showed, after 24 h of incubation with different glucose concentrations, a significantly increased production of IL-1ß and TNF in all evaluated groups when compared with healthy controls. However, a significant increase of IL-1ß secretion by T2D/RA was observed when compared with other groups. The analysis of relative mRNA expression confirmed these data. After 24 h of incubation with different concentrations of glucose, our results showed a significant increase in NLRP3 expression. In this work, an increased production of IL-1ß by MO obtained from patients affected by both RA and T2D via NLRP3-inflammasome activation may suggest a potential IL-1ß targeted therapy in these patients.
Assuntos
Artrite Reumatoide/imunologia , Proteínas de Transporte/imunologia , Diabetes Mellitus Tipo 2/imunologia , Interleucina-1beta/biossíntese , Leucócitos Mononucleares/metabolismo , Adulto , Artrite Reumatoide/patologia , Caspase 1/imunologia , Células Cultivadas , Diabetes Mellitus Tipo 2/patologia , Ativação Enzimática/imunologia , Feminino , Glucose/metabolismo , Humanos , Hiperglicemia/metabolismo , Inflamassomos/imunologia , Inflamação/imunologia , Interleucina-1beta/genética , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR , RNA Mensageiro/biossíntese , Fator de Necrose Tumoral alfa/biossínteseRESUMO
The aim of this study was to investigate the expression of the interleukin (IL)-36 axis in patients with primary Sjögren's syndrome (pSS). Blood and minor labial salivary glands (MSG) biopsies were obtained from 35 pSS and 20 non-Sjögren's syndrome patients (nSS) patients. Serum IL-36α was assayed by enzyme-linked immunosorbent assay (ELISA). IL-36α, IL-36R, IL-36RA, IL-38, IL-22, IL-17, IL-23p19 and expression in MSGs was assessed by reverse transcription-polymerase chain reaction (RT-PCR), and tissue IL-36α and IL-38 expression was also investigated by immunohistochemistry (IHC). αß and γδ T cells and CD68(+) cells isolated from MSGs were also studied by flow cytometry and confocal microscopy analysis. IL-36α was over-expressed significantly in the serum and in the salivary glands of pSS. Salivary gland IL-36α expression was correlated with the expression levels of IL-17, IL-22 and IL-23p19. IL-38, that acts as inhibitor of IL-36α, was also up-regulated in pSS. αß(+) CD3(+) T cells and CD68(+) cells were the major source of IL-36α in minor salivary glands of pSS. γδ T cells were not significantly expanded in the salivary glands of pSS but produced more IL-17, as their percentage correlated with the focus score. Higher expression of IL-36α and IL-36R was also demonstrated in γδ T cells isolated from pSS compared to controls. In this study we demonstrate that a significant increase in circulating and tissue levels of IL-36α occurs in pSS patients.
Assuntos
Interleucina-1/imunologia , Receptores de Interleucina/imunologia , Glândulas Salivares/imunologia , Síndrome de Sjogren/imunologia , Linfócitos T/imunologia , Adulto , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-1/genética , Interleucina-17/genética , Interleucina-17/imunologia , Subunidade p19 da Interleucina-23/genética , Subunidade p19 da Interleucina-23/imunologia , Interleucinas/genética , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Interleucina/genética , Glândulas Salivares/patologia , Transdução de Sinais , Síndrome de Sjogren/genética , Síndrome de Sjogren/patologia , Linfócitos T/patologia , Interleucina 22RESUMO
The aim of this study was to elucidate more clearly the role of interleukin (IL)-18 in modulating the IL-22 pathway in primary Sjögren's syndrome (pSS) patients and in pSS-associated lymphomas. Minor salivary glands (MSGs) from patients with pSS and non-specific chronic sialoadenitis (nSCS), parotid glands biopsies from non-Hodgkin lymphomas (NHL) developed in pSS patients, were evaluated for IL-18, IL-22, IL-22 receptor 1 (IL-22R1), IL-22 binding protein (IL-22BP) and signal transducer and activator of transcription-3 (STAT-3) expression. MSGs IL-22R1-expressing cells were characterized by confocal microscopy and flow cytometry in pSS, nSCS and healthy controls . The effect of recombinant IL-18 and IL-22 on peripheral blood mononuclear cells (PBMCs) from pSS and nSCS was studied by flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR). MSGs of pSS and NHL were characterized by an imbalance between IL-22 and IL-22BP protein expression, with IL-18 and IL-22BP being expressed in a mutually exclusive manner and IL-18 and IL-22R1 being correlated directly. Aberrant expression of IL-22R1, induced by IL-18, was observed only among tissue and circulating myeloid cells of pSS patients and macrophages of NHL tissues of pSS patients, but not nSCS. IL-22R1 expression on PBMC of pSS was functional, as its stimulation with recombinant IL-22 significantly up-regulated the expression of STAT-3, IL-17 and IL-22. An IL-18-dependent aberrant expression of IL-22R1 on cells of haematopoietic origin seems to be a specific immunological signature of patients with pSS and pSS-associated lymphomas.
Assuntos
Interleucina-18/imunologia , Linfoma não Hodgkin/imunologia , Receptores de Interleucina/imunologia , Sialadenite/imunologia , Síndrome de Sjogren/imunologia , Adulto , Idoso , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-18/farmacologia , Interleucinas/imunologia , Interleucinas/farmacologia , Aparelho Lacrimal/imunologia , Aparelho Lacrimal/patologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Células Mieloides/imunologia , Células Mieloides/patologia , Cultura Primária de Células , Receptores de Interleucina/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Glândulas Salivares/imunologia , Glândulas Salivares/patologia , Sialadenite/genética , Sialadenite/patologia , Transdução de Sinais , Síndrome de Sjogren/genética , Síndrome de Sjogren/patologia , Interleucina 22RESUMO
The aim of our study was to evaluate methotrexate (MTX) and methylprednisolone (MP) effect on peripheral Th17 and Treg subsets in patients with rheumatoid arthritis (RA). We enrolled 15 patients (10 early RA and 5 long-standing disease) with active RA and 10 age-matched healthy donors as controls. Frequencies of Th17 and Treg were quantified using flow cytometry before and after in vitro addition of MTX, MP or both drugs. Our results showed a reduction in the overall Th17 population followed by an increase in Th17 IL-10(+) and Treg, after in vitro treatment of PBMCs with the drugs in patients with early RA. Long-standing disease patients showed a less evident increase in Treg cells and less enhancement of IL-10 Th17 cells. We suggest that the treatment with MTX and MP could ameliorate RA disease activity by normalizing the distribution/imbalance of Th17/Treg and indicate a new regulatory role of IL-17(+) cells in RA patients.
Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide/imunologia , Interleucina-10/metabolismo , Metotrexato/farmacologia , Metilprednisolona/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Adulto , Antirreumáticos/uso terapêutico , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismoRESUMO
The mechanism by which human leukocyte antigen B27 (HLA-B27) contributes to ankylosing spondylitis (AS) remains unclear. Genetic studies demonstrate that association with and interaction between polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 influence the risk of AS. It has been hypothesised that ERAP1-mediated HLA-B27 misfolding increases endoplasmic reticulum (ER) stress, driving an interleukin (IL) 23-dependent, pro-inflammatory immune response. We tested the hypothesis that AS-risk ERAP1 variants increase ER-stress and concomitant pro-inflammatory cytokine production in HLA-B27(+) but not HLA-B27(-) AS patients or controls. Forty-nine AS cases and 22 healthy controls were grouped according to HLA-B27 status and AS-associated ERAP1 rs30187 genotypes: HLA-B27(+)ERAP1(risk), HLA-B27(+)ERAP1(protective), HLA-B27(-)ERAP1(risk) and HLA-B27(-)ERAP1(protective). Expression levels of ER-stress markers GRP78 (8 kDa glucose-regulated protein), CHOP (C/EBP-homologous protein) and inflammatory cytokines were determined in peripheral blood mononuclear cell and ileal biopsies. We found no differences in ER-stress gene expression between HLA-B27(+) and HLA-B27(-) cases or healthy controls, or between cases or controls stratified by carriage of ERAP1 risk or protective alleles in the presence or absence of HLA-B27. No differences were observed between expression of IL17A or TNF (tumour necrosis factor) in HLA-B27(+)ERAP1(risk), HLA-B27(+)ERAP1(protective) and HLA-B27(-)ERAP1(protective) cases. These data demonstrate that aberrant ERAP1 activity and HLA-B27 carriage does not alter ER-stress levels in AS, suggesting that ERAP1 and HLA-B27 may influence disease susceptibility through other mechanisms.
Assuntos
Aminopeptidases/genética , Estresse do Retículo Endoplasmático , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/genética , Espondilite Anquilosante/patologia , Adulto , Chaperona BiP do Retículo Endoplasmático , Feminino , Antígeno HLA-B27/genética , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor , Espondilite Anquilosante/metabolismo , Adulto JovemRESUMO
Primary Sjögren's syndrome (pSS) is an autoimmune disorder affecting exocrine glands and characterized in most cases by a rather mild clinical picture. However, a subgroup of pSS patients experience systemic extraglandular involvement leading to a worsening of disease prognosis. Current therapeutic options for the treatment of pSS are mainly empirical, often translated by other autoimmune diseases, and recent systematic reviews have highlighted the lack of evidence-based recommendations for most of the drugs commonly employed in the spectrum of extraglandular involvement. Because of the well-established role of B-lymphocytes in the pathogenesis of pSS, a B-cell targeting therapy may represent a new and intriguing therapeutic approach; in this context, growing evidence suggests that B-cell depletion by rituximab (RTX) is also effective in pSS. Of interest, besides clinical efficacy, RTX also showed biologic effects, consistently affecting the inflammation and the lymphoid organization that occur in target tissue. Moreover, the good results observed in the published trials after RTX treatment in pSS should represent the starting point to develop evidence-based guidelines for the use of biologic therapy in this disease.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Síndrome de Sjogren/tratamento farmacológico , Humanos , Contagem de Linfócitos , RituximabRESUMO
Giant cell arteritis is an inflammatory vasculopathy that preferentially affects medium-sized and large arteries. A viral cause has been suspected but not confirmed in polymyalgia rheumatica and giant-cell arteritis. We report the case of a 81-year-old female who suffered from chronic active Epstein-Barr virus infection and developed giant cell temporal arteritis.