RESUMO
OBJECTIVE: Autoantibodies (AutoAbs) have been observed in osteoarthritis (OA) with broad antigenicity, although their prevalence and role remain unclear. Post-translational modification (PTMs) of proteins (oxidation, carbamylation, citrullination) is associated with synovitis and can lead to AutoAb development. Given the prevalence of synovitis, we explored whether AutoAbs to PTM-antigens are common in OA compared with rheumatoid arthritis (RA). METHODS: Serum (n = 895) was obtained from healthy controls, OA and RA patients; and arthritic synovial fluid (SF, n = 290). ELISAs were used to quantify anti-citrullinated peptide (ACPA), anti-carbamylated protein (anti-CarP), anti-oxidized collagen (anti-ROS-CI/CII) antibodies. RESULTS: In sera, positivity for PTM-antigens AutoAbs was observed at a lower frequency in OA with 64.1% (95%CI: 57.2-70.1%) more ACPA+ and 29.8% (21.0-37.3%) more anti-CarP + patients in RA (both P < 0.0001). Levels of ACPA, anti-CarP were also lower in OA (P < 0.0001). Anti-ROS-CII positivity was lower in OA compared to RA (16.6%, 4.8-28.6%) less frequent, P = 0.033) but not anti-native-CII. There was no impact of age/gender on AutoAbs associations with diseases either looking at positivity or levels. In SF, OA patients were often ACPA+ (45.9%) although less frequently than in RA (P = 0.004). Anti-CarP were rarely observed (<5% all samples). All collagen AutoAbs were more frequent in RA compared to OA (all P < 0.010) but only levels of anti-CII and anti-ROS-CII were significantly higher in they RA (P < 0.050). CONCLUSION: Although the frequency of AutoAbs for PTM proteins were lower in OA sera compared to RA, a higher proportion of OA SF were positive. The relative retention of AutoAbs in the OA joint requires further investigation.
Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Osteoartrite/sangue , Osteoartrite/imunologia , Processamento de Proteína Pós-Traducional , Sinovite/sangue , Sinovite/imunologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Objectives: Predictors of arthritis development are highly warranted among patients with anti-citrullinated protein antibodies (ACPAs) and musculoskeletal symptoms to optimize clinical management. We aimed to identify clinical and laboratory predictors of arthritis development, including biochemically assessed alcohol consumption, among ACPA-positive patients with musculoskeletal pain.Method: 82 ACPA-positive individuals with musculoskeletal pain but no clinical arthritis were followed for a median of 72 months (interquartile range 57-81 months). We evaluated the prognostic value of baseline clinical and laboratory factors including smoking, symptom duration, age, gender, shared epitope, rheumatoid factor (RF), anti-carbamylated protein antibodies, ACPA levels, erythrocyte sedimentation rate, C-reactive protein levels, tender joint count, patient-reported general well-being, 28-joint Disease Activity Score, and alcohol consumption as measured by phosphatidyl ethanol (PEth) levels in whole blood.Results: During follow-up, 48% developed at least one arthritis. Multivariable analysis revealed an increased risk of arthritis development with RF positivity [hazard ratio (HR) = 2.3, 95% confidence interval (CI) 1.1-4.8, p = 0.028] and higher ACPA levels (HR = 1.0, 95% CI 1.000-1.001, p = 0.002). High levels of RF (HR = 4.4, 95% CI 1.7-11) entailed the highest HR in this ACPA-positive population. Neither clinical characteristics nor alcohol consumption measured by PEth conferred significant prognostic value.Conclusions: ACPA levels and concurrent presence of RF are independent predictors of arthritis development among ACPA-positive patients with musculoskeletal pain. The results are compatible with a dose-response relationship between RA-related autoantibodies and risk of arthritis development.
Assuntos
Anticorpos Antiproteína Citrulinada/sangue , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Dor Musculoesquelética/imunologia , Adulto , Idoso , Artrite Reumatoide/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor Musculoesquelética/sangue , Fator Reumatoide/sangueRESUMO
Carbamylation is a post-translational modification that can be detected on a range of proteins, including immunoglobulin (Ig)G, in several clinical conditions. Carbamylated IgG (ca-IgG) was reported to lose its capacity to trigger complement activation, but the mechanism remains unclear. Because C1q binds with high affinity to hexameric IgG, we analyzed whether carbamylation of IgG affects binding of C1q, hexamerization and complement-dependent cytotoxicity (CDC). Synovial tissues of rheumatoid arthritis (RA) patients were analyzed for the presence of ca-IgG in vivo. Synovial tissues from RA patients were analyzed for the presence of ca-IgG using mass spectrometry (MS). Monomeric or hexameric antibodies were carbamylated in vitro and quality in solution was controlled. The capacity of ca-IgG to activate complement was analyzed in enzyme-linked immunosorbent (ELISAs) and cellular CDC assays. Using MS, we identified ca-IgG to be present in the joints of RA patients. Using in vitro carbamylated antibodies, we observed that ca-IgG lost its capacity to activate complement in both solid-phase and CDC assays. Mixing ca-IgG with non-modified IgG did not result in effective inhibition of complement activation by ca-IgG. Carbamylation of both monomeric IgG and preformed hexameric IgG greatly impaired the capacity to trigger complement activation. Furthermore, upon carbamylation, the preformed hexameric IgG dissociated into monomeric IgG in solution, indicating that carbamylation influences both hexamerization and C1q binding. In conclusion, ca-IgG can be detected in vivo and has a strongly reduced capacity to activate complement which is, in part, mediated through a reduced ability to form hexamers.
Assuntos
Artrite Reumatoide/imunologia , Ativação do Complemento/imunologia , Complemento C1q/imunologia , Imunoglobulina G/imunologia , Idoso , Sequência de Aminoácidos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Artrite Reumatoide/metabolismo , Linhagem Celular Tumoral , Complemento C1q/metabolismo , Testes Imunológicos de Citotoxicidade , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina G/química , Imunoglobulina G/metabolismo , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Carbamilação de Proteínas/imunologia , Multimerização Proteica/imunologia , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismo , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismoRESUMO
OBJECTIVE: Inflammation and innate immune responses may contribute to development and progression of Osteoarthritis (OA). Chondrocytes are the sole cell type of the articular cartilage and produce extracellular-matrix molecules. How inflammatory mediators reach chondrocytes is incompletely understood. Previous studies have shown that chondrocytes express mRNA encoding complement proteins such as C1q, suggesting local protein production, which has not been demonstrated conclusively. The aim of this study is to explore C1q production at the protein level by chondrocytes. DESIGN: We analysed protein expression of C1q in freshly isolated and cultured human articular chondrocytes using Western blot, ELISA and flow cytometry. We examined changes in mRNA expression of collagen, MMP-1 and various complement genes upon stimulation with pro-inflammatory cytokines or C1q. mRNA expression of C1 genes was determined in articular mouse chondrocytes. RESULTS: Primary human articular chondrocytes express genes encoding C1q, C1QA, C1QB, C1QC, and secrete C1q to the extracellular medium. Stimulation of chondrocytes with pro-inflammatory cytokines upregulated C1QA, C1QB, C1QC mRNA expression, although this was not confirmed at the protein level. Extracellular C1q bound to the chondrocyte surface dose dependently. In a pilot study, binding of C1q to chondrocytes resulted in changes in the expression of collagens with a decrease in collagen type 2 and an increase in type 10. Mouse articular chondrocytes also expressed C1QA, C1QB, C1QC, C1R and C1S at the mRNA level. CONCLUSIONS: C1q protein can be expressed and secreted by human articular chondrocytes and is able to bind to chondrocytes influencing the relative collagen expression.
Assuntos
Condrócitos/metabolismo , Complemento C1q/genética , Complemento C1r/genética , Complemento C1s/genética , Osteoartrite do Joelho/genética , RNA Mensageiro/metabolismo , Animais , Cartilagem Articular/citologia , Colágeno Tipo II/genética , Colágeno Tipo X/genética , Regulação da Expressão Gênica , Humanos , Camundongos , Osteoartrite do Joelho/metabolismo , Projetos PilotoRESUMO
INTRODUCTION: C1q is an essential part of the classical pathway of complement activation. Genetic deficiencies, caused by homozygous mutations in one of the C1q genes, are rare and are strongly associated with development of systemic lupus erythematosus (SLE). Here we describe a C1q-deficient patient with a compound heterozygous mutation. MATERIAL AND METHODS: Serum was analysed with enzyme-linked immunosorbent assay (ELISA) and Western blot for the presence of C1q, and DNA and RNA sequencing was performed to identify the mutations and confirm that these were located on different chromosomes. RESULTS: The medical history of the patient includes SLE diagnosis at age 11 years with cerebral involvement at age 13, various infections, osteonecrosis and hemophagocytic syndrome. Using ELISA and Western blot, we confirmed the absence of C1q in the serum of the patient. Using DNA sequencing, two mutations in the C1QC gene were identified: c.100G > A p.(Gly34Arg) and c.205C > T p.(Arg69X). With RNA sequencing we confirmed that the mutations are located on different chromosomes. DISCUSSION: The patient described in this case report has a compound heterozygous mutation in C1QC resulting in C1q deficiency.
Assuntos
Complemento C1q/genética , Lúpus Eritematoso Sistêmico/genética , Mutação , Adulto , Feminino , Homozigoto , Humanos , Análise de Sequência de DNA , Análise de Sequência de RNARESUMO
The complement system is an important part of the innate immune defence. It contributes not only to local inflammation, removal and killing of pathogens, but it also assists in shaping of the adaptive immune response. Besides a role in inflammation, complement is also involved in physiological processes such as waste disposal and developmental programmes. The complement system comprises several soluble and membrane-bound proteins. The bulk of the soluble proteins is produced mainly by the liver. While several complement proteins are produced by a wide variety of cell types, other complement proteins are produced by only a few related cell types. As these data suggest that local production by specific cell types may have specific functions, more detailed studies have been employed recently analysing the local and even intracellular role of these complement proteins. Here we review the current knowledge about extrahepatic production and/or secretion of complement components. More specifically, we address what is known about complement synthesis by cells of the human immune system.
Assuntos
Ativação do Complemento , Proteínas do Sistema Complemento/biossíntese , Leucócitos/imunologia , Macrófagos/imunologia , Mastócitos/imunologia , Imunidade Adaptativa , Animais , Linfócitos B/imunologia , Proteínas do Sistema Complemento/imunologia , Humanos , Imunidade Inata , Fatores Imunológicos , Inflamação , Células Matadoras Naturais/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Linfócitos T/imunologiaRESUMO
OBJECTIVES: To determine the prevalence of anticitrullinated protein antibodies (ACPAs) and their association with known rheumatoid arthritis (RA) risk factors in the general population. METHODS: Lifelines is a multidisciplinary prospective population-based cohort study in the Netherlands. Cross-sectional data from 40â 136 participants were used. The detection of ACPA was performed by measuring anti-CCP2 on the Phadia-250 analyser with levels ≥6.2â U/mL considered positive. An extensive questionnaire was taken on demographic and clinical information, including smoking, periodontal health and early symptoms of musculoskeletal disorders. RA was defined by a combination of self-reported RA, medication use for the indication of rheumatism and visiting a medical specialist within the last year. RESULTS: Of the total 40â 136 unselected individuals, 401 (1.0%) had ACPA level ≥6.2â U/mL. ACPA positivity was significantly associated with older age, female gender, smoking, joint complaints, RA and first degree relatives with rheumatism. Of the ACPA-positive participants, 22.4% had RA (15.2% had defined RA according to our criteria and 7.2% self-reported RA only). In participants without RA, 311 (0.8%) were ACPA-positive. In the non-RA group, older age, smoking and joint complaints remained significantly more frequently present in ACPA-positive compared with ACPA-negative participants. CONCLUSIONS: In this large population-based study, the prevalence of ACPA levels ≥6.2â U/mL was 1.0% for the total group and 0.8% when excluding patients with RA. Older age, smoking and joint complaints were more frequently present in ACPA-positive Lifelines participants. To our knowledge, this study is the largest study to date on ACPA positivity in the general, mostly Caucasian population.
Assuntos
Artralgia/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Peptídeos Cíclicos/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/epidemiologia , Artralgia/epidemiologia , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Menarca , Pessoa de Meia-Idade , Análise Multivariada , Países Baixos , Paridade , Periodontite/epidemiologia , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Fumar/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: Anti-carbamylated protein (anti-CarP) antibodies are reported to associate with more radiographic progression within the total rheumatoid arthritis (RA) population and anti-citrullinated peptide antibody (ACPA)-negative subgroup. We explored the association of anti-CarP with radiographic progression in RA and aimed to replicate the association and evaluate the added value of anti-CarP antibodies in relation to ACPA and rheumatoid factor (RF). METHODS: 576 Swedish and 628 Dutch patients with RA (2394 and 3247 sets of radiographs, respectively) were longitudinally studied. Replication was restricted to the Swedish patients. In both cohorts, the association of anti-CarP with radiographic progression was determined in strata of patients with similar ACPA and RF status; results of both cohorts were combined in fixed-effect meta-analyses. The net percentage of patients for whom the radiographic progression in 5â years was additionally correctly classified when adding anti-CarP to a model including ACPA and RF was evaluated. RESULTS: Anti-CarP associated with radiographic progression in the total Swedish RA population (beta=1.11 per year, p=8.75×10-13) and in the ACPA-negative subgroup (beta=1.14 per year, p=0.034). Anti-CarP associated with more radiographic progression in the strata of ACPA-positive/RF-negative, ACPA-negative/RF-positive and ACPA-positive/RF-positive patients with RA (respective p values 0.014, 0.019 and 0.0056). A model including ACPA and RF correctly classified 54% and 57% of the patients; adding anti-CarP to this model did not increase these percentages (54% and 56% were correctly classified). CONCLUSIONS: Anti-CarP antibodies associated with more severe radiographic progression in the total and ACPA-negative RA population. Anti-CarP-positivity had a statistically significant additive value to ACPA and RF, but did not improve correct classification of patients.
Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico por imagem , Autoanticorpos/sangue , Carbamatos/imunologia , Fator Reumatoide/sangue , Adulto , Idoso , Artrite Reumatoide/imunologia , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/imunologia , RadiografiaRESUMO
OBJECTIVES: In rheumatoid arthritis (RA), seropositive and seronegative disease may be two entities with different underlying pathophysiological mechanisms, long-term outcomes and disease presentations. However, the effect of the conjoint presence of multiple autoantibodies, as proxy for a more pronounced humoral autoimmune response, on clinical phenotype remains unclear. Therefore, this study investigates the association between the number of autoantibodies and initial clinical presentation in two independent cohorts of patients with early RA. METHODS: Autoantibody status (rheumatoid factor, anticitrullinated protein antibodies and anticarbamylated protein antibodies) was determined at baseline in the Leiden Early Arthritis Cohort (n=828) and the Swedish BARFOT (Better Anti-Rheumatic Farmaco-Therapy, n=802) study. The association between the number of autoantibodies and baseline clinical characteristics was investigated using univariable and multivariable ordinal regression. RESULTS: In both cohorts, the following independent associations were found in multivariable analysis: patients with a higher number of RA-associated antibodies were younger, more often smokers, had a longer symptom duration and a higher erythrocyte sedimentation rate at presentation compared with patients with few autoantibodies. CONCLUSIONS: The number of autoantibodies, reflecting the breadth of the humoral autoimmune response, is associated with the clinical presentation of RA. Predisease pathophysiology is thus reflected by the initial clinical phenotype.
Assuntos
Artrite Reumatoide/sangue , Autoanticorpos/sangue , Peptídeos Cíclicos/imunologia , Fator Reumatoide/imunologia , Adulto , Fatores Etários , Idoso , Alelos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Sedimentação Sanguínea , Feminino , Humanos , Imunidade Humoral , Masculino , Pessoa de Meia-Idade , Fenótipo , FumarRESUMO
OBJECTIVE: Patients with rheumatoid arthritis (RA)-related autoantibodies have an increased mortality rate. Different autoantibodies are frequently co-occurring and it is unclear which autoantibodies associate with increased mortality. In addition, association with different causes of death is thus far unexplored. Both questions were addressed in three early RA populations. METHODS: 2331 patients with early RA included in Better Anti-Rheumatic Farmaco-Therapy cohort (BARFOT) (n=805), Norfolk Arthritis Register (NOAR) (n=678) and Leiden Early Arthritis Clinic cohort (EAC) (n=848) were studied. The presence of anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF) and anticarbamylated protein (anti-CarP) antibodies was studied in relation to all-cause and cause-specific mortality, obtained from national death registers. Cox proportional hazards regression models (adjusted for age, sex, smoking and inclusion year) were constructed per cohort; data were combined in inverse-weighted meta-analyses. RESULTS: During 26â 300 person-years of observation, 29% of BARFOT patients, 30% of NOAR and 18% of EAC patients died, corresponding to mortality rates of 24.9, 21.0 and 20.8 per 1000 person-years. The HR for all-cause mortality (95% CI) was 1.48 (1.22 to 1.79) for ACPA, 1.47 (1.22 to 1.78) for RF and 1.33 (1.11 to 1.60) for anti-CarP. When including all three antibodies in one model, RF was associated with all-cause mortality independent of other autoantibodies, HR 1.30 (1.04 to 1.63). When subsequently stratifying for death cause, ACPA positivity associated with increased cardiovascular death, HR 1.52 (1.04 to 2.21), and RF with increased neoplasm-related death, HR 1.64 (1.02 to 2.62), and respiratory disease-related death, HR 1.71 (1.01 to 2.88). CONCLUSIONS: The presence of RF in patients with RA associates with an increased overall mortality rate. Cause-specific mortality rates differed between autoantibodies: ACPA associates with increased cardiovascular death and RF with death related to neoplasm and respiratory disease.
Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/mortalidade , Autoanticorpos/sangue , Peptídeos Cíclicos/imunologia , Fator Reumatoide/sangue , Idoso , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Causas de Morte , Europa (Continente) , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fator Reumatoide/imunologia , Fatores de RiscoRESUMO
OBJECTIVE: The objective of this paper is to analyse serum levels of anti-C1q, C1q circulating immune complexes (CIC), complement activation and complement components in systemic lupus erythematosus (SLE) patients during the first central nervous system neuropsychiatric (NP) event and to define the possible association between these results and clinical and laboratory characteristics. METHODS: A total of 280 patients suspected of having NP involvement due to SLE were recruited in the Leiden NPSLE-clinic. All SLE patients were classified according to the ACR 1982 revised criteria for the classification of SLE. The clinical disease activity was measured by the SLE Disease Activity Index 2000 (SLEDAI-2K) and NP diagnoses were classified according to the 1999 ACR case definitions for NPSLE. We measured in serum of all patients anti-C1q and C1q CIC levels, the activation capacity of complement (CH50 and AP50) and different complement components (C1q, C3, C4). RESULTS: In 92 patients the symptoms were attributed to SLE. NPSLE patients consisted of 63 patients with focal NPSLE and 34 patients with diffuse NPSLE. Anti-C1q antibodies were significantly higher and CH50, AP50 and C3 were significantly lower in NPSLE patients compared with SLE patients without NPSLE. This association was specially marked for diffuse NPSLE while no differences were found for focal NPSLE. After using potential predictors, decreased C4 remained significantly associated with focal NPSLE, but only when antiphospholipid antibodies (aPL) were included in the model. C3 and AP50 were independently associated with diffuse NPSLE. When SLEDAI-2K was included in the model these two associations were lost. When individual NPSLE syndromes were analysed, psychosis and cognitive dysfunction showed significantly lower values of complement activation capacity and all complement components. No significant associations were seen for other individual NPSLE syndromes. CONCLUSION: The associations between diffuse NPSLE and anti-C1q, C3/AP50 and focal NPSLE and C4 may be explained by disease activity and the presence of aPL, respectively. The role of complement activation and complement components in lupus psychosis and cognitive dysfunction merits further research.
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Anticorpos Antifosfolipídeos/sangue , Complemento C1q/imunologia , Via Alternativa do Complemento/imunologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto JovemRESUMO
Rheumatic diseases, such as rheumatoid and psoriatic arthritis are systemic inflammatory conditions characterized by a chronic form of arthritis, often leading to irreversible joint damage. Early treatment for patients with rheumatic diseases is required to reduce or prevent joint injury. However, early diagnosis can be difficult and currently it is not possible to predict which individual patient will develop progressive erosive disease or who may benefit from a specific treatment according to their clinical features at presentation. Biomarkers are therefore required to enable earlier diagnosis and predict prognosis in both rheumatoid arthritis and psoriatic arthritis. In this review we will examine the evidence and current status of established and experimental biomarkers in rheumatoid and psoriatic arthritis for three important purposes; disease diagnosis, prognosis and prediction of response to therapy.
Assuntos
Artrite Psoriásica/sangue , Artrite Reumatoide/sangue , Autoanticorpos/sangue , Biomarcadores/sangue , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/imunologia , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Citrulina/imunologia , Diagnóstico Precoce , Humanos , Prognóstico , Fator Reumatoide/imunologia , Sensibilidade e EspecificidadeRESUMO
Coeliac disease is characterized by intolerance to gliadin and related gluten components present in wheat, barley and rye. Coeliac disease patients harbour antibodies directed against alloantigens such as gliadin, but also against the autoantigen transglutaminase-2 (TG2). The type and quality of antibody responses provides insight into the underlying immune activation processes. Therefore, in this study we have analysed the avidity of the antibody response directed against the autoantigen TG2 and compared this with antibody responses against the alloantigens gliadin and Escherichia coli. We observed that the immunoglobulin (Ig)A autoantibody response directed against TG2 is of low avidity compared with the IgA response against the alloantigens gliadin and E. coli in the same patients; the same was true for IgG, both in IgA-deficient and in -sufficient coeliac patients. The observed avidities appear not to be related to disease stage, antibody levels, age or duration of exposure to gluten. In conclusion, in coeliac disease there is a clear difference in avidity of the antibody responses directed against the auto- and alloantigens, indicating different regulation or site of initiation of these responses.
Assuntos
Afinidade de Anticorpos , Autoanticorpos/imunologia , Doença Celíaca/imunologia , Escherichia coli/imunologia , Proteínas de Ligação ao GTP/imunologia , Gliadina/imunologia , Transglutaminases/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Autoanticorpos/sangue , Criança , Pré-Escolar , Glutens/metabolismo , Hordeum/imunologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lactente , Isoanticorpos/imunologia , Pessoa de Meia-Idade , Proteína 2 Glutamina gama-Glutamiltransferase , Secale/imunologia , Triticum/imunologia , Adulto JovemRESUMO
OBJECTIVES: Anticitrullinated protein antibodies (ACPA) are specific for rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. Previously we have shown that ACPA display a considerably lower avidity as compared with antibodies against recall antigens. Nonetheless, ACPA-avidity did vary between patients. As antibody mediated effects are influenced by antibody-avidity, we now investigated ACPA-avidity in relation to biological activity and clinical outcome. METHODS: We determined the avidity of ACPA and related this with severity of joint damage in two Dutch early-RA cohorts containing 199 and 132 patients respectively. Differences in effector functions of low- and high-avidity ACPA were studied. RESULTS: Extensive variation in ACPA-avidity between patients was observed. This allowed the analysis of the relationship between avidity and severity. The presence of low-avidity ACPA is associated with a higher rate of joint destruction. This finding was replicated in an independent cohort. Analysis of the properties of low-versus high-avidity ACPA revealed that low-avidity ACPA are less hampered in their ability to bind 'new' citrullinated antigens. Although no differences could be observed regarding cellular activation via Fc-γ receptors, low-avidity ACPA were more potent in activating the complement system. CONCLUSIONS: Patients with low-avidity ACPA display a higher rate of joint destruction. Low-avidity ACPA display a higher potency to interact with more citrullinated antigens in time and show that low-avidity ACPA are more potent in complement activation. These data indicate that (low) avidity impacts on the biological activity of ACPA and associates with a worse radiological outcome.
Assuntos
Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/imunologia , Articulações/imunologia , Peptídeos Cíclicos/imunologia , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Afinidade de Anticorpos/imunologia , Antígenos/imunologia , Artrografia , Estudos de Coortes , Proteínas do Sistema Complemento/imunologia , Epitopos/imunologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Rodent models for arthritis implicate a role for complement in disease development and progression. In humans, complement deposition has been observed in inflamed synovia of rheumatoid arthritis (RA) patients. In this study we analysed whether genetic variants of complement component C1q predispose to RA. We genotyped single nucleotide polymorphisms (SNPs) in and around the C1q genes, C1qA, C1qB and C1qC, in a Dutch set of 845 RA cases and 1046 controls. Replication was sought in a sample set from North America (868 cases/1193 controls), and a meta-analysis was performed in a combined samples set of 8000 cases and 23 262 controls of European descent. We determined C1q serum levels in relation to C1q genotypes. In the discovery phase, five of the 13 SNPs tested in the C1q genes showed a significant association with RA. Additional analysis of the genomic area around the C1q genes revealed that the strongest associating SNPs were confined to the C1q locus. Within the C1q locus we observed no additional signal independent of the strongest associating SNP, rs292001 [odds ratio (OR) = 0·72 (0·58-0·88), P = 0·0006]. The variants of this SNP were associated with different C1q serum levels in healthy controls (P = 0·006). Interestingly, this SNP was also associated significantly in genome-wide association studies (GWAS) from the North American Rheumatoid Arthritis Consortium study, confirming the association with RA [OR = 0·83 (0·69-1·00), P = 0·043]. Combined analysis, including integrated data from six GWAS studies, provides support for the genetic association. Genetic variants in C1q are correlated with C1q levels and may be a risk for the development of RA.
Assuntos
Artrite Reumatoide/genética , Complemento C1q/genética , Polimorfismo de Nucleotídeo Único , Artrite Reumatoide/epidemiologia , Canadá/epidemiologia , Estudos de Coortes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Grécia/epidemiologia , Humanos , Países Baixos/epidemiologia , RNA Mensageiro/genética , Receptor EphA8/genética , Receptor EphB2/genética , Estados Unidos/epidemiologiaRESUMO
Since the identification of antibodies directed against citrullinated protein antibodies (ACPA) as specific serological markers for rheumatoid arthritis (RA) the insight into the pathogenesis of RA has made significant progress. It is now realised that RA does not represent one disease entity, as ACPA-positive and ACPA-negative RA differ in several important aspects. For example, the most prominent genetic risk factors, the human leucocyte antigen shared epitope alleles only predispose to ACPA-positive RA, but not to ACPA-negative disease. Likewise, ACPA-positive RA is characterised by a more severe disease course as well as by a lower chance to enter drug-free remission. More recently, it became apparent that next to ACPA, another autoantibody system is also present in RA patients that is directed against a structurally similar determinant. These antibodies recognise carbamylated proteins and thus are called anticarbamylated protein (anti-CarP) antibodies. During carbamylation lysine residues are post-translationally modified to a homocitrulline, the antigenic identity crucial for recognition by anti-CarP antibodies. In this review we will discuss novel insight into the immune responses directed against citrullinated and carbamylated proteins.
Assuntos
Artrite Reumatoide/imunologia , Autoantígenos/imunologia , Autoimunidade/imunologia , Formação de Anticorpos , Citrulina/análogos & derivados , Citrulina/imunologia , HumanosRESUMO
OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and are present years before the onset of symptoms. The avidity of autoantibodies can have a strong impact on their effector potency. This study was undertaken to analyze the avidity of ACPAs in serum samples obtained from ACPA-positive healthy individuals (predisease), patients with early disease, and patients with established RA as well as the avidity maturation over time in samples from healthy subjects who later developed RA. METHODS: We measured ACPA avidity in serum samples from ACPA-positive healthy individuals, symptomatic individuals, and patients with established RA in 5 collections from The Netherlands, Canada, and Austria. We determined the dynamics of avidity maturation of ACPAs from the predisease stage to established disease in 1 case from the native North American population and in 10 cases from a Dutch blood donor cohort. RESULTS: The overall ACPA response was characterized by low-avidity antibodies. Higher-avidity ACPAs were observed in symptomatic patients only, while low-avidity ACPAs were observed in both healthy subjects and patients. In longitudinal samples obtained from subjects prior to disease onset, ACPA avidity increased over time until disease onset. No further avidity maturation was observed after disease onset. CONCLUSION: Our findings indicate that avidity maturation of the ACPA response takes place prior to disease onset.
Assuntos
Afinidade de Anticorpos/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Imunização Secundária , Peptídeos Cíclicos/imunologia , Estudos Longitudinais , Fatores de TempoRESUMO
OBJECTIVE: Undifferentiated, early inflammatory arthritis (EIA) can differentiate into seropositive or seronegative rheumatoid arthritis (RA), peripheral spondyloarthritis (SpA) or remain as seronegative undifferentiated inflammatory arthritis (UIA). Little is known about immune pathways active in the early stages of SpA and seronegative UIA, in contrast to detailed knowledge of seropositive RA. The aim of this study was to examine if specific immune pathways were active in synovial CD4+ and CD8+ T cells in EIA. METHODS: Synovial fluid (SF) samples from 30 patients with EIA were analysed for expression of IL-17A, IFNγ and TNFα in CD8+ or CD4+ T cells. Final clinical diagnoses were made at least 12 months after sample collection, by two independent clinicians blind to the study data. RESULTS: Flow cytometry analysis of all EIA samples indicated considerable variation in synovial IL-17A+CD8+ T cells (Tc17) cell frequencies between patients. The group with a final diagnosis of SpA (psoriatic arthritis or peripheral SpA, n=14) showed a significant enrichment in the percentage of synovial Tc17 cells compared with the group later diagnosed with seronegative UIA (n=10). The small number of patients later diagnosed with seropositive RA (n=6) patients had few Tc17 cells, similar to our previous findings in established disease. In contrast, RA SF contained a significantly higher percentage of CD8+IFNγ+ T cells compared with SpA or seronegative UIA. CONCLUSION: These results suggest that adaptive T cell cytokine pathways differ not only between RA and SpA but also seronegative UIA early in the disease process, with a particular activation of Tc17 pathways in early SpA.