RESUMO
Antibody-based blocking of vascular endothelial growth factor (VEGF) reduces choroidal neovascularization (CNV) and retinal edema, rescuing vision in patients with neovascular age-related macular degeneration (nAMD). However, poor response and resistance to anti-VEGF treatment occurs. We report that targeting the Notch ligand Jagged1 by a monoclonal antibody reduces neovascular lesion size, number of activated phagocytes and inflammatory markers and vascular leakage in an experimental CNV mouse model. Additionally, we demonstrate that Jagged1 is expressed in mouse and human eyes, and that Jagged1 expression is independent of VEGF signaling in human endothelial cells. When anti-Jagged1 was combined with anti-VEGF in mice, the decrease in lesion size exceeded that of either antibody alone. The therapeutic effect was solely dependent on blocking, as engineering antibodies to abolish effector functions did not impair the therapeutic effect. Targeting of Jagged1 alone or in combination with anti-VEGF may thus be an attractive strategy to attenuate CNV-bearing diseases.
Assuntos
Neovascularização de Coroide , Fator A de Crescimento do Endotélio Vascular , Humanos , Camundongos , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais/metabolismo , Neovascularização de Coroide/patologia , Anticorpos Bloqueadores/uso terapêutico , Transdução de Sinais/fisiologia , Modelos Animais de Doenças , Inibidores da Angiogênese/uso terapêuticoRESUMO
BACKGROUND: Damaging alterations in the BRCA1 gene have been extensively described as one of the main causes of hereditary breast and ovarian cancer (HBOC). BRCA1 alterations can lead to impaired homologous recombination repair (HRR) of double-stranded DNA breaks, a process which involves the RING, BRCT and coiled-coil domains of the BRCA1 protein. In addition, the BRCA1 protein is involved in transcriptional activation (TA) of several genes through its C-terminal BRCT domain. METHODS: In this study, we have investigated the effect on HRR and TA of 11 rare BRCA1 missense variants classified as variants of uncertain clinical significance (VUS), located within or in close proximity to the BRCT domain, with the aim of generating additional knowledge to guide the correct classification of these variants. The variants were selected from our previous study "BRCA1 Norway", which is a collection of all BRCA1 variants detected at the four medical genetic departments in Norway. RESULTS: All variants, except one, showed a significantly reduced HRR activity compared to the wild type (WT) protein. Two of the variants (p.Ala1708Val and p.Trp1718Ser) also exhibited low TA activity similar to the pathogenic controls. The variant p.Trp1718Ser could be reclassified to likely pathogenic. However, for ten of the variants, the total strength of pathogenic evidence was not sufficient for reclassification according to the CanVIG-UK BRCA1/BRCA2 gene-specific guidelines for variant interpretation. CONCLUSIONS: When including the newly achieved functional evidence with other available information, one VUS was reclassified to likely pathogenic. Eight of the investigated variants affected only one of the assessed activities of BRCA1, highlighting the importance of comparing results obtained from several functional assays to better understand the consequences of BRCA1 variants on protein function. This is especially important for multifunctional proteins such as BRCA1.
Assuntos
Neoplasias da Mama , Genes BRCA1 , Reparo de DNA por Recombinação , Ativação Transcricional , Feminino , Humanos , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Predisposição Genética para Doença , Células Germinativas/metabolismoRESUMO
BACKGROUND: Anti-pentraxin 3 (PTX3) antibodies were associated with the absence of lupus glomerulonephritis in humans. AIM: To explore the effects of anti-PTX3 antibodies in New Zealand Black/White (NZB/NZW F1) mice and their inherent mechanisms of action. MATERIALS AND METHODS: 30 NZB/NZW F1 mice were subdivided into 3 groups of 10 mice each and subcutaneously injected with PTX3, alum and PBS (group 1), alum and PBS (group 2) or PBS alone (group 3), 3 times 3 weeks apart, before development of renal disease. Mice were followed until natural death. Histological analysis and immunohistochemistry were performed on harvested kidneys. Effects of anti-PTX3 antibodies on C1q binding to immobilized PTX3-anti-PTX3 immune complexes were evaluated in vitro using human SLE sera. Qualitative characterization of human IgG anti-PTX3 was performed. RESULTS: Only group 1 mice developed anti-PTX3 antibodies. Anti-dsDNA and anti-C1q antibodies appeared significantly later and at lower levels in group 1 mice vs. controls (p < 0.0001). Proteinuria-free and overall survival were significantly increased in group 1 mice vs. controls (p < 0.05 and p = 0.03, respectively). Histopathological analysis showed that glomerular and tubular PTX3 staining and renal lesions were increased in controls compared with immunized mice. Addition of human SLE sera positive for anti-PTX3 antibodies to C1q and fixed PTX3 interfered with C1q binding to PTX3-anti-PTX3 immune complexes. Qualitative characterization of human IgG anti-PTX3 showed an increased proportion of IgG4. CONCLUSIONS: Anti-PTX3 antibodies delay lupus-like nephritis and prolong survival of NZB/NZW F1 mice. In vitro observations suggest anti-PTX3 antibodies may dampen complement activation via their Fc fragment, likely hindering renal inflammation.
Assuntos
Autoanticorpos/imunologia , Proteína C-Reativa/imunologia , Nefrite Lúpica/imunologia , Componente Amiloide P Sérico/imunologia , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacologia , Autoanticorpos/sangue , Autoanticorpos/farmacologia , Biomarcadores , Biópsia , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Ativação do Complemento/imunologia , Complemento C1q/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Imunização , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imuno-Histoquímica , Testes de Função Renal , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/metabolismo , Nefrite Lúpica/mortalidade , Camundongos , Camundongos Endogâmicos NZB , Substâncias Protetoras , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , Fatores de TempoRESUMO
Galectin-3 (gal-3) is a ß-galactoside-binding lectin, which regulates cell-cell and extracellular interactions during self/non-self-antigen recognition and cellular activation, proliferation, differentiation, migration and apoptosis. It plays a significant role in cellular and tissue pathophysiology by organizing niches that drive inflammation and immune responses. Gal-3 has some therapeutic potential in several diseases, including chronic inflammatory disorders, cancer and autoimmune diseases. Gal-3 exerts a broad spectrum of functions which differs according to its intra- or extracellular localization. Recombinant gal-3 strategy has been used to identify potential mode of action of gal-3; however, exogenous gal-3 may not reproduce the functions of the endogenous gal-3. Notably, gal-3 induces monocyte-macrophage differentiation, interferes with dendritic cell fate decision, regulates apoptosis on T lymphocytes and inhibits B-lymphocyte differentiation into immunoglobulin secreting plasma cells. Considering the influence of these cell populations in the pathogenesis of several autoimmune diseases, gal-3 seems to play a role in development of autoimmunity. Gal-3 has been suggested as a potential therapeutic agent in patients affected with some autoimmune disorders. However, the precise role of gal-3 in driving the inflammatory process in autoimmune or immune-mediated disorders remains elusive. Here, we reviewed the involvement of gal-3 in cellular and tissue events during autoimmune and immune-mediated inflammatory diseases.
Assuntos
Doenças Autoimunes , Autoimunidade/efeitos dos fármacos , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Galectina 3 , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Galectina 3/imunologia , Galectina 3/farmacologia , Humanos , Macrófagos/imunologia , Macrófagos/patologia , Monócitos/imunologia , Monócitos/patologia , Plasmócitos/imunologia , Plasmócitos/patologia , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
Pentraxin 3 (PTX3) is an acute-phase protein involved in C1q clearance. The presence of anti-C1q and the absence of anti-PTX3 antibodies were associated with lupus glomerulonephritis (LGLN). Our aim was to assess soluble and kidney-expressed PTX3 and their relationships with anti-C1q and anti-PTX3 antibodies in LGLN. Serum PTX3, anti-C1q, anti-dsDNA, and anti-PTX3 antibodies were tested in 130 systemic lupus erythematosus (SLE) patients, 130 healthy and 127 disease controls. Twenty-nine renal biopsies from SLE patients were analyzed and PTX3 immunostaining was quantified by morphometric analysis. Parametric and nonparametric statistics were performed. PTX3 serum levels were lower in SLE versus controls, but they were correlated with proteinuria in LGLN patients (p = 0.001). LGLN patients had higher anti-C1q and lower anti-PTX3 antibody levels than those without (p < 0.0001). LGLN was more prevalent in anti-C1q(+)/anti-PTX3(-) than in anti-C1q(+)/anti-PTX3(+) patients (p < 0.001). No LGLN was observed in anti-C1q(-)/anti-PTX3(+) patients. PTX3 was expressed in glomeruli and renal interstitium. Renal PTX3 was correlated with proteinuria (p = 0.024) and interstitial fibrosis (p = 0.023). PTX3 staining and fibrosis were higher in anti-PTX3(-) than anti-PTX3(+) patients. In conclusion, PTX3 is expressed in glomeruli of LGLN patients, primarily in anti-PTX3(-) patients, where it is correlated with renal fibrosis. Anti-C1q/anti-PTX3 antibody profile seems to be useful in LGLN assessment.
Assuntos
Reação de Fase Aguda/metabolismo , Autoanticorpos/metabolismo , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Rim/metabolismo , Nefrite Lúpica/imunologia , Proteinúria/imunologia , Componente Amiloide P Sérico/metabolismo , Adolescente , Adulto , Autoantígenos/imunologia , Proteína C-Reativa/imunologia , Complemento C1q/imunologia , DNA/imunologia , Feminino , Fibrose , Humanos , Rim/imunologia , Rim/patologia , Nefrite Lúpica/diagnóstico , Masculino , Pessoa de Meia-Idade , Proteinúria/diagnóstico , Componente Amiloide P Sérico/imunologia , Adulto JovemRESUMO
The aim of this study was to identify specific biomarkers that could be used to screen for psoriatic arthritis (PsA), as well as to assess disease activity and treatment outcome in affected patients. Forty-three outpatients considered eligible for anti-TNF-α treatment (etanercept 50 mg/week) were enrolled. Serum samples of vascular endothelial growth factor (VEGF), metalloproteinase-3 (MMP3), pentraxin 3 (PTX3), and high-sensitive C-reactive protein (hs-CRP) were collected at baseline (t0) and after 6 (t6), 12 (t12), and 24 months (t24) of treatment. Baseline values were compared with those of a group of healthy controls matched for age and sex. Disease activity scores and functional tests (DAS28, BASDAI, PASI, BASFI, HAQ, VAS pain, and VAS patient global disease activity) after treatment were found to be significantly different from baseline values. At baseline, MMP3, hs-CRP and VEGF values in the PsA-patients were found to be significantly higher with respect to levels in the controls. There were no differences in the PTX3 values. MMP3 was significantly lower at t6 (P < 0.0001), t12 (P < 0.0001) and t24 (P < 0.0001). hs-CRP and VEGF were significantly lower, respectively, at t12 (P < 0.01; P < 0.05) and t24 (P < 0.05; P < 0.01). PTX3 was significantly higher at t24 (P < 0.05). A correlation was found between MMP3 and hs-CRP (r = 0.45, P = 0.0005). MMP3, hs-CRP, and VEGF appear to be useful for the early detection of PsA and to monitor disease progression. The rise in PTX3 did not appear to be linked to the inflammatory state of the disease but might be an expression of the atherosclerotic process frequently observed in PsA.
Assuntos
Artrite Psoriásica/sangue , Artrite Psoriásica/diagnóstico , Biomarcadores/sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Metaloproteinase 3 da Matriz/sangue , Pessoa de Meia-Idade , Medição da Dor , Componente Amiloide P Sérico/análise , Índice de Gravidade de Doença , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
OBJECTIVES: To evaluate the role of serum IgG, IgM and IgA anti-dsDNA antibody isotypes in the diagnosis of systemic lupus erythematosus (SLE), and their association with clinical features and disease activity, in a large cohort of SLE patients. METHODS: Sera of 200 SLE patients (mean age 34±10.3 years; 26 male and 174 female; median duration of disease 115 months, range 7-378), and of 206 controls, including 19 Sjögren's syndrome, 27 rheumatoid arthritis, 26 psoriatic arthritis, 15 idiopathic inflammatory myopathies (IIM), 13 systemic sclerosis, 49 infectious diseases and 57 healthy subjects, were tested for anti-dsDNA IgG, IgM and IgA isotypes. RESULTS: Selecting a cutoff corresponding to 95% specificity, the sensitivity of IgG, IgM and IgA anti-dsDNA antibodies in SLE was 55%, 30% and 49%, respectively; 12.5%, 1% and 7.5% of SLE patients had positive IgG, IgM or IgA isotype alone, respectively. SLE patients with glomerulonephritis showed higher levels of IgA anti-dsDNA (pâ=â0.0002), anti-dsDNA IgG/IgM (pâ=â0.001) and IgA/IgM (p<0.0001) ratios than patients without renal disease. No significant associations have been found between anti-dsDNA isotypes and other clinical features. IgA anti-dsDNA (pâ=â0.01) (but not IgG or IgM) and IgG/IgM ratio (pâ=â0.005) were significantly higher in patients with more active disease (ECLAM score >4). CONCLUSIONS: The detection of IgA anti-dsDNA autoantibodies seems to improve our ability to diagnose SLE and to define lupus nephritis phenotype and active disease. By contrast, IgM anti-dsDNA antibodies might be protective for renal involvement. These data support the hypothesis that anti-dsDNA antibody class clustering may help to refine SLE diagnosis and prognosis.
Assuntos
Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Isotipos de Imunoglobulinas/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Isotipos de Imunoglobulinas/sangue , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/sangue , Nefrite Lúpica/imunologia , Masculino , Curva ROC , Estudos Soroepidemiológicos , Adulto JovemRESUMO
Inflammatory myopathies are a group of acquired diseases, characterized by immunoflogistic processes primarily involving the skeletal muscle. According to recent classification criteria, four major diseases have been identified: polymyositis (PM), dermatomyositis (DM), sporadic inclusion body myositis (IBM), and necrotizing autoimmune myositis (NAM). Autoantibodies can be found in the sera of most patients with myositis. Myositis-specific autoantibodies (MSAs) are markers of very specific disease entities within the spectrum of myositis, and target proteins involved in key processes of protein synthesis. Myositis autoantigens comprise the well-defined aminoacyl-tRNA synthetases, the Mi-2 helicase/histone deacetylase protein complex, and the signal recognition particle (SRP) ribonucleoprotein, together with novel targets such as TIF1-γ, MDA5, NXP2, SAE, and HMGCR. Recent studies suggest that autoantigens drive a B cell antigen-specific immune response in muscles. Interestingly, an increased expression of Jo-1 and Mi-2 in regenerating fibers in muscle biopsies from PM and DM patients compared to normal was demonstrated. Myositis autoantigen up-regulation was observed in neoplastic tissues, thus representing a potential link between cancer and autoimmunity in myositis. Non-immunological mechanisms seem to participate to the pathogenesis of inflammatory myopathies; induction of endoplasmic reticulum stress response in response to abnormal muscle regeneration and inflammation has recently been reported in patients with myositis. This review article provides an update of new emerging insights about the clinical and pathophysiologic role of principal autoantibodies in myositis.
Assuntos
Aminoacil-tRNA Sintetases/metabolismo , Autoanticorpos/imunologia , Autoantígenos/metabolismo , Dermatomiosite/sangue , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Músculo Esquelético/metabolismo , Partícula de Reconhecimento de Sinal/metabolismo , Aminoacil-tRNA Sintetases/imunologia , Autoanticorpos/metabolismo , Autoantígenos/imunologia , Biomarcadores/metabolismo , Dermatomiosite/imunologia , Dermatomiosite/fisiopatologia , Histidina-tRNA Ligase/imunologia , Histidina-tRNA Ligase/metabolismo , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/imunologia , Fibras Musculares Esqueléticas/imunologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/imunologia , Músculo Esquelético/patologia , Regeneração , Partícula de Reconhecimento de Sinal/imunologiaRESUMO
Serine protease inhibitors (serpins) are evolutionary old, structurally conserved molecules which encompass nearly all branches of life. More than 1,000 serpins were characterized to date which are subdivided into 16 subgroups (A-P) according to their common ancestry; among them, 37 are found in humans. Serpins were termed after their capability to inhibit serine proteases, but mounting evidence suggests that they may achieve a greater deal of functions, ranging from embryological growth to synaptic plasticity, development of both myeloid and lymphoid immune cells, and modulation of apoptosis. Serpins are mainly extracellular molecules, although some of them (namely, ov-serpins or clade B serpins) mostly act inside the cells, being either ubiquitously or tissue-specifically expressed. Among newly characterized serpin functions, regulation of cellular proliferation through apoptosis modulation and proteasome disturbance seems to play a major role. Accordingly, several serpins were found to be hyperexpressed in tumor cells. Indeed, apoptosis dysregulation is likely to be a cornerstone in both tumorigenesis and autoimmunity, since uncontrolled cellular viability results in tumor proliferation, while inefficient disposal of apoptotic debris may favor the rescue of autoreactive immune cells. Such a process was widely documented in systemic lupus erythematosus (SLE). Interestingly, alterations in the expression of some serpins, e.g., the ov-serpin SERPINB3, are being unraveled in patients affected with SLE and other autoimmune disorders, suggesting that a failure in serpin function might affect immune homeostasis and self-tolerance, thereby contributing to autoimmunity. Here, we provide an overview of serpin origin, function, and dysfunction, focusing on human serpins and ov-serpins, with a hub on SERPINB3.
Assuntos
Antígenos de Neoplasias/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Neoplasias/imunologia , Inibidores de Serina Proteinase/imunologia , Serpinas/imunologia , Animais , Antígenos de Neoplasias/genética , Apoptose , Autoimunidade , Processos de Crescimento Celular , Desenvolvimento Fetal , Regulação da Expressão Gênica/imunologia , Homeostase , Humanos , Tolerância a Antígenos Próprios , Serpinas/genética , Serpinas/metabolismo , Transmissão SinápticaRESUMO
Systemic lupus erythematosus (SLE) is a multisystemic, autoimmune disease, encompassing either mild or severe manifestations. SLE was originally labeled as being an immune complex-mediated disease, but further knowledge suggested its pathogenesis is motlier than that, involving complex interactions between predisposed individuals and their environment. People affected with SLE have their immune system skewed toward aberrant self-recognition usually after encountering a triggering agent. Defeats in early and late immune checkpoints contribute to tolerance breakdown and further generation and expansion of autoreactive cell-clones. B and T cells play a master role in SLE, however clues are emerging about other cell types and new light is being shed on SLE autoantibodies, since some of them display really harmful potential (pathogenic antibodies), while others are just connected with disease development (pathological antibodies) and may even be protective. Autoantibody generation is elicited by abnormal apoptosis and inefficient clearance of cellular debris causing intracellular autoantigens (e.g. nucleosomes) to persist in the extracellular environment, being further recognized by autoreactive cells. Here we explore the complexity of SLE pathogenesis through five core issues, i.e. genetic predisposition, B and T cell abnormalities, abnormal autoantigen availability, autoantibody generation and organ damage, relying on current knowledge and recent insights into SLE development.
Assuntos
Lúpus Eritematoso Sistêmico/etiologia , Animais , Apoptose/imunologia , Autoanticorpos/imunologia , Autoimunidade , Linfócitos B/imunologia , Linfócitos B/metabolismo , Epigênese Genética , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
INTRODUCTION: Myositis specific autoantibodies (MSAs) are useful in the diagnosis of idiopathic inflammatory myopathies and in the definition of disease subsets. The aim of this study was to set up an unlabelled protein immunoprecipitation technique for MSA identification in the sera of myositis patients, in order to identify and investigate new antibody reactivity, undetectable by currently used methods. METHODS: Sera of 183 patients with connective tissue diseases (75 adult dermatomyositis, 12 juvenile dermatomyositis, 43 polymyositis, 53 other connective tissue diseases) and 30 healthy controls were screened by an in-house procedure of unlabelled protein immunoprecipitation. In the same sera MSAs and myositis associated antibodies were determined by immunoblotting and immunoprecipitation for RNA. RESULTS: The analytical specificity of unlabelled protein immunoprecipitation was demonstrated by testing reference sera with known antibody reactivity. Sera from five patients, affected with dermatomyositis (5/75=7%), immunoprecipitated two proteins of 40 and 90 kDa apparent molecular weights respectively, consistent with the subunits of the small ubiquitin like modifier activating enzyme heterodimer (SAE1/SAE2). The identity of putative SAE immunoprecipitated proteins was confirmed by immunoblotting on immunoprecipitates using commercial monospecific antibodies to SAE1 and SAE2. Major clinical features were compared between anti-SAE positive and negative patients. Interestingly, anti-SAE positive patients had mainly skin and muscle manifestations while dysphagia, interstitial lung disease, arthritis and constitutional symptoms were absent. CONCLUSIONS: Unlabelled protein immunoprecipitation is a specific analytical approach, appropriate for the identification of the recently described anti-SAE autoantibody. We confirmed the role of anti-SAE antibody as marker of dermatomyositis.
Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Miosite/imunologia , Enzimas Ativadoras de Ubiquitina/imunologia , Adolescente , Adulto , Aminoacil-tRNA Sintetases , Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Biomarcadores/sangue , Criança , Estudos de Coortes , Dermatomiosite/sangue , Dermatomiosite/diagnóstico , Dermatomiosite/imunologia , Diagnóstico Diferencial , Humanos , Immunoblotting , Imunoprecipitação/métodos , Itália , Células Jurkat , Pessoa de Meia-Idade , Miosite/sangue , Miosite/diagnóstico , Polimiosite/sangue , Polimiosite/diagnóstico , Polimiosite/imunologia , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: To evaluate disease activity patterns and flare occurrence in a cohort of systemic lupus erythematosus (SLE) patients. METHODS: Patients registered in our lupus Database, diagnosed with SLE between 1991 and 2004 and followed up quarterly from 2004 to 2010 were considered in the study. Disease activity patterns were defined using SLE Disease Activity Index-2000 (SLEDAI-2K), excluding serology, as follows: clinical quiescent disease (CQD), SLEDAI-2K=0 in the three annual visits; minimal disease activity (MDA), SLEDAI-2K=1 in one or more annual visits; chronic active disease (CAD), SLEDAI-2K≥2 in at least two annual visits; relapsing-remitting disease (RRD), SLEDAI-2K≥2 in one out of 3 annual visits. Flare was defined as an increase in SLEDAI-2K≥4 from the previous visit, according to SELENA-SLEDAI flare index. RESULTS: One hundred and sixty-five patients fulfilled the inclusion criteria. During the 7 year follow-up, 109 (66%) patients experienced at least one period of active disease (CAD, RRD and MDA), whereas 56 patients (34%) had a persistent CQD. The mean±SD number of patients in each pattern per year was: CAD 52.4±5.8 (31.7%), RRD 16.1±6.8 (9.7%), MDA 9.7±1.7, (5.9%), CQD 87±10.5 (52.6%). Annual flare-rate was 0.19 flare per patient/year and mean±SD number of flares was higher in CAD compared with RRD patients (p<0.01). At the multivariate analysis positive anti-dsDNA antibodies, low C3 or C4, male sex, longer lag time between SLE onset and diagnosis, higher number of flares, and use of immunosuppressant were independently associated with active disease including CAD and RRD patterns. CONCLUSIONS: Two-thirds of our patients developed at least one period of active disease during the 7-year follow-up despite tight monitoring and standard treatment.
Assuntos
Lúpus Eritematoso Sistêmico/diagnóstico , Adulto , Anti-Inflamatórios/uso terapêutico , Anticorpos Antinucleares/sangue , Biomarcadores/sangue , DNA/imunologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Itália , Modelos Logísticos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Recidiva , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Around 1980 antinuclear antibody testing became widely used in routine laboratory practice leading to a tapering in the lag time between SLE onset and diagnosis. Since then nothing relevant has been introduced which could help us in making the diagnosis of SLE earlier than now. Notably, there is increasing evidence that early diagnosis and treatment could increase SLE remission rate and improve patient prognosis. Although it has been shown that autoantibodies appear before clinical manifestations in SLE patients, currently we cannot predict which autoantibody positive subjects will eventually develop the disease. Thus, great effort should be made in order to identify new biomarkers able to improve our diagnostic potential. B lymphocyte stimulator (BLyS), anti-ribosomal P protein and anti-C1q antibodies are among the most promising. In recent years, some therapeutic options have emerged as appropriate interventions for early SLE treatment, including antimalarials, vitamin D, statins and vaccination with self-derived peptides. All these immune modulators seem to be particularly useful when introduced in an early stage of the disease.
Assuntos
Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/terapia , Humanos , Imunoterapia , Fatores de TempoRESUMO
OBJECTIVE: Serological testing for myositis-specific or associated autoantibodies [myositis-specific antibody (MSA) and myositis-associated antibody (MAA)] is useful for the diagnosis of idiopathic inflammatory myopathies (IIMs). However, available assays are neither standardized nor validated. The objective is to evaluate the accuracy of a commercial line blot assay for myositis diagnosis. METHODS: IgG antibodies against Jo-1, PL-7, PL-12, PM/Scl, Ku, Mi-2 and Ro52 antigens were detected by a line blot and in-house RNA immunoprecipitation or immunoblot. We tested sera from 208 IIM patients, 50 healthy subjects and 180 control patients (11 non-autoimmune myopathy, 23 muscular dystrophy, 11 UCTD, 68 SLE, 36 SSc, 22 SS and 9 arthropathy). RESULTS: MSAs or MAAs were detected in 98 (47%) out of the 208 IIM patients by line blot: anti-Jo-1 in 43 (21%), anti-PL-7 or anti-PL-12 in 8 (4%), anti-Mi-2 in 9 (4%), anti-PM/Scl in 9 (4%), anti-Ku in 10 (5%) and anti-Ro52 in 49 (24%). Overall specificity was: 100% for anti-Jo-1, anti-PL-7 or PL-12 and anti-PM/Scl; 96% for anti-Ku; 98% for anti-Mi-2; and 76% for anti-Ro52. In-house testing confirmed line blot results regarding anti-Jo-1, anti-PM/Scl and anti-Ku, while it was more accurate than line blot in detecting anti-Mi-2 (7 vs 4% sensitivity, 100 vs 98% specificity), and anti-aminoacyl-tRNA synthetase (anti-ARS) non-Jo-1 antibodies (11 vs 4% sensitivity, 97 vs 99% specificity). CONCLUSIONS: Line blot could be a suitable serological test in the diagnostic workup for myositis, and it represents a reliable alternative to more time-consuming procedures. Continuous effort is recommended in order to improve its accuracy.
Assuntos
Autoanticorpos , Immunoblotting/métodos , Miosite/imunologia , Kit de Reagentes para Diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Estudos de Casos e Controles , Criança , Feminino , Humanos , Immunoblotting/normas , Itália , Masculino , Pessoa de Meia-Idade , Miosite/metabolismo , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Testes Sorológicos/métodos , Testes Sorológicos/normas , Estatística como Assunto , Suécia , Adulto JovemRESUMO
Impairment of the clearance of apoptotic material seems to contribute to autoantigen exposure, which can initiate or maintain an autoimmune response in predisposed individuals. Complement component C1q, Creactive protein (CRP), serum amyloid P (SAP), mannose-binding lectin (MBL), apolipoprotein A-1 (Apo A-1) and long pentraxin 3 (PTX3) are molecules involved in the removal of apoptotic bodies and pathogens, and in other antiinflammatory pathways. For this reason they have been called "protective" molecules. C1q has a key role in the activation of the complement cascade and acts as a bridging molecule between apoptotic bodies and macrophages favouring phagocytosis. In addition to other functions, CRP, SAP and MBL bind to the surface of numerous pathogens as well as cellular debris and activate the complement cascade, thus stimulating their clearance by immune cells. The role of PTX3 is more controversial. In fact, PTX also promotes the clearance of microorganisms, but the activation of the complement cascade through C1q and removal of apoptotic material can be either stimulated or inhibited by this molecule. Antibodies against protective molecules have been recently reported in systemic lupus erythematosus and other autoimmune rheumatic diseases. Some of them seem to be pathogenetic and others protective. Thus, protective molecules and their cognate antibodies may constitute a regulatory network involved in autoimmunity. Dysregulation of this system might contribute to the development of autoimmune diseases in predisposed individuals.
RESUMO
Multiple factors are thought to contribute to the development of immune response to self, including differences in genotypes, hormonal milieu, and environmental factors. This review focuses on the pivotal role of infection in the induction of autoimmune disorders. Although the development of autoimmune phenomena linked to infections is a common finding, the onset of autoimmune diseases is a rare event, arising from a combination of genetic susceptibility and environmental factors. There are several mechanisms through which pathogens can initiate or perpetuate autoimmunity. Some of them are antigen-specific, including molecular mimicry, expression of modified, cryptic, or new antigenic determinants, and superantigens. Others are nonspecific and collectively known as "bystander activation." They include enhanced processing and presentation of self-antigens, immune cell activation, cytokine release, and cell apoptosis/necrosis. Infections may also trigger organ-specific autoimmune diseases, but studies carried out until now have provided conflicting and inconclusive results regarding the role of viral and bacterial agents. Infections and autoimmune diseases have multifaceted and multidirectional relationships. It has been suggested recently that infections cannot only induce or precipitate autoimmune diseases, but they may also protect from autoimmunity or even abrogate an ongoing autoimmune process depending on the interaction between microorganisms and host. Therefore, we should look at microorganisms, not only as causes of infections but also as potential agents able to modulate the immune system. On the other hand, numerous evidences have emerged regarding the higher susceptibility of autoimmune patients to infections, possibly as a result of immunosuppressive therapy and treatment with biologic agents.
Assuntos
Autoimunidade/imunologia , Infecções/imunologia , Animais , Suscetibilidade a Doenças/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , VacinaçãoRESUMO
This study aimed to determine the influence of autoantibodies, polymorphisms in the serotonin pathway, and human leukocyte antigen (HLA) class II genes on age at chronic fatigue syndrome (CFS) onset and symptoms. Eighty-one CFS patients were enrolled, and clinical data were recorded. Autoantibodies to different components of the central nervous system were tested. Polymorphisms in the promoter of the serotonin transporter gene (l/s) and a single nucleotide polymorphism in the serotonin receptor-2A gene (A/G) as well as HLA class II alleles were determined. Multivariate logistic-regression analyses were carried out. The mean age at CFS onset +/- SD was 33.5 +/- 12.5 years. An age at CFS onset (ACFSO) during the third decade of life was associated with the serotonin receptor AA genotype and the HLA-DRB1*03 allele. An ACFSO during the fourth decade of life was associated with the HLA-DRB1*07 allele, whereas an ACFSO > or = 43 years was associated with having at least one copy of the serotonin G allele. Concerning CFS symptoms, the serotonin AG genotype was protective against depressive symptoms. Although having at least one copy of the serotonin A allele and being female were associated with risk for arthralgia, the presence of antineuronal cell antibodies was protective against this. Episodes of unexplained fever were associated with the HLA-DRB1*11 allele. None of the genetic or serological features was associated with myalgia. None of the antibodies determined correlated with any ACFSO or other symptoms. Our results reveal that in CFS, like other autoimmune diseases, different genetic features are related to age at CFS onset and symptoms.
Assuntos
Autoanticorpos/sangue , Síndrome de Fadiga Crônica/genética , Antígenos HLA-DR/genética , Polimorfismo Genético , Receptor 5-HT2A de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Fatores Etários , Idade de Início , Alelos , Artralgia/genética , Artralgia/imunologia , Ensaio de Imunoadsorção Enzimática , Síndrome de Fadiga Crônica/epidemiologia , Síndrome de Fadiga Crônica/imunologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Cadeias HLA-DRB1 , Humanos , Itália , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Fatores Sexuais , Adulto JovemRESUMO
Commercial blot assays are advanced applications of immunoblotting or dot immunobinding methodologies for the detection of specific autoantibodies in autoimmune diseases. Line(Dot) blots in particular have cost-effectively optimized a sort of multiparametric assay for simultaneous determination of several autoantibody reactivities. Efficient and wide-spectrum potentialities of recombinant DNA technology and proteomics are fruitfully employed by manufacturers in order to obtain highly purified antigens or novel targets to be spotted on blot matrices thus continuously implementing their multianalytic platforms. At present most widely used commercial blot assays for the diagnosis of connective tissue diseases can detect autoantibodies to several Extractable Nuclear Antigens or myositis and/or scleroderma associated autoantigens. They actually represent an important step-forward in the methodological panorama designed for the autoimmunity laboratory. However continuous effort in order to validate and improve clinical reliability of commercially available blot assays should be carried out. In this short review, our preliminary contribution on the validation of a commercial line blot assay for the laboratory diagnosis of autoimmune myositis is briefly reported.
Assuntos
Autoanticorpos/sangue , Autoantígenos/imunologia , Doenças Autoimunes/diagnóstico , Immunoblotting/métodos , Miosite/diagnóstico , Doenças Reumáticas/diagnóstico , HumanosRESUMO
OBJECTIVES: To review the physiological and physiopathological roles of pentraxin 3 (PTX3), focusing on autoimmunity and vascular pathology. METHODS: A systematic literature review using the keywords "pentraxin 3," "innate immunity," "apoptosis," "autoimmunity," and "endothelial dysfunction" from 1990 to 2007 was performed. All relevant articles and pertinent secondary references in English were reviewed. RESULTS: PTX3 has a large number of multiple functions in different contexts. PTX3 plays an important role in innate immunity, inflammation, vascular integrity, fertility, pregnancy, and also in the central nervous system. In innate immunity, its normal function is to increase the immune response to selected pathogens while also exerting control over potential autoimmune reactions. It maintains a tightly homeostatic equilibrium in the local immune microenvironment by avoiding an exaggerated immune response and controlling peripheral tolerance to self-antigens. In contrast, in some autoimmune diseases, PTX3 appears to be involved in the development of autoimmune phenomena. A possible explanation for these apparent paradoxical functions may be related to the highly polymorphic PTX3 gene. CONCLUSION: PTX3 is physiologically a protective molecule. However, in several autoimmune diseases PTX3 appears to facilitate the development of autoimmunity. The PTX3 gene could influence the development of autoimmune reactions and vascular involvement in human pathology.