RESUMO
Rheumatic fever (RF) and chronic rheumatic heart disease (RHD) are complications of oropharyngeal infection caused by Streptococcus pyogenes. Despite the importance of the complement system against infections and autoimmunity diseases, studies on the role of the lectin pathway in RF and RHD are scarce. Thus, our aim was to evaluate the association of ficolin-3 serum levels, FCN3 polymorphisms and haplotypes with the susceptibility to RF and RHD. We investigated 179 patients with a history of RF (126 RHD and 53 RF only) and 170 healthy blood donors as control group. Ficolin-3 serum concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Three FCN3 single nucleotide polymorphisms (SNPs rs532781899, rs28362807 and rs4494157) were genotyped through the sequence-specific PCR method. Lower ficolin-3 serum levels were observed in RF patients when compared to controls (12.81 µg/mL vs. 18.14 µg/mL respectively, p < 0.0001, OR 1.22 [1.12-1.34]), and in RHD in comparison to RF only (RFo) (12.72 µg/mL vs. 14.29 µg/mL respectively, p = 0.016, OR 1.38 [1.06-1.80]). Low ficolin-3 levels (<10.7 µg/mL) were more common in patients (39.5 %, 30/76) than controls (20.6 %, 13/63, p = 0.018, OR = 2.51 [1.14-5.31]), and in RHD (44.4 %, 28/63) than RFo (15.4 %, 2/13, p = 0.007, OR = 3.08 [1.43-6.79]). On the other hand, FCN3 polymorphism/haplotypes were not associated with ficolin-3 serum levels or the disease. Low ficolin-3 levels might be associated with RF, being a potential marker of disease progression.
Assuntos
Suscetibilidade a Doenças , Lectinas/genética , Febre Reumática/etiologia , Febre Reumática/metabolismo , Cardiopatia Reumática/etiologia , Adulto , Alelos , Biomarcadores , Feminino , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Lectinas/sangue , Lectinas/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Febre Reumática/diagnóstico , Cardiopatia Reumática/diagnóstico , Cardiopatia Reumática/metabolismoRESUMO
Rheumatic fever (RF) and rheumatic heart disease (RHD) follow untreated S. pyogenes throat infections in children who present susceptible genes that favor the development of autoimmune reactions. In this review, we focus on the genes that confer susceptibility and on the autoimmune reactions that occur due to molecular mimicry between human-tissue proteins and streptococcal M protein. Polyarthritis is the initial manifestation, which can evolve to carditis and severe valve damage; these culminate in rheumatic heart disease (RHD) or Sydenham's chorea, which affects the central nervous system. A perspective on vaccine development to prevent the disease is also discussed.
Assuntos
Cardiopatia Reumática/metabolismo , Cardiopatia Reumática/prevenção & controle , Vacinas/uso terapêutico , Autoimunidade , Coreia/etiologia , Coreia/imunologia , Coreia/metabolismo , Coreia/prevenção & controle , Citocinas/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Mimetismo Molecular , Febre Reumática/etiologia , Febre Reumática/imunologia , Febre Reumática/metabolismo , Febre Reumática/prevenção & controle , Cardiopatia Reumática/etiologia , Cardiopatia Reumática/imunologia , Streptococcus pyogenesRESUMO
Fructose 1,6-bisphosphate (FBP) is an endogenous intermediate of the glycolytic pathway. Exogenous administration of FBP has been shown to exert protective effects in a variety of ischemic injury models, which are attributed to its ability to sustain glycolysis and increase ATP production. Here, we demonstrated that a single treatment with FBP markedly attenuated arthritis, assessed by reduction of articular hyperalgesia, joint swelling, neutrophil infiltration and production of inflammatory cytokines, TNF and IL-6, while enhancing IL-10 production in two mouse models of arthritis. Our mechanistic studies showed that FBP reduces joint inflammation through the systemic generation of extracellular adenosine and subsequent activation of adenosine receptor A2a (A2aR). Moreover, we showed that FBP-induced adenosine generation requires hydrolysis of extracellular ATP through the activity of the ectonucleosides triphosphate diphosphohydrolase-1 (ENTPD1, also known as CD39) and ecto-5'-nucleotidase (E5NT, also known as CD73). In accordance, inhibition of CD39 and CD73 abolished anti-arthritic effects of FBP. Taken together, our findings provide a new insight into the molecular mechanism underlying the anti-inflammatory effect of FBP, showing that it effectively attenuates experimental arthritis by activating the anti-inflammatory adenosinergic pathway. Therefore, FBP may represent a new therapeutic strategy for treatment of rheumatoid arthritis (RA).
Assuntos
Adenosina/metabolismo , Anti-Inflamatórios/farmacologia , Artrite Experimental/metabolismo , Frutosedifosfatos/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , 5'-Nucleotidase/antagonistas & inibidores , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Antígenos CD , Apirase/antagonistas & inibidores , Artrite Experimental/tratamento farmacológico , Artrite Experimental/etiologia , Artrite Experimental/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Espaço Extracelular/metabolismo , Glicólise , Masculino , Camundongos , Receptor A2A de Adenosina/metabolismo , Febre Reumática/tratamento farmacológico , Febre Reumática/metabolismoRESUMO
Due to its importance both in the clearance of pathogens that contribute as rheumatic etiological agents and in the disposal of apoptotic bodies and potential autoimmune initiators, deficiencies of the components of the lectin pathway of complement have been found to increase susceptibility and modulate the severity of most rheumatic disorders. This chapter introduces the general aspects of the structure, function, and genetics of lectin pathway components and summarizes current knowledge of the field regarding rheumatic diseases predisposition and modulation.
Assuntos
Artrite Reumatoide/metabolismo , Lectina de Ligação a Manose da Via do Complemento/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Lectinas de Ligação a Manose/metabolismo , Febre Reumática/metabolismo , Síndrome de Sjogren/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Lectinas de Ligação a Manose/química , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/imunologia , Polimorfismo Genético , Febre Reumática/imunologia , Febre Reumática/fisiopatologia , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/fisiopatologiaRESUMO
Molecular mimicry between streptococcal and human proteins is considered as the triggering factor leading to autoimmunity in rheumatic fever (RF) and rheumatic heart disease (RHD). Here, we present a review of the genetic susceptibility markers involved in the development of RF/RHD and the major immunopathological events underlying the pathogenesis of RF and RHD. Several human leucocyte antigen (HLA) class II alleles are associated with the disease. Among these alleles, HLA-DR7 is predominantly observed in different ethnicities and is associated with the development of valvular lesions in RHD patients. Cardiac myosin is one of the major autoantigens involved in rheumatic heart lesions and several peptides from the LMM (light meromyosin) region were recognized by peripheral and intralesional T-cell clones from RF and RHD patients. The production of TNF-alpha and IFN-gamma from heart-infiltrating mononuclear cells suggests that Th-1 type cytokines are the mediators of RHD heart lesions while the presence of few interleukin-4 producing cells in the valve tissue contributes to the maintenance and progression of the valvular lesions.
Assuntos
Febre Reumática/genética , Febre Reumática/imunologia , Cardiopatia Reumática/genética , Cardiopatia Reumática/imunologia , Sequência de Aminoácidos , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Humanos , Dados de Sequência Molecular , Febre Reumática/metabolismo , Febre Reumática/patologia , Cardiopatia Reumática/metabolismo , Cardiopatia Reumática/patologiaRESUMO
Molecular mimicry between streptococcal and human proteins has been proposed as the triggering factor leading to autoimmunity in rheumatic fever (RF) and rheumatic heart disease (RHD). This article summarises studies on genetic susceptibility markers involved in the development of RF/RHD. It also focuses on the molecular mimicry in RHD mediated by the responses of B and T cells of peripheral blood, and T cells infiltrating heart lesions, against streptococcal antigens and human tissue proteins. The molecular basis of T-cell recognition is assessed through the definition of heart-crossreactive antigens. The production of cytokines from peripheral and heart-infiltrating mononuclear cells suggests that T helper 1 (Th1)-type cytokines are the mediators of RHD heart lesions. An insufficiency of interleukin 4 (IL-4)-producing cells in the valvular tissue might contribute to the maintenance and progression of valve lesions.
Assuntos
Febre Reumática , Cardiopatia Reumática , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/microbiologia , Humanos , Febre Reumática/imunologia , Febre Reumática/metabolismo , Febre Reumática/microbiologia , Cardiopatia Reumática/imunologia , Cardiopatia Reumática/metabolismo , Cardiopatia Reumática/microbiologia , Streptococcus pyogenes/imunologiaRESUMO
We have explored the therapeutic potential of statins in patients with different inflammatory rheumatic diseases refractory to conventional therapy. We found that simvastatin (80mg o.d. for eight days) induced a rapid and significant reduction in proteinuria levels in three systemic lupus erythematosus (SLE) patients. A similar kind of therapy had a marked beneficial effect in a patient with Wegener's granulomatosis and a patient with erythema nodosum. On the other hand, five patients with rheumatoid arthritis (RA) who received atorvastatin for eight days (20mg/day) showed reduction in C-reactive protein levels and a clinical improvement that was classified as an ACR20 response. Prior to the administration of statins, all these patients had received aggressive conventional therapy with no satisfactory response. A significant reduction in spontaneous apoptosis of peripheral blood lymphocytes and expression of CD69 and HLA-DR was observed in SLE patients after simvastatin therapy. These results prompted us to perform a pilot short-time comparative (simvastatin versus chloroquine) open clinical trial in 15 patients with RA who were receiving methotrexate as a single disease modifying antirheumatic drug with no satisfactory response. Most patients (9/10) who received simvastatin (40mg/day) showed an ACR50 or better response after eight weeks, whereas such a response was not observed in any patient (0/5) treated with chloroquine. Our preliminary results indicate that statins may be an important therapeutic tool for the treatment of inflammatory rheumatic diseases.