RESUMO
The complement system plays a crucial role in orchestrating the activation and regulation of inflammation within the human immune system. Three distinct activation pathways-classical, lectin, and alternative-converge to form the common lytic pathway, culminating in the formation of the membrane-attacking complex that disrupts the structure of pathogens. Dysregulated complement system activity can lead to tissue damage, autoimmune diseases, or immune deficiencies. In this study, the antimicrobial activity of human serum was investigated by using a bioluminescent microbe probe, Escherichia coli (pEGFPluxABCDEamp). This probe has previously been used to determine the antimicrobial activity of complement system and the polymorphonuclear neutrophils. In this study, blocking antibodies against key serum activators and components, including IgG, complement component 1q, factor B, and properdin, were utilized. The influence of body temperature and acute phase proteins, such as C reactive protein (CRP) and serum amyloid alpha (SAA), on the complement system was also examined. The study reveals the critical factors influencing complement system activity and pathway function. Alongside crucial factors like C1q and IgG, alternative pathway components factor B and properdin played pivotal roles. Results indicated that the alternative pathway accounted for approximately one third of the overall serum antimicrobial activity, and blocking this pathway disrupted the entire complement system. Contrary to expectations, elevated body temperature during inflammation did not enhance the antimicrobial activity of human serum. CRP demonstrated complement activation properties, but at higher physiological concentrations, it exhibited antagonistic tendencies, dampening the response. On the other hand, SAA enhanced the serum's activity. Overall, this study sheds a light on the critical factors affecting both complement system activity and pathway functionality, emphasizing the importance of a balanced immune response.
Assuntos
Temperatura Corporal , Proteína C-Reativa , Ativação do Complemento , Complemento C1q , Fator B do Complemento , Properdina , Proteína Amiloide A Sérica , Humanos , Proteína C-Reativa/metabolismo , Proteína C-Reativa/imunologia , Complemento C1q/imunologia , Complemento C1q/metabolismo , Proteína Amiloide A Sérica/metabolismo , Proteína Amiloide A Sérica/imunologia , Properdina/imunologia , Properdina/metabolismo , Fator B do Complemento/metabolismo , Fator B do Complemento/imunologia , Temperatura Corporal/imunologia , Escherichia coli/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologiaRESUMO
Despite the existence of potent anti-inflammatory biological drugs e.g., anti-TNF and anti IL-6 receptor antibodies, for treating chronic inflammatory and autoimmune diseases, these are costly and not specific. Cheaper oral available drugs remain an unmet need. Expression of the acute phase protein Serum Amyloid A (SAA) is dependent on release of pro-inflammatory cytokines IL-1, IL-6 and TNF-α during inflammation. Conversely, SAA induces pro-inflammatory cytokine secretion, including Th17, leading to a pathogenic vicious cycle and chronic inflammation. 5- MER peptide (5-MP) MTADV (methionine-threonine-alanine-aspartic acid-valine), also called Amilo-5MER, was originally derived from a sequence of a pro-inflammatory CD44 variant isolated from synovial fluid of a Rheumatoid Arthritis (RA) patient. This human peptide displays an efficient anti-inflammatory effects to ameliorate pathology and clinical symptoms in mouse models of RA, Inflammatory Bowel Disease (IBD) and Multiple Sclerosis (MS). Bioinformatics and qRT-PCR revealed that 5-MP, administrated to encephalomyelytic mice, up-regulates genes contributing to chronic inflammation resistance. Mass spectrometry of proteins that were pulled down from an RA synovial cell extract with biotinylated 5-MP, showed that it binds SAA. 5-MP disrupted SAA assembly, which is correlated with its pro-inflammatory activity. The peptide MTADV (but not scrambled TMVAD) significantly inhibited the release of pro-inflammatory cytokines IL-6 and IL-1ß from SAA-activated human fibroblasts, THP-1 monocytes and peripheral blood mononuclear cells. 5-MP suppresses the pro-inflammatory IL-6 release from SAA-activated cells, but not from non-activated cells. 5-MP could not display therapeutic activity in rats, which are SAA deficient, but does inhibit inflammations in animal models of IBD and MS, both are SAA-dependent, as shown by others in SAA knockout mice. In conclusion, 5-MP suppresses chronic inflammation in animal models of RA, IBD and MS, which are SAA-dependent, but not in animal models, which are SAA-independent.
Assuntos
Artrite Reumatoide/imunologia , Receptores de Hialuronatos/genética , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Esclerose Múltipla/imunologia , Peptídeos/genética , Proteína Amiloide A Sérica/imunologia , Animais , Anti-Inflamatórios/uso terapêutico , Autoimunidade , Células Cultivadas , Biologia Computacional , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Knockout , Peptídeos/uso terapêutico , Proteína Amiloide A Sérica/genéticaRESUMO
Despite its critical roles in immune responses against tuberculosis infection and immune pathology, the molecular details of interleukin (IL)-1ß production in tuberculosis infection remain elusive. To explore IL-1ß production in tuberculosis infection, we infected mouse bone marrow-derived macrophages (BMDM) with Mycobacterium tuberculosis (Mtb) H37Rv, its early secreted antigenic target protein of 6 kDa (ESAT-6) gene deletion (H37Rv:Δ3875) or complemented strain (H37Rv:Δ3875C) and evaluated IL-1ß production. H37Rv induced significantly increased IL-1ß production by BMDMs compared to non-infected BMDMs. In contrast, H37Rv:Δ3875 induced significantly less mature IL-1ß production despite eliciting comparable levels of pro-IL-1ß and IL-8 from BMDMs compared to H37Rv and H37Rv:Δ3875C. Blocking either NLRP3 or K+ efflux diminished H37Rv-induced IL-1ß production by BMDMs. Infection of mice intranasally with H37Rv:Δ3875 induced less IL-1ß production in the lungs compared with H37Rv. Intranasal delivery of ESAT-6 but not CFP10 induced production of IL-1ß in mouse lungs and RNA-Seq analysis identified serum amyloid A (SAA) 3 as one of the highly expressed genes in mouse lungs. Infection of mice with H37Rv but not H37Rv:Δ3875 induced expression of lung SAA3 mRNA and protein, consistent with the effect of intranasal delivery of ESAT-6. Silencing SAA3 reduced Mtb-induced IL-1ß production by BMDMs. We conclude that SAA3 plays critical role in ESAT-6 dependent IL-1ß production by macrophages in tuberculosis infection.
Assuntos
Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Interleucina-1beta/biossíntese , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Proteína Amiloide A Sérica/imunologia , Animais , Feminino , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína Amiloide A Sérica/genética , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologiaRESUMO
Amyloid A nephropathy is a possible complication of chronic inflammatory disease. Proteinuria and kidney failure are the main features of the disease. Tocilizumab (TCZ), an IL6-R antibody approved for rheumatoid arthritis, is a promising choice for histologically demonstrated nephropathy. We describe a case of kidney amyloid associated with Sweet syndrome treated with TCZ. The patient was affected by Sweet syndrome associated with proteinuria. Kidney biopsy showed amyloid deposits. During the follow-up, cutaneous and renal findings were refractory to many immunosuppressive regimen (cyclophosphamide, leflunomide, interferon and steroid). After few years, the patient developed rapidly progressive nephropathy associated with nephrotic syndrome (proteinuria up to 6 g/die). A second kidney biopsy was performed and it showed worsening of amyloid nephropathy. Thus, TCZ was administrated (8 mg/kg once a month) and it stabilized kidney function and induced partial remission of the nephrotic syndrome in the following 2 years.
Assuntos
Amiloidose/diagnóstico , Anticorpos Monoclonais Humanizados/uso terapêutico , Rim/patologia , Receptores de Interleucina-6/antagonistas & inibidores , Síndrome de Sweet/diagnóstico , Amiloidose/complicações , Amiloidose/tratamento farmacológico , Amiloidose/imunologia , Amiloidose/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Biópsia , Humanos , Rim/ultraestrutura , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/etiologia , Proteinúria/etiologia , Indução de Remissão , Insuficiência Renal/diagnóstico , Insuficiência Renal/etiologia , Proteína Amiloide A Sérica/imunologia , Síndrome de Sweet/complicações , Síndrome de Sweet/patologiaRESUMO
We report two cases of idiopathic multicentric Castleman disease (iMCD) with nephrotic syndrome (NS) treated with tocilizumab. Case 1 was a 58-year-old man diagnosed with iMCD prior to the onset of NS. Renal biopsy revealed membranous nephropathy, which was considered to be secondary membranous nephropathy associated with iMCD. Case 2 was a 49-year-old woman diagnosed with iMCD prior to NS. Renal biopsy revealed renal amyloidosis positive for Congo red staining and amyloid A protein immunostaining. In both the cases, the proteinuria improved after the initiation of glucocorticoid and tocilizumab therapy. Tocilizumab may be a good therapeutic choice for iMCD with NS.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Síndrome Nefrótica/tratamento farmacológico , Receptores de Interleucina-6/antagonistas & inibidores , Amiloidose/diagnóstico , Amiloidose/imunologia , Amiloidose/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Biópsia , Hiperplasia do Linfonodo Gigante/complicações , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/patologia , Quimioterapia Combinada , Feminino , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/patologia , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Rim/patologia , Rim/ultraestrutura , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/etiologia , Proteína Amiloide A Sérica/imunologia , Proteína Amiloide A Sérica/metabolismo , Resultado do TratamentoAssuntos
Hipersensibilidade , Animais , Asma/tratamento farmacológico , Asma/imunologia , Cosméticos/efeitos adversos , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/imunologia , Hipersensibilidade/prevenção & controle , Hipersensibilidade/terapia , Interleucina-33/antagonistas & inibidores , Interleucina-33/imunologia , Ferro/química , Ferro/imunologia , Lactoglobulinas/química , Lactoglobulinas/imunologia , Camundongos , Hipersensibilidade a Leite/imunologia , Hipersensibilidade a Amendoim/imunologia , Hipersensibilidade a Amendoim/prevenção & controle , Hipersensibilidade a Amendoim/terapia , Prurido/induzido quimicamente , Prurido/complicações , Prurido/imunologia , Prurido/prevenção & controle , Pyroglyphidae/imunologia , Proteína Amiloide A Sérica/deficiência , Proteína Amiloide A Sérica/imunologia , Pele/imunologia , Pele/patologia , Linfócitos T/imunologia , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/imunologiaRESUMO
The ability of HDL to inhibit inflammation in adipocytes and adipose tissue is reduced when HDL contains serum amyloid A (SAA) that is trapped by proteoglycans at the adipocyte surface. Because we recently found that the major extracellular matrix proteoglycan produced by hypertrophic adipocytes is versican, whereas activated adipose tissue macrophages produce mainly biglycan, we further investigated the role of proteoglycans in determining the antiinflammatory properties of HDL. The distributions of versican, biglycan, apolipoprotein A1 (the major apolipoprotein of HDL), and SAA were similar in adipose tissue from obese mice and obese human subjects. Colocalization of SAA-enriched HDL with versican and biglycan at the cell surface of adipocyte and peritoneal macrophages, respectively, was blocked by silencing these proteoglycans, which also restored the antiinflammatory property of SAA-enriched HDL despite the presence of SAA. Similar to adipocytes, normal HDL exerted its antiinflammatory function in macrophages by reducing lipid rafts, reactive oxygen species generation, and translocation of Toll-like receptor 4 and NADPH oxidase 2 into lipid rafts, effects that were not observed with SAA-enriched HDL. These findings imply that SAA present in HDL can be trapped by adipocyte-derived versican and macrophage-derived biglycan, thereby blunting HDL's antiinflammatory properties.
Assuntos
Adipócitos/imunologia , Biglicano/imunologia , Lipoproteínas HDL/imunologia , Macrófagos Peritoneais/imunologia , Obesidade/imunologia , Proteína Amiloide A Sérica/imunologia , Versicanas/imunologia , Adipócitos/patologia , Adulto , Animais , Apolipoproteína A-I/genética , Apolipoproteína A-I/imunologia , Biglicano/antagonistas & inibidores , Biglicano/genética , Dieta Hiperlipídica/efeitos adversos , Feminino , Regulação da Expressão Gênica , Humanos , Resistência à Insulina/imunologia , Lipoproteínas HDL/genética , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/etiologia , Obesidade/genética , Obesidade/patologia , Ligação Proteica , Transporte Proteico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Proteína Amiloide A Sérica/genética , Nitrato de Prata/administração & dosagem , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Versicanas/antagonistas & inibidores , Versicanas/genéticaRESUMO
BACKGROUND: There are limited data on the outcome of transplant recipients with familial Mediterranean fever (FMF)-associated AA amyloidosis. The aim of the present study is to evaluate demographic, clinical, laboratory, and prognostic characteristics and outcome measures of these patients. METHODS: Eighty-one renal transplant recipients with FMF-associated AA amyloidosis (group 1) and propensity score-matched transplant recipients (group 2, n = 81) with nonamyloidosis etiologies were evaluated in this retrospective, multicenter study. Recurrence of AA amyloidosis was diagnosed in 21 patients (group 1a), and their features were compared with 21 propensity score-matched recipients with FMF amyloidosis with no laboratory signs of recurrence (group 1b). RESULTS: The risk of overall allograft loss was higher in group 1 compared with group 2 (25 [30.9%] versus 12 [14.8%]; P = 0.015 [hazard ratio, 2.083; 95% confidence interval, 1.126-3.856]). Patients in group 1 were characterized by an increased risk of mortality compared with group 2 (11 [13.6%] versus 0%; P = 0.001 [hazard ratio, 1.136; 95% confidence interval, 1.058-1.207]). Kaplan-Meier analysis revealed that 5- and 10-year patient survival rates in group 1 (92.5% and 70.4%) were significantly lower than in group 2 (100% and 100%; P = 0.026 and P = 0.023, respectively). Although not reaching significance, overall, 5- and 10-year graft survival rates (57.1%, 94.7%, and 53.8%, respectively) in group 1a were worse than in group 1b (76.2%, 95%, and 77.8%, respectively; P = 0.19, P = 0.95, and P = 0.27, respectively). CONCLUSIONS: AA amyloidosis is associated with higher risk of mortality after kidney transplantation. Inflammatory indicators should be monitored closely, and persistent high levels of acute-phase reactants should raise concerns about amyloid recurrence in allograft.
Assuntos
Amiloidose/cirurgia , Febre Familiar do Mediterrâneo/complicações , Rejeição de Enxerto/mortalidade , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Adulto , Aloenxertos/imunologia , Aloenxertos/patologia , Amiloidose/imunologia , Amiloidose/mortalidade , Amiloidose/patologia , Biópsia , Febre Familiar do Mediterrâneo/imunologia , Febre Familiar do Mediterrâneo/mortalidade , Febre Familiar do Mediterrâneo/cirurgia , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto/imunologia , Humanos , Estimativa de Kaplan-Meier , Rim/imunologia , Rim/patologia , Falência Renal Crônica/imunologia , Falência Renal Crônica/mortalidade , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Proteína Amiloide A Sérica/imunologia , Proteína Amiloide A Sérica/metabolismo , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE OF REVIEW: The immune determinants of granuloma formation and disease progression in sarcoidosis have not been completely disclosed, and the role of both innate and the adaptive immunity is still under investigation. RECENT FINDINGS: M2 macrophage polarization, previously thought to be a specific feature of a progressing and fibrosing disease, has been related to the initial steps of granuloma formation both in animal and in-vitro models. The dysregulation of specific metabolic pathways and autophagy has been associated with disease activity and progression. T cells have been reported to be strongly influenced by a macrophage-driven microenvironment and more dangerous when acquiring hybrid phenotypes (e.g. Th17.1) or even becoming anergic, leading to disease chronicization. Locally released serum amyloid A was suggested to induce a more pro-inflammatory Th17 transcription program. The possible role of in-situ humoral immunity and bone marrow-derived mesenchymal stromal cells has also been highlighted. SUMMARY: Evidence points at microenvironment and cell functional features rather than cell polarization or differentiation as determinants of pathogenesis. In terms of therapeutic implications, future advances will rely on molecular disease profiling, aiming at personalized and combined therapeutic approaches.
Assuntos
Microambiente Celular/imunologia , Sarcoidose/imunologia , Proteína Amiloide A Sérica/imunologia , Células Th17/imunologia , Imunidade Adaptativa , Autofagia/imunologia , Diferenciação Celular , Anergia Clonal/imunologia , Expressão Gênica , Humanos , Imunidade Inata/imunologia , Macrófagos , Macrófagos Alveolares , Células Th1/imunologiaRESUMO
Serum amyloid A1 (SAA1) is an acute phase protein produced mainly by the liver to participate in immunomodulation in both sterile and non-sterile inflammation. However, non-hepatic tissues can also synthesize SAA1. It remains to be determined whether SAA1 synthesized locally in the placenta participates in parturition via eliciting inflammatory reactions. In this study, we investigated this issue by using human placenta and a mouse model. We found that SAA1 mRNA and protein were present in human placental villous trophoblasts, which was increased upon syncytialization as well as treatments with lipopolysaccharides (LPS), tumor necrosis factor-α (TNF-α), and cortisol. Moreover, significant increases in SAA1 abundance were observed in the placental tissue or in the maternal blood in spontaneous deliveries without infection at term and in preterm birth with histological chorioamnionitis. Serum amyloid A1 treatment significantly increased parturition-pertinent inflammatory gene expression including interleukin-1ß (IL-1ß), IL-8, TNF-α, and cyclooxygenase-2 (COX-2), along with increased PGF2α production in syncytiotrophoblasts. Mouse study showed that SAA1 was present in the placental junctional zone and yolk sac membrane, which was increased following intraperitoneal administration of LPS. Intraperitoneal injection of SAA1 not only induced preterm birth but also increased the abundance of IL-1ß, TNF-α, and COX-2 in the mouse placenta. Conclusively, SAA1 can be synthesized in the human placenta, which is increased upon trophoblast syncytialization. Parturition is accompanied with increased SAA1 abundance in the placenta. Serum amyloid A1 may participate in parturition in the presence and absence of infection by inducing the expression of inflammatory genes in the placenta.
Assuntos
Parto/metabolismo , Placenta/metabolismo , Proteína Amiloide A Sérica/biossíntese , Adulto , Animais , Corioamnionite/genética , Corioamnionite/imunologia , Corioamnionite/metabolismo , Membranas Extraembrionárias/imunologia , Membranas Extraembrionárias/metabolismo , Feminino , Expressão Gênica , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Parto/genética , Parto/imunologia , Placenta/imunologia , Gravidez , Nascimento Prematuro/genética , Nascimento Prematuro/imunologia , Nascimento Prematuro/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Amiloide A Sérica/genética , Proteína Amiloide A Sérica/imunologia , Trofoblastos/imunologia , Trofoblastos/metabolismoRESUMO
Maintenance of homeostasis at body barriers that are constantly challenged by microbes, toxins and potentially bioactive (macro)molecules requires complex, highly orchestrated mechanisms of protection. Recent discoveries in respiratory research have shed light on the unprecedented role of airway epithelial cells (AEC), which, besides immune cells homing to the lung, also significantly contribute to host defence by expressing membrane-bound and soluble pattern recognition receptors (sPRR). Recent evidence suggests that distinct, evolutionary ancient, sPRR secreted by AEC might become activated by usually innocuous proteins, commonly referred to as allergens. We here provide a systematic overview on sPRR detectable in the mucus lining of AEC. Some of them become actively produced and secreted by AECs (like the pentraxins C-reactive protein and pentraxin 3; the collectins mannose binding protein and surfactant proteins A and D; H-ficolin; serum amyloid A; and the complement components C3 and C5). Others are elaborated by innate and adaptive immune cells such as monocytes/macrophages and T cells (like the pentraxins C-reactive protein and pentraxin 3; L-ficolin; serum amyloid A; and the complement components C3 and C5). Herein we discuss how sPRRs may contribute to homeostasis but sometimes also to overt disease (e.g. airway hyperreactivity and asthma) at the alveolar-air interface.
Assuntos
Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Proteína C-Reativa/imunologia , Homeostase/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Mucosa Respiratória/imunologia , Alérgenos/administração & dosagem , Animais , Asma/genética , Asma/patologia , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/patologia , Proteína C-Reativa/genética , Colectinas/genética , Colectinas/imunologia , Complemento C3/genética , Complemento C3/imunologia , Complemento C5/genética , Complemento C5/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica , Homeostase/genética , Humanos , Lectinas/genética , Lectinas/imunologia , Receptores de Reconhecimento de Padrão/genética , Mucosa Respiratória/patologia , Proteína Amiloide A Sérica/genética , Proteína Amiloide A Sérica/imunologia , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/imunologiaRESUMO
Serum amyloid A (SAA), one of the major highly conserved acute-phase proteins in most mammals, is predominantly produced by hepatocytes and also by a variety of cells in extrahepatic tissues. It is well-known that the expression of SAA is sharply increased in bacterial infections. However, the exact physiological function of SAA during bacterial infection remains unclear. Herein, we showed that SAA expression significantly increased in abscesses of Staphylococcus aureus cutaneous infected mice, which exert direct antibacterial effects by binding to the bacterial cell surface and disrupting the cell membrane in acidic conditions. Mechanically, SAA disrupts anionic liposomes by spontaneously forming small vesicles or micelles under acidic conditions. Especially, the N-terminal region of SAA is necessary for membrane disruption and bactericidal activity. Furthermore, we found that mice deficient in SAA1/2 were more susceptible to infection by S. aureus In addition, the expression of SAA in infected skin was regulated by interleukin-6. Taken together, these findings support a key role of the SAA in host defense and may provide a novel therapeutic strategy for cutaneous bacterial infection.
Assuntos
Antibacterianos/metabolismo , Imunidade Inata , Proteína Amiloide A Sérica/metabolismo , Infecções Estafilocócicas/imunologia , Infecções Cutâneas Estafilocócicas/imunologia , Proteínas de Fase Aguda/imunologia , Proteínas de Fase Aguda/metabolismo , Animais , Antibacterianos/farmacologia , Aderência Bacteriana , Membrana Celular/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Interleucina-6/fisiologia , Camundongos , Proteína Amiloide A Sérica/imunologia , Proteína Amiloide A Sérica/farmacologia , Staphylococcus aureus/citologia , Staphylococcus aureus/ultraestruturaRESUMO
Expression of the acute phase protein serum amyloid A (SAA) is dependent on the release of the pro-inflammatory cytokines IL-1, IL-6 and TNF-α during infection and inflammation. Hepatitis C virus (HCV) upregulates SAA-inducing cytokines. In line with this, a segment of chronically infected individuals display increased circulating levels of SAA. SAA has even been proposed to be a potential biomarker to evaluate treatment efficiency and the course of disease. SAA possesses antiviral activity against HCV via direct interaction with the viral particle, but might also divert infectivity through its function as an apolipoprotein. On the other hand, SAA shares inflammatory and angiogenic activity with chemotactic cytokines by activating the G protein-coupled receptor, formyl peptide receptor 2. These latter properties might promote chronic inflammation and hepatic injury. Indeed, up to 80 % of infected individuals develop chronic disease because they cannot completely clear the infection, due to diversion of the immune response. In this review, we summarize the interconnection between SAA and cytokines in the context of HCV infection and highlight the dual role SAA could play in this disease. Nevertheless, more research is needed to establish whether the balance between those opposing activities can be tilted in favor of the host defense.
Assuntos
Citocinas/imunologia , Hepatite C/imunologia , Hepatite C/fisiopatologia , Proteína Amiloide A Sérica/imunologia , Animais , Citocinas/genética , Hepacivirus , Humanos , Inflamação , Fígado/imunologia , Fígado/patologia , Camundongos , Receptores de Formil Peptídeo/genética , Receptores de Formil Peptídeo/imunologia , Receptores de Lipoxinas/genética , Receptores de Lipoxinas/imunologia , Proteína Amiloide A Sérica/análiseRESUMO
Serum amyloid A (SAA) is an acute-phase protein indicative of inflammation. In murine colonic epithelial cells, lipopolysaccharide (LPS), a gram-negative bacterial antigen, strongly enhanced mRNA expression of SAA3, but not SAA1 or SAA2, suggesting that SAA3 might respond to bacterial infection in other epithelia. We examined SAA1/2 and SAA3 mRNA expression in murine alveolar epithelial cells exposed to LPS or the gram-positive bacterial antigen, lipoteichoic acid (LTA), using real-time PCR. LPS enhanced SAA3 mRNA expression at lower concentrations than did LTA, whereas SAA1/2 mRNA expression was not enhanced by either LPS or LTA. These results suggest that SAA3 expression is enhanced in lung epithelium upon bacterial infection as part of innate immunity, with higher sensitivity to LPS than to LTA.
Assuntos
Proteína Amiloide A Sérica , Células Epiteliais Alveolares/metabolismo , Animais , Linhagem Celular , Imunidade Inata , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/metabolismo , Camundongos , RNA Mensageiro/metabolismo , Proteína Amiloide A Sérica/genética , Proteína Amiloide A Sérica/imunologia , Proteína Amiloide A Sérica/metabolismo , Ácidos Teicoicos/metabolismoRESUMO
Serum amyloid A (SAA) is an acute phase protein with pro-inflammatory cytokine-like properties. Recent studies have revealed that SAA promoted interleukin-17 (IL-17) production by various cells, including γδ T cells. γδ T cells are innate immune cells and express Toll-like receptor 2 (TLR2) on their surface, which is one of the SAA receptors. In this study, we investigated the relationship between γδ T cells and SAA1 through TLR2, by using hepatic SAA1-overexpressing transgenic (TG) mice. By injecting CU-CPT22, which is a TLR2 inhibitor, into the mice, we confirmed that SAA1 induced IL-17 in γδ T cells through TLR2. In vitro studies have confirmed that SAA1 increased IL-17 secretion in γδ T cells in combination with IL-23. We also observed a thickened epidermis layer and granulocyte penetration into the skin similar to the pathology of psoriasis in TG mice. In addition, strongly expressed SAA1 and penetration of γδ T cells in the skin of TG mice were detected. The exacerbation of psoriasis is associated with an increase in IL-17 levels. Therefore, these symptoms were induced by IL-17-producing γδ T cells increased by SAA1. Our study confirmed that SAA1 was a prominent protein that increased IL-17 levels through TLR2 in γδ T cells, confirming the possibility that SAA1 may exacerbate inflammatory diseases through γδ T cells.
Assuntos
Interleucina-17/biossíntese , Psoríase/patologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Proteína Amiloide A Sérica/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Células Cultivadas , Subunidade p19 da Interleucina-23/biossíntese , Subunidade p19 da Interleucina-23/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Psoríase/imunologia , RNA Mensageiro/biossíntese , Receptor 2 Toll-Like/antagonistas & inibidoresRESUMO
Hidradenitis suppurativa (HS) (also designated acne inversa) is a chronic inflammatory disease characterized by painful purulent skin lesions and progressive destruction of skin architecture. Despite the high burden for the patients, pathogenetic pathways underlying HS alterations remain obscure. When we examined the HS cytokine pattern, IL-1ß turned out to be a highly prominent cytokine, overexpressed even compared with psoriatic lesions. Analyses of IL-1ß-induced transcriptome in various cell types showed overlapping profiles, with upregulations of molecules causing immune cell infiltration and extracellular matrix degradation, and of specific cytokines including IL-6, IL-32, and IL-36. Matching cellular IL-1 receptor levels, dermal fibroblasts showed both the strongest and broadest IL-1ß response, which was not clearly shared or strengthened by other cytokines. The IL-1ß signature was specifically present in HS lesions and could be reversed by application of IL-1 receptor antagonist. Search for blood parameters associated with IL-1ß pathway activity in HS identified serum amyloid A, which was synergistically induced by IL-1ß and IL-6 in hepatocytes. Consequently, strongly elevated blood serum amyloid A levels in HS correlated positively with the extent of inflammatory skin alterations. In summary, the IL-1ß pathway represents a pathogenetic cascade, whose activity may be therapeutically targeted and monitored by blood SAA levels.
Assuntos
Hidradenite Supurativa/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Receptores de Interleucina-1/metabolismo , Adulto , Biópsia , Estudos de Casos e Controles , Células Cultivadas , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Hepatócitos/imunologia , Hepatócitos/metabolismo , Hidradenite Supurativa/sangue , Hidradenite Supurativa/patologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Queratinócitos/imunologia , Queratinócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Receptores de Interleucina-1/antagonistas & inibidores , Proteína Amiloide A Sérica/análise , Proteína Amiloide A Sérica/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Pele/citologia , Pele/imunologia , Pele/patologia , Regulação para Cima , Adulto JovemRESUMO
INTRODUCTION: Cryopyrin associated periodic syndrome is a rare auto inflammatory disease including three clinical entities with a common genetic cause. Among these three entities, Muckle-Wells syndrome is described as an intermediate phenotype associated with a progressive sensorineural hearing loss and AA amyloidosis. The present case reports a renal AA amyloidosis associated with an IgA nephropathy, revealing a Muckle-Wells syndrome. OBSERVATION: The case is reported of a 38-years-old patient who presented a renal failure revealed concomitantly with a macroscopic hematuria exploration. Urological investigations were performed with negative results. The patient had no particular background except urticarial rashes, unlabeled inflammatory rheumatism and a grandmother's amyloidosis. Renal biopsy revealed glomerular, vascular and interstitial AA amyloidosis associated to an IgA nephropathy. This amyloidosis was known to be a part of Muckle-Wells syndrome, and a NLRP3 gene study confirmed the diagnosis. CONCLUSION: Cryopyrin associated periodic syndrome is a rare disease and the clinical diagnosis suspicion need genetic confirmation. AA amyloidosis is known to happen in Muckle-Wells syndrome. Other occasional renal impairments are described in this syndrome whereas the IgA nephropathy association remains poorly characterized.
Assuntos
Amiloidose/etiologia , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Glomerulonefrite por IGA/etiologia , Falência Renal Crônica/etiologia , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Autoanticorpos/análise , Autoanticorpos/imunologia , Síndromes Periódicas Associadas à Criopirina/complicações , Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/patologia , Hematúria/etiologia , Humanos , Interleucina-1/antagonistas & inibidores , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doenças Reumáticas/etiologia , Proteína Amiloide A Sérica/imunologia , Urticária/etiologiaRESUMO
Studies comparing endogenous and recombinant serum amyloid A (SAA) have generated conflicting data on the proinflammatory function of these proteins. In exploring this discrepancy, we found that in contrast to commercially sourced recombinant human SAA1 (hSAA1) proteins produced in Escherichia coli, hSAA1 produced from eukaryotic cells did not promote proinflammatory cytokine production from human or mouse cells, induce Th17 differentiation, or stimulate TLR2. Proteomic analysis of E. coli-derived hSAA1 revealed the presence of numerous bacterial proteins, with several being reported or probable lipoproteins. Treatment of hSAA1 with lipoprotein lipase or addition of a lipopeptide to eukaryotic cell-derived hSAA1 inhibited or induced the production of TNF-α from macrophages, respectively. Our results suggest that a function of SAA is in the binding of TLR2-stimulating bacterial proteins, including lipoproteins, and demand that future studies of SAA employ a recombinant protein derived from eukaryotic cells.
Assuntos
Leucócitos Mononucleares/imunologia , Proteína Amiloide A Sérica/imunologia , Células Th17/imunologia , Receptor 2 Toll-Like/agonistas , Adulto , Animais , Diferenciação Celular , Citocinas/metabolismo , Escherichia coli/genética , Proteínas de Escherichia coli/imunologia , Células HEK293 , Humanos , Mediadores da Inflamação/metabolismo , Lipoproteínas/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/genética , Proteína Amiloide A Sérica/genéticaRESUMO
Serum amyloid A (SAA) is a sensitive inflammatory marker rapidly increased in response to infection, injury or trauma during the acute phase. Resolution of the acute phase and SAA reduction are well documented, however the exact mechanism remains elusive. Two inducible SAA proteins, SAA1 and SAA2, with their variants could contribute to systemic inflammation. While unconjugated human variant SAA1α is already commercially available, the variants of SAA2 are not. Antibodies against SAA have been identified in apparently healthy blood donors (HBDs) in smaller, preliminary studies. So, our objective was to detect anti-SAA and anti-SAA1α autoantibodies in the sera of 300 HBDs using ELISA, characterize their specificity and avidity. Additionally, we aimed to determine the presence of anti-SAA and anti-SAA1α autoantibodies in intravenous immunoglobulin (IVIg) preparations and examine their effects on released IL-6 from SAA/SAA1α-treated peripheral blood mononuclear cells (PBMCs). Autoantibodies against SAA and SAA1α had a median (IQR) absorbance OD (A450) of 0.655 (0.262-1.293) and 0.493 (0.284-0.713), respectively. Both anti-SAA and anti-SAA1α exhibited heterogeneous to high avidity and reached peak levels between 41-50 years, then diminished with age in the oldest group (51-67 years). Women consistently exhibited significantly higher levels than men. Good positive correlation was observed between anti-SAA and anti-SAA1α. Both anti-SAA and anti-SAA1α were detected in IVIg, their fractions subsequently isolated, and shown to decrease IL-6 protein levels released from SAA/SAA1α-treated PBMCs. In conclusion, naturally occurring antibodies against SAA and anti-SAA1α could play a physiological role in down-regulating their antigen and proinflammatory cytokines leading to the resolution of the acute phase and could be an important therapeutic option in patients with chronic inflammatory diseases.
Assuntos
Autoanticorpos/sangue , Interleucina-6/metabolismo , Leucócitos Mononucleares/imunologia , Proteína Amiloide A Sérica/imunologia , Adolescente , Adulto , Idoso , Envelhecimento/sangue , Envelhecimento/imunologia , Células Cultivadas , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Essentials Inflammation plays a key role in the development of colorectal cancer. Understanding mechanisms of cancer initiation might reveal new anticancer preventive strategy. Hyperactive platelets promote tumor formation by fostering immune evasion of cancer. Platelet inhibition by clopidogrel prevents carcinogenesis by restoring antitumor immunity. SUMMARY: Background Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, although the mechanisms are not fully understood. Beyond thrombosis and hemostasis, platelets are key actors in inflammation; they have also been shown to be involved in cancer. However, whether platelets participate in the link between inflammation and cancer is unknown. Objective To investigate the contribution of platelets and platelet-derived proteins to inflammation-elicited colorectal tumor development. Methods We used a clinically relevant mouse model of colitis-associated cancer. Platelet secretion and platelet reactivity to thrombin were assessed at each stage of carcinogenesis. We conducted an unbiased proteomic analysis of releasates of platelets isolated at the pretumoral stage to identify soluble factors that might act on tumor development. Plasma levels of the identified proteins were measured during the course of carcinogenesis. We then treated the mice with clopidogrel to efficiently inhibit platelet release reaction. Results At the pretumoral stage, hyperactive platelets constituted a major source of circulating protumoral serum amyloid A (SAA) proteins. Clopidogrel prevented the early elevation of the plasma SAA protein level, decreased colitis severity, and delayed the formation of dysplastic lesions and adenocarcinoma. Platelet inhibition hindered the expansion and function of immunosuppressive myeloid cells, as well as their infiltration into tumors, but increased the number of tissue CD8+ T cells. Platelets and releasates of platelets from mice with cancer were both able to polarize myeloid cells towards an immunosuppressive phenotype. Conclusions Thus, platelets promote the initiation of colitis-associated cancer by enhancing myeloid cell-dependent immunosuppression. Antiplatelet agents may help to prevent inflammation-elicited carcinogenesis by restoring antitumor immunity.