RESUMO
Thrombotic microangiopathy (TMA) is a rare renal complication of patients with chronic lymphocytic leukemia (CLL) and is often associated with peripheral features. We present the first case of CLL patients with renal-limited TMA. A 70-year-old female patient with a history of well-controlled type 2 diabetes and baseline albuminuria of 87.2 mg/g 1 year prior and CLL was on active surveillance only. Her baseline white blood cell (WBC) was 202.6 x 103/µl. She presented with nephrotic syndrome with proteinuria of 10 g/g and a subsequent unremarkable serologic work-up. A kidney biopsy revealed diabetic glomerulosclerosis and chronic TMA. Initially, she was treated conservatively with angiotensin receptor blockade and sodium glucose cotransporter-2 inhibition but progressed with increased proteinuria of 17 g/g. Complement functional panel testing was pursued and showed dysregulation of the classical and alternative complement pathways. We decided to treat CLL which was suspected to be the culprit. At 9 months post-ibrutinib initiation, there was a 90% reduction in the WBC as well as a 94% reduction in proteinuria (17 g/g to 0.97 g/g). This case emphasizes the role of complement dysregulation in the pathogenesis of TMA in CLL patients. Treatment of CLL can restore complement dysregulation and improve renal outcomes.
RESUMO
Successful advancement in the treatment of diabetes mellitus is not possible without well-established methodology for beta cell mass calculation. Here, we offer the protocol to assess beta cell mass during embryonic development in the mouse. The described protocol has detailed steps on how to process extremely small embryonic pancreatic tissue, cut it on the cryostat, and stain tissue slides for microscopic analysis. The method does not require usage of confocal microscopy and takes advantage of enhanced automated image analysis with proprietary as well as open-source software packages.
RESUMO
Regulation of the equilibrium between proteases and their inhibitors is fundamental to health maintenance. Consequently, developing a means of targeting protease activity to promote tissue regeneration and inhibit inflammation may offer a new strategy in therapy development for diabetes and other diseases. Specifically, recent efforts have focused on serine protease inhibitors, known as serpins, as potential therapeutic targets. The serpin protein family comprises a broad range of protease inhibitors, which are categorized into 16 clades that are all extracellular, with the exception of Clade B, which controls mostly intracellular proteases, including both serine- and papain-like cysteine proteases. This review discusses the most salient, and sometimes opposing, views that either inhibition or augmentation of protease activity can bring about positive outcomes in pancreatic islet biology and inflammation. These potential discrepancies can be reconciled at the molecular level as specific proteases and serpins regulate distinct signaling pathways, thereby playing equally distinct roles in health and disease development.
Assuntos
Diabetes Mellitus/metabolismo , Serpinas/metabolismo , Transdução de Sinais , Animais , Diabetes Mellitus/genética , Humanos , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Serpinas/classificação , Serpinas/genéticaRESUMO
Pancreatic endocrine cell development is dependent on the rescue of the neurogenin3 (Ngn3) transcription factor from repression by Notch. The signals that prevent Notch signaling, thereby allowing the formation of pancreatic endocrine cells, remain unclear. We show that inhibiting serpinB13, a cathepsin L (CatL) protease inhibitor expressed in the pancreatic epithelium, caused in vitro and in vivo cleavage of the extracellular domain of Notch1. This was followed by a twofold increase in the Ngn3+ progenitor cell population and enhanced conversion of these cells to express insulin. Conversely, both recombinant serpinB13 protein and CatL deficiency down-regulated pancreatic Ngn3+ cell output. Mouse embryonic exposure to inhibitory anti-serpinB13 antibody resulted in increased islet cell mass and improved outcomes in streptozotocin-induced diabetes at 8 weeks of age. Moreover, anti-serpinB13 autoantibodies stimulated Ngn3+ endocrine progenitor formation in the pancreas and were associated with delayed progression to type 1 diabetes (T1D) in children. These data demonstrate long-term impact of serpinB13 activity on islet biology and suggest that promoting protease activity by blocking this serpin may have prophylactic potential in T1D.
Assuntos
Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular , Camundongos , Proteínas do Tecido NervosoRESUMO
Mutations in natriuretic peptide receptor 2 (Npr2) gene cause a rare form of short-limbed dwarfism, but its physiological effects have not been well studied. Human and mouse genetic data suggest that Npr2 in the kidney plays a role in salt homeostasis. Herein, we described anatomic changes within renal papilla of Npr2 knockout (Npr2-/-) mice. Dramatic reduction was found in diuresis, and albuminuria was evident after administration of 1% NaCl in drinking water in Npr2-/- and heterozygous (Npr2+/-) mice compared with their wild-type (Npr2+/+) littermates. There was indication of renal epithelial damage accompanied by high numbers of red blood cells and inflammatory cells (macrophage surface glycoproteins binding to galectin-3) and an increase of renal epithelial damage marker (T-cell Ig and mucin domain 1) in Npr2-/- mice. Addition of 1% NaCl tended to increase apoptotic cells (cleaved caspase 3) in the renal papilla of Npr2-/- mice. In vitro, genetic silencing of the Npr2 abolished protective effects of C-type natriuretic peptide, a ligand for Npr2, against death of M-1 kidney epithelial cells exposed to 360 mmol/L NaCl. Finally, significantly lower levels of expression of the NPR2 protein were detected in renal samples of hypertensive compared with normotensive human subjects. Taken together, these findings suggest that Npr2 is essential to protect renal epithelial cells from high concentrations of salt and prevent kidney injury.
Assuntos
Injúria Renal Aguda/prevenção & controle , Hipertensão/patologia , Medula Renal/efeitos dos fármacos , Receptores do Fator Natriurético Atrial/fisiologia , Cloreto de Sódio/toxicidade , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Feminino , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Medula Renal/metabolismo , Medula Renal/patologia , Masculino , Camundongos , Camundongos KnockoutRESUMO
AIMS/HYPOTHESIS: We previously reported that exposure to antibodies neutralising serpin B13, a protease inhibitor expressed in exocrine pancreatic ducts, promotes beta cell proliferation, underscoring the importance of a functional relationship between exocrine and endocrine pancreas. The aim of the present study was to identify the molecular events that link inhibition of serpin B13 to islet cell proliferation. METHODS: We used an in vitro culture system consisting of isolated pancreatic islets, an extract of pancreatic ductal epithelium and a monoclonal antibody (mAb) to serpin B13 or IgG isotype control. In vivo studies involved treatment of mice with these mAbs. RESULTS: The catalytic activity of cathepsin L (CatL), a cysteine protease target of serpin B13, was augmented in the pancreas of mice injected with serpin B13 mAb. Furthermore, the addition of serpin B13 mAb to the islets, together with the pancreatic ductal epithelium lysate, caused CatL-dependent cleavage of E-cadherin and concomitant upregulation of REG genes, ultimately leading to beta cell proliferation. Direct blockade of E-cadherin with mAb also markedly enhanced REG gene induction, while chemical inhibition of ß-catenin, a binding target of E-cadherin, prevented the serpin B13 mAb-induced upregulation of REG genes. CONCLUSIONS/INTERPRETATION: Our work implicates the CatL-E-cadherin-REG pathway in the regulation of islet cell proliferation in response to signals generated in exocrine pancreatic tissue and demonstrates that protease activity may promote adaptive changes in the islets. DATA AVAILABILITY: Microarray data that support the findings of this study have been deposited in Gene Expression Omnibus (GEO) with the accession no. GSE125151.
Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Catepsina L/metabolismo , Ilhotas Pancreáticas/metabolismo , Serpinas/metabolismo , Animais , Anticorpos Monoclonais , Proliferação de Células , Feminino , Expressão Gênica , Células HEK293 , Humanos , Ilhotas Pancreáticas/citologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Pâncreas Exócrino/metabolismo , Ductos Pancreáticos/citologia , Transdução de Sinais , alfa 1-Antitripsina/metabolismoRESUMO
Podocytes contain an intricate actin cytoskeleton that is essential for the specialized function of this cell type in renal filtration. Serum response factor (SRF) is a master transcription factor for the actin cytoskeleton, but the in vivo expression and function of SRF in podocytes are unknown. We found that SRF protein colocalizes with podocyte markers in human and mouse kidneys. Compared with littermate controls, mice in which the Srf gene was conditionally inactivated with NPHS2-Cre exhibited early postnatal proteinuria, hypoalbuminemia, and azotemia. Histologic changes in the mutant mice included glomerular capillary dilation and mild glomerulosclerosis, with reduced expression of multiple canonical podocyte markers. We also noted tubular dilation, cell proliferation, and protein casts as well as reactive changes in mesangial cells and interstitial inflammation. Ultrastructure analysis disclosed foot process effacement with loss of slit diaphragms. To ascertain the importance of SRF cofactors in podocyte function, we disabled the myocardin-related transcription factor A and B genes. Although loss of either SRF cofactor alone had no observable effect in the kidney, deficiency of both recapitulated the Srf-null phenotype. These results establish a vital role for SRF and two SRF cofactors in the maintenance of podocyte structure and function.
Assuntos
Actinas/metabolismo , Podócitos/metabolismo , Podócitos/ultraestrutura , Fator de Resposta Sérica/fisiologia , Transativadores/genética , Fatores de Transcrição/genética , Actinina/genética , Actinas/genética , Animais , Citoesqueleto , Dilatação Patológica/genética , Feminino , Humanos , Túbulos Renais Distais/patologia , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Knockout , Podócitos/fisiologia , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Repressoras/genética , Fator de Resposta Sérica/genética , Proteínas WT1RESUMO
Type 1 diabetes mellitus (T1D) is characterized by a heightened antibody (Ab) response to pancreatic islet self-antigens, which is a biomarker of progressive islet pathology. We recently identified a novel antibody to clade B serpin that reduces islet-associated T cell accumulation and is linked to the delayed onset of T1D. As natural immunity to clade B arises early in life, we hypothesized that it may influence islet development during that time. To test this possibility healthy young Balb/c male mice were injected with serpin B13 mAb or IgG control and examined for the number and cellularity of pancreatic islets by immunofluorescence and FACS. Beta cell proliferation was assessed by measuring nucleotide analog 5-ethynyl-2'-deoxyuridine (5-EdU) incorporation into the DNA and islet Reg gene expression was measured by real time PCR. Human studies involved measuring anti-serpin B13 autoantibodies by Luminex. We found that injecting anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of â¼80 pancreatic islets per animal, and ultimately led to increase in the beta cell mass. These findings are relevant to human T1D because our analysis of subjects just diagnosed with T1D revealed an association between baseline anti-serpin activity and slower residual beta cell function decline in the first year after the onset of diabetes. Our findings reveal a new role for the anti-serpin immunological response in promoting adaptive changes in the endocrine pancreas and suggests that enhancement of this response could potentially help impede the progression of T1D in humans.
Assuntos
Formação de Anticorpos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Serpinas/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Formação de Anticorpos/efeitos dos fármacos , Glicemia/metabolismo , Peptídeo C/imunologia , Proliferação de Células/efeitos dos fármacos , Criança , Desoxiuridina/análogos & derivados , Desoxiuridina/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/sangue , Feminino , Humanos , Imunização Passiva , Células Secretoras de Insulina/efeitos dos fármacos , Modelos Lineares , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Regulação para Cima/efeitos dos fármacosAssuntos
Doença de Fabry/diagnóstico , Paraproteinemias/diagnóstico , Insuficiência Renal/diagnóstico , Biópsia , Diagnóstico Diferencial , Terapia de Reposição de Enzimas/métodos , Doença de Fabry/complicações , Doença de Fabry/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Paraproteinemias/complicações , Paraproteinemias/terapia , Insuficiência Renal/complicações , Insuficiência Renal/terapiaRESUMO
Activation of ß-cell EphA5 receptors by its ligand ephrinA5 from adjacent ß-cells has been reported to decrease insulin secretion during hypoglycemia. Given the similarities between islet and ventromedial hypothalamus (VMH) glucose sensing, we tested the hypothesis that the EphA5/ephrinA5 system might function within the VMH during hypoglycemia to stimulate counterregulatory hormone release as well. Counterregulatory responses and glutamine/glutamate concentrations in the VMH were assessed during a hyperinsulinemic-hypoglycemic glucose clamp study in chronically catheterized awake male Sprague-Dawley rats that received an acute VMH microinjection of ephrinA5-Fc, chronic VMH knockdown, or overexpression of ephrinA5 using an adenoassociated viral construct. Local stimulation of VMH EphA5 receptors by ephrinA5-Fc or ephrinA5 overexpression increased, whereas knockdown of VMH ephrinA5 reduced counterregulatory responses during hypoglycemia. Overexpression of VMH ephrinA5 transiently increased local glutamate concentrations, whereas ephrinA5 knockdown produced profound suppression of VMH interstitial fluid glutamine concentrations in the basal state and during hypoglycemia. Changes in ephrinA5/EphA5 interactions within the VMH, a key brain glucose-sensing region, act in concert with islets to restore glucose homeostasis during acute hypoglycemia, and its effect on counterregulation may be mediated by changes in glutamate/glutamine cycling.
Assuntos
Efrina-A5/farmacologia , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Hipoglicemia/metabolismo , Receptor EphA5/metabolismo , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Animais , Glicemia , Efrina-A5/genética , Efrina-A5/metabolismo , Epinefrina/sangue , Epinefrina/metabolismo , Regulação da Expressão Gênica , Glucagon/sangue , Glucagon/metabolismo , Glucose/metabolismo , Insulina/sangue , Insulina/metabolismo , Masculino , Norepinefrina/sangue , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor EphA5/genética , Núcleo Hipotalâmico Ventromedial/metabolismoRESUMO
Secretion of anti-serpin B13 autoantibodies in young diabetes-prone nonobese diabetic mice is associated with reduced inflammation in pancreatic islets and a slower progression to autoimmune diabetes. Injection of these mice with a monoclonal antibody (mAb) against serpin B13 also leads to fewer inflammatory cells in the islets and more rapid recovery from recent-onset diabetes. The exact mechanism by which anti-serpin activity is protective remains unclear. We found that serpin B13 is expressed in the exocrine component of the mouse pancreas, including the ductal cells. We also found that anti-serpin B13 mAb blocked the inhibitory activity of serpin B13, thereby allowing partial preservation of the function of its target protease. Consistent with the hypothesis that anti-clade B serpin activity blocks the serpin from binding, exposure to exogenous anti-serpin B13 mAb or endogenous anti-serpin B13 autoantibodies resulted in cleavage of the surface molecules CD4 and CD19 in lymphocytes that accumulated in the pancreatic islets and pancreatic lymph nodes but not in the inguinal lymph nodes. This cleavage was inhibited by an E64 protease inhibitor. Consequently, T cells with the truncated form of CD4 secreted reduced levels of interferon-γ. We conclude that anti-serpin antibodies prevent serpin B13 from neutralizing proteases, thereby impairing leukocyte function and reducing the severity of autoimmune inflammation.
Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Autoanticorpos/biossíntese , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Serpinas/genética , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Antígenos CD19/genética , Antígenos CD19/imunologia , Antígenos CD4/genética , Antígenos CD4/imunologia , Inibidores de Cisteína Proteinase/farmacologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Feminino , Expressão Gênica , Imunidade Humoral/efeitos dos fármacos , Interferon gama/biossíntese , Interferon gama/imunologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/imunologia , Leucina/análogos & derivados , Leucina/farmacologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos NOD , Serpinas/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Intracellular (clade B) OVA-serpin protease inhibitors play an important role in tissue homeostasis by protecting cells from death in response to hypo-osmotic stress, heat shock, and other stimuli. It is not known whether these serpins influence immunological tolerance and the risk for autoimmune diseases. We found that a fraction of young autoimmune diabetes-prone NOD mice had elevated levels of autoantibodies against a member of clade B family known as serpinB13. High levels of anti-serpinB13 Abs were accompanied by low levels of anti-insulin autoantibodies, reduced numbers of islet-associated T cells, and delayed onset of diabetes. Exposure to anti-serpinB13 mAb alone also decreased islet inflammation, and coadministration of this reagent and a suboptimal dose of anti-CD3 mAb accelerated recovery from diabetes. In a fashion similar to that discovered in the NOD model, a deficiency in humoral activity against serpinB13 was associated with early onset of human type 1 diabetes. These findings suggest that, in addition to limiting exposure to proteases within the cell, clade B serpins help to maintain homeostasis by inducing protective humoral immunity.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Serpinas/imunologia , Adolescente , Animais , Western Blotting , Criança , Pré-Escolar , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Transfecção , Adulto JovemRESUMO
Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that plays a critical role in cell motility. Movement and retraction of podocyte foot processes, which accompany podocyte injury, suggest focal adhesion disassembly. To understand better the mechanisms by which podocyte foot process effacement leads to proteinuria and kidney failure, we studied the function of FAK in podocytes. In murine models, glomerular injury led to activation of podocyte FAK, followed by proteinuria and foot process effacement. Both podocyte-specific deletion of FAK and pharmacologic inactivation of FAK abrogated the proteinuria and foot process effacement induced by glomerular injury. In vitro, podocytes isolated from conditional FAK knockout mice demonstrated reduced spreading and migration; pharmacologic inactivation of FAK had similar effects on wild-type podocytes. In conclusion, FAK activation regulates podocyte foot process effacement, suggesting that pharmacologic inhibition of this signaling cascade may have therapeutic potential in the setting of glomerular injury.
Assuntos
Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Glomerulonefrite/prevenção & controle , Podócitos/enzimologia , Proteinúria/prevenção & controle , Actinas/metabolismo , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Feminino , Proteína-Tirosina Quinases de Adesão Focal/genética , Deleção de Genes , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Podócitos/efeitos dos fármacos , Podócitos/patologia , Proteinúria/metabolismo , Proteinúria/patologia , Pirimidinas/farmacologiaRESUMO
The propensity of T cells to generate coordinated cytokine responses is critical for the host to develop resistance to pathogens while maintaining the state of immunotolerance to self-antigens. The exact mechanisms responsible for preventing the overproduction of proinflammatory cytokines including interferon (IFN)-gamma are not fully understood, however. In this study, we examined the role of a recently described Ras GTPase effector and repressor of the Raf/MEK/ERK cascade called impedes mitogenic signal propagation (Imp) in limiting the induction of T-cell cytokines. We found that stimulation of the T cell receptor complex leads to the rapid development of a physical association between Ras and Imp. Consistent with the hypothesis that Imp inhibits signal transduction, we also found that disengagement of this molecule by the Ras(V12G37) effector loop mutant or RNA interference markedly enhances the activation of the NFAT transcription factor and IFN-gamma secretion. A strong output of IFN-gamma is responsible for the distinct lymphocyte traffic pattern observed in vivo because the transgenic or retroviral expression of Ras(V12G37) caused T cells to accumulate preferentially in the lymph nodes and delayed their escape from the lymphoid tissue, respectively. Together, our results describe a hitherto unrecognized negative regulatory role for Imp in the production of IFN-gamma in T cells and point to Ras-Imp binding as an attractive target for therapeutic interventions in conditions involving the production of this inflammatory cytokine.
Assuntos
Antígenos CD4/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Citocinas/biossíntese , Regulação da Expressão Gênica , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Animais , Linhagem Celular , Citocinas/metabolismo , Humanos , Inflamação , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Ligação Proteica , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de SinaisRESUMO
We here describe a novel CD4 T cell adoptive transfer model of severe experimental autoimmune encephalomyelitis in (C57BL6xB10.PL)F1 mice. This FI cross developed severe disease characterized by extensive parenchymal spinal cord and brain periventricular white matter infiltrates. In contrast, B10.PL mice developed mild disease characterized by meningeal predominant infiltrates. As determined by cDNA microarray and quantitative real time PCR expression analysis, histologic and flow cytometry analysis of inflammatory infiltrates, and attenuation of disease in class I-deficient and CD8-depleted F1 mice; this severe disease phenotype appears to be regulated by CNS infiltration of CD8 T lymphocytes early in the disease course.
Assuntos
Encéfalo/patologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Meninges/patologia , Medula Espinal/patologia , Transferência Adotiva/métodos , Animais , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/terapia , Regulação da Expressão Gênica/imunologia , Imunofenotipagem , Antígeno de Macrófago 1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína Básica da Mielina/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
Toll-like receptors (TLRs) are an essential component of innate immunity, the first line of defense against invading pathogens. However, in addition to activating antimicrobial effector responses directly, TLRs lead to the induction of signals that control the activation of adaptive responses including autoimmune responses and allorecognition. This ability of TLR to control both innate and adaptive immunity has a broad applicability to the development of novel immunotherapies and antimicrobial strategies. This review discusses the basic biology of TLR and their contribution to renal disease.
Assuntos
Imunidade Inata/fisiologia , Nefropatias/imunologia , Receptores Toll-Like/metabolismo , Animais , Progressão da Doença , Humanos , Nefropatias/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Small GTPase Ras is capable of mediating activation in T lymphocytes by using Raf kinase-dependent signaling pathway. Other effectors of Ras exist, however, suggesting that targets of Ras alternative to Raf may also contribute to T cell functions. Here we demonstrate that Ras(V12G37) mutant that fails to bind Raf, potently increases intracellular calcium concentration and cytokine production in primary antigen-stimulated T cells. From three known effectors which retain the ability to interact with Ras(V12G37), overexpression of phospholipase C epsilon but not that of RIN1 or Ral guanine nucleotide exchange factors enhanced cytokine and nuclear factor-activated T cell reporter T cell responses. Hence T cell activation can be critically regulated by the Ras effector pathway independent from Raf that can be mimicked by phospholipase C epsilon.