RESUMO
B cells orchestrate pro-survival and pro-apoptotic inputs during unfolded protein response (UPR) to translate, fold, sort, secrete and recycle immunoglobulins. In common variable immunodeficiency (CVID) patients, activated B cells are predisposed to an overload of abnormally processed, misfolded immunoglobulins. Using highly accurate transcript measurements, we show that expression of UPR genes and immunoglobulin chains differs qualitatively and quantitatively during the first 4 h of chemically induced UPR in B cells from CVID patients and a healthy subject. We tested thapsigargin or tunicamycin as stressors and 4-phenylbutyrate, dimethyl sulfoxide and tauroursodeoxycholic acid as chemical chaperones. We found an early and robust decrease of the UPR upon endoplasmic reticulum (ER) stress in CVID patient cells compared to the healthy control consistent with the disease phenotype. The chemical chaperones increased the UPR in the CVID patient cells in response to the stressors, suggesting that misfolded immunoglobulins were stabilized. We suggest that the AMP-dependent transcription factor alpha branch of the UPR is disturbed in CVID patients, underlying the observed expression behavior.
Assuntos
Linfócitos B/efeitos dos fármacos , Imunodeficiência de Variável Comum/genética , Dimetil Sulfóxido/farmacologia , Fenilbutiratos/farmacologia , Ácido Tauroquenodesoxicólico/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Cultivadas , Imunodeficiência de Variável Comum/metabolismo , Imunodeficiência de Variável Comum/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/imunologia , Humanos , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Tapsigargina/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Tunicamicina/farmacologia , Resposta a Proteínas não Dobradas/genéticaRESUMO
Regulated transcriptional readthrough during stress maintains genome structure and ensures access to genes that are necessary for cellular recovery. A broad number of genes, including of the bacterial sensor Toll-like receptor 4 (TLR-4), are markedly transcribed on initiating the systemic inflammatory response. Here we study the transcriptional patterns of tlr4 and of its modulator grp78 during human sepsis, and establish their correlations with the outcome of patients. We measured the daily tlr4 and grp78 RNA expression levels in peripheral blood of septic patients, immediately after admission to intensive care, and modeled these RNA values with a sine damping function. We obtained negative correlations between the transcription of tlr4 and grp78 RNA in the survivor group. In contrast, such relation is lost in the deceased patients. Loss of transcriptional homeostasis predicted by our model within the initial 4 days of hospitalization was confirmed by death of those patients up to 28 days later.
Assuntos
Proteínas de Choque Térmico/imunologia , Modelos Biológicos , Sepse/imunologia , Receptor 4 Toll-Like/imunologia , Transcrição Gênica/imunologia , Adulto , Idoso , Intervalo Livre de Doença , Chaperona BiP do Retículo Endoplasmático , Feminino , Proteínas de Choque Térmico/sangue , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/sangue , RNA Mensageiro/imunologia , Sepse/sangue , Sepse/mortalidade , Taxa de Sobrevida , Receptor 4 Toll-Like/sangueRESUMO
Chaperone production is an essential step for proper folding of certain proteins. Accumulation of misfolded/unfolded proteins within the endoplasmic reticulum (ER) lumen triggers a signalling pathway named unfolded protein response (UPR). Upon activation, the UPR pathway augments transcription of ER chaperones increasing protein folding, decreases protein translation to ameliorate the ER overload, increases protein degradation, and activates the apoptotic programme if all previous measures fail. In this review, we will cover the chaperones involved in folding of proteins related to the immune response, followed by an overview of the UPR pathway. Lastly, we will discuss data from this last decade that demonstrate how the improper activation of the UPR pathway has been uncovered as a mechanism responsible for failure to mount a proper immune response, both innate and adaptive.
Assuntos
Linfócitos B/imunologia , Retículo Endoplasmático/imunologia , Imunidade Inata/imunologia , Chaperonas Moleculares/imunologia , Resposta a Proteínas não Dobradas/imunologia , Animais , Humanos , Modelos Imunológicos , Dobramento de ProteínaAssuntos
Íleo/cirurgia , Jejuno/cirurgia , Obesidade/terapia , Animais , Peso Corporal , Modelos Animais de Doenças , Feminino , Masculino , CoelhosRESUMO
Liver failure is a serious complication when small bowel bypass is used for control of obesity. To analyse the changes in liver microscopic morphology and liver fatty acids content, 42 rabbits divided in two groups were studied. The 21 animals of group I had 50% of the distal jejuno-ileum excluded and anastomosed to the cecum. The proximal 50% were anastomosed to the distal 5 cm of the ileum. The 21 animals of group II were used as controls and were submitted to a laparotomy and small bowel manipulation. Liver histology and fatty acids content were studied at the time of these operations and in the 21st postoperative day. No signficant histologic changes were noticed in both groups. A significant decrease in liver fatty acids content was observed in groups I and II. However, the decrease in group II was less pronounced than in group I. This last observation appears to support the theory of liver lipid metabolism impairment after small bowel bypass, even in the absence of obesity.