Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance.Whereas the pivotal role of dendritic cells in determining the balance between immunopathology ...Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance.Whereas the pivotal role of dendritic cells in determining the balance between immunopathology and protective immunity to the fungus is well established,we determined that epithelial cells(ECs)also contributes to this balance.Mechanistically,EC-mediated protection occurred through a Toll-like receptor 3/Toll/IL-1 receptor domain-containing adaptor-inducing interferon(TLR3/TRIF)-dependent pathway converging on indoleamine 2,3-dioxygenase(IDO)via non-canonical nuclear factor-kB activation.Consistent with the high susceptibility of TRIF-deficient mice to pulmonary aspergillosis,bone marrow chimeric mice with TRIF unresponsive ECs exhibited higher fungal burdens and inflammatory pathology than control mice,underexpressed the IDO-dependent T helper 1/regulatory T cell(Th1/Treg)pathway and overexpressed the Th17 pathway with massive neutrophilic inflammation in the lungs.Further studies with interferon(IFN)-c,IDO or IL-17R unresponsive cells confirmed the dependency of immune tolerance to the fungus on the IFN-c/IDO/Treg pathway and of immune resistance on the MyD88 pathway controlling the fungal growth.Thus,distinct immune pathways contribute to resistance and tolerance to the fungus,to which the hematopoietic/non-hematopoietic compartments contribute through distinct,yet complementary,roles.展开更多
Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis(AIH)are still not full elucidated.Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we...Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis(AIH)are still not full elucidated.Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we hypothezied that deficiencies or mutations in the gene encoding CTLA4 protein may be involved in AIH susceptibility and trigger the autoimmune response.We investigated 3 distinct polymorphic sites(t49A>G,CT60 G>A and e318C>T)of the CTLA4 gene in 50 AIH patients and 100 healthy controls using the KASP genotyping technology.A significant positive association with AIH susceptibility was found for the GG genotype in t49 position of the CTLA4 gene which was significantly higher in AIH patients compared to controls(28%vs 9%,pZ0.003,ORZ3.93[1.56e9.88]).The CTLA4 A/A genotype in position CT60 was more significantly frequent in controls comparing to AIH patients and could be considered as a protective genotype for the tunisian patients.CTLA4 genotyping in position318 did not show any statistically significant difference in genotype or allele distribution.The CTLA4 gene polymorphism in position t49 is associated to AIH susceptibility in the Tunisian population.Mutation in the CTLA4 gene may lead to a modification of the CTLA4 protein structure that could have functional relevance in AIH pathogenesis and onset.展开更多
基金by the Specific Targeted Research Project‘Sybaris’(LSHE-CT-2006),contract number 037899(FP7)by the Italian Projects PRIN 2007KLCKP8_004(to LR)and 2007XYB9T9_001(to SB).CC and AC were financially supported by fellowships from Fundac¸a˜o para a Cieˆncia e Tecnologia,Portugal(contracts SFRH/BD/65962/2009 and SFRH/BPD/46292/2008,respectively).
文摘Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance.Whereas the pivotal role of dendritic cells in determining the balance between immunopathology and protective immunity to the fungus is well established,we determined that epithelial cells(ECs)also contributes to this balance.Mechanistically,EC-mediated protection occurred through a Toll-like receptor 3/Toll/IL-1 receptor domain-containing adaptor-inducing interferon(TLR3/TRIF)-dependent pathway converging on indoleamine 2,3-dioxygenase(IDO)via non-canonical nuclear factor-kB activation.Consistent with the high susceptibility of TRIF-deficient mice to pulmonary aspergillosis,bone marrow chimeric mice with TRIF unresponsive ECs exhibited higher fungal burdens and inflammatory pathology than control mice,underexpressed the IDO-dependent T helper 1/regulatory T cell(Th1/Treg)pathway and overexpressed the Th17 pathway with massive neutrophilic inflammation in the lungs.Further studies with interferon(IFN)-c,IDO or IL-17R unresponsive cells confirmed the dependency of immune tolerance to the fungus on the IFN-c/IDO/Treg pathway and of immune resistance on the MyD88 pathway controlling the fungal growth.Thus,distinct immune pathways contribute to resistance and tolerance to the fungus,to which the hematopoietic/non-hematopoietic compartments contribute through distinct,yet complementary,roles.
基金supported by the Northern Portugal Regional Operational Programme(NORTE 2020)the Portugal 2020 Partnership Agreement,through the European Regional Development Fund(FEDER)(NORTE-01-0145-FEDER-000013)the Fundacao para a Ciencia e Tecnologia(FCT)(IF/00735/2014 to AC and SFRH/BPD/96176/2013 to CC).
文摘Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis(AIH)are still not full elucidated.Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we hypothezied that deficiencies or mutations in the gene encoding CTLA4 protein may be involved in AIH susceptibility and trigger the autoimmune response.We investigated 3 distinct polymorphic sites(t49A>G,CT60 G>A and e318C>T)of the CTLA4 gene in 50 AIH patients and 100 healthy controls using the KASP genotyping technology.A significant positive association with AIH susceptibility was found for the GG genotype in t49 position of the CTLA4 gene which was significantly higher in AIH patients compared to controls(28%vs 9%,pZ0.003,ORZ3.93[1.56e9.88]).The CTLA4 A/A genotype in position CT60 was more significantly frequent in controls comparing to AIH patients and could be considered as a protective genotype for the tunisian patients.CTLA4 genotyping in position318 did not show any statistically significant difference in genotype or allele distribution.The CTLA4 gene polymorphism in position t49 is associated to AIH susceptibility in the Tunisian population.Mutation in the CTLA4 gene may lead to a modification of the CTLA4 protein structure that could have functional relevance in AIH pathogenesis and onset.
