Dectin- 1 isoforms contribute to distinct Th 1/Th 17 cell activation in mucosal candidiasis

The recognition of p-glucans by dectin-1 has been shown to mediate cell activation, cytokine production and a variety of antifungal responses. Here, we report that the functional activity of dectin-1 in mucosal immunity to Candida albicans is influenced by the genetic background of the host. Dectin-1 was required for the proper control of gastrointestinal and vaginal candidiasis in C57BIJ6, but not BALB/c mice; in fact, the latter showed increased resistance in the absence of dectin-1. The susceptibility of dectin-l-deficient C57BL/6 mice to infection was associated with defects in IL-17A and aryl hydrocarbon receptor-dependent IL-22 production and in adaptive Th I responses. In contrast, the resistance of dectin- 1-deficient BALB/c mice was associated with increased IL-17A and IL-22 production and the skewing towards Thl/Treg immune responses that provide immunological memory. Disparate canonical/ noncanonical NF-KB signaling pathways downstream of dectin-1 were activated in the two different mouse strains. Thus, the net activity of dectin-1 in antifungal mucosal immunity is dependent on the host＇s genetic background, which affects both the innate cytokine production and the adaptive Th1/Th17 cell activation upon dectin-1 signaling.

Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

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.

Cytotoxic T lymphocyte antigen-4 gene polymorphisms and susceptibility to type 1 autoimmune hepatitis in the Tunisian population

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.