The mechanisms permitting nonpolymorphic CD1 molecules to present lipid antigens that differ considerably in polar head and aliphatic tails remain elusive. It is also unclear why hydrophobic motifs ...in the aliphatic tails of some antigens, which presumably embed inside CD1 pockets, contribute to determinants for T-cell recognition. The 1.9-Å crystal structure of an active complex of CD1b and a mycobacterial diacylsulfoglycolipid presented here provides some clues. Upon antigen binding, endogenous spacers of CD1b, which consist of a mixture of diradylglycerols, moved considerably within the lipid-binding groove. Spacer displacement was accompanied by F’ pocket closure and an extensive rearrangement of residues exposed to T-cell receptors. Such structural reorganization resulted in reduction of the A’ pocket capacity and led to incomplete embedding of the methyl-ramified portion of the phthioceranoyl chain of the antigen, explaining why such hydrophobic motifs are critical for T-cell receptor recognition. Mutagenesis experiments supported the functional importance of the observed structural alterations for T-cell stimulation. Overall, our data delineate a complex molecular mechanism combining spacer repositioning and ligand-induced conformational changes that, together with pocket intricacy, endows CD1b with the required molecular plasticity to present a broad range of structurally diverse antigens.
Immunization with heat shock proteins (HSPs) induces Ag-specific CTL responses. The specificity of the immune response is based on peptides associated with HSPs. To investigate how exogenous ...HSP/peptide complexes gain access to the MHC class I-restricted Ag presentation pathway, we incubated the monocytic cell line P388D1 and the dendritic cell line D2SC/1 with gold-labeled HSPs gp96 and HSC70. We show that HSPs bind specifically to the surface of these APCs and are internalized spontaneously by receptor-mediated endocytosis, demonstrating the existence of specific receptors for HSPs on these cells. In addition, we observe colocalization of internalized HSPs and surface MHC class I molecules in early and late endosomal structures. These findings provide possible explanations for the immunogenicity of HSP/peptide complexes and for the transfer of HSP-associated peptides onto MHC class I molecules.
Un apport artériel pial à la vascularisation des méningiomes intracrâniens est associé à des difficultés de clivage, à un œdème péri-tumoral important, à un grade OMS plus élevé ainsi qu’à un risque ...plus élevé de récidive. La composante artérielle piale est par ailleurs inaccessible à une embolisation pré-chirurgicale. Celle-ci ne peut actuellement être objectivée que grâce à une angiographie. L’objectif de notre étude était de prédire son existence en IRM conventionnelle à l’aide d’un score diagnostique.
Le score diagnostique a été construit par régression logistique à partir des données angiographiques et remnographiques de patients pris en charge pour méningiome supra-tentoriel dans notre institution entre 2010 et 2018. Ses performances diagnostiques ont été testées dans une seconde institution. Les relations entre le score, les résultats chirurgicaux et les données anatomo-pathologiques ont également été étudiées.
Le modèle de régression logistique a été appliqué sur les données de 54 patients et 4 critères ont été retenus comme prédictifs de vascularisation piale (Tableau 1). Sur ces patients ainsi que 18 patients d’une seconde institution, le score a permis de prédire avec fiabilité l’existence d’une vascularisation piale (Tableau 2) (Se : 97,8 % ; Sp 76,9 % ; VPP : 88,2 % ; VPN : 95,2 %) avec une bonne reproductibilité inter-observateur. Un score élevé a également été associé à un risque accru de méningiome atypique (OMS II et III) et de récidive.
Cette étude est la première à proposer un score fiable et reproductif capable de prédire en IRM conventionnelle l’existence d’une vascularisation piale pour des méningiomes supra-tentoriels.
L’embolisation pré-opératoire des méningiomes intra-crâniens permet de réduire les pertes de sang et d’améliorer la résécabilité de la tumeur lors de la chirurgie. Peu d’études ont évalué les risques ...et les bénéfices liés à l’utilisation de l’Onyx dans cette indication. Le but de cette étude était d’étudier la sûreté et l’efficacité de l’embolisation à l’Onyx dans une série de volumineux méningiomes intra-crâniens en comparaison d’une série appariée n’ayant pas bénéficié de l’embolisation.
Nous avons procédé à une étude rétrospective intéressant des patients consécutifs porteurs de méningiomes prouvés histologiquement et embolisés à l’Onyx entre 2010 et 2018. Les complications liées à l’embolisation ont été rapportées. Deux échantillons appariés composés de méningiomes embolisés à l’Onyx et de méningiomes non embolisés ont été constitués afin de déterminer les bénéfices de la procédure.
Résultats 44 méningiomes embolisés à l’Onyx chez 44 patients ont été inclus dans cette étude. 44 méningiomes non embolisés leur ont été comparés. Les deux groupes étaient semblables en termes d’âge, de sexe, de taille tumorale, d’importance de l’œdème péri-lésionnel et de grade OMS. Les patients du groupe embolisation ont eu un meilleur devenir avec un taux moindre de transfert en soins de suite (50,0 % vs 79,5 % ; p<0,01), de récidive (15,4 % vs 35,9 % ; p<0,04), de résection incomplète et de complications chirurgicales. Seulement trois complications majeures ont été rapportées consistant en des pertes de fonction visuelle.
Cette étude est la première étude comparative à montrer les bénéfices de l’embolisation pré-chirurgicale à l’Onyx dans le cas de volumineux méningiomes intra-crâniens. Les patients embolisés présentaient notamment des taux moindres de complications chirurgicales, de résection incomplète ainsi que de récidive, avec un faible risque procédural.
Birbeck granules are unusual rod-shaped structures specific to epidermal Langerhans cells, whose origin and function remain undetermined. We investigated the intracellular location and fate of ...Langerin, a protein implicated in Birbeck granule biogenesis, in human epidermal Langerhans cells. In the steady state, Langerin is predominantly found in the endosomal recycling compartment and in Birbeck granules. Langerin internalizes by classical receptor-mediated endocytosis and the first Birbeck granules accessible to endocytosed Langerin are those connected to recycling endosomes in the pericentriolar area, where Langerin accumulates. Drug-induced inhibition of endocytosis results in the appearance of abundant open-ended Birbeck granule-like structures appended to the plasma membrane, whereas inhibition of recycling induces Birbeck granules to merge with a tubular endosomal network. In mature Langerhans cells, Langerin traffic is abolished and the loss of internal Langerin is associated with a concomitant depletion of Birbeck granules. Our results demonstrate an exchange of Langerin between early endosomal compartments and the plasma membrane, with dynamic retention in the endosomal recycling compartment. They show that Birbeck granules are not endocytotic structures, rather they are subdomains of the endosomal recycling compartment that form where Langerin accumulates. Finally, our results implicate ADP-ribosylation factor proteins in Langerin trafficking and the exchange between Birbeck granules and other endosomal membranes.
Most of the peptides presented by major histocompatibility complex (MHC) class I molecules require processing by proteasomes. Tripeptidyl peptidase II (TPPII), an aminopeptidase with endoproteolytic ...activity, may also have a role in antigen processing. Here, we analyzed the processing and presentation of the immunodominant human immunodeficiency virus epitope HIV-Nef(73-82) in human dendritic cells. We found that inhibition of proteasome activity did not impair Nef(73-82) epitope presentation. In contrast, specific inhibition of TPPII led to a reduction of Nef(73-82) epitope presentation. We propose that TPPII can act in combination with or independent of the proteasome system and can generate epitopes that evade generation by the proteasome-system.
Over the last few years, several patients with defects in the HLA class I presentation pathway have been described. Analysis of their clinical symptoms and immunological parameters have led to the ...identification of several unexpected findings which are of importance to understand the role of HLA class I-dependent immune responses in host defense. Here, we will describe and compare clinical manifestations and immunological findings of patients with defects in the peptide transporter proteins (TAP complex), tapasin and CD8 molecules.
Antigen-presenting cells and tolerance induction VON BUBNOFF, D; DE LA SALLE, H; WESSENDORF, J ...
Allergy (Copenhagen),
2002, 2002-Jan, 2002-01-00, 20020101, Letnik:
57, Številka:
1
Journal Article
Recenzirano
T cell tolerance induction to foreign and self-antigens has occupied research since the beginning of the understanding of the immune system. Much controversy still exists on this question even though ...new methods became available to investigate immunoregulatory mechanisms. Antigen-presenting cells play a pivotal role in transferring information from the periphery of the organism to lymphoid organs. There, they initiate not only the activation of naive T cells but seem to deliver important signals which result in T cell unresponsiveness with antigen-specific tolerance induction.
SUMMARY
Antigen‐presenting cells (APCs) are crucial in regulating the outcome of T cell responses. Certain APCs are able to down‐regulate T cell proliferation in vitro by inducing the enzyme ...indoleamine 2,3‐dioxygenase (IDO) upon interferon‐γ (IFN‐γ) stimulation. IDO is the rate‐limiting enzyme in the catabolism of the essential amino acid tryptophan. A lack of extracellular tryptophan creates environments in which cells become starved for this amino acid. The high‐affinity receptor for IgE, FcɛRI, is the principal receptor for the binding of specific IgE in type I‐mediated allergies. We demonstrated recently that IDO is overexpressed in FcɛRI‐stimulated monocytes. In the present study, we performed quantification of IDO gene induction after treatment of atopic (FcɛRIhigh) and non‐atopic (FcɛRIlow/–) monocytes with IgE/anti‐IgE and IFN‐γ. By quantitative PCR ELISA, we found IDO molecule induction in atopic monocytes was enhanced about 50‐fold over non‐atopic monocytes after ligation of FcɛRI. Stimulation with IFN‐γ at a concentration of 100 U/ml in culture medium caused an increase in IDO gene copy numbers in atopics of about fourfold over that of non‐atopics. This comparative quantification study demonstrates clearly the regulation of IDO gene expression by FcɛRI and discloses differences thereof in atopic and non‐atopic cells upon inflammatory stimuli.
Objectives This study attempted to determine the prognostic indicators of low-back pain in an occupational health setting. Methods The identification of prognostic factors of (i) functional ...disability after 3 months' follow-up, (ii) functional disability after 12 months' follow-up, and (iii) time to return to work among 120 workers who reported to an occupational health unit and were off work with low-back pain for at least 10 days. Crude and adjusted odds ratios and hazard ratios with 95% confidence intervals were estimated for the 3 outcome measures. Results Factors related to a longer time to return to work were radiating pain, high functional disability at the beginning of the study, problems in relations with colleagues, and high work tempo and work quantity. High functional disability at the beginning of the study and a high avoidance coping style predicted functional disability at 3 months. Functional disability at 12 months was more accurately predicted by work-related and psychosocial factors. Conclusions Especially radiating pain and functional disability predict a long duration of low-back pain in occupational health practice. Occupational physicians should also note work-related and psychosocial characteristics.
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