* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Folie 1 - MH
Immunocontraception wikipedia , lookup
Sociality and disease transmission wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Gluten immunochemistry wikipedia , lookup
Social immunity wikipedia , lookup
Duffy antigen system wikipedia , lookup
Complement system wikipedia , lookup
Molecular mimicry wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Sjögren syndrome wikipedia , lookup
Immune system wikipedia , lookup
DNA vaccination wikipedia , lookup
Adaptive immune system wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
X-linked severe combined immunodeficiency wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
The immune geography of IgA induction and function AJ Macpherson, KD McCoy, F-E Johansen and P Brandtzaeg Mucosal Immunology (Nature Publishing Group) Volume 1, Number 1, January 2008 Review presented by Semrah Kati 12/08/2008 overview general introduction Ig A basics Ig A secretion function of sIg A class switch B-cell homing example general introduction host-microbes relations density of microbes [organisms/g] soil, oceans lower intestine ~ 108 OR LESS :o) ~ 1012 extremly good habitat contributes to 60% of faecal mass Comprises more than 1000 species! AM O´Hara and F Shanahan, EMBO reports, VOL7, NO7, 2006 host-microbes relations adaptive co-evolution of mammals and bacteria establishment of commensal1 and symbiotic relationships contributed to development of immune system and maintenance of normal physiology various functions of commensal bacterias: K Suzuki et al., seminars in immunology, review, 2007 1: (latin) cum mensa – (engl.) sharing a table AM O´Hara and F Shanahan, EMBO reports, VOL7, NO7, 2006 differentiation of distinct immune response sites humoral immunity at mucosal surface ≠ serum immune response distinguish between secretory and systemic immune response secretory immune response distinct mucosal immune response at mucosal surfaces distinct Ig isotype (Ig A), which comprises ~70% of all Ig produced in mammals Ig A induction by commensal intestinal microbes, function of Ig A response in maintaining mutualism between host and microbe is far less clear Ig A basics immune globulin A (IgA)- basics playing critical role in mucosal immunity found in mucous secretions, including tears, saliva, intestinal juice, colostrum, vaginal fluid and secretions from the prostate and respiratory epithelium; additionally found in small amounts in the blood functional activity mainly neutralisation of pathogens and exotoxins, poorly activates the complement system, weakly opsonises distribution mainly transported through epithelium as dimer; somethimes diffusion to extravascular areas as monomer average serum concentration: 2,1 mg/ml (Ig G1: 9 mg/ml, Ig E: 0,00003 mg/ml) CA Janeway et al., Immunobiology, 5th Ed., 2002, Spektrum immune globulin A (IgA)- basics immune globulin isotypes differ in the constant region of the heavy chain of the Ig-classes and sub-classes (effector function): heavy chain: α – 2 subclasses Ig A 1: mainly systemic immune system Ig A 2: mainly secretory effector sites, distal gut, more resistant to proteases than Ig A1(13aa deletion at hinge region) removed recognition site for Ig A1-specific proteases secretion Ig A forms mainly dimers and larger polymers (pIgA) linked by J-chain (joining-chain), a 15 kDa polypeptide binding the cystein residues at the end of the constant heavy chain produced by Ig A+ mucosal plasma cells higher antigen avidity CA Janeway et al., Immunobiology, 5th Ed., 2002, Spektrum www.wikipedia.org Ig A secretion transportcytosis transportcytosis of IgA antibody across polarized epithelia is clathrin-mediated by the poly-Ig receptor (pIgR), a specialized transport protein secretory component (SC) of sIg A part of the sacrificial transport receptor pIgR (leupeptinsensitive endoprotease) constitutively expressed CA Janeway et al., Immunobiology, 5th Ed., 2002, Spektrum ponent (SC) secretory component and pathogenicity sIg A in harsh intestinal environment mucophilic properties hibits scavenger properties with respect athogens A immunodeficiency M production (hyper-IgM-Syndrom) table than sIgA, because no covalent SC ensation less consistent in airways than in susceptibility to infections in respiratory otype A Phalipon and B Corthesy, Trends Immunol., 2003 www.wikipedia.org sIg A function of sIg A function of Ig A in different systems – non-pathogens intestinal bacteria 1014 – human cells in the body 1013 Ig A highly induced sIg A protection mechanisms far less clear • • • • • • Ig A dimer has large hydraulic diameter glycosylation of sIg A helps trapping of sIg A-bound antigen in the mucus clearance system from basolateral surface back to lumen (receptor-mediated epithelial Ig A transport) sIg A barrier effect needs only low antibody affinities to redundant surface epitopes of bacteria stabilization of a biofilm layer of bacteria uptake of sIg A complexed with antigen via M cells increases sampling of intestinal bacteria, oral tolerance monomeric Ig A2 with wide speration of antigen binding sites function of Ig A in different systems – microbial pathogens sIg A protection properties, „first line of defense“ • • • • toxin-neutralizing sIg A inhibit early invasion and horizontal fecal-oral spread of pathogens redundant role compensation by antibodies of other isotypes (Ig M and Ig G) or by innate immune mechanisms class switch Ig A class switch recombination (CSR) induction CSR requires 2 signals: 1) cytokines: TGF-β, contributed by IL-2, 4-6, 10 2) ligation of CD40 on B-cell with CD40L on T-cell 2) not essential! Ig A production partially T-cell independent other costimulatory signals TNF-family: BAFF (B-cell activating factor of the TNF-family) APRIL (A proliferation-inducing ligand) TGFβ: BAFF-R: BCMA: TACI: transforming growth factor β TNF: tumor necrosis factor BAFF-receptor B-cell maturation antigen transmembrane activator and CAML (calcium-modulating cyclophilin ligand) interactor some CSR induction investigations APRIL-TACI interaction necessary for Ig A induction (redundancy of Ig A CSR next to CD40-CD40L requirements?) intestinal DC from PP and mesenteric lymph nodes secrete permanently RA synergizes with IL- 5, 6 to induction of Ig A production in Bcells induction of small intestine homing receptor CCR9 DC: PP: RA: dendritic cells Peyer´s patches retinoic acid gene organisation The organisation of Ig heavy-chain C-region genes in humans; 2 CHα gene loci. exon 1 3´untranslated RNA exon 2 hinge region exon 3 18aa extension at the C-terminal end of sIg A (secretory tail piece for SC binding) transmembrane & cytoplasmic tail sequence Intron-exon structure of constant α heavy chain gene. Ig A class switch recombination (CSR) after V(D)J recombination Ig M expressed on surface of B-cells cytokines initiate transcription of α primary transcript, which forms through Iexon, S-region and Cα exons a germline transcript and a spliced out S-region transcript S-region transcript then hybridizes and stabilizes template DNA strand of S-region (RNA-DNA-hybrid) AID introduces dsDNA breaks at S-region and DNA repair rearranged heavy chain constant region and DNA switch circle intronic enhancer I-exon: initiation exon S-region: intronic switch region AID: activation-induced cytidine deaminase B-cell homing B-cell homing tissue-specific expression of chemokines and their receptors on memory/effector cells help in localization and retention, e.g. systemic lymphocytes use CD62L-PNad interactions at HEV for tethering, firm arrest by chemokine-triggered integrin activation, extravasation occurs through αLβ2-integrin interaction with endothelial ICAM-1 mucsosal effector site: adhesion chemokine-triggered integrin activation through α4β7-integrin interacting with mucosal addressin MAdCAM-1 shared expression of adhesion and chemokine receptor pairs common system, still regionalization & compartmentalization HEV: high endothelial venule PNad: periphrial lymph node addressins MAdCAM-1: mucosal addressin cell adhesion molecul-1 MLN: mesenteric lymph nodes NALT: nasopharynx-associated lymphoid tissue VCAM-1: vascular cell-adhesion molecule-1 classical Ig A+ B-cell tour from intestinal lympoid tissue 1) Ig A induction in mucosal B-cells 2) Ig A+ plasmablast recirculation and homing to intestinal mucosa 3) terminal B-cell differentiation to plasma cells with local Ig A production (after ~17d) 4) export of Ig A through intestinal epithelial cell layer different tissue sites contribute to Ig A induction P Brandtzaeg et al., Mucosal Immunology, 2008 example examples proposed mode of action of sIg A-antigen immune complexes after uptake by PP in the intestine: 1) pathogen activates T-cells via APC proinflammatory cytokines 2) sIg A-antigen complex masks microbeassociated molecular patterns no activation of proinflammatory pathways 3) surface interaction of sIg A with CD4 T cells downregulate activation maintenance of homeostasis PP: Peyer´s patches B Corthésy, Journal of Immunology, 2007 DC: dendritic cells Thanks for your attention! Any questions?