1 / 26

The immune geography of IgA induction and function

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

alec
Télécharger la présentation

The immune geography of IgA induction and function

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 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

  2. overview • general introduction • Ig A basics • Ig A secretion • function of sIg A • class switch • B-cell homing • example

  3. general introduction

  4. host-microbes relations density of microbes [organisms/g] soil, oceans ~ 108OR LESS :o) lower intestine ~ 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

  5. 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

  6. 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

  7. Ig A basics

  8. 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

  9. 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

  10. Ig A secretion

  11. 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 (leupeptin- sensitive endoprotease)  constitutively expressed CA Janeway et al., Immunobiology, 5th Ed., 2002, Spektrum

  12. secretory component and pathogenicity • secretory component (SC) • stabilizes sIg A in harsh intestinal environment and gives mucophilic properties free SC exhibits scavenger properties with respect to enteric pathogens • pathogenicity selective Ig A immunodeficiency  higher sIgM production (hyper-IgM-Syndrom)  sIgM less stable than sIgA, because no covalent binding of SC • sIgM compensation less consistent in airways than in gut (higher susceptibility to infections in respiratory tract)  mild phenotype sIg A A Phalipon and B Corthesy, Trends Immunol., 2003 www.wikipedia.org

  13. function of sIg A

  14. function of Ig A in different systems – non-pathogens monomeric Ig A2 with wide speration of antigen binding sites • 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

  15. 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

  16. class switch

  17. 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: transforming growth factor βTNF: tumor necrosis factor BAFF-R: BAFF-receptor BCMA: B-cell maturation antigen TACI: transmembrane activator and CAML (calcium-modulating cyclophilin ligand) interactor

  18. 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 B-cells  induction of small intestine homing receptor CCR9 DC: dendritic cells PP: Peyer´s patches RA: retinoic acid

  19. gene organisation exon 1 3´untranslated RNA exon 2 transmembrane & cytoplasmic tail sequence hinge region 18aa extension at the C-terminal end of sIg A (secretory tail piece for SC binding) exon 3 The organisation of Ig heavy-chain C-region genes in humans; 2 CHα gene loci. Intron-exon structure of constant αheavy chain gene.

  20. Ig A class switch recombination (CSR) intronic enhancer • after V(D)J recombination Ig M expressed on surface of B-cells • cytokines initiate transcription of α primary transcript, which forms through I- exon, 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 I-exon: initiation exon S-region: intronic switch region AID: activation-induced cytidine deaminase

  21. B-cell homing

  22. 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 regio- nalization & compartmentalization HEV: high endothelial venule MLN: mesenteric lymph nodes PNad: periphrial lymph node addressins NALT: nasopharynx-associated lymphoid tissue MAdCAM-1: mucosal addressin cell adhesion molecul-1 VCAM-1: vascular cell-adhesion molecule-1

  23. 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) exportof Ig A through intestinal epithelial cell layer different tissue sites contribute to Ig A induction P Brandtzaeg et al., Mucosal Immunology, 2008

  24. example

  25. 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 microbe- associated 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

  26. Thanks for your attention! Any questions?

More Related