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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

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The immune geography of IgA induction and function

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  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?

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