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 Kati12/08/2008

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 ~ 108 OR LESS :o)lower intestine ~ 1012

extremly good habitat contributes to 60% of faecal mass

AM O´Hara and F Shanahan, EMBO reports, VOL7, NO7, 2006

Comprises more than 1000 species!

K Suzuki et al., seminars in immunology, review, 20071: (latin) cum mensa – (engl.) sharing a tableAM O´Hara and F Shanahan, EMBO reports, VOL7, NO7, 2006

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:

host-microbes relations

humoral immunity at mucosal surface ≠ serum immune response

distinguish between

secretory and systemic immune response

secretory immune response

distinct mucosal immune response at mucosal surfacesdistinct 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

differentiation of distinct immune response sites

Ig A 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 monomeraverage serum concentration: 2,1 mg/ml

(Ig G1: 9 mg/ml, Ig E: 0,00003 mg/ml)

immune globulin A (IgA)- basics

CA Janeway et al., Immunobiology, 5th Ed., 2002, Spektrum

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 subclassesIg A 1: mainly systemic immune systemIg 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

immune globulin A (IgA)- basics

CA Janeway et al., Immunobiology, 5th Ed., 2002, Spektrumwww.wikipedia.org

Ig A secretion

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

transportcytosis

CA Janeway et al., Immunobiology, 5th Ed., 2002, Spektrum

secretory component (SC)

stabilizes sIg A in harsh intestinal environment and gives mucophilic propertiesfree 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

secretory component and pathogenicity

A Phalipon and B Corthesy, Trends Immunol., 2003www.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 withwide 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, 102) 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 β TNF: tumor necrosis factorBAFF-R: BAFF-receptorBCMA: B-cell maturation antigenTACI: 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 B-cells

induction of small intestine homing receptor CCR9

DC: dendritic cellsPP: Peyer´s patchesRA: retinoic acid

gene organisation

The organisation of Ig heavy-chain C-region genes in humans; 2 CHα gene loci.

Intron-exon structure of constant α heavy chain gene.

exon 1

exon 2

exon 3hinge region 18aa extension at the

C-terminal end of sIg A(secretory tail piece for SC binding)

transmembrane & cytoplasmic tail sequence

3´untranslated RNA

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 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 exonS-region: intronic switch regionAID: activation-induced cytidine deaminase

intronic enhancer

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-triggeredintegrin activation through α4β7-integrin interacting withmucosal addressin MAdCAM-1

shared expression of adhesionand chemokine receptor pairs common system, still regio-nalization & compartmentalization

HEV: high endothelial venule MLN: mesenteric lymph nodesPNad: periphrial lymph node addressins NALT: nasopharynx-associated lymphoid tissueMAdCAM-1: mucosal addressin cell adhesion molecul-1 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

P Brandtzaeg et al., Mucosal Immunology, 2008

different tissue sitescontribute to Ig Ainduction

example

PP: Peyer´s patchesB Corthésy, Journal of Immunology, 2007DC: dendritic cells

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 cytokines2) sIg A-antigen complex masks microbe- associated molecular patterns no activation of proinflammatory pathways3) surface interaction of sIg A with CD4 T cells downregulate activation maintenance of homeostasis

Thanks for your attention!

Any questions?