Transcript Folie 1 - MH

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
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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“
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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?