ETIOPATHOGENESIS OF IBD

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ETIOPATHOGENESISOF IBD
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CURRENT VIEW

• DYSREGULATED IMMUNE RESPONSE AGAINST PART OF THE
  COMMENSAL FLORA IN A GENETICALLY SUSCEPTIBLE
  PERSON

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• GUT IMMUNE SYSTEM

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OVERVIEW
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OVERVIEW

• A single layer of epithelial cells separates the
  intestinal lamina propria from the gut flora.
• It is protected by a thick layer of mucus,
  bactericidal defensins, neutrophils and large
  amounts of antigen-specific secretory IgA.
• The intestinal immune system can be functionally
  divided into inductive sites, which include the
  mesenteric lymph nodes, Peyer's patches (in the
  small intestine), colonic patches and isolated
  lymphoid follicles (ILFs), and into effector
  sites, which include the epithelium and the
  lamina propria.
• In the epithelium, intraepithelial lymphocytes
  (IELs) monitor epithelial damage and might
  recognize microbial antigens.
• The lamina propria contains large numbers of T
  cells, IgA-producing plasma cells and
  macrophages. It also contains many dendritic
  cells (DCs), which migrate to mesenteric lymph
  nodes through the lymph and present antigens to T
  cells.
• The FOLLICLE-ASSOCIATED EPITHELIUM (FAE), which
  covers Peyer's patches, contains MICROFOLD (M)
  CELLS, which transport lumenal antigens to the
  sub-epithelial dome of Peyer's patches for
  sampling by DCs that can also sample antigens
  from apoptotic epithelial cells.
• ILFs, similar to Peyer's patches, contain B
  cells, DCs and M cells (which are located in the
  adjacent FAE). Recent evidence indicates that
  cryptopatches, which contain DCs and
  Lin-cKITinterleukin-7 receptor -chain (IL-7R )
  cells, differentiate into ILFs. Lin-cKITIL-7R
  cells are also found scattered in ILFs and in the
  sub-epithelial dome of Peyer's patches. HEV, high
  endothelial venule.

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OVERVIEW
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TH1 VS TH2
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• INNATE IMMUNE SYSTEM
• KEY TO THE UNDERSTANDING OF IBD

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OVERVIEW

• physical and biochemical adaptations to maintain
  barrier integrity including actin-rich
  microvillar extensions (a),
• epithelial-cell tight junctions (b),
• apically attached and secreted mucins that form
  a glycocalyx (c) and the
• production of various antimicrobial peptides (d).
  
• Specialized intestinal epithelial cells known as
  M (microfold) cells overlie Peyer's patches and
  lymphoid follicles to facilitate luminal
  sampling. M cells exhibit reduced mucin secretion
  and have modified apical and basolateral surfaces
  (e) to promote uptake and transport of luminal
  contents to professional antigen-presenting cells
  that inhabit the subepithelial dome (SED) of the
  Peyer's patches and lymphoid follicles (f).
  Specialized dendritic cell (DC) subsets can also
  extend dendrites between the tight junctions of
  intestinal epithelial cells to sample luminal
  contents (g).

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MUCIN FUNCTONS
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TREFOIL PEPTIDE
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TIGHT JUNCTIONS
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CELLS OF INNATE IMMUNE SYSTEM
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PRRTLRsand NLRs
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INNATE SIGNALLING SYSTEM
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NF-KB
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INITIATING EVENTS

• IBD represents a state of sustained immune
  response.
• The question arises as to whether this is an
  appropriate response to an unrecognized pathogen
  or an inappropriate response to an innocuous
  stimulus

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INFECTIOUS AGENTS

• Chlamydia, Listeria monocytogenes, cell
  walldeficient Pseudomonas species, reovirus,
  Paramyxovirus (measles virus) has been implicated
  
• Among the most enduring hypotheses is that
  Mycobacterium paratuberculosis is the causative
  agent of Crohn's disease. This notion dates to
  Dalziel's observation in 1913 that idiopathic
  granulomatous enterocolitis in humans is similar
  to Johne's disease, a granulomatous bowel disease
  of ruminants caused by M. paratuberculosis.
• M. paratuberculosis is extremely fastidious in
  its culture requirements, and some proponents of
  this hypothesis have speculated that the presence
  of M. paratuberculosis as a spheroplast may
  confound efforts to confirm the theory. Efforts
  to confirm this theory have included attempts to
  culture the organism demonstrate it by
  immunohis-tochemistry, in situ hybridization, and
  polymerase chain reaction methodology and
  empiric treatment with antimycobacterial
  antibiotics. Most investigation in this area has
  been inconclusive, providing insufficient
  evidence to either prove or reject the
  hypothesis.

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COMMENSAL BACTERIAS

• Experiments in genetic animal models of IBD have
  suggested strongly that in a genetically
  susceptible host, one need not invoke a classic
  pathogen as the cause of IBD, but rather
  nonpathogenic commensal enteric flora are
  sufficient to induce a chronic inflammatory
  response.
• In diverse models, animals raised under germ-free
  conditions show diminished or delayed expression
  of the IBD phenotype. On introduction of defined
  bacterial flora, however, the expected phenotype
  of bowel inflammation becomes manifest- NO
  GERM-NO COLITIS

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COMMENSAL BACTERIA
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COMMENSAL BACTERIAS

• Commensal bacteria are present at a high density
  in the intestinal lumen (up to 1012 bacteria per
  gram of luminal contents).
• Most commensal bacteria reside outside the layer
  of mucus that covers the intestinal epithelial
  cells.
• Some bacteria can be killed by antibacterial
  molecules, such as defensins, which are produced
  by the epithelial cells.
• Bacteria that penetrate the enterocyte
  epithelial layer are rapidly killed by the
  macrophages in the lamina propria.
• Commensal bacteria can also penetrate the
  specialized follicle-associated epithelium,
  containing M cells, which lies over the Peyer's
  patches.
• These bacteria are also rapidly killed by
  macrophages, but small numbers can survive for
  several days in dendritic cells (DCs).
• This enables the interaction of DCs with T and B
  cells in the Peyer's patches and/or the migration
  of DCs to the draining mesenteric lymph nodes.
  (DCs that contain live bacteria induce
  IgA-producing plasma cells more effectively than
  heat-killed bacteria.)
• Although DCs loaded with commensal bacteria can
  traffic to the mesenteric lymph nodes, the lymph
  nodes function as a barrier, and the loaded DCs
  cannot penetrate farther to reach the systemic
  secondary-lymphoid tissues. The result is that
  the induction of immune responses by live
  bacteria is confined to the mucosa itself.
  Following activation, B- and T-cell blasts can
  leave the mesenteric lymph nodes through the
  efferent lymph, enter the bloodstream at the
  thoracic duct and home back to the intestinal
  mucosa.

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• In light of the diversity of substances and
  bacteria within the intestinal lumen, it is
  remarkable that the gut is not perpetually
  inflamed. WHY?

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MUCOSAL TOLERANCE

• The presence of low-level physiologic
  inflammation within the healthy intestinal mucosa
  represents a state of preparedness to deal with
  potentially harmful agents
• A more vigorous response would not be appropriate
  if directed toward the innocuous commensal flora
  of the gut.
• Inflammation is kept in check through an active
  process termed immune tolerance.
• Tolerance is mediated in part by subsets of CD4
  helper T cells that are generated in the
  intestinal mucosa and secrete the down-regulatory
  cytokines, transforming growth factor (TGF)-ß1
  and interleukin (IL)-10. Two specific T cell
  populationsT regulatory 1 (Tr1) and T helper 3
  (Th3) cellsappear to have similar roles in
  maintaining mucosal tolerance in the intestine
• As in the animal models of IBD, evidence in
  humans who have IBD also points to an
  over-responsiveness of mucosal T cells to the
  enteric flora

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Intrinsic Control of Activated Innate Immune
Responses

• Activation of innate immune cells induces a
  number of compensatory inhibitory pathways that
  down-regulate the inflammatory response.
• These protective mechanisms limit tissue injury
  and prevent perpetuation and expansion of the
  inflammatory response once the initial stimulus
  has been cleared.
• Intestinal epithelial cells and lamina propria
  macrophages are relatively unresponsive to
  bacterial stimuli by virtue of low membrane
  expression of TLR, MD2, and CD 14.
• In addition, intestinal epithelial cells have a
  uniquely adapted NF?B signaling pathway of
  incomplete, delayed degradation of NF?B as well
  as large amounts of preformed intracellular IL-1
  receptor antagonist (icIL-1RA) that can be
  released on cell lysis.
• These adaptations permit these cells to maintain
  a nonactivated phenotype in a hostile environment

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IL-10

• IL-10 is a key endogenous regulator of innate
  immune responses.
• ACTIVATION is slower than stimulation of
  proinflammatory molecules such as IL-12 p40,
  providing a mechanism of transient activation of
  inflammatory responses with subsequent inhibition
• IL-10 blocks NF?B signaling by several proposed
  mechanisms inhibition of IKK activity, PI3
  kinase and AKT, and phosphorylated p65 subunit
  binding to DNA by blocking chromatin remodeling
  The consequences of this blockade is inhibition
  of transcription of multiple proinflammatory
  molecules, including IL-1, TNF, IL-6, IL-12,
  chemokines, MHC II and costimulatory molecules.
• IL-10-deficient mice develop TH1-mediated
  colitis

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• a Food proteins and products of commensal
  bacteria are taken up by dendritic cells (DCs)
  and in the absence of inflammation, prostaglandin
  E2 (PGE2) (produced constitutively by mesenchymal
  cells and macrophages), and transforming growth
  factor- (TGF- ) and perhaps interleukin-10
  (IL-10), which are produced by epithelial cells,
  result in the partial maturation of DCs in the
  Peyer's patch or lamina propria. The antigen is
  then presented to naive CD4 T cells in the
  mesenteric lymph node (MLN) or Peyer's patch.
  These T cells differentiate into regulatory T
  cells, which produce IL-10 and interferon- (IFN-
  ), and/or T helper (TH) 3 cells, which produce
  TGF- . The immunological consequences are local
  IgA production, systemic tolerance and local
  immune homeostasis. b When pathogens are
  encountered, local inflammation is induced by the
  effects of pathogen products mediated through
  Toll-like receptors (TLRs) that are expressed by
  mesenchymal cells, macrophages and epithelial
  cells. As a result, DCs in the Peyer's patch or
  lamina propria mature completely after taking up
  antigen and produce IL-12. After migrating to the
  MLN, these DCs prime gut-homing TH1 cells, which
  produce IFN- and cause further inflammation.
  CCR, CC-chemokine receptor LPS,
  lipopolysaccharide PAMP, pathogen-associated
  molecular pattern.

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• Basal recognition of commensal bacteria by
  intestinal epithelial cells (IECs) may influence
  the secretion of cytokines, including thymic
  stromal lymphopoietin (TSLP), transforming growth
  factor- (TGF ) and interleukin-10 (IL-10), that
  can directly influence the expression of
  pro-inflammatory cytokines by dendritic cell (DC)
  and macrophage populations that resident in the
  lamina propria and Peyer's patches. Signals
  derived from commensal bacteria may influence
  tissue-specific 'licensing' of accessory-cell
  functions resulting in the expansion and/or
  survival of T cells with regulatory capacities,
  including regulatory T cells, T regulatory type 1
  (TR1) cells, T helper 2 (TH2) cells and TH3
  cells. In addition to TSLP, TGF and IL-10, other
  IEC-derived factors, including APRIL (a
  proliferation-inducing ligand), B-cell-activating
  factor (BAFF), secretory leukocyte peptidase
  inhibitor (SLPI), prostaglandin E2 (PGE2) and
  other metabolites have the capacity to directly
  regulate the functions of both antigen-presenting
  cells and lymphocytes in the intestinal
  microenvironment. TLR5, Toll-like receptor 5
  SED, subepithelial dome.

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• Pattern-recognition receptors, including
  Toll-like receptors (TLRs) and nucleotide-binding
  oligomerization domain (NOD)-like receptors
  (NLRs), are expressed by most intestinal
  epithelial cells. TLRs recognize conserved
  microbial-associated molecular motifs including
  bacterial-derived lipopolysaccharide (LPS),
  lipoproteins, flagellin and unmethylated
  CpG-containing DNA. TLR ligation results in the
  recruitment of adaptor proteins such as MyD88
  (myeloid differentiation primary-response gene
  88), and TRIF (TIR-domain-containing adaptor
  protein inducing interferon- ) and subsequent
  activation of several signalling modules
  including the nuclear factor- B (NF- B) and
  mitogen-activated protein (MAP) kinase pathways.
  NLRs, including NOD1 and NOD2, recognize
  bacterial-derived peptidoglycan, a main component
  of the bacterial cell wall, and activate NF- B
  and MAP kinases through the recruitment of
  receptor-interacting protein 2 (RIP2). Activation
  of PRRs promotes a cascade of signalling events
  that result in expression of pro-inflammatory
  cytokines and chemokines. Basolateral and
  intracellular localization of most PRRs in or on
  intestinal epithelial cells is proposed as one
  mechanism to limit the recognition of commensal
  bacteria and initiation of innate immune
  responses. I B, inhibitor of NF- B IKK, I B
  kinase NALPs, NACHT-, LRR- and
  pyrin-domain-containing proteins.

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ROLE OF BACTERIAS

• In resting cells, nuclear factor- B (NF- B) is
  sequestered in the cytoplasm by inhibitor of NF-
  B (I B), which masks nuclear localization
  sequences. Following stimulation through
  Toll-like receptors (TLRs) or nucleotide-binding
  oligomerization domain (NOD)-like receptors
  (NLRs), classical NF- B activation is the result
  of I B kinase (IKK)-mediated phosphorylation of I
  B, which targets the inhibitor for ubiquitylation
  and subsequent proteasomal degradation. Commensal
  and attenuated pathogenic bacteria have been
  shown to inhibit innate signalling pathways in
  intestinal epithelial cells. For example,
  Yersinia spp. inhibit the NF- B pathway at the
  levels of I B phosphorylation, whereas attenuated
  Salmonella spp. block the polyubiquitylation and
  degradation of I B that is required for efficient
  nuclear translocation of NF- B. By contrast,
  Bacteroides thetaiotaomicron can also inhibit the
  NF- B pathway by hijacking the peroxisome-prolifer
  ation-activated receptor- (PPAR ) pathway.
  MyD88, myeloid differentiation primary-response
  gene 88 NALP, NACHT-, LRR- and
  pyrin-domain-containing protein RIP2,
  receptor-interacting protein 2 TRIF,
  TIR-domain-containing adaptor protein inducing
  interferon-

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ROLE OF BACTERIAS

• Pathogenic bacteria such as Salmonella
  typhimurium trigger I B kinase activation, I B
  degradation and nuclear translocation of p50/p65
  NF- B subunits. Some commensal bacteria offset
  these affects by promoting the nuclear export of
  activated p65 through associations with
  peroxisome proliferator-activated receptor (PPAR)
  , thereby terminating promoter activation. Other
  commensal bacteria inhibit I B degradation.

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• WHAT HAPPENS IN IBD??
• CROHNS PREDOMINANT TH-1 RESPONSE
• UC- A MODIFIED TH-2 RESPONSE

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GENETICALLY SUSCEPTIBLE
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• a, Schematic representation of cell-specific
  NOD2/CARD15 signalling pathways. In intestinal
  epithelial cells/Paneth cells and
  antigen-presenting cells, muramyl dipeptide (MDP)
  found in bacterial proteoglycans is recognized by
  the leucine rich repeats (LRR) domains of NOD2
  and leads to the activation of NF- B. In Paneth
  cells, NOD2-mediated NF- B activation leads to
  the induction of defensins. Mutations in NOD2
  attenuate selective -defensin production and
  protect epithelial cells from bacterial
  infection. In antigen-presenting cells, NOD2
  signalling is modulated by TLR signalling inputs
  and, via interaction with procaspase 1, regulates
  pro-inflammatory cytokine production. b,
  Potential roles for autophagy in IBD. Autophagy
  is essential for cellular homeostasis, providing
  a mechanism of response among all cell types to
  limit the harmful effects of diverse exogenous
  and endogenous stresses. The schematic flow
  diagram depicts the multiple stages at which
  autophagy may have a role in intestinal
  physiology, acute stages of inflammatory injury
  and the resolution phase of IBD. PRR, pattern
  recognition receptor ROS, reactive oxygen
  species.

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• (a) During gut homeostasis, while maintaining a
  polarized configuration (with intact tight
  junctions), enterocytes are tolerant to TLR
  stimulation by normal microflora, and NF- B
  activation is low. Secretion of -defensin by
  Paneth cells helps control the amount of
  intestinal microflora. PGN, peptidoglycan CpG,
  CpG oligo deoxynucleotides DC, dendritic cell.
  (b) Activation of IKK and NF- B in response to
  trichuris infection results in TSLP secretion,
  which 'instructs' dendritic cells to induce a TH2
  response with eosinophils and immunoglobulin E
  (IgE)secreting B cells, thus eradicating the
  parasite. The -defensins and -defensins
  secreted by Paneth cells and enterocytes,
  respectively, control the microflora. p50 and
  p65, NF- B subunits. (c) Deficiency in IKK or
  NEMO (possibly representing ectodermal dysplasia
  with immune deficiency) leads to a lack of TSLP
  and -defensin production, causing dendritic
  cells to secrete IL-12 and IL-23, which induces a
  TH1 and IL-17-secreting T helper (TH-17) response
  and, consequently, a chronic inflammatory
  reaction. Tissue damage ensues, due to the
  accumulation of neutrophils and other
  inflammatory cells and the secretion of
  proapoptotic cytokines such as TNF. M ,
  macrophage G-CSF, granulocyte colony-stimulating
  factor. (d) In Paneth cells, gain-of-function
  mutations in the gene encoding Nod2 (mNod2) with
  hypersensitivity to muramyl dipeptide (MDP)
  result in excessive NF- B activation, with
  secretion of a hypothetical cytokine that forces
  DCs to release IL-12 and IL-23. The outcome is
  induction of a TH1 and an IL-17-secreting T
  helper response that promotes tissue damage and
  Crohn's colitis. Alternatively, loss-of-function
  mutations in the gene encoding Nod2 compromise
  NF- B activation and the production of a
  TSLP-like factor, also resulting in TH1-driven
  colitis. IFN- , interferon- .
• Kim Caesar

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• Luminal antigens are transported to the
  nasopharynx-associated lymphoid tissue (NALT) and
  Peyer's patches through microfold (M) cells that
  are present in the epithelium overlying NALT and
  Peyer's-patch follicles. Dendritic cells process
  and present antigens to T cells in these lymphoid
  tissues. CD4 T cells that are stimulated by
  dendritic cells then preferentially induce
  IgA-committed B-cell development in the germinal
  centre of the lymphoid follicle. After IgA class
  switching and affinity maturation, B cells
  rapidly migrate from NALT and Peyer's patches to
  the regional cervical lymph nodes and mesenteric
  lymph nodes respectively, through the efferent
  lymphatics. Finally, antigen-specific CD4 T
  cells and IgA B cells migrate to effector sites
  (such as the nasal passage and intestinal lamina
  propria) through the thoracic duct and blood
  circulation. IgA B cells and plasmablasts then
  differentiate into IgA-producing plasma cells in
  the presence of cytokines (such as interleukin-5
  (IL-5) and IL-6) that are produced by T helper 2
  (TH2) cells, and they subsequently produce
  dimeric (or polymeric) forms of IgA. These
  dimeric forms of IgA then become secretory IgA by
  binding to polymeric Ig receptors (which become
  the secretory component in the process of
  secretory IgA formation) that are displayed on
  the monolayer of epithelial cells lining the
  mucosa. Secretory IgA is then released into the
  nasal passage and intestinal tract. TCR, T-cell
  receptor.

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• Depicted here is a generalized pathway of the
  mucosal inflammation underlying inflammatory
  bowel disease (IBD) and potential points of
  therapeutic intervention. a Secretion of
  inductive cytokines, such as interleukin-12
  (IL-12) or IL-13, can be inhibited with nuclear
  factor- B (NF- B) inhibitors or, more
  specifically, with various cytokine-specific
  monoclonal antibodies. This can occur in the
  mucosal follicle, as shown, or at more downstream
  sites. b The traffic of effector cells into the
  lamina propria can be blocked by inhibitors or
  monoclonal antibodies specific for integrins or
  chemokine receptors involved in homing, such as
  4 7. c Tumour-necrosis factor (TNF) expressed
  on the surface of effector cells can be
  crosslinked by antibodies specific for TNF
  leading to apoptosis of effector cells. d
  Regulatory T-cell induction or function could be
  enhanced so as to counteract effector T-cell
  function. This can be achieved by the delivery of
  vectors encoding regulatory cytokines.

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MICROBIAL ENTRY
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INNATE AND ACQUIRED IMMUNE SYSTEM
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• Simple columnar epithelial cells exhibit

• physical and biochemical adaptations to maintain
  barrier integrity including actin-rich
  microvillar extensions (a), epithelial-cell tight
  junctions (b), apically attached and secreted
  mucins that form a glycocalyx (c) and the
  production of various antimicrobial peptides (d).
  Specialized intestinal epithelial cells known as
  M (microfold) cells overlie Peyer's patches and
  lymphoid follicles to facilitate luminal
  sampling. M cells exhibit reduced mucin secretion
  and have modified apical and basolateral surfaces
  (e) to promote uptake and transport of luminal
  contents to professional antigen-presenting cells
  that inhabit the subepithelial dome (SED) of the
  Peyer's patches and lymphoid follicles (f).
  Specialized dendritic cell (DC) subsets can also
  extend dendrites between the tight junctions of
  intestinal epithelial cells to sample luminal
  contents (g).

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• a Lymphoid-tissue inducer (LTi) cells are
  required for initiation of lymph-node and
  Peyer's-patch development in the fetus. They were
  originally described as CD3-CD4CD45 cells96,
  and they are derived from fetal liver-cell
  precursors97, 98. These cells are recruited to
  the lymph-node and Peyer's-patch anlagen,
  probably by chemokines such as CXC-chemokine
  ligand 13 (CXCL13), which interacts with
  CXC-chemokine receptor 5 (CXCR5) and they
  interact with specialized mesenchymal cells,
  through cell-surface-expressed 4-integrins16.
  LTi cells express lymphotoxin- 1 2 (LT- 1 2), the
  expression of which is upregulated by
  interleukin-7 (IL-7) or other ligands of the IL-7
  receptor -chain (IL-7R )64, and they activate
  mesenchymal cells through the LT- receptor (LT-
  R). As a result, mesenchymal cells produce more
  chemokines (including CXCL13, CC-chemokine ligand
  19 (CCL19) and CCL21), express intercellular
  adhesion molecule 1 (ICAM1) and vascular
  cell-adhesion molecule 1 (VCAM1), and establish
  the first positive-feedback loop for the
  recruitment of LTi cells. A few days before
  birth, lymphocytes and dendritic cells (DCs) are
  recruited to the lymph-node and Peyer's-patch
  anlagen. Because T cells and B cells themselves
  express LT- 1 2 (Ref. 80), recruitment of
  lymphocytes is amplified by a second
  positive-feedback loop and culminates in the
  formation of a mature lymph node or Peyer's
  patch, with segregated T-cell zones and B-cell
  follicles, high endothelial venules (HEVs) and
  additional specialized mesenchymal cells. b
  Evidence indicates that the formation of isolated
  lymphoid follicles in the young and adult
  intestine recapitulates the fetal development of
  lymph nodes and Peyer's patches12.

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• Fetal intestinal lymphoid-tissue inducer (LTi)
  cells might persist in the lamina propria of
  newborns, where they could cluster into
  cryptopatches, together with dendritic cells
  (DCs), during the second week of life. The
  formation of cryptopatches depends on the
  interleukin-7 receptor -chain (IL-7R ) and on
  lymphotoxin- 1 2 (LT- 1 2), which is possibly
  expressed by LTi-like cells, but it is
  independent of the gut flora12, 18, 58. In
  response to a growing local gut flora, colonic
  cryptopatches differentiate into isolated
  lymphoid follicles (ILFs) during the second to
  third week of life9, 10 (Fig. 3). The formation
  of ILFs requires LTi-like cells, LT- 1 2 and
  IL-7R , as well as the gut flora and
  tumour-necrosis factor (TNF)9, 10, 12. It remains
  to be determined whether chemokines and adhesion
  molecules, such as intercellular adhesion
  molecule 1 (ICAM1) and vascular cell-adhesion
  molecule 1 (VCAM1), expressed by mesenchymal
  cells are required for ILF formation, similar to
  lymph-node and Peyer's-patch development (Fig.
  2). Increased numbers of ILFs, which are also
  hyperplastic, form in the small intestine in
  response to excessive numbers of gut flora68 or
  during inflammation14, 66, 67, 79, both of which
  are perturbations that could result in the
  production of TNF. Pathogens, such as Salmonella
  spp. and Yersinia spp., are taken up by DCs
  present in ILFs and can elicit antigen-specific
  IgA responses15. ILFs might also produce IgA to
  maintain homeostasis of the gut flora, as well as
  in response to inflammation. M cell, microfold
  cell.

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• The effector compartment consists of the
  scattered lamina-propria lymphocytes and the
  intraepithelial lymphocytes (IELs) that are
  embedded in the epithelial-cell layer, which is
  held together by tight junctions. M cells act as
  specific entry ports for antigen, facilitating
  the uptake of luminal antigens and their
  subsequent delivery to the initiation compartment
  of the organized lymphoid tissues, including the
  Peyer's patches and the mesenteric lymph nodes
  (MLNs). Naive T cells activated in the Peyer's
  patch and MLN upregulate expression of the
  integrin 4 7, which interacts with mucosal
  addressin cell-adhesion molecule 1 (MADCAM1),
  expressed on the endothelium of the
  intestinal-tissue high endothelial vessels
  (HEVs), thereby facilitating homing to the
  mucosal effector compartments. The chemokine
  CC-chemokine ligand 25 (CCL25), which is produced
  by epithelial cells of the small intestine, is
  also involved in the migration of lymphocytes to
  the intestinal mucosa, and its receptor, CCR9, is
  expressed by almost all lymphocytes of the small
  intestine. The integrin E 7 is expressed by IELs
  and interacts with E-cadherin, which is expressed
  by the epithelial cells, facilitating tethering
  of the IELs to the intestinal epithelium.

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• The epithelial-cell layer is impermeable to
  passive transport of materials from the lumen, as
  it is held together firmly by tight junctions. M
  cells that reside in the apical side of the gut
  epithelium form entry portals for the active
  uptake of gut antigen and transport of antigen to
  professional antigen-presenting cells, in
  particular dendritic cells (DCs) of the Peyer's
  patch. The epithelial cells can also mediate
  active endocytosis, and present processed antigen
  bound to MHC class I or class II molecules to
  intraepithelial lymphocytes (IELs)/lamina-propria
  lymphocytes (LPLs), or transfer processed antigen
  to mucosal DCs. Mucosal DCs can also directly
  sample luminal antigen using dendrites that form
  tight junctions with the neighbouring epithelial
  cells.

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• CD8 -T-cell receptor ( -TCR)
  intraepithelial lymphocytes (IELs) can respond to
  self-based alert signals delivered by stressed
  epithelial cells, and initiate an immune response
  to induce maturation of mucosal dendritic cells
  (DCs). They further exhibit regulatory ability by
  downmodulating active immune responses by
  conventional T cells. The CD8 -TCR IELs
  might also act to repair damaged epithelium.