Mucosal Immune System
• Mucosal Immune System: lymphoid organs associated with : (MALT)
– Gastrointestinal tract + oral cavity + pharynx & glands associated with thesetissues GALT
– Upper and lower respiratory tract NALT, BALT – Urogenital tract
– Lactating breast
• Mucosal surfaces thin & permeable barrier:
– Vulnerable to infection
– Portals of entry for a vast array of foreign antigens that are not pathogenic i.e. food
– Colonized by commensal microorganisms/microbiota
• Colon : 1012 organisms/ml colon content
• 100-200 Peyer patches in human small intestine
• Rich B cells > sistemic peripheral lymphoid organs
• The intestine has distinctive routes and mechanisms of antigen uptake
• Antigen uptake by M cells through endocytosis/phagocytosis transported through transcytosis
T cells activate B cells plasma cells IgA
• The mucosal immune system contains large numbers of effector lymphocytes even in the absence of disease display many characteristics of a chronic inflammatory response due to antigens bombarding mucosal surface
• The circulation of lymphocytes within the mucosal immune system is controlled by tissue- specific adhesion molecules and chemokine receptors
• GALT lymphocyte + α4β7;
endothelia : MAdCAM-1
• Tissue specific priming determine vaccination route
• Priming of lymphocytes in one mucosal tissue can induce protective immunity at other mucosal surfaces
• effector T and B cells primed in lymphoid organs draining the small intestine (mesenteric lymph nodes and Peyer's patches) return to the small intestine;
• effector T and B cells primed in the respiratory tract migrate most efficiently back to the respiratory mucosa.
antigen-specific effector cells to the mucosal organs
• There are overlap between mucosal recirculation routes common mucosal immune system, i.e. due to MAdCAM-1
Unique populations of dendritic cells control mucosal immune responses
• Dendritic cells found in the Peyer’s patches in two main areas:
– Subepithelial dome region DC acquire antigen from M cells dendritic cells CD11b
+CD8α
-, expressed CCR6
Beneath the epithelium – in resting conditions produce IL-10
prevent priming T-cells to become pro-inflammatory T cells
DC are recruited into the Epithelial cells of the Peyer patches during infection
– DC in T-cell area of Peyer’s patches : dendritic cells CD11b
-CD8α
+, not expressed CCR6 produced IL-12
• DC in the wall of the intestine outside Peyer’s patches lamina propria
– Contribute to maintaining tolerance to harmless antigens in the
intestine especially derived from food proteins
• Unique populations of dendritic cells control mucosal immune responses
mononuclear cells have been seen extending processes between the cells of the epithelium without disturbing its integrity. The cell process could pick up and internalize antigen from the gut lumen and then retract.
soluble antigens such as food proteins might be transported directly across or between enterocytes, or there might be M cells in the surface epithelium outside Peyer's patches
enterocytes can capture and internalize antigen: antibody complexes by means of the FcRn on their surface and transport them across the epithelium by transcytosis. At the basal face of the epithelium, lamina propria dendritic cells expressing FcRn and other Fc receptors pick up and internalize the complexes.
an enterocyte infected with an intracellular pathogen undergoes apoptosis and its remains are phagocytosed by the dendritic cell.
Capture antigen by dendritic cells in the lamina propria
• The intestinal epithelium is a unique compartment of the immune system:
– 90% T cells (IEL=intraepithelial lymphocytes))
•
80% CD8+T cells in small intestines• Large intestines : a greater proportion : CD4+
Type a IEL
Type b IEL - Not self-reactive effector cells
• Secretory IgA is the class of antibody associated with the mucosal immune system
• mIgA blood; dimer IgA mucosal
• B cells switching Ig driven by IL-5, IL-6, IL-10, IL-21
• Ratio IgA1:IgA2 :
– Blood & Upper respiratory : 10:1 – Small intestine: 3:2
– Colon : 2:3
• IgA2 more resistant to cleavage
• Some pathogens i.e.
Haemophilus influenza, Neisseria gonorrhoea protease cleave IgA1
• IgA-expressing B lymphocytes expressed homing integrin α4β7, chemokine CCR9, CCR10
Transcytosis of lgA antibody across epithelia is mediated by the polymeric lg receptor (plgR), a specialized transport protein.
• Hepatobilitary route (only some animals): dimeric IgA not bound pIgR taken up into the portal veins taken up into hepatocytes & transported by
transcytosis into an adjacent bile duct
• IgA can neutralize bacterial LPS & virus inside
epithelial cells
• IgA may be compensated by secretory IgM
• IgM is a J-chain-linked polymer bound efficiently by pIgR in gut mucosa
– found in IgA deficiency person
Intestinal pathogens and infectious disease in human
Intestinal pathogens and infectious disease in human
• Epithelial cells innate defence against pathogens
– Injury and stress stimulates MIC-a, MIC-b in
enterocytes
• The outcome of infection by intestinal pathogens is determined by a complex interplay between the microorganism and the host immune response
outcome of infection by intestinal pathogens is determined by a complex interplay between the microorganism and the host
immune response
Many enteric pathogens exploit host mechanisms of antigen uptake via M cells and inflammation as part of their invasive strategy
• transported through M cells by transcytosis, and initiate infection in other tissues distant from the entrance : Poliovirus, reoviruses, and some retroviruses
• Infect the same tissue as entrance : Prions
• entry into the M cell use M cells
molecules/compartments : Salmonella enterica Typhi, Shigella species; Yersinia pestis, H. pylori
• Host inflammatory response support invasive process of the pathogen : phagocytes which engulfed pathogen – induce IL-1β & TNF-α loosen tight junction between epithelial cells remove normal barrier to bacterial invasion
• Modulate host inflammatory response : Yersinia – yop protein inhibit inflammatory response, block phagocytosis & intracellular killing of microbes
• Pathogen + innate adaptive immune system
