MUCOSAL IMMUNE SYSTEM

1. MUCOSAL IMMUNE SYSTEM October 31, 2008 Deborah A. Lebman, PhD dlebman@vcu.edu Goodwin Research Lab Rm 290 Reading: Janeway’s Immunobiology, Chapter 11

2. ORGANIZATION OF THE MUCOSAL IMMUNE SYSTEM Mucosal sites represent a large surface area exposed to the environment The vast majority of infections invade via mucosal surfaces Microorganisms that live in mucosal tissues are essential to our health The mucosa is exposes to a variety of antigens, e.g., food. An immune response to these antigens would do more harm than good

3. FEATURES OF THE MUCOSAL IMMUNE SYSTEM THE MUCOSAL IMMUNE SYSTEM IS THE LARGEST SEGMENT OF THE BODIES IMMUNE DEFENSE MECHANISMS

4. THE MUCOSAL IMMUNE SYSTEM: GALT

5. THE MUCOSAL IMMUNE SYSTEM: NALT

6. ANTIGEN ENTRY INTO MUCOSAL SITES

7. THE EPITHELIUM OF PP CONTAINS SPECIALIZED CELLS M cells are distinguished by membrane ruffles/microvilli

8. M CELLS ARE RESPONSIBLE FOR ANTIGEN UPTAKE M cells facilitate antigen entry. THEY ARE NOT APC M cell “hands” off intact antigen to lymphocyte or dendritic cell Enteric pathogens know how to exploit M cells

9. DENDRITIC CELLS FACILITATE ANTIGEN UPTAKE

10. LYMPHOCYTE CIRCULATION You can come home again!!!

11. Figure 10-20 A COMMON MUCOSAL IMMUNE SYSTEM Lymphocytes stimulated in mucosal sites traffic to mucosal sites

12. LYMPHOCYTES ACTIVATED IN INTESTINAL TISSUES RETURN TO INTESTINAL TISSUE B cell homing/recirculation is similar to that of T cells B cells and T cells are activated in “inductive” sites (PP, SLN) and specifcally traffic to effector sites (intestinal lamina propria

13. CHEMOKINES AND ADHESION MOLECULES DIRECT HOMING Integrin (a4b7):Addressin (MadCAM) Interactions Chemokine Receptor(CCR9/10): Chemokine (CCL25/28) Interactions

14. MUCOSAL IMMUNE RESPONSES

15. THE IgA RESPONSE Effective immunization against enteric pathogens is associated with an IgA response IgA2 vs IgA1: More resistant to proteases IgA vs IgM : Higher affinity, inability to bind C’ (less inflammatory) Most IgA is from the gi tract/PP

16. EFFECTOR SITES: EPITHELIUM AND LAMINA PROPRIA Generally cells have characteristics of activated cells Lamina propria contains the whole range of immune cells Epithelium contains CD8 T cells

17. INTRAEPITHELIAL LYPMPHOCYTES (IELs) 10-15% of epithelial cells are IELs IELs are mostly (90%) CD8 T cells Restricted usage of V regions/limited specificities Two types: conventional CD8 ab and CD8aa

18. FUNCTIONS OF IEL (CONVENTIONAL T CELLS) CD8ab cells protect against infection and are similar to peripheral CD8 cells in their behavior

19. FUNCTIONS OF IELs (CD8aa) Regardless of whether cells have a:b or g:d TCR, they do not recognize antigen via MHC class I They do not undergo thymic selection;many are self reactive Cytotoxic and express pro-inflammatory cytokines Innate immunity? NKG2D binds MICA and MICB which are elevated during cell injury or stress

20. MUCOSAL IMMUNE RESPONSES

21. MUCOSAL EPITHELIAL CELLS ARE AN ACTIVE BARRIER Epithelial cells interact with bacteria via intracellular receptors (TLR or NODs) Activation of these receptors in turn causes activation of NFkB Promoters for a wide array of pro-inflammatory mediators are activated by NFkB

22. PATHOGEN EXPLOITATION OF MUCOSAL IMMUNITY: SALMONELLA Salmonella enters via M cells, epithelial cells or with the help of dendritic cells

23. TO RESPOND OR NOT TO RESPOND?

24. DEMONSTRATION OF ORAL TOLERANCE Concept: Exposure to non-living, non-replicating antigens in the gut leads to local and systemic non-responsiveness Benefit: Food antigens are always present systemically. Without oral tolerance chronic, systemic inflammation

25. THE ROLE OF COMMENSAL BACTERIA IN TOLERANCE AND IMMUNITY Commensal bacteria stimulate epithelium to produce cytokines and other factors that prevent dendritic cell maturation Invasive bacteria stimulate dendritic cells to mature Immature dendritic cells induce T regulatory cells (TGFb producers) Mature T cells induce T helpers