1. IMMUNE RESPONSE AT MUCOSAL SURFACES
April 9, 2009
11:00-12:00

2. ORGANIZATION OF THE MUCOSAL IMMUNE SYSTEM
INDUCTIVE SITES:
EFFECTOR SITES:
NALT
Nasal mucosa
Upper respiratory tract
Lacrimal glands
Salivary glands
Mammary glands
Intestinal tract
Genitourinary tract
Tonsils, adenoids
BALT
GALT PP
Solitary lymphoid nodules
Appendix

3. A GASTROENTEROLOGISTS VIEW OF PEYER’S PATCHES

4. A PATHOLOGISTS VIEW OF PEYER’S PATCHES

5. AN IMMUNOLOGISTS VIEW OF PP

6. How do antigens breech mucosal barriers?

7. M CELLS: A SPECIALIZED CELL FOR ANTIGEN UPTAKE
Identifying feature: microfolds vs microvilli
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

8. ALTERNATE ROUTES OF ANTIGEN ENTRY
Pathogen is taken up by M cell
Pathogen invasion of luminal epithelium
Pathogen is taken up by dendrites sampling the gut lumen
Pathogen is transported by s-IgA?

9. You can come home again!!!

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

11. Figure 10-21 DIRECTING LYMPHOCYTES TO MUCOSAL SITES
Integrin (a4b7):Addressin (MadCAM) Interactions
Chemokine Receptor(CCR9/10): Chemokine (CCL25/28) Interactions

12. Figure 10-22 DIRECTING LYMPHOCYTES TO INFLAMED SKIN
CLA on lympocytes binds
E-selectin on endothelium
T cell adhesion molecule interaction with endothelium
(CLA and E-selectin)
T cell chemokine receptor (CCR10): keratinocyte chemokine (CCL27)

13. EXPRESSION OF ADHESION MOLECULES IS DETERMINED BY
ROUTE OF IMMUNIZATION
Route of immunization
Adhesion molecules on Ab
secreting cells in blood
Parenteral
l-selectin, no a4b7
Enteric
(oral or rectal)
No l-selectin, a4b7
Nasal
L-selectin, a4b7

14. The Mucosal “Team”

15. SECRETORY IgA: THE FIRST LINE OF DEFENSE
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. GI T CELLS
Conventional ab TCR
T cells with gd TCR or abTCR/CD8aa :
Develop locally (no thymic selection)
The roles of Vd1 T cells:
Elimination of injured
epithelial cells
Direct a TH1 response

17. THE ROLES OF COMMENSAL FLORA
Provide metabolites
Protect from pathogens
Can be pathogenic
Immunogenic
Important for GALT
development
TLR4 signaling which
is important for
homeostasis

18. TO RESPOND OR NOT TO RESPOND, THAT IS THE
QUESTION

19. Figure 10-27 PATHOGENIC ORGANISMS INDUCE INFLAMMATION I
Intracellular Shigella activates NFkB
NFkB activates transcription of pro-inflammatory genes

20. PATHOGENIC ORGANISMS INDUCE INFLAMMATION II
Helicobacter pylori
Ulcers
Chronic inflammation increases
cancer susceptibility
MALT lymphomas
De novo follicle formation
Treat with antibiotics

21. ORAL TOLERANCE
Feeding non-living antigens (food) leads to
local and systemic non-responsiveness

22. FACTORS RESPONSIBLE FOR ORAL TOLERANCE
Ability of stimulus to cause inflammation
Antigen presentation by enterocytes
leads to anergy (signal 1 only)
Induction of Tr that secrete
TGFb

23. MUCOSAL IMMUNE RESPONSES
Another Answer: Several types of DC; the DC that presents ag determines response or no response

24. FAILURES IN MUCOSAL IMMUNITY
Inflammatory bowel disease
Ulcerative colitis
Crohn’s Disease
Celiac Disease