Gi 12: Mucosal Immunity

Front 1

What are the special challenges to the immune system in the GI tract?

Back 1

- Tolerance to food antigens
- Tolerance to microbiota but responsiveness to pathogens
- Enormous surface area

Front 2

What are the special anatomic features of the immune system in the GI tract?

Back 2

- Tonsils
- Peyer's patches
- Lamina propria follicles

Front 3

What are the specialized cells / molecules in the immune system in the GI tract? Functions?

Back 3

- Epithelial cells: mucus secretion
- M cells: luminal sampling
- Paneth cells: defensin (antimicrobial) secretion
- Secretory IgA, IgM: neutralization
- DC subsets: luminal sampling

Front 4

What are the special challenges to the immune system in the respiratory system?

Back 4

Exposure to a mix of airborne pathogens and innocuous microbes and particles

Front 5

What are the special anatomic features of the immune system in the respiratory system?

Back 5

Adenoids

Front 6

What are the specialized cells / molecules in the immune system in the respiratory system? Functions?

Back 6

- Ciliated epithelial cells: mucus and defensin secretion
- Secretory IgA, IgM, IgG: neutralization

Front 7

What are the special challenges to the immune system in the cutaneous immune system?

Back 7

Large surface area

Front 8

What are the special anatomic features of the immune system in the cutaneous immune system?

Back 8

Keratinizing stratified epithelium

Front 9

What are the specialized cells / molecules in the immune system in the cutaneous immune system? Functions?

Back 9

- Keratinocyte: secretes keratin, cytokines, defensin
- Langerhans cells
- DC subsets

Front 10

What is the structure that is found at the crossroads of the GI tract and respiratory tract?

Back 10

Waldeyer's Ring

Front 11

What are the components of Waldeyer's Ring?

Back 11

- Palatine tonsils (most superior)
- Tubal tonsils
- Adenoids
- Lingual tonsil (most inferior)

Front 12

What is found within the tonsils of Waldeyer's ring?

Back 12

Follicles: consists of Parafollicular Cortex (darker area) and Germinal Center (lighter area)

Front 13

What is found in the Germinal Center of a follicle?

Back 13

B cells

Front 14

What is found in the Parafollicular Cortex of a follicle?

Back 14

T cells

Front 15

What are the characteristics of the mucosal immunity in the esophagus?

Back 15

- Has some mucosal immunity but this tends to be a fairly sterile environment (no endogenous bacteria)
- No large grouping of follicles

Front 16

What are the characteristics of the mucosal immunity in the stomach?

Back 16

- Similar to esophagus
- Acid is its main defense against bacteria
- H. pylori is the only bacteria that can really colonize here

Front 17

What are the characteristics of the mucosal immunity in the small and large intestines?

Back 17

Much more developed because the transit times are slower so there is a greater microbiota

Front 18

What kind of epithelium is found in the oral cavity?

Back 18

Stratified squamous, partially keratinized

Front 19

What kind of epithelium is found in the esophagus?

Back 19

Stratified squamous, non-keratinized

Front 20

What kind of epithelium is found in the stomach?

Back 20

Simple columnar epithelium with goblet cells

Front 21

What kind of epithelium is found in the small intestine?

Back 21

Simple columnar epithelium with goblet cells, crypts, and villi

Front 22

What kind of epithelium is found in the colon?

Back 22

Simple columnar epithelium with crypts but no villi

Front 23

What kind of epithelium is found in the anus?

Back 23

Non-keratinized stratified epithelium

Front 24

Which part of the GI tract does this represent? How does it function for mucosal immunity?

Back 24

Esophagus:
- Epithelium is stratified squamous and constantly sloughing off
- If bacteria adhere to epithelium, they are quickly sloughed before they can get in
- Purple dots in Lamina Propria are neutrophils, macrophages, and lymphocytes (physiologic inflammation to be ready for an infection)

Front 25

Which part of the GI tract does this represent? How does it function for mucosal immunity?

Back 25

Stomach:
- Immune cells are littered throughout the lamina propria (a lot more of these immune cells near the epithelial surface and less near the submucosal surface)

Front 26

Which part of the GI tract does this represent? How does it function for mucosal immunity?

Back 26

Small Intestine:
- Increasing accumulation of immune cells within lamina propria
- Slower migration patterns / less propulsive contractions, so there are more bacteria in this environment so need more immune cells
- Immune cells found in lamina propria in the villi

Front 27

What would a sign of a diseased/infected specimen?

Back 27

If you started seeing immune cells in the submucosal space that means they are proliferating and spilling out of the lamina propria

Front 28

What is the first place that the arterioles/venules and lacteals drain from the villi in the small intestine?

Back 28

Lamina Propria Follicle: spans the lamina propria and may span into the submucosa

Eventually drains into the mesenteric lymph nodes

Front 29

What is the arrow pointing out?

Back 29

Lamina Propria Follicle (contains B and T cells)

Front 30

What is this an image of in the ileum?

Back 30

Peyer's Patch
- Left black arrow: Parafollicular cortex (darker, contains T cells)
- White arrow: Germinal center (lighter, contains B cells)
- Right black arrow: Follicle Associated Epithelium (in close association with the Peyer's patch so that the bacteria can go directly into the T and B cell rich area)

Front 31

What cells channel bacteria into the Peyer's patches?

Back 31

M cells

Front 32

What kind of receptors recognize free antigens?
What kind of receptors recognize cell-associated antigens?

Back 32

- Free antigens: B cell receptors
- Cell-associated antigens: T cell receptors

Front 33

Which part of the GI tract does this represent? How does it function for mucosal immunity?

Back 33

AppendixAppendix
- Has a colonic like epithelial surface
- Crypts but no villi
- Immune cells in the lamina propria
- Lymph follicles underneath epithelium contains germinal center (light w/ B cells) and parafollicular cortex (dark w/ T cells)

Front 34

Which part of the GI tract does this represent? How does it function for mucosal immunity?

Back 34

Colon:
- Crypts but no villi
- Basal level of immune cells in lamina propria
- Physiologically inflamed immune tissue (not infected)

Front 35

How do immune cells move into tissues?

Back 35

Mediators:
- MADCAM1
- α4β7

Front 36

What are the barrier / structural cells of the mucosal immune system?

Back 36

Epithelial cells

Front 37

What are the innate immune cells of the mucosa?

Back 37

- Dendritic cells
- Macrophages
- NK cells
- Neutrophils
- Eosinophils
- Mast cells

Front 38

What are the adaptive immune cells of the mucosa?

Back 38

T cells:
- CD4: Th1, Th2, Th17
- CD8

B cells:
- IgA producing

Front 39

What molecules help maintain the tight junctions between epithelial cells?

Back 39

- Claudin
- Occludin
- E-cadherin
- Tight junctions
- Adherens junctions

Front 40

What Antigen Presenting Cells contribute to mucosal immunity?

Back 40

- Dendritic cells
- Activated macrophages
- Follicular dendritic cells (only found in germinal centers)

Front 41

What are the two responses an intestinal dendritic cell can have? How do you know which is happening?

Back 41

- Inflamed immune response - presence of IL-6
- Tolerance response - presence of Retinoic Acid

Front 42

What do TLR receptors that recognize antigen extracellularly release?

Back 42

NFkB

Front 43

What do TLR receptors that recognize antigen intracellularly release?

Back 43

IFN

Front 44

What "gut-homing" molecules are found on IgA-secreting B cells and effector T cells, to help these cells re-circulate back to the gut mucosa?

Back 44

1) α4β7 integrin (recognizes MadCAM in GI endothelium)
2) CCR9 (recognizes CCL25 - mucosal trafficking signal)

Front 45

What kind of cells is α4β7 integrin found on? What is its function on these cells?

Back 45

- Found on IgA secreting B cells and effector T cells trying to get to the gut
- Binds to MadCAM (mucosal addressin) on gut endothelial cells

Front 46

What kind of cells is CCR9 found on? What is its function on these cells?

Back 46

- Found on IgA secreting B cells and effector T cells trying to get to the gut
- Binds to CCL25 - a mucosal trafficking signal to help these cells return to gut

Front 47

What can Dendritic cells in Peyer's patches or mesenteric lymph nodes present? How?

Back 47

Retinoic Acid (RA) from dietary vitamin A through expression of retinal dehydrogenases

Front 48

Why is there elevated retinoic acid in gut tissues?

Back 48

Intestinal epithelial cells also express retinal dehydrogenases

Front 49

How do IgA-secreting B cells and effector T cells get back to the gut mucosa?

Back 49

- Follow the gradient of CCL25 (mucosal trafficking signal which is recognized by CCR) on these cells)
- Once it gets to the GI, the α4β7 being expressed on these cells binds to MadCAM on the GI endothelium

Front 50

What cytokines are produced by Th1 cells? What are these defending against? Role in disease?

Back 50

- Release IFN-γ
- Defending against intracellular microbes
- Involved in immune-mediated chronic inflammatory diseases (eg, IBD and infectious enterocolitis) (often auto-immune)

Front 51

What cytokines are produced by Th2 cells? What are these defending against? Role in disease?

Back 51

- Release IL-4, IL-5, and IL-13
- Defending against helminthic parasites
- Involved in allergies

Front 52

What cytokines are produced by Th17 cells? What are these defending against? Role in disease?

Back 52

- Release IL-17 and chemokines
- Defending against extracellular bacteria and fungi
- Involved in immune-mediated chronic inflammatory diseases (often autoimmune)

Front 53

What is the function of complement in the GI?

Back 53

- System of serum and cell surface proteins that interact with one another and other molecules of the immune response to generate effectors of innate and adaptive immune systems

- All pathways lead to C3 convertase→ C5 convertase → MAC complex on microbial surface

Front 54

How do plasma cells class switch in the gut? What does it require?

Back 54

Two mechanisms:
- T-dependent
- T-independent
- Requires soluble and membrane proteins

Front 55

What is the T-dependent mechanism of class switching in the gut?

Back 55

- DCs in Peyer's patch present Ag and activate naive T cells to Th1 cells
- CD40L on Th1 cells and *TGFβ* from DCs activates naive B cells

Front 56

What is the T-independent mechanism of class switching in the gut?

Back 56

- TLRs on DC stimulates release of TGFβ, APRIL, BAFF with IL6, and Retinoic Acid
* Combination of TGF-β and Retinoic Acid converts naive B cells into an IgA producing plasma cell

Front 57

What is the most prevalent immunoglobulin in the gut?

Back 57

IgA (green)

Front 58

How do IgA polymerize?

Back 58

- IgA link together via J chain which links to Poly-Ig receptor expressed on the basolateral surface of the mucosal epithelial cells
- This allows IgA produced by plasma cells to move from inside of the body to the gut lumen

Front 59

What is an immunogen?

Back 59

An antigen that induces an immune response

Front 60

What is an antigen?

Back 60

A molecule that binds to (is recognized) by antibody or T cells

Front 61

What factors make a protein more immunogenic (induce a larger immune response)?

Back 61

- Larger size
- Intermediate dose (high or low has decreased immunogenicity)
- Subcutaneous dosage > Intraperitoneal > IV or Intragastric
- Complex composition
- Particulate and denatured
- Many differences compared to self protein
- Slow release adjuvants / bacteria
- Effective interaction w/ host MHC

Front 62

What factors make a protein less immunogenic (induce a smaller immune response)?

Back 62

- Smaller size (MW<2500)
- High or low dose
- Intragastric or IV route
- Simple composition
- Soluble and native
- Few differences compared to self protein
- Rapid release adjuvants / no bacteria
- Ineffective interaction w/ host MHC

Front 63

What is hypersensitivity?

Back 63

Excessive or aberrant immune response following challenge with antigen

Front 64

What causes hypersensitivity?

Back 64

1. Dysregulated or uncontrolled response to foreign antigens resulting in tissue damage and injury
2. Failure of self-tolerance followed by immune responses directed against self-antigens (auto-immune)

Front 65

What are the types of hypersensitivity reactions? Type of immune response?

Back 65

- I: IgE response (immediate)
- II: IgG/IgM response
- III: immune complex mediated
- IV: T cell mediated

Front 66

What type of hypersensitivity is Type I? Pathological immune mechanism? Mechanism of tissue injury and disease?

Back 66

- Immediate hypersensitivity
- IgE mediated
- Mast cells and eosinophils and their mediators (vasoactive amines, lipids, cytokines) cause tissue injury and disease (inflammation)

Front 67

What type of hypersensitivity is Type II? Pathological immune mechanism? Mechanism of tissue injury and disease?

Back 67

- Antibody mediated: IgM and IgG
- Opsonization and phagocytosis, complement and Fc recruitment of leukocytes

Front 68

What type of hypersensitivity is Type III? Pathological immune mechanism? Mechanism of tissue injury and disease?

Back 68

- Immune complex mediated
- Complement and Fc recruitment of leukocytes causes tissue injury and disease

Front 69

What type of hypersensitivity is Type IV? Pathological immune mechanism? Mechanism of tissue injury and disease?

Back 69

- T cell mediated
- CD4: macrophage activated, inflammation
- CD8: target cell killing, inflammation

Front 70

What is immunologic tolerance?

Back 70

Specific unresponsiveness of the normal immune system to an individuals own self-antigens

Front 71

What are the characteristics of T cell tolerance?

Back 71

Long-lived, more complete

Front 72

What are the characteristics of B cell tolerance?

Back 72

Short-lived, less complete than in T cells and is quiescent in the absent of T cell help

Front 73

What determines whether an antigen will induce tolerance?

Back 73

- Immunologic maturity: neonates and elderly are immunologically immature and respond poorly to antigens
- Antigenic structure and dose: simpler the molecule and very high or low doses elicits tolerance
- Immunosuppressive therapy: enhances tolerance

Front 74

What are the principle factors in the development of auto-immune disease?

Back 74

- Inheritance of susceptibility genes which may contribute to FAILURE of self-tolerance
- Environmental triggers which may activate self-reactive lymphocytes
- Uncontrolled immune response

Front 75

How common are auto-immune disorders?

Back 75

1-2% of individuals (however many may be classified as "auto-immune" without formal evidence that the response is specific for self-antigen)

Front 76

Many auto-immune diseases have been linked to mutations in what genes? Characteristics?

Back 76

Genes encoding MHC
- Incidence of a particular auto-immune disease is often greater in individuals who inherit a particular HLA allele = "relative risk"
- Mutations in HLA genes are NOT by themselves the cause of the disease (many with these mutations do not develop disease)

Front 77

How do mutations in MHC contribute to auto-immune disease?

Back 77

- Inefficient in displaying self-antigens → defect in central tolerance
- Antigen presentation by those MHC may not stimulate Treg cells → defect in peripheral tolerance

Front 78

How do you treat auto-immune diseases?

Back 78

Relies on reducing the immune response sufficiently to eliminate symptoms:
- Systemic immune suppression (corticosteroids, antimetabolites, and nucleoside analogs)
- Non-systemic immune suppression (Abs to TNF (infliximab) and soluble TNFR (etanrecept)
- Plasmapheresis or competitive FcR inhibition