Gi #9: Immunology Of The Gi Tract

Front 1

Luminal defense and Epithelial barriers make up the _______ immunity of the GI tract.

Describe luminal factors that protect the gut.

Back 1

Innate Immunity (First line of defense)

Non-immunologic mxns= lysozyme, HCl, digestive enzymes of pancreas, bile detergents. Intestinal motility and mucous secretion. Colon- host flora, antibacterial peptides (colcins), acidic pH, anaerobic environment.

Front 2

What are the two most important components of the Epithelial barrier/

Back 2

1. Intercellular tight junction complexes (regulate transport of particles and solutes)

2. Epithelial cells ( regulate transport across cell, contain Defensins and anti-microbial peptides)

Front 3

What are the 4 major cell types of the Epithelial Barrier?

What is the mot important cell of the Epithelial Barrier?

Back 3

Epithelial cells, Goblet cells, M cells (microfold), Paneth cells

Most important = Epithelial Cell (it secretes IgA, transduces signal from lumen, signals APCs and expresses MHC I & II so it can stimulate immune system by itself).

Front 4

What 3 things do the white cells shown in this image produce that protect against foreign particles?

Back 4

Goblet cells--

1. Mucin glycoprotein

2. Trefoil peptides (antimicrobial, activate NFkB and stimulate EGF receptors, aids in defense).

3. Beta Defensins (pro-inflammatory cytokines, ex: TNF and IL1-b)

Front 5

What special property of Epithelial cells help them clear cytotoxins?

What is the role of Cathelcidins?

Back 5

EC has Multidrug resistance gene (eliminates toxic intra-cytoplasmic substances).

Cathelcidins = expressed by PMNs & EC, can neutralize LPS of gram negative bacteria.

Front 6

What is the role of the pink cells shown here? Where are they located?

Why do they stain pink?

Back 6

Paneth cells- innate immune system. Located at base of small intestine crypts.

Eosinophilic as a result of granules that they release (alpha defensins, beta defensins)

Front 7

What is the role of the ZOT toxin? In what infectious agent does it exist?

What compound implicated in Celiac disease, works in a similar way?

Back 7

ZOT = Cholera B toxin (opens tight junctions allowing bacteria to penetrate lamina propria). *Zonulin occludens toxin, disrupts polymerization of actin)

Celiac disease = gliadin (glides in, acts similar to Cholera B)

Front 8

Role of Dendritic cells in defense?

Back 8

Dendritic cells = APCs that lie beneath EC. Sample intestinal environment by sending cytoplasmic projections through tight junctions. Present antigen to T-cell and help activate it.

Front 9

Where in the GI tract do intestinal macrophages reside?

What lineage are NK cells derived from? What do they secrete? What is their role in self-recognition?

Back 9

Macrophages= Peyer's patch, Kupffer cells of liver, and mesenteric nodes

NK cells- from lymphocytic lineage. Secrete INF-g (potent activator of macrophages). Recognize MHCI cells with KIR (killer inhibitor receptor) and inhibit cytotoxicity.

Front 10

What are the four components that make up GALT?

Back 10

Gut associated lymphoid tissue =
Lymphatic tissue, Lamina propria, Intraepithelial Lymphocytes (IELs), and Mesenteric Lymph Nodes

Front 11

Where do you see most of the structures shown above? What is the function of these structures?

What is the function of the cells found within the surface folds called?

Back 11

In small intestine (ileum). Some smaller ones in colon as well.

They are a sampling station for antigens. There are no crypts or villi, instead M-cells (microfold) are there are and they take up antigen and present it to the APCs and macrophages.

Front 12

A mixture of inflammatory cells (T, B, macrophage, NK, eosinophils, mast, etc) are found in the _______ of the GALT.

What is the role of MadCAM-1 in T-cells?

Back 12

Lamina propria

MadCAM1 = ligand that binds to T-lymphocyte homing receptor α4β7, and directs CD4+ T cells back to the GALT tissue (specifically to the high endothelial venules that they then enter).

*remember, T lymphocytes, once activated leave the peyer's patch, go to mesenteric lymph node and activate B cells, then go through lyphatic and systemic circulation and enter back in to the GALT.

Front 13

In what conditions might you see eosinophils in the lamina propria?

Where are mast cells localized within the lamina propria? How are they stimulated and what do they release?

Back 13

Helminthic disease, eosinophilic syndromes. (NAACP)

Mast cells (localized to nerve terminals). Stimulated by IgE and Substance P (neuropeptide). Release histamine, serotonin, proinflammatory cytokines.

Front 14

The plasma cells in the lamina propria mostly secrete what immunoglobulin?

Th-17 cells have been implicated as being important in what GI disease?

Back 14

IgA mostly (some IgM) *note, secretory IgM helps protect those who are deficient in IgA

Th-17 = new line of cells, important in IBD (inflammatory bowel disease)

Front 15

What cells can you make out in this image? How are they distinguished from lymphocytes?

Increased numbers of these cells in the colon have been implicated in __________. Increased numbers of these cells in the small intestine have been implicated in ________.

Back 15

Intraepithelial lymphocytes (larger than usual lymphocytes, and they lie between epithelial cells)

Too many IELs in small bowel = Celiac disease
Too many IELs in the colon = Lymphocytic colitis

Front 16

What is the role of intraepithelial lymphocytes? Most IEL's are CD___+?

Back 16

They are both cytotoxic and immunoregulatory. Mostly they are CD8+ (suppressor/ cytotoxic type).

Front 17

What are the largest lymph nodes in the body?

How are lymphocytes directed to peripheral lymph nodes? to mucosal tissues?

Back 17

Mesenteric lymph nodes (they serve as an area for dendritic cells to encounter and activate T and B cells, the T cells then pass through circulation and enter MALT).

α4β7 directs to mucosal tissue
L-selectin directs to peripheral lymph nodes

Front 18

What is the structure of the principal antibody in intestinal mucosal secretions?

Where is the sIgA receptor found?

Back 18

Secretory IgA --> dimer containing two IgA's linked by a J-chain. *note, there are 2 subclasses, IgA1 and IgA2

sIgA receptor in intestines, biliary tract, lactating breast (provide initial IgA protection to neonate), saliva, and sweat.

Front 19

Describe how IgA becomes secretory IgA.

Back 19

IgA is taken up by poly-Ig receptor (basolateral surface of epithelial cell). The receptor binds the J-chain.

IgA is endocytosed, transported in vesicle to lumen, and receptor is cleaved leaving reusable transmembrane portion.

Front 20

What is the difference in structure between serum and secretory IgA?

Which subtype is more commonly found in serum? What is the major source of Serum IgA vs. Secretory IgA?

Back 20

Serum IgA = monomeric (vs. sIgA which is dimeric)
Serum IgA is made in the bone marrow and IgA1 is most common subtype

*note sIgA is made mostly in intestine and IgA2 is most common subtype

Front 21

How does IgA aid in defense?

Back 21

Enhances non-specific defense (lactoferrin, lactoperoxidase). It inhibits Bacterial adhesion, neutralizes toxins.

Note- not a potent activator of complement

Front 22

A lymphocyte can become one of what three choices?

What is central vs. peripheral tolerance?

Back 22

Tolerance, Ignorance (no response from lymphocyte), or Activation (full response)

Central tolerance = immature lympho develop when they encounter antigens in thymus and BM
Peripheral = MATURE lympho encounter antigen in PERIPHERY

Front 23

Would you expect an increased immune response to someone who was fed a soluble protein antigen and then received it systemically or someone who received an antigen systemically without being fed?

Back 23

Feeding a soluble antigen beforehand reduces the immune response when the antigen is injected later on.

Front 24

Name two inhibitory cytokines secreted by T-regulatory cells.

Besides T-regs, what are other key cell players of tolerance?

Back 24

IL-10 and TGF-B = inhibitory cytokines

CD8+ suppressor cells, IELs (have both cytotoxic and immunoregulatory function, and Myeloid derives suppressor cells (MDSCs = macrophages)

Front 25

What are the three characteristic changes seen on the right histologic specimen (left is normal)?

What is the disease?

Back 25

Celiac disease=

1. Villous atrophy, 2. Crypt Hyperplasia, 3. Increased IEL's (seen as increase in blue staining cells)

Front 26

Describe the pathogenesis of Celiac disease (what happens when a patient eats wheat?)

Back 26

Wheat/Rye/Barley --> gliadin --> able to glide through epithelium because of increased intestinal permeability --> encounters TTG which activates gliadin (deaminates it) --> this binds to HLADQ2/8 --> stimulates T and B cell release

You get antibodies to Tissue Transglutaminase

Front 27

A patient is having weight loss, abdominal pain, and diarrhea. They have developed a papular vesicular rash on their extensor surface that is incredibly itchy. What is the treatment?

Back 27

Patient is having malabsorption from celiac disease. This is associated with Dermatitis herpetiformis.

Gluten free diet & dapsone (for the skin condition)

Front 28

How do you test for Celiac disease? What concomitant test should you order?

Back 28

1st- serum Ttg antibody test (usualyl ELISA) = most cost effective. (serum antibody to IgA endomysial is $$$$)

*always get an IgA level (because IgA deficiency is common in these patients so you want to make sure IgA ttg isn't falsely low)

2nd- endoscopy with a biopsy (because false positive serology can occur)