First Aid, Chapter 1 Immune Mechanisms, Mucosal Immunity

Question 1

What is the mechanism of protection by oral vaccines such as polio?

Answer 1

Secretory immunity (IgA), ie they use the mucosal immune system to provide protection.

Question 2

What percentage of proteins are absorbed in immunologically active form?

Answer 2

2%

Question 3

What are the three main regions of the GI tract mucosa?

Answer 3

Epithelial layer, lamina propria, and Peyer’s patches

Question 4

Where are Peyer’s patches most prominent?

Answer 4

small intestine

Question 5

What is the major site of IgA and B lymphocyte development that begins from signals from dendritic cells and T lymphocytes?

Answer 5

Peyer’s patches

Question 6

What are M cells? Are they APCs? How do help with antigen interaction?

Answer 6

• Specialized membranous cells that play a role in delivering antigens to Peyer’s patches.
• M cells are not APCs. M cells within the Peyer’s patch help create an invaginated subdomain or pocket, where memory T lymphocytes, naïve B cells, and memory B lymphocytes interact with antigen.

Question 7

What is the predominant cell type in Peyer’s patches? Where are these cells located within the Peyer’s patches?

Answer 7

Interfollicular regions with CD4+ T lymphocytes

Question 8

Other than CD4 lymphocytes, what other cells play a role in Peyer’s patches?

Answer 8

B lymphocytes, M cells

Question 9

Where are B lymphocytes located in Peyer’s patches?

Answer 9

Central region is B-lymphocyte rich area that contains germinal centers.

Question 10

How do M cells assist in transporting antigens?

Answer 10

M cells assist in transport of antigens such as protein, bacteria, virus, and noninfectious particles from the gut lumen to APCs and lymphoid tissue via transcytosis.

Question 11

How do M cells promote the immune response and tolerance?

Answer 11

“Sampling” of the antigens that M cells help transport is important in the development of the immune response and tolerance.

Question 12

What is the predominant T lymphocyte type in the lamina propria?

Answer 12

Mixed population of cells, including activated CD4+ T lymphocytes scattered throughout

Question 13

What are cell types that are present in the lamina propria? What is their function?

Answer 13

Activated B lymphocytes and plasma cells - IgA

T lymphocytes - memory phenotypes, produce cytokines IFNy, IL-4, and IL-5

Mast cells - fight parasites

Eosinophils - allergic response, fight parasites

Question 14

What is the predominant T lymphocyte in the epithelial layer? What other cells are there and what is their function?

Answer 14

CD8 T lymphocytes

Paneth cells - participates in innate immunity

Intestinal epithelial cells - important in nutrient absorption, Transports secretory IgA, Act as nonprofessional APCs by recognizing bacterial and viral motifs such as TLRs.

Intraepithelial lymphs - predominantly effector and effector memory cells

Question 15

What part of the intestine are T lymphocytes localized to? Why?

Answer 15

—Localize to small intestine due to a4B7 + CCR9.

Question 16

What are the 5 T reg lymphocytes found in the intestinal immunity?

Answer 16

• Th3 cells, a subset of CD4+ cells that secrete TGFβ
• TR1 cells, CD4 cells that secrete IL-10
• CD4+CD25+ regulatory T lymphocytes
• CD8+ suppressor T lymphocytes
• y or δ T lymphocytes

Question 17

Where are intraepithelial lymphs (IEL) located? What is migration influenced by? What do IEL subunits express?

Answer 17

Intraepithelial lymphocytes (IELs): Reside above the basement membrane, between epithelial cells. Migration is influenced by CCR9 or CCL25 and CD103 or E cadherin. All IEL subunits express CD8aa, which is a characteristic of activated mucosal T lymphocytes. IELs are mostly effector and effector memory cells with mainly CD8+.

Question 18

What are the phenotypes of intraepithelial lymphocytes?

Answer 18

• yd T cells: CD8+ –10% of total population
• ab T lymphocytes: CD4+ or CD8+
• Double-negative T lymphocytes: aB T lymphocytes with no coreceptor

Question 19

What cells in the intestine play a role in oral tolerance?

Answer 19

ACPs, especially intestinal epithelial cells, dendritic cells, and Treg cells play central role in oral tolerance.

Question 20

How does Th2 allergic skewing happen in the gut?

Answer 20

APCs in the gut lumen and elsewhere in the body present the potentially allergenic proteins to the T lymphocytes that, in a genetically predisposed individual, results in Th2 allergic response.

Question 21

What cells in the gut particularly promote oral tolerance and how?

Answer 21

Intestinal epithelial cells process luminal antigens and present it to T lymphocytes on a MHC class II complex; but these lack a “second signal,” thus suggesting their potential to play a role in tolerance induction.

Question 22

What cells promote Tregs in the gut? Where are they located? How do they promote them?

Answer 22

Dendritic cells residing within lamina propria and a noninflammatory environment of Peyer’s patches express IL-10 and IL-4. IL-10 promotes Tregs.

Question 23

When is gut flora established? Are probiotics helpful in preventing atopic disease?

Answer 23

Commensal gut flora can influence mucosal immune response. Gut flora are established within 24 hours after birth and depend on both maternal flora and local environment. Studies feeding lactating moms and their offspring Lactobacillus GG suggest that probiotics may be of benefit in preventing atopic dermatitis, possibly by enhancing Th1 cytokine response (IFNγ). Whether probiotics will be useful to prevent food allergy has yet be determined.

Question 24

How are high-dose tolerance and low-dose tolerance different/established?

Answer 24

High-dose tolerance involves deletion of effector T lymphocytes.

Low-dose tolerance is mediated by activation of regulatory T lymphocytes with suppressor functions.

Question 25

What are the gut homing lymphocyte integrins?

Answer 25

Gut homing lymphocyte integrins are a4B7 and MAdCAM-1.

Question 26

What are two mechanisms by which oral tolerance is inhibited in the newborn/infants?

Answer 26

• Developmental immaturity of components of gut barrier (decreased enzymatic activity in newborn period and secretory IgA) accounts for high prevalence of food allergy in infancy.
• Studies show that neutralizing pH (decreased acidity from antacids) can promote allergy sensitization by changes to the physiologic barrier.

Question 27

How does IgA neutralize microbes?

Answer 27

IgA binds to microbes and toxins present in lumen and neutralizes them by blocking entry/absorption into the host.

Question 28

Why is there more IgA produced in the body than any other antibody?

Answer 28

Because of the size of the intestinal surface.

Question 29

How much IgA is secreted daily by a normal adult? What is class switching to IgA stimulated by?

Answer 29

A normal adult secretes 2 g of IgA per day. More IgA is produced than any other antibody. Switching to the IgA isotype is stimulated by TGFβ and IL-5.

Question 30

What tissue primarily synthesizes IgA? Is IgA transport across the mucosal lumen efficient?

Answer 30

IgA synthesis occurs primarily in gut mucosal lymphoid tissue (lamina propria), and transport across mucosal lumen is efficient (i.e., not lost to the bloodstream).

Question 31

Describe where IgA+ B lymphocytes migrate from and to. How is the arrival regulated?

Answer 31

• IgA+ B lymphocytes migrate from Peyer’s patches to mesenteric lymph nodes. They circulate in lymphatics, ending up in lamina propria of gut.
• Arrival in laminal propria is regulated by site-specific adhesion molecules, a4B7 + and MAdCAM-1.

Question 32

What is the form of secretory IgA? What is the form of serum IgA? How is IgA transported across the epithelium?

Answer 32

IgA is secreted in dimerized form that is held together by J chain. Serum IgA is a monomer. IgA is transported across the epithelium by a poly-Ig receptor.

Question 33

What are the steps that occur after the dimerized IgA + poly-Ig receptor are on the luminal surface?

Answer 33

Once the dimerized IgA + poly-Ig receptor is on the luminal surface, the receptor is proteolytically cleaved, leaving behind its transmembrane and cytoplasmic forms. The IgA molecule plus extracellular domain of receptor is released into the intestinal lumen. Poly-Ig receptor transports IgA into bile, milk, sputum, saliva, and sweat as well as IgM into intestinal secretions.

Question 34

Does breast feeding protect against atopic disease? What is in colostrum? When is the colostrum present? What are other components of breast milk?

Answer 34

Provides immune protection and decreases incidence of food allergies. Colostrum has very high levels of IgA in the first 4 days postpartum, then drops to serum levels. Other components of breast milk include lysozyme, lactoferrin, and TNFα.