24 Mucosal Immunity

Question 1

Gut environmental interactions and host defense

• The gut mucosa,
  
  • spanning /
  • exposed to/
  • lined only by /
• The normal gut flora
  
  • consists of/
  • the individual intestinal bacteria/
  • marked differences in gut flora diversity and abundance in the various segments of the digestive tract/

Answer 1

• The gut mucosa,
  
  • spanning 200-400m2 (tennis court = 264m2)
  • exposed to a vast array of foreign antigens in the form of food, normal gut flora, and pathogens,
  • lined only by a single epithelial cell layer.
• The normal gut flora
  
  • consists of 1014 or 100 trillion bacteria, from over 400 species,
  • the individual intestinal bacteria outnumber our total cells 10:1.
  • marked differences in gut flora diversity and abundance in the various segments of the digestive tract, with a significant increase in bacteria in the distal ileum and colon, where inflammatory bowel disease (IBD) typically originates.

Question 2

Gut environmental interactions and host defense

• The challenges for the gut mucosal immune system
• To facilitate this mission/
• Failure to maintain gut immune homeostasis can lead to /

Answer 2

• The challenges for the gut mucosal immune system
  
  • constantly monitor environmental interactions
  • foster tolerance for food and normal flora while defending against pathogens.
• To facilitate this mission, the general tone of the healthy gut mucosal immune system - in contrast to the systemic immune system - is one of suppression or downregulated immune responses.
• Failure to maintain gut immune homeostasis can lead to GI diseases such as celiac disease and IBD, the latter of which is thought to be caused by an aberrant immune response against normal gut flora.

Question 3

Gut environmental interactions and host defense

• Gut host defense is provided by/
• Multiple non-immunologic factors enhance host defense including/
• The normal gut flora also enhance host defense by/

Answer 3

• Gut host defense is provided by
  
  • 1) non-immunologic factors
  • 2) the gut mucosal immune system involving both
    
    • a) innate
    • b) adaptive immunity.
    • The gut mucosal immune system is also known as the gut associated lymphoid tissue or GALT.
• Multiple non-immunologic factors enhance host defense including gut secretions (saliva, digestive enzymes, gastric acid, bile, water and electrolytes), peristalsis, mucosal products (mucus, defensins), and the epithelial barrier including tight junctions.
• The normal gut flora also enhance host defense by limiting the growth of pathogens such as Clostridium difficle.

Question 4

Gut innate immunity (p.9-10)

• the innate immune
  
  • consists of/
• Epithelial cells

Answer 4

• The second line of defense against pathogens in the gut is the innate immune system,
  
  • consists of non-immune cells (epithelial cells) and immune cells (dendritic cells and macrophages).
• Epithelial cells
  
  • passive barrier,
  • actively initiate innate immune responses
  • can facilitate antigen presentation to induce adaptive immune responses.

Question 5

Gut innate immunity (p.13-14)

• Innate immune cells including epithelial cells express/
• The receptors activate cell signaling pathways that lead to/

Answer 5

• Innate immune cells including epithelial cells express evolutionary conserved pattern recognition receptors, such as the Toll-like receptors, that can rapidly detect microbe-specific molecules (ex. Toll-like receptor 4 (TLR-4) that recognizes bacterial lipopolysaccharide (LPS)).
• The receptors activate cell signaling pathways that lead to the gene expression of cytokines that promote innate immune responses.

Question 6

Gut innate immunity

• Paneth cell
  
  • promotes/
  • have been implicated in/
• IBD susceptibility loci associated with Paneth cells include/

Answer 6

• A particular type of epithelial cell known as the Paneth cell
  
  • promotes host defense against bacteria via the secretion of anti-microbial enzymes and defensin proteins.
  • have been implicated in IBD via genome wide association studies.
• IBD susceptibility loci associated with Paneth cells include NOD2 and ATG16L1, both of which are expressed prominently by Paneth cells and are thought to play a role in bacterial handling.

Question 7

Gut innate immunity:
The primary immune cells of the gut innate immune system (p.22)

• Dendritic cells
• Macrophages
• Both
• Gut macrophages in the healthy gut vs. bacterial products
  
  • This relative hypo-responsiveness is essential in/
  • Similarly, certain gut dendritic cells (ex. CD103+) promote/

Answer 7

• Dendritic cells
  
  • sample luminal contents via their dendrites,
• Macrophages
  
  • scavenge the lamina propria consuming pathogens and macromolecules.
• Both
  
  • professional antigen presenting cells (APCs)
  • activate and regulate adaptive immune responses during health and disease via cell-cell interactions with lymphocytes and production of cytokines such as tumor necrosis factor alpha (TNF-alpha), the target of the IBD therapeutic neutralizing antibodies infliximab and related anti-TNF antibodies.
• Gut macrophages in the healthy gut are somewhat attenuated compared to blood derived monocytes in response to bacterial products.
  
  • This relative hypo-responsiveness is essential in limiting inflammation in the presence of physiologic levels of bacterial antigen.
  • Similarly, certain gut dendritic cells (ex. CD103+) promote tolerance for normal flora and food antigens and are essential for maintaining gut homeostasis.

Question 8

Gut adaptive immunity (p.16-20)

• The gut as an immunologic organ
  
  • The healthy gut is in a state of/
• GALT (gut associated lymphoid tissue)
  
  • composed of/
  • further composed of/

Answer 8

• The gut is the largest immunologic organ in the body, housing > 1012 lymphoid cells including 80% of all B cells and containing more antibody than any other organ.
  
  • The healthy gut is in a state of controlled inflammation, driven by the presence of the gut flora.
• The gut’s immune system, known collectively as the GALT (gut associated lymphoid tissue),
  
  • composed of organized structures such as mesenteric lymph nodes, Peyer’s patches of the small intestine and the appendix, and solitary lymphoid follicles in the large bowel.
  • further composed of diffuse lymphoid tissue in the gut lamina propria, in which highly activated memory lymphocytes reside.

Question 9

Gut adaptive immunity (p.11+16)

• Peyer’s patches,
  
  • essential for/
  • overlaid by/
• Certain pathogens such as Salmonella/
• Naïve lymphocytes

Answer 9

• Peyer’s patches,
  
  • essential for the induction of an adaptive immune response against pathogens.
  • overlaid by a specialized gut epithelium, composed of a unique type of epithelial cell called a microfold cell or a M cell, which is responsible for sampling pathogens in the lumen.
• Certain pathogens such as Salmonella take advantage of M cells to invade.
• Naïve lymphocytes
  
  • are “educated” in Peyer’s patches and the like
  • then exit into the circulation, where they traffic to all mucosal associated lymphoid tissues (lung, tonsil, adenoid, gut, and genitourinary tract).

Question 10

Gut adaptive immunity (p.18+26)

• The fully mature activated lymphocytes then migrate back into the gut via/
  
  • target complex for the IBD therapeutic neutralizing antibody vedolizumab
• Lymphocytes populations are incredibly diverse in the gut, especially T lymphocytes.
• The two major types of T lymphocytes
  
  • CD4+ T “helper” cells
  • CD8+ T “killer” cells

Answer 10

• The fully mature activated lymphocytes then migrate back into the gut via a targeted recruitment mechanism mediated by alpha4-beta7 (alpha4beta7) integrin on the lymphocytes and MAdCAM-1 on the endothelial cells.
  
  • The gut homing alpha4beta7 integrin is the target complex for the IBD therapeutic neutralizing antibody vedolizumab.
• Lymphocytes populations are incredibly diverse in the gut, especially T lymphocytes.
• The two major types of T lymphocytes
  
  • CD4+ T “helper” cells, which make up 60% of lamina propria T cells, regulate adaptive immune responses and recognize extracellular antigens presented by APCs via MHCII complexes.
  • CD8+ T “killer” cells kill infected cells and recognize intracellular antigens presented by all cells via MHCI complexes.

Question 11

Gut adaptive immunity

• CD4+ T lymphocytes further differentiate into/
• Th1 cells
  
  • promote/
  • major producers of/
• Th2 cells
  
  • promote/
  • major producers of/
• Th17 cells
  
  • promote/
  • major producers of/

Answer 11

• CD4+ T lymphocytes further differentiate into a diverse set of cells based on pro-inflammatory cytokine expression profiles including T-helper 1 (Th1), Th2 and Th17 cells.
• Th1 cells
  
  • promote cellular immunity for the eradication of intracellular pathogens (ex. Salmonella)
  • major producers of the cytokine interferon gamma (IFN-γ).
• Th2 cells
  
  • promote humoral immunity for defense against extracellular pathogens (ex. helminthic parasites)
  • major producers of the interleukin (IL)-4.
• Th17 cells
  
  • promote mucosal immunity against bacterial and fungal infections
  • major producers of IL-17.

Question 12

Gut adaptive immunity

• The CD4+ Th1 and Th2 subsets are thought to reciprocally regulate each other via/
• Th17 cells have also been implicated in/
• Multiple Th17 associated loci have been identified including/

Answer 12

• The CD4+ Th1 and Th2 subsets are thought to reciprocally regulate each other via their specific cytokines to prevent uncontrolled inflammation as seen in Crohn’s disease (a form of IBD), which traditionally has been associated with excessive Th1 immunity.
• Th17 cells have also been implicated in IBD pathogenesis via recent genome wide association studies and concurrent animal experiment.
• Multiple Th17 associated loci have been identified including the IL-23 receptor subunit gene IL23R, which is essential for the development of Th17 cells.

Question 13

Gut adaptive immunity (p.12+21)

• intraepithelial lymphocyte (IEL)
  
  • ?
  • positioned at/
  • location
  • express/
  • roles
• The predominant lymphocyte in the gut

Answer 13

• intraepithelial lymphocyte (IEL).
  
  • A unique CD8+ lymphocyte found in the gut
  • positioned at a critical interface between the lumen and epithelium
  • appear to stay localized rather than traffic in and out of the gut.
  • express the uncommon γδ T cell receptor (TCR) – in contrast to the common αβ TCR.
  • have cytotoxic and immunoregulatory roles.
• The predominant lymphocyte in the gut is the B lymphocyte, and specifically IgA plasma B cells,
  
  • 30 to 40% of mucosal mononuclear cells are plasma cells.

Question 14

Gut adaptive immunity:
IgA (p.21)

• ?
• in secretions it exists as/
  
  • bound/
  • coated/
• The secretory component serves to/
• does not activate/

Answer 14

• the most abundant antibody in mucosal secretions,
• in secretions it exists as a dimer
  
  • bound together by the “J chain”
  • coated with the “secretory component” derived from the polymeric Ig receptor produced by epithelial cells.
• The secretory component serves to
  
  • facilitate transport across the epithelial to the gut lumen via epithelial transcytosis,
  • protect IgA from degradation.
• promotes host defense by blocking microbial binding to the epithelium.
• does not activate complement or bind to Fc receptors and thus does not mediate inflammatory responses.

Question 15

Oral tolerance (p.43)

• the antithesis of/
• defined by/
• prevents/
• There are three mechanisms postulated on how oral tolerance is mediated,
  
  • all pertaining to/
  • all in the absence of/

Answer 15

• the antithesis of systemic immunization
• defined by antigen-specific non-responsiveness when an antigen is administered orally rather than subcutaneously or intramuscularly.
• prevents harmful immune responses to harmless antigens such as certain foods antigens (ex. gliadin, inciting antigen in celiac disease).
• There are three mechanisms postulated on how oral tolerance is mediated,
  
  • all pertaining to how T cells respond when presented antigen,
  • all in the absence of inflammation like what occur with pathogens.

Question 16

Three mechanisms postulated on how oral tolerance is mediated

• transient downregulation of the T cell receptor
  
  • followed by/
  • This occurs in experimental animals if you/
• anergy
  
  • ?
  • T cells require/
  • This response also occurs with/
• diverse set of regulatory T cells
  
  • mediate/
  • The regulatory T cells include/
  • FoxP3+ Tregs in particular are induced by/

Answer 16

• transient downregulation of the T cell receptor
  
  • followed by apoptosis mediated clonal deletion of the antigen-specific cells
  • This occurs in experimental animals if you feed them large quantities of an antigen — which is likely not as relevant in humans or human disease.
• anergy,
  
  • antigen-specific T cells, when presented with the antigen by tissue epithelial cells in the absence of co-stimulatory signals, become refractory to subsequent activation.
  • T cells require both antigen presentation and costimulatory signals from the APC to become fully activated.
  • This response also occurs with a high dose of antigen.
• diverse set of regulatory T cells
  
  • mediate antigen-specific suppression of inflammation via the production of anti-inflammatory cytokines in response to both low and high doses of antigen.
  • The regulatory T cells include Th3 lymphocytes that produce transforming growth factor beta (TGF-beta), Tr1 lymphocytes that produce IL-10, and FoxP3+ Tregs that produce both TGF-beta and IL-10.
  • FoxP3+ Tregs in particular are induced by tolerogenic CD103+ dendritic cells.