Mucosal Immunity - Dwinell Flashcards Preview

M2 GI/Nutrition > Mucosal Immunity - Dwinell > Flashcards

Flashcards in Mucosal Immunity - Dwinell Deck (36):
1

What are M cells?

Where are they located?

 

Specialized non-villous cells within the intestinal epithelium that can endocytose / pahgocytose pathogens and deliver them to dendritic cells in an underlying Peyer's Patch.

2

What are tolerogenic dendritic cells?

Can you name some specific functions they have?

A subset of dendritic cells with functions that promote antigenic tolerance (as opposed to the immune stimulation). They are important in preventing activation of the immune system toward self and benign non-self (e.g. food) antigens, and are believed to do so via:

  • Induction of anergy in effector lymphocytes
  • Promoting apoptosis of effector T cells
  • Promoting the expansion of Tregs
  • Production of anti-inflammatory cytokines

3

Secretion of what set of three cytokines identifies a cell as a tolerogenic dendritic cell?

  1. Retinoic acid
  2. TSLP (thymic stromal lymphoprotein)
  3. TGFb

4

Several immune cell trafficking signals exist to direct immune cells to the gut mucosa. Name such a signal that is:

  1. An integrin expressed by immune cells?
  2. A chemokine expressed by immune cells?
  3. A endothelial "addressin"?
  4. An epithelial trafficking cytokine?

  1. a4b7
  2. CCR9
  3. MadCAM
  4. CCL25

5

  1. What enzyme allows mucosal dendritic cells to produce retinoic acid (RA)?
  2. What is the RA derived from?
  3. What other cell contains this enzyme, leading to an increased RA concentration in gut tissues?

  1. Retinal dehydrongenase
  2. Vitamin A
  3. Intestinal epithelial cells

6

So, an M cell has handed off a pathogenic bateria to a dendritic cell hanging out in a Peyer's Patch.

The DC needs to wake up the lazy B cells and get them producing IgA to protect the intestinal mucosa.

Describe two mechanisms that this B cell class switching can be accomplished through. In specific, what mediators are involved in each path?

  1. T cell dependent
    • DCs present Ag to and activate naive T cells to TH1
    • CD40 on TH1 cells and TGFb from the DCs
  2. T cell independent
    • TLR activation on the DCs stimulates release of a barrage of class switching-promoting cytokines, including:
      • TGFb
      • APRIL
      • BAFF
      • IL6
      • Retinoic acid

[It seems odd that TGFb and RA are activating, wheras TGFb, RA, and TSLP together are the mark of the generally immune-inhibitory tolerogenic DC. I'm not sure why this is.]

7

Immunology review:

  1. The 1st signal of T cell activation is recognition of ________ on the APC by __________ on the T cell.
  2. The 2nd signal of T cell activation is binding of ________ on the APC by ________ on the T cell.

  1. [MHC+peptide Ag], TCR
  2. CD80 or 86, CD28

8

What is the 1st signal of B cell activation?

The 2nd signal?

1st: Ag binds membrane-bound IgM

2nd: Costimulation via a complement receptor (e.g. CD21) or a TLR

9

What intestinal tissue layer do IgA-secreting plasma cells inhabit?

How much total IgA do these plasma cells produce per day?

Lamina Propria

2-4g/day

10

As IgA is secreted by plasma cells in the lamina propria, what linker peptide allows the IgA to form dimers?

What produces this linker?

J chain

Also made by the plasma cells

(Note: J chain is also the central linker peptide for pentameric IgM)

11

What polypeptide binds IgA in the lamina propria and transports it through the mucosal epithelium and into the gut lumen?

How is this polypeptide modified as it passes through the epithelial cell? 

poly-Ig receptor

proteolytic cleavage of the terminal end of the polypeptide

12

What T cell lineages are emphasized in the gut mucosa under normal conditions?

Why?

TH17 & Tregs

Promote consistent tolerance toward food and beneficial microbiome bacteria

13

Define:

  1. Immunogen
  2. Antigen
  3. Tolerogen

A molecule that:

  1. Induces an immune response
  2. Is recognized / bound by Ab (B cells) or T cells
  3. Induces immune unresponsiveness to subsequent doses of the molecule

14

The gut has to carefully choose what substances to respond (immunity) and not respond (tolerance) to. Characteristics of a given substance influence this decision.

How does size of a substance influence its immunogenicity?

Large = increased immunogenicity

Small (<2kd) = decreased

15

The gut has to carefully choose what substances to respond (immunity) and not respond (tolerance) to. Characteristics of a given substance influence this decision.

How does dose of a substance influence its immunogenicity?

Intermediate dose = increased immunogenicity

High or low dose = decreased

16

The gut has to carefully choose what substances to respond (immunity) and not respond (tolerance) to. Characteristics of a given substance influence this decision.

How does route of a substance influence its immunogenicity?

SubQ > Intraperitoneal > Intravenous > Intragastric

(SubQ is most immunogenic)

17

The gut has to carefully choose what substances to respond (immunity) and not respond (tolerance) to. Characteristics of a given substance influence this decision.

How does composition of a substance influence its immunogenicity?

Complex = more immunogenic

Simple = less

18

The gut has to carefully choose what substances to respond (immunity) and not respond (tolerance) to. Characteristics of a given substance influence this decision.

How do adjuvants influence a substance's immunogenicity?

Presence of bacteria act as an adjuvant --> increased immunogenicity

Few/no bacteria ---> less

19

The gut has to carefully choose what substances to respond (immunity) and not respond (tolerance) to. Characteristics of a given substance influence this decision.

How does the interaction with the MHC complex of a substance influence its immunogenicity?

Effective interaction = increased immunogenicity

Ineffective interaction = decreased

20

What are potential consequences of loss of tolerance toward food?

  • Food allergies
  • Celiac disease
  • Inflammatory bowel diseases

21

What is oral tolerance?

Mucosal tolerance?

Oral: Local & systemic immune unresponsiveness induced by oral administration of foods

Mucosal: Local & systemic immune unresponsiveness induced by the commensal microbiota

22

  1. What is the predominant mediator of humoral immunity in the gut?
  2. Of cellular immunity?
  3. Of tolerance? 

  1. IgA
  2. TH17
  3. Treg

23

Again, what is master transcription regulator protein in Treg cells?

Foxp3

24

What are the three principle factors in the development of autoimmune diseases?

  • Inheritance of susceptibility genes
    • HLA or non-HLA
  • Environmental triggers
    • Activate self-reactive or tolerized (suppressed) lymphocytes
  • Immune hyper sensitivity
    • Over-activation to typically innocuous Ags

25

How much of the world's population is estimated to suffer from some form of autoimmune disease?

1-2%

26

Immunology Review!

What are the primary immune mediators in:

  1. Type I Hypersensitivity?
  2. Type II?
  3. Type III?
  4. Type IV?

  1. IgE, mast cells, & eosinophils
  2. IgM & IgE, complement, leukocytes
  3. Immune complexes, complement, leukocytes
  4. T cells, macrophage activation, inflammation

27

Name two-non HLA genes that are thought to predispose to autoimmune diseases when mutated (or atypical alleles).

  1. Nod2
  2. ATG16

28

What are two ways in which MHC mutations may contribute to autoimmune disease?

  1. Inefficient display of self-antigens
  2. Poor stimulation of Tregs

29

What are some general treatment approaches for autoimmune diseases?

  • Systemic immune suppression
    • Infection risk
  • Non-systemic suppression
    • anti-TNF Abs (Infliximab)
    • Soluble TNFR (Etanercept)
  • Plasmapheresis
  • Competitive FcR inhibiton

30

What is the function of tissue transglutaminase?

How is this related to celiac disease?

Among other functions, tissue transglutaminase deamidates the wheat gliadin peptide to make it more water-soluble. This is believed to contribute to the development of celiac disease, as deamidated gliadin appears to be significantly more immunogenic than regular gliadin.

31

Which HLA alleles is celiac disease associated with?

HLA-DQ2 & HLA-DQ8

32

Antibodies directed against what proteins can be found in the context of celiac disease?

  • tissue transglutaminase (diagnostic!)
  • gliadin peptide
  • endomysium
    • Thin layer of connective tissue that ensheaths individual muscle fibers
    • Curiously, the anti-endomysium Abs do not cause muscle symptoms, but are useful in Dx of celiac (Wiki)

33

What type of hypersensitivity disorder is celiac disease?

Type IV - as per our lecture

Despite the presence of anti-tissue transglutaminase and anti-gliadin Abs, it appears that the majority of damage is secondary to TH1 T cell activation (deaminated gliadin is presented to Class II MHC) and the subsequent inflammatory changes. There does seem to be a little controversy over this point.

34

What HLA mutations are associated with Inflammatory Bowel Diseases?

HLA-DR & HLA-B27

35

What type of hypersensitivity reaction is Crohn's disease? Ulcerative colitis? What is the major mediator in each?

Both CD and UC are Type IV, however...

CD: TH1 cell mediated

UC: TH2 cell mediated

36

  1. What is a complication of food allergies seen in the upper GI tract?
  2. What is a rarer complication of food allergies seen in the lower GI tract? Describe it.

  1. Eosinophillic Esophagitis
  2. Food Protein-Induced Enterocolitis Syndrome (FPIES)
    • Typically occurs in infants
    • Severe systemic response to particular food, 1-4hrs post-ingestion
    • Causes vomiting & diarrhea
      • When severe, can lead to acidosis and shock
    • Believed to be T cell mediated