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SMP - MIM Part 1 > Lecture 11 - Acquired Immunity at the Barrier Epithelia > Flashcards

Lecture 11 - Acquired Immunity at the Barrier Epithelia Flashcards

1
Q

Largest immunological organ of the body?

A

Barrier epithelium

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2
Q

On what has most of the work on the mucosal immune system been focused on? What to note?

A

The small intestine, but it can be applied to other mucosal epithelia of the body

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3
Q

Why do we call it the COMMON mucosal immune system? Implication?

A

Once effector T and B cells have been generated in the Peyer’s patch and B cells become committed to the production of IgA => traffic to mesenteric LN to become imprinted to express cell adhesion molecules to be recognized by mucosal epithelia, to secrete specific cytokines, and to express specific integrins and cytokines on their surface => leave the lymphatics through the thoracic ducts => traffic back to inductive site OR effector site

Information from one site can be supplied to another mucosa

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4
Q

How are IgA transported to the barrier epithelia surface?

A

Via the polyimmunoglobulin receptor (Poly-Ig receptor) => when the receptor is cleaved at the apical surface of epithelium, it leaves behind the bulk of the glycoprotein called the secretary component

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5
Q

8 features of the mucosal immune system? Which is most important?

A
  1. > 80% of the body’s activated B cells are located in the gut
  2. > 80% of terminally differentiated B cells in the lamina propria are IgA immunocytes that produce polymeric IgA
  3. More IgA synthesized per day than all other isotypes combined (intestines alone receive 3-5 g of secreted IgA daily)
  4. Induction of IgA is compartmentalized to the mucosal immune system itself
  5. There are intimate interactions between mucosal epithelia and lymphoid tissues (which lie within and just below the epithelial surface): discrete compartments of diffuse lymphoid tissue (e.g. Peyer’s patches), isolated lymphoid tissues (aka cryptopatches), tonsils
  6. Specialized antigen-uptake mechanisms in lymphoid tissues associated with the mucosal immune system
  7. Activated memory T cells predominate, even in the absence of infection, with nonspecifically activated effector/regulatory T cells present
  8. ***Active down regulation of immune responses to food and harmless antigens through interesting phenotypes of macrophages and dendritic cells to suppress or down regulate the immune response
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6
Q

Is IgA pro-inflammatory?

A

NOPE - it does not fix complement

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7
Q

3 functions of IgA?

A
  1. Agglutinate microorganisms
  2. Neutralize toxins
  3. Allow the flow of secretions across these barrier epithelia to flush the immune complexes away
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8
Q

Example of specialized antigen-uptake mechanisms in lymphoid tissues associated with the mucosal immune system?

A

Phagocytic M cells (microfold cells) that sit on top of the Peyer’s patch (in the lamina propria and within the epithelium itself) that sample antigen in the lumen of the small intestine => antigens do not arrive through lymphatics, but rather through phagocytic cells that overlie lymph nodes and communicate with the body

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9
Q

How do intestinal epithelial cells contribute to innate and adaptive immunity in the gut? 3 mechanisms

A
  1. The epithelial cells produce antimicrobial peptides, chemokines, and cytokines to condition DCs, macrophages, and B cells and recruit/activate neutrophils and monocytes
  2. Very rapid turnover of the epithelium as part of the innate immune system (every 2 days)
  3. Inflammatory response is tightly controlled and limited to resolving the infection then shutting down quickly
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10
Q

What is one of the most important factors that distinguishes the mucosal immune system to the systemic immune system?

A

Intestinal macrophages eliminate pathogens without creating inflammation

Instead, the intestinal macrophages are an antigen disposal cell that has lost its antigen presenting capability

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11
Q

Pathway of epithelial cell expression of cytokines?

A

Bacteria recognized by TLRs on the cell surface or in intracellular vesicles => bacteria and their products entering the cytosol are recognized by NOD1 and 2 => NFϰB activation => induces the epithelial cells to express inflammatory cytokines

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12
Q

How are all of the natural portals of entry to the body protected?

A

By secondary lymphoid tissue

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13
Q

What is an inductive site? Example?

A

Where the immune response is initiated by an antigen meeting and APC and then forming a cognate interaction with CD4 T cells

Example: Waldeyer’s ring, which consists of the lingual, palatine, tubal, and pharyngeal tonsils, and scattered lymphoid tissues in the nasal and oral cavities

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14
Q

3 inductive sites of the GIT?

A
  1. Peyer’s patches
  2. Isolated lymphoid follicles
  3. Appendix
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15
Q

Other name for pharyngeal tonsils?

A

Adenoids

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16
Q

Best studied inductive sites in the mucosal immune system?

A

Peyer’s patches

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17
Q

Is the mucosal lymphoid tissue supplied by afferent lymphatics?

A

NOPE

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18
Q

Lymphocytes in Peyer’s patches?

A

More B cells than T cells

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19
Q

Lymphocytes in isolated lymphoid follicles of the GIT?

A

Mainly B cells

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20
Q

What is the lamina propria of the GIT?

A

Connective tissue below the epithelium

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21
Q

Describe the structure of a Peyer’s patch. 3 parts

A
  1. ‘Dome epithelium’ consisting of microfold cells (M cells) with their basal surface invaginated like a cup
  2. DCs and macrophages sit immediately below the M cells, filling the cup to receive antigen handed off from the M cells
  3. Below these APCs are T and B cell zones just like a classic lymph node
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22
Q

What are the 2 DISTINCT compartments of the mucosal immune system? What immune cells are found in each?

A
  1. Epithelium: CD8+ cytotoxic T cells

2. Lamina propria: CD4+ helper T cells (mainly), DCs, MOs, mast cells, IgA, plasma cells

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23
Q

What do we call the immune cells within the epithelium of the mucosal immune system?

A

Intraepithelial lymphocytes (IEL)

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24
Q

3 types of IELs?

A
  1. CD8αβ heterodimers with αβ TCRs: act like conventional CD8 cytotoxic T cells by recognizing peptides derived from pathogens bound to classical MHC class I molecules on infected epithelial cells and killing infected cells by releasing perforin and granzyme
  2. CD8αα homodimers with γδ TCRs
  3. CD8αα homodimers with αβ TCRs
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25
Q

Chemokine receptor on CD4+ T cells in the lamina propria of the GIT?

A

CCR9

26
Q

What are the 9 cells of the mucosal immune system?

A
  1. Epithelial cells
  2. Macrophages (non-inflammatory)
  3. Dendritic cells (several phenotypes)
  4. CD4+ Treg and TH2 T cells serving as TFH cells for IgA class switch
  5. CD4+ TH17 T cells
  6. CD8+αβ T cells (classical)
  7. CD8+αα T cells
  8. γδ T cells (some express CD8+αα)
  9. Mucosa-associated invariant T cells (MAIT) cells (innate anti-bacterial and anti-viral)
27
Q

What can we compare MAIT cells to?

A

Mucosal iNKT cells

28
Q

What epithelial stress proteins do the mucosal γδ T cells recognize?

A
  1. Unusual MHC molecules: MIC-A and MIC-B

2. IL-15

29
Q

How are intestinal macrophages non-inflammatory?

A
  1. Do not secret inflammatory cytokines
  2. Are not professional APCs
  3. Do not have Fcγ or Fcα, LPS, C3b and IL-2 & IL-3 receptors
  4. Ligation of PRR fails to activate NFκB
  5. Cannot perform chemotaxis
  6. Cannot perform respiratory burst
  7. Cannot co-stimulate
30
Q

Only 2 similarities between blood and intestinal macrophages?

A

Both can phagocytose and kill

31
Q

5 different DC phenotypes?

A
  1. CD11b+ CD8α-
  2. CD11b- CD8α+
  3. CD11b- CD8α-
  4. CD103+
  5. CD103-
32
Q

Cytokines produced by CD11b+ CD8α- DCs?

A
  1. IL-10 when resting

2. IL-23 when activated => drives differentiation to TH17 cells

33
Q

Location of CD11b+ CD8α- DCs?

A

Sub-epithelial dome of Peyer’s patch

34
Q

2 functions of CD11b- CD8α+ DCs?

A
  1. TH2 polarizing ability

2. IgA class switching

35
Q

Cytokine produced by CD11b- CD8α+ and CD11b- CD8α- DCs?

A

IL-12

36
Q

2 functions of CD11b- CD8α+ and CD11b- CD8α- DCs?

A
  1. TH1 polarizing ability

2. Activate naive T cells

37
Q

Location of CD11b- CD8α+ DCs?

A

T-cell zone of Peyer’s patch

38
Q

Location of CD11b- CD8α- DCs?

A

Peyer’s patch

39
Q

3 functions of CD103+ DCs?

A

Traffics from lamina propria to mesenteric LNs to:

  1. Imprints on the lymphocytes that leave the Peyer’s patches to return to the mucosal surfaces
  2. Converts some of these cells into regulatory T cells by the immunosuppressant cytokines IL-10 and TGF-beta
  3. Produce retinoic acid and IDO, which drives T-cells coming from the Peyer’s patches to become
    regulatory T-cells
40
Q

2 roles of mesenteric LNs?

A
  1. Act as a firewall: their role is to make sure none of these DCs get into the systemic immune system into the blood where they can go to regular lymph nodes and activate naïve B cells and T cells
  2. They are one of the foci for
    the induction of regulatory T-cells: any self reactive T-cells become regulatory T-cells
41
Q

Location of CD103- DCs?

A

Mesenteric LNs

42
Q

2 functions of CD103- DCs?

A
  1. Pro-inflammatory

2. TH1/TH17 polarizing ability

43
Q

Largest assembly of LN in the human body?

A

Mesenteric LNs

44
Q

Other than on some mucosal DCs, on what other immune cells is CD11b expressed?

A

Expressed by many leukocytes in the innate immune system, including monocytes, granulocytes, macrophages, and NKCs

45
Q

Other than on some mucosal DCs, on what other immune cells is CD103 expressed?

A

CD103 is expressed widely onIEL T cells (both αβ T cells andγδ T cells) and on some regulatory T cells

46
Q

How to tell if a DC is able to activate a naive T cell?

A

CD103+ and CXCR1-

47
Q

2 types of sites in the mucosal immune system?

A
  1. Inductive sites

2. Effector sites

48
Q

4 mechanisms of antigen transport by across the GIT epithelium?

A
  1. Non-specific transport across epithelium: soluble antigens such as food proteins might be transported directly across or between enterocytes, or through M cells in the surface epithelium
  2. FcRn-dependent transport (fetal Fc receptor) via transcytosis through enterocytes => at the basal face of the epithelium, lamina propria dendritic cells expressing FcRn and other Fc receptors pick up and internalize the complexes
  3. Apoptosis-dependent transfer: enterocyte infected with an intracellular pathogen undergoes apoptosis and its remains are phagocytosed by the dendritic cell
  4. Antigen capture: mononuclear cells have been seen extending processes between the cells of the epithelium without disturbing its integrity and the cell process can pick up and internalize antigen from the gut lumen and then retract
49
Q

What immune cells regulate the induction of tolerance and immunity in the intestine?

A

Mucosal DCs

50
Q

How do DCs regulate the induction of tolerance and immunity in the intestine?

A
  1. Normal conditions: DCs can acquire antigens from foods or commensal organisms => they take these antigens to the draining mesentericLN, where they present them to naive CD4 T cells => constitutive production by epithelial cells and mesenchymal cells of molecules such as TGF-β, thymic stromal lymphopoietin (TSLP), prostaglandin E2(PGE2), and retinoid acid (from diet) maintain the local DC in a quiescent state with low levels of co-stimulatory molecules and IL-10 secretion (inhibitory cytokine), so that when they present antigen to naive CD4 T cells, anti-inflammatory or regulatory T cells are generated => DCs recirculate back to the intestinal wall and maintain tolerance to the harmless antigens
  2. Invasion by pathogens or a massive influx of commensal bacteria: PPR ligation of MAMPs overcomes homeostatic mechanisms, resulting in full activation of local DCs and their expression of co-stimulatory molecules and pro-inflammatory cytokines such as IL-12 => presentation of antigen to naive CD4 T cells in the mesenteric LN causes differentiation into effector TH1 and TH2 cells => full immune response
51
Q

How does the B cell IgA class switch occur? 2 pathways.

A
  1. T-dependent pathway: CD40 ligation by effector T cell expressed CD40L (at junction of paracortex and B cell follicle) => initiates B cell signaling to activate the NFκB pathway
  2. T-independent pathways:
    NFκB can also be induced through BAFF and APRIL, which are produced by a variety of cell types including DCs and intestinal epithelial cells (these secrete TSLP which stimulates APRIL secretion from intestinal DCs)
52
Q

Is the T-independent pathway of IgA class switch important in humans?

A

Unclear

53
Q

9 factors involved in the B cell switch to IgA?

A
  1. TGFβ
  2. iNOS (inducible nitric oxide synthase)
  3. Retinoic acid
  4. IL-4
  5. IL-5
  6. IL-10
  7. IL-21
  8. BAFF (B-cell activating factor)
  9. APRIL (a proliferation-inducing ligand)
54
Q

Other term for imprinting?

A

Homing

55
Q

What is a well known trafficking pathway from an inductive site to an effector site?

A

Enteromammary circuit: B cells from the small intestine would not only travel back to small intestine, but also to the mammary gland, particularly under the influence of
hormones

56
Q

Why are trafficking pathways from an inductive site to an effector site important?

A
  1. When a newborn that was essentially sterile in the uterus is delivered, it starts to acquire its commensal microbiota largely from the mother, so it would thus be beneficial for the mother to have antibodies of the IgA isotype that recognized those commensals present in her breast milk
  2. Vaccine development: for example, the pathway from the nasal associated lymphoid tissue to the urogenital tract is important in developing vaccines against sexually transmitted organisms
57
Q

When do B cells become terminally differentiated plasma cells in the mucosal immune system? What happens then?

A
  1. When they return to their effector site they secrete dimeric IgA covalently bound by the poly-Ig receptor on the basal surface of glandular epithelial cells
  2. Poly-Ig – dimeric IgA – J-chain complex is transported into an endosome through the enterocyte to fuses with the apical surface
  3. The Poly-Ig receptor is cleaved, releasing the secretory component
  4. Some IgA covalently binds to the mucus and some is free
58
Q

What happens to IgA-antigen complexes in the lamina propria?

A

Bound by poly-Ig receptors

59
Q

At what 3 locations can IgA bind and neutralize antigens?

A
  1. At the mucosal surface
  2. By intercepting pathogen containing endosomes during its traffic to the mucosal surface (these can be antigens coming in the other direction: for example, a virus entering epithelial cells can find its way into these endosomes and be bound by IgA; therefore, the IgA can carry the virus away in its path to the apical
    surface)
  3. In the lamina propria after being secreted by the plasma cell and before it binds to the Poly-Ig receptor for transport
60
Q

How many lymphocytes per epithelial cells in the GIT?

A

10-15

61
Q

Where do IELs lie exactly?

A

They lie between epithelial cells on the basement membrane separating the lamina propria from the epithelium

62
Q

What is the most common immune deficiency is selective to? Symptoms?

A

IgA => asymptomatic

SMP - MIM Part 1 (14 decks)

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