Mim: Mucosal Immunity

Front 1

SIgA
principle form?
other components?

Back 1

Secretory Immunoglobulin A
major player in the human body's mucosal immune system

principle form: dimer

Extra Components:
-J "joining" Chain, which joins the two IgA monomers together
-Secretory Component (SC), an extra glycoprotein, which is the product of glandular epithelial cells that transport SIgA to external surfaces

Front 2

what immunoglobulin dominates the mucosal immune system?

Back 2

IgA

Front 3

where are the majority of activated B cells located?

Back 3

more than 80% are located in the gut, associated with the mucus membranes
-a majority of these B cells are committed to IgA synthesis
**more IgA is synthesized per day than all other Ig isotopes combined

Front 4

properties of SIgA and IgA

Back 4

IgA in blood is monomeric; and usually IgA1

SIgA is dimeric

SIgA is highly glycosylated
-bc they include a J chain and an SC, both of which are rich in carbohydrates

IgA is a non-inflammatory Ig because IgA wants to be able to dispose of Ag without causing inflammation, which can cause collateral damage to barrier epithelium

functions: aggregation, neutralization, opsonization

Front 5

how do we get IgA into external secretions?

Back 5

1. IgA is secreted as a dimer from a plasma cell
2. at the basolateral surface of epithelial cells, there are Poly-Ig receptors which bind covalently to IgA
3. Poly-Ig Receptor-bound IgA can be taken up by endocytosis, transported in vacuole to apical surface and released into external secretions

can also intercept Ags that have penetrated the epithelial cells and transport them out of the lamina propria

Front 6

If IgA is so important, how is it that IgA is the most common Ig deficiency, but the people affected are entirely health?

Back 6

IgM is another polymeric Ig that can bind to the Poly-Ig receptor; therefore, many patients with selective deficiency of IgA compensate by secreting secretory IgM

Front 7

Why don't don't people who secrete IgA, secrete IgM as well?

Back 7

IgM associates non-covalently with the receptor, while IgA associates covalently

Front 8

distinctive features of the mucosal immune system

Back 8

In the above slide are shown some of the distinctive features of the mucosal immune system. First realize that lymphoid tissues lie within and just below the epithelial surface. The mucosal lymphoid tissues comprise those that resemble classical secondary lymph nodes (Peyer’s patches; tonsils) and isolated follicles sometimes refered to as cryptopatches. Antigens do not arrive through afferent lymphatics, rather there are highly phagocytic cells that overlie the lymph nodes and communicate with the outside world. In additon, dendritic cells situated in the lamina propria can extend dendrites through the epithelium and sample the surface of the barrier epithelia. Histological examination of the epithelia show many actived T cells and memory cells even whne there is no infection. Regulatory T cells are present in abundance. Consistent with the statement tha the default position of the mucosal immube system is immunosuppression there are many inhibitory macrophages and suppressive dendritic cells.

Front 9

Inductive Sites

Back 9

where the immune responses occur in the mucosal tissue

1. Waldeyer's Ring- the protective ring of the mouth and nose; consists of the pharyngeal tonsils, adenoid tonsils, and lingual tonsils, which are all IgA inductive sites
-in the natural portals of entry- nose, mouth, and genitourinary tract- there are protective rings of lymphoid tissue

2. Appendix: the inductive site in the large bowel

3. Lymphoid Aggregates: the inductive site in the rectum

4. Peyer's Patches: the inductive sites in the small bowel

Front 10

peyer's patches

Back 10

just like the lymphoid tissues in the neck EXCEPT they don't have any afferent lymphatics
-no immune cells are brought to the Peyer's Patch in the lymph; instead they are brought in by blood vessels
-they can, however, drain out of the Peyer's patch via the efferent lymphatics

Front 11

M-Cells

Back 11

micro fold cells in peer's patches

highly phagocytic cells that will take up anything they can get a hold of in the lumen and hand off any luminal Ag to DC's that sit directly beneath them
-then the dendritic cells interact with/activate naive T-cells

Front 12

capture of antigens from the intestinal lumen by DC's

Back 12

DC's can extend an arm in between the enterocytes and pluck Ag's out from the luminal surface

Front 13

what happens after the DC presents naive T-cells with Ag from the M Cell?

Back 13

the T-cells can:
a.) deliver help to B-cells in the Peyer's patch, or
b.) go to the mesenteric lymph nodes (the largest group of lymph nodes in the body). From there, the cells leave the mesenteric lymph nodes via the lymphatics and enter the circulatory system.
-These T-cells circulate in the blood and either return to the mucosal surface or they seed other sites

Front 14

the common mucosal system and seeding

Back 14

Peyer's Path: seeds back to the small intestine, but ALSO seeds to the mammary glands
-mom can provided passive protection to child

NALT: seeds back to origin and ALSO seeds to the urogenital tract
-for venereal disease vaccines, rather than having to induce immunization by local application of Ag, we can immunize via the nose and produce high levels of Abs in the urogenital tract

In the Inductive Sites, surface IgM+ B cells class switch and become committed to IgA production
-these B and T cells then leave the mucosa and enter draining lymph nodes. Then they enter the bloodstream via the Thoracic Duct and circulate until they come back home in mucosal epithelia. Lymphocytes don't simply home back to their inductive site, but may also seed remote mucosae

Front 15

what are the 2 locations for lymphoid cells in the mucosal immune system

Back 15

1. In the Lamina Propria
-heterogenous mixture of cells, dominated by CD4+ T-cells, but you also have mast cells, eosinophils, plasma B-Cells, etc

2. In the Epithelium
-CD8+ T-Cells
-major role in the maintenance of the integrity of the barrier epithelium

Front 16

Intraepithelial Lymphocytes (IELs)

Back 16

2 different types of CD8+ T-cells that lie within the epithelial lining the gut

1. alpha/beta CD8+ T-Cells look for virally infected mucosal epithelia cells

2. gamma/delta CD8+ T-Cells look for the expression of stress proteins on the surface of cells or the up-regulation of non-classical MHC molecules, MICA and MICB

Front 17

How does the mucosal immune system differentiate between innocuous (harmless) non-self and pathogens?

Back 17

immunosuppressive cytokines, TGF-beta and IL-10

the mucosal immune system is bathed in cytokines, specifically TGF-beta, which is an immunosuppressive cytokine
-under these conditions, you get dendritic cells that, at best, can be weakly activated- they have very low levels of co-stimulatory molecules

on top of that, these dendritic cells are also secreting an immunosuppressive cytokine, IL-10

if a T-cell interacts with a feebly activated dendritic cell, it gets turned into a regulatory T-cell thats going to dampen down the immune response too


if breached by a microorganism, the activated DC will secrete IL-12, which is an immune system activating cytokine

Front 18

origin and diversity of intestinal macrophages in healthy and inflamed intestine

Back 18

there are a variety of different macrophages in the mucosal immune system
-there are suppressive macrophages under resting conditions that secrete IL-10 and TGF-beta

when you have a breach, you get an inflammatory macrophage being recruited from the blood; and this inflammatory macrophage is primed to release a series of pro-inflammatory cytokines, creating an environment to activate naive T-cells

Front 19

Regulatory T-cells

Back 19

they largely produce IL-10 and TGF-beta

in addition to being immunosuppressive, TGF-beta also induces class switching into IgA