13 - Barrier Immunity

Question 1

barrier immunity

Answer 1

immune systems generally associated with skin and mucosal tissues

Question 2

MALT

Answer 2

the immune systems specifically associated with mucosal immunity.

mucosal-associated lymphoid tissue

Question 3

what type of cell lines the barrier surfaces?

Answer 3

epithelial cells.

The epidermis of skin, mouth, reproductive and urinary tracts have several layers of epithelial cells, while intestinal and respiratory only have 1.

Epithelial cells are diverse in phenotype and function. Some produce a protective mucus layer, some secrete antimicrobial peptides (AMPs) that kill or inactivate bacteria, some have beating cilia that sweep pathogens away.

Question 4

What immune cells are associated with barrier immunity?

Answer 4

cells of both the adaptive and innate immune systems reside in and migrate through barrier tissues. these include epithelial cells, DCs, macrophages, innate lymphoid cells, invariant and conventional T cells, and B cells.

mesenteric lymph nodes specifically drain the itestine. APCs that coe from barrier tissues often induce lymphocytes to express adhesion molecules (addressins) and chemokine receptors that direct them to the site of infection.

Question 5

tolerogenic

Answer 5

when a barrier is healthy and in homeostatic balace, the immune system is in a tolerogenic mode

the tolerizing response is dominated by TGF-β and IL-10 cytokines, regulatory T cells, and IgA-producing B cells.

IgA interacts with commensal microbes, preventing them from penetrating the epithelial barriers and initiating an inflammatory response.

Question 6

The Gastointestinal tract (GI)s sections and tissue layers

Answer 6

the GI tract contains trillions of microorganisms that influence our health in many different ways.

the small intestine is the site of most digestion ans absorption and has three sections (duodenum, jejunum, and ileum). The large intestine, or colon, is responsible for absorbing water and expelling waste thet includes the highest number and diversity of bacteria.

the small instestine is lined by microscopic folds (villi and crypts)

The lamina propria is the tissue layer just under the gut epithelial leyer, and is the site of most immune cell activity

Question 7

transcytosis

Answer 7

the process of shuttling molecules through epithelial cells

Question 8

enterocyte

Answer 8

the most common cell in the epithelium of the samll intestine, and the one traditionally associated with its digestive function

Question 9

goblet cells

Answer 9

distributed throughout the intestine (highest [c] in large intestine).

ability to produce mucus, secrete AMPs that inhibit the activity of luminal microbes that come too close to the membrane.

also sense and transport Ag and live microbes from the lumen to APCs in the lamina propria.

can secrete regulatory cytokines

Question 10

microfild (M) cells

Answer 10

highly specialized for transcytosis of Ag across the epithelium.

Question 11

Paneth cells

Answer 11

secretory cells that inhabit the intestinal crypts.

At least two cruical roles:

1) act as supportive companions of stem cells and secrete factors that sustain them.
2) secrete a variety of AMPs that protect the gut epithelium.

Question 12

Tuft cells

Answer 12

highly specialized, expand in response to worm infection.

Question 13

intraepithelial lymphocytes (IELs)

Answer 13

present in large numbers, particularly in the upper small intestine (jejunum). Many express CD8, some have been identified as tissue-resident memory cells that can respond rapidly in an Ag-specific manner.

Question 14

The gut immune system maintains a barrier between the microbiome and the epithelium

Answer 14

Under healthy conditions, the intestinal immune system maintains a healthy distance between epithelial cell surfaces and the commensal microbiome.

Goblet cells and Paneth cells create mucus, which provides a physical barrier, particularly in the large intestine.

Paneth cells and enterocytes generate antimicrobial peptides, defensins, lysozymes, and REG3 family members, which have the capacity to kill microbes that come too close

B cells in the intestinal mucosa secrete IgA, which is transcytosed from the lamina propria into the lumeb where it interacts with commensal microbes. IgA binding inhibits contact with the epithelium and also has anti-inflammatory properties.

Question 15

There are multiple ways to deliver antigens from the intestinal lumen to APCs

Answer 15

M cells and goblet cells carry Ags across the barrier by transcytosis

cells expressing receptors for IgA carry IgA-Ag complexes across the barrier

APCs that extend processed into the lume bind and process Ags directly

Question 16

Immune homeostasis in the intestine is promotes by several innate and adaptive cell types

Answer 16

under healthy conditions, epithelial cells are stimulated by commensal microbes that interact with PRRs (often TLRs). These interactions result in the production of TGF-β, retinoic acis (RA) and thymic stromal lymphoprotein (TSLP), which all maintain a tolerogenic enviroment, in part by inducing Treg cells (also IL-10 is needed for this).

Other immune cells that are generated include IgA-secreting B cells, ILC3 and TH17, and IELs.

ILC3 and TH17 help maintain homeostasis by producing IL-22, which stimulates epithelial cells to produce protective AMPs. They can however also contribute to inflammatory responses.

Question 17

The small and large intestines have different immune systems

Answer 17

the small and large intestines contains different communities of microorganisms and distinct immune cell populations

The large intestine has shorter villi, more microorganisms, and more goblet cells, which produce more protective mucus. It is also more susceptible to tumors.

The small intenstine has Peyer’s patches (large does not). The large intestine has a higher concentration of ILFs (isolated lymphoid follicles).

Question 18

Commensal microbes help maintain tolerogenic tone in the intestine

Answer 18

Several bacterial species help tune the intestinal immune system and enhance its ability to protect form pathogenic organisms by stimulating the production of anti-inflammatory intestinal immune cells (Treg, IgA+ B cells, and TH17 (and more)).

In the absence of microorganisms, the intestine does not develop normally and the immune system is underdeveloped both locally and systemically

Single microorganisms and even single microbial antigens can restore intestinal and imune health in germ-free mice

Introducing specidic microbes through eating (probiotics) or fecal transplantation could enhance intestinal health, as well as the intestinal and systemic immune systems (C. difficile).

Question 19

pathobionts

Answer 19

commensal bacteria that have the capacity to cause disease in compromised hosts

Question 20

The gut immune system recognizes and responds to harmful pathogens

Answer 20

inflammatory responses in the gut can be initiated by infection of/damage to the epithelial barrier by pathogens, toxins, or trauma.

To infect the host, the pathogens must first compete with the commensal bacteria for nutrients and space. Some pathogenic bacteria can metabolize molecules that the “good” bacteria can’t, or they can live off of byproducts secreted by the good bacteria.

two phases of the response to pathogens:

• inductive phase (initiation and shaping)
• effector phase (mature immune cells actively work)

Question 21

The inductive phase

Answer 21

initiated by epithelial cells and APCs (activated through PRRs). TLR5 (for bacterial flagellin) tends to induce inflammation. TLR2 induces tolerogenic. NLRs also activate inflammation

TLR5 is only located on the basolatal, not the apical, surface of epithelial cells. Thus, it will only be triggered if a bacteria is where it is not supposed to be.

activated APCs alert naïve T cells to the presence and general identity of the pathogen. Instead of becoming Tregs, they will become TH1 and TH17 OR TH2 and TH9 lineages (depends on the microbe). Instead of IgA class switchine, T cells and APCs will encourage class switching of B cells ot more proinflammatory IgG classes.

Question 22

The effector phase

Answer 22

• recruitment of cells and strategies that expel/clear the invading organism.
• depends on the type of pathogen.
• resolution of the response also requires the repair of epithelial cells.

Question 23

Type 1 response in gut

Answer 23

• f.ex. Salmonella, Clostridium difficile, Citrobacter and E. coli
  Salmonella = the example here.

some defensins in the gut kill Salmonella. Some IgAs can also bind and stop S from having access to the epithelial layer, but S has other ways in (transcytosed by M cells)

S rec by TLRs 4, 5, 9, and NLRs. these are expressed in epithelial cells, APCs, ILCs. These cells together mount a Type 1 response.

The IL-23-TH17 cell axis:
PRRs -> IL-23 -> enhances IL-17 + IL-22 (by TH17 and ILC3).
IL-22 upregulates AMPs (f.ex REG3).
IL-17 enhances production of chemokines that attract neutrophils (particularly good at clearing S and also produces additional IL-22 and IL-17.

NLRs:
induce inflammasone activity in macrophages + activate caspase-1 ->IL-1β and IL18 -> induces T cell and ILC subsets to produce IFN-γ.

IgG antibodies are good at controlling an active infection.

Question 24

Type 2 response in gut

Answer 24

respnse to parasites
type 2 is charecterized by ILC2 & CD4+ TH2 cells & generation of type 2 cytokines IL-4, IL-5 and IL-13.

Initiated by alarmins (TSLP, IL-25, IL-33 released by epithelial cells). These act on many type 2 cells (ILC2s, mast cells, basophils, CD4+ TH2 (induce release of the cytokines above)).

Tuft cells (brush cells) "taste" products of worms,protozoa and other parasites. This induces production of IL-25 -> ILC2s secrete IL-13 -> positive feedback & goblet cells produce+secrete mucus -> worms cleared physically. 
IL-4 (from eosinophils and basophils) -> (naïve T -> TH2) -> enhance B cell class switching to IgE.

IgE bind to worms (Ag-binding sites) and to granulocytes via constant regions (eosinophils), induce the release of the granules, killing worms.

Question 25

dysbiosis

Answer 25

disruption of a healthy microbiome in the gut

Question 26

IBD

Answer 26

irritable bowel diease. chronic inflammation
two dieases: Crohn’s disease and ulcerative colitis.

Crohn’s: inappropriate type 1 response. patchy aggregates of inflammatory macrophages in mucosa.
Ulcerative: inappropriate type 2 response. active inflammation of mucosa with infiltration of neutrophils, reduced mucus boundaries, and direct damage to epithelium (ulcers).

Causes not fully understood, but may be associated with diet, microbiome, and failiure to induce homoestasis (may have a genetic component. Typically treated with immunosupressive drugs and anti-inflammatory therapies.

Question 27

Celiac’s disease (CD)

Answer 27

autoimmune response to dietary glutens (and other wheat-associated molecules) that have penetrated the epithelial barrier. It is charecterized by damaging TH1 response and is typically trated with a gluten free diet.

Question 28

Upper and lower respiratory tract

Answer 28

upper = mouth and nose
Lower = trachea, (glottis flap), bronchi, brochioles, alveoli

Question 29

epithelial layer of resp tract cells:

Answer 29

Shared with intestinal:

• goblet cells
• M cells
• transepithelial processed of APCs
• multipotent stem cells that replace damaged or dead cells.

Unique:
- apical surfaces have cilia. Tigether with mucus from goblet cells, these form a mucociliary boundry (actively sweeps pathogens away and expel them).

• club cell (secretory), most prevalent in lower airways of humans.
• alveolar macrophages (dust cells). regulate inflammation/tolerogenic response at this very delicate site.

Question 30

NALTs and BALTs

Answer 30

NALTs = nasal-associated lymphoid tissue. part of tonsils. supports activation of T and B cells.

BALTs = bronchus-associated lymphoid tissue. Common in some animals, in humans it is not that well organized, therefore called iBALTS (inducible).

Question 31

Inflammatory response in respiratory tracts

Answer 31

similar to that of intestinal tract.

Question 32

Respiratory immune response to a Virus

Answer 32

influenza virus gains access when hemagglutinin protein (virus) binds to sialic acid (epithelial cell). This induces endocytosis, virus releases ssRNA into cytoplasm.

TLR7 and REG-I binds the flu RNA, NLRs bind to flu-specific surface proteins. This sets off cascades, resulting in production of IL-1β, type I IFNs and the alarmin IL-33.

NKs rec cells with the hemagglutinin in their surface (happens just before the budding of new virus particles). this + IFN I secretion, limits the infection.

APCs that have been exposed to the flu migrate to NALT and iBALT to activate T and B cells.

Question 33

The skin as an immune system

Answer 33

shares many similarities to the mucosal immune system, but is distinguished by its multilayered epithelium (epidermis), which is associated with a unique population of DCs, as well as high concnetration of tissue resident CD8+ T cells.

The dermis includes most of the immune cell types found in the lamina propria of mucosal tissues, circulating CD4+ memory T cells, and an abundance of regulatory T cells that help to maintain immune homeostasis

Commensal bacteria interact with both epidermal and dermal cells to generate immune protection to other organisms, including Leishmania parasites

Immune responses in the skin can have systemic protective effects.