Innate immunity and inflammation

Question 1

What is inflammation and what is its purpose?

Answer 1

Inflammation- delivery of cells that circulate in the blood, as well as proteins and fluid into infected or injured tissue. Promotes defense against microbes and repair of injured tissue

Question 2

What is a leukocyte?

Answer 2

A white blood cell

Question 3

What are the two main types of leukocytes?

Answer 3

1. Neutrophiles (polymorphonuclear leukocytes)
2. Monocytes

Question 4

What is the innate immune system?

Answer 4

• The innate immune system is all the immune defenses that exist before any exposure to a pathogen

Question 5

How does the immune system react to repeated infections? Is it fast or slow?

Answer 5

• The innate immune system is all the immune defenses that exist before any exposure to a pathogen
  o Will respond the same way to repeated infections
  o Rapid responses

Question 6

Describe, step by step, the process of inflammation when a microbe invades the tissue (innate immune response)

Answer 6

1. When microbes invade the tissues, microbes and microbial products bind to innate immune receptors on sentinel cells
2. Sentinel cells become activated and release pro-inflammatory molecules
3. Pro-inflammatory molecules bind to receptors on the vessel endothelial cells
4. Signaling promotes the expression of adhesion molecules on the surface of the endothelium
5. Ligands on leukocytes bind to the adhesion molecules
6. Low affinity interactions cause the leukocyte to roll on the endothelium, slowing it down until high affinity interactions bring the cell to stable arrest
7. Stable arrested neutrophils flatten and migrate between endothelial cells
8. Neutrophils detect, [phagocytose and kill ingested microbes
9. Eventually, neutrophils undergo apoptosis
10. Stable arrested monocytes flatten and migrate between the endothelial cells
11. Monocytes in the tissue differentiate into macrophages
12. Macrophages detect, phagocytose and kill ingested microbes and phagocytose apoptotic neutrophils

Question 7

Where do sentinel cells reside? What are the 3 types of sentinel cells?

Answer 7

Immune cells (mast cells, dendritic cells, macrophages) called sentinel cells reside in the tissues

Question 8

Where do the leukocytes reside? What are the two main types of leukocytes?

Answer 8

Immune cells called leukocytes (neutrophils and monocytes) circulate in the blood

Question 9

What is the most abundant of white blood cells?

Answer 9

Neutrophils

Question 10

How do neutrophils kill bacteria? What happens to it after it does so?

Answer 10

 Microbe binds to receptors-> neutrophil responds by signals that activate the cell
* Microbe gets internalized in the cell into a phagosome/endosome and dies as neutrophil undergoes apoptosis (after a few hours of eating the microbe)
o Phagocytosis
* Receptor gets internalized as well with the microbe

Question 11

What is the role of monocytes? What transformation do they undergo to do so?

Answer 11

o Monocytes-become macrophages: PHAGOCYTOSIS
 Only exist in the blood
 When it moves into the tissues, it becomes a macrophage (a big eater)
 Has an innate receptor-> bind microbes-> internalize microbe-> kills the microbe
 Can also eat dead cells (and can eat dead neutrophils)
 Receptor gets internalized as well with the microbe

Question 12

Where do leukocytes come from?

Answer 12

• Leukocytes come from the bone marrow and the hematopoietic stem cell
  o Gives rise to progeny that differentiate into the types of white blood cells

Question 13

Which sentinel cell releases granules/histamine when activated?

Answer 13

Mast cell

Question 14

Which innate immune response cells respond to microbes through phagocytosis?

Answer 14

-Neutrophils
-Monocytes
-Tissue-resident macrophages

Question 15

Which innate immune response cells respond to microbes by secreting pro-inflammatory cytokines?

Answer 15

-Dendritic cells
-Tissue resident macrophages
-Mast cells

Question 16

How do sentinel cells call in circulating leukocytes into the tissue in response to microbial infection?

Answer 16

o Microbes cross epithelial barrier-> activates receptors on sentinel cells-> they release pro-inflammatory cytokines-> inflammatory cytokines/mediators diffuse and bind to receptors on cells lining blood vessels (endothelial cells)-> activates endothelial cells which leads to ability of leukocytes/fluid/proteins to get out into the tissue -> causes increased expression of molecules on the luminal side of the endothelium, including of adhesion molecules
 Adhesion molecules promote sticking of one cell to another cells-> important for blood cells to stick to them

Question 17

How do adhesion molecules help circulating leukocytes out of the tissue? Give an example of two receptors/molecules involved in this process differently.

Answer 17

o Neutrophils: slows it down using low affinity binding, then high affinity binding, which causes it to flatten out and leave the tissue
 Neutrophils have adhesion molecules on their surface, which bind to adhesion molecules on endothelium/other molecules
 One of the adhesion molecules on the endothelium is called e-selectin, and the molecule on the leukocyte that selectively binds to it is called selectin-ligand
* This interaction is a low-affinity interaction: it doesn’t bind tightly
* Means that as the blood moves along, it breaks and reforms interactions with adhesion molecules further upon the bloodstream-> this slows the neutrophil down
 This slowing of the neutrophil allows another interaction to occur with another endothelial receptor called ICAM-1, which binds to an integrin on the neutrophil (specifically called LFA-1)
* This interaction is a high affinity (strong) interaction, leading to the neutrophil coming to a stop (stable arrest)
 Neutrophil will then flatten out and crawl through the spaces of the endothelial cells and get out into the tissue
* Neutrophils will then get into the tissue-> phagocytose the microbes-> throw toxic chemicals at it to kill it (like free radicals)-> neutrophils then die from apoptosis after a short time

o Blood monocytes-> shows up after the neutrophils have been released into the tissue-> turn into macrophages and clean up the apoptotic neutrophil-> tissue returns to homeostasis

Question 18

What is the difference between the interaction of the e-selectin receptor to its ligand compared to the ICAM-1 receptor to the ligand. Give purpose and ligand name for each. Also give how they help each other out.

Answer 18

 One of the adhesion molecules on the endothelium is called e-selectin, and the molecule on the leukocyte that selectively binds to it is called selectin-ligand
* This interaction is a low-affinity interaction: it doesn’t bind tightly. Its purpose is to slow the neutrophil down.
 This slowing of the neutrophil allows another interaction to occur with another endothelial receptor called ICAM-1, which binds to an integrin on the neutrophil (specifically called LFA-1)
* This interaction is a high affinity (strong) interaction, leading to the neutrophil coming to a stop (stable arrest)

Question 19

What is pus and how does it form?

Answer 19

• Microbes activate sentinel cells which release cytokines
• Cytokines act on the endothelium to cause neutrophils to collect in the tissue
• Fluids and components (including DNA and bacteria killed by neutrophils) of apoptotic neutrophils form pus

Question 20

What is psoriasis and what is its prevalence?

Answer 20

• Psoriasis is a common inflammatory disease that most frequently affects the skin
  o More than 2% of people worldwide suffer from it dependent on geographical region

Question 21

What are the symptoms of psoriasis?

Answer 21

• Symptoms:
  o Plaques
   Skin thickening in several layers
  o Pustules
   Filled with immune cell infiltrate- means that leukocytes have migrated into the skin
   Pustules become plaque as it heals
  o Arthritis
   Psoriatic arthritis can affect joint itself, can be an enthesitis (tendinis, dactylitis, spine disease…)
  o Shedding

Question 22

What are possible causes of psoriasis and is it a long-term or short term disease?

Answer 22

-long lasting
-o Genetic component
 41% have a first degree relative with psoriasis
o Environmental stimulus that starts off the process
 Trauma to the skin
 Infections (strep…) which trigger the innate immune system
* Dendritic cells which produce cytokines (interferon alpha (type I interferon), TNFalpha, other interleukins)-> they simulate other innate mechanisms/adaptive

Question 23

What is a popular treatment to treat psoriasis and what is its drawback?

Answer 23

• Anti-TNF drugs are useful in treating this disease, shutting down innate/adaptive stimulation
  o Anti-TNF also works directly on skin cells, which targets growth and proliferation
  o Risks:
   Cause suppression of immune system-> can get stuff like tuberculosis…
   Have to check blood every 3-6 months to make sure everything’s working normally
   Have to call immediately if there’s any sign of infection
• Increased risk of infection
• Vaccinations have to be up to date
   TNF has effects on the endothelium which facilitates diapedesis

Question 24

What kind of disease was psoriasis thought to be and why?

Answer 24

• Historically thought to be proliferative disease due to skin thickness
• Inflammation drives skin to grow faster and do plaques

Question 25

What is the definition of enthesitis?

Answer 25

Inflammation of the site where a tendon or ligament inserts into a bone

Question 26

What is the definition of dactylitis?

Answer 26

Inflammation of an entire digit

Question 27

What is the definition of intertriginous

Answer 27

Referring to areas where skin rubs together

Question 28

What is the definition of palmoplantar pustulosis?

Answer 28

• chronic pustules that form on hands and feet