Immunology Lec 4 - Innate Immunity Pt 3

Question 1

what is inflammation

Answer 1

A complex reaction of the innate immune system in vascularized tissues that involves accumulation and activation of leukocytes and plasma proteins at a site of infection, toxin exposure, or cell injury. Inflammation is initiated by changes in blood vessels that promote leukocyte recruitment and movement of fluid and plasma proteins into tissue. Local adaptive immune responses can promote inflammation. Although inflammation serves a protective function in controlling infections and promoting tissue repair, it also can cause tissue damage and disease

Question 2

what are the five hallmarks of inflammation

Answer 2

heat, redness, swelling, pain, loss of function

Question 3

how does inflammation lead to sickness behaviour

Answer 3

Sickness behavior is part of the response of the body to inflammatory stimuli. Multiple systemic effects are due to the four major cytokines secreted by sentinel cells (mast cells, macrophages
and dendritic cells). The major sickness‐inducing cytokines are interleukin (IL)‐1, IL‐6, tumour
necrosis factor (TNF)‐α; the DAMP high‐mobility group box‐1 (HMGB1) also contributes

Question 4

what is the common acute phase protein in all domestic aniamls

what is a major source of APP

Answer 4

SAA is common

liver is a major source

Question 5

5 APP in domestic animals and what they do

Answer 5

-Alpha‐1‐acid glycoprotein binds lipopolysacharide (LPS; from gram‐negative bacteria), inhibiting its activity, and down‐regulates neutrophils and complement.

-C‐reactive protein a soluble pattern‐recognition receptor (PRR) that binds
residues and polysaccharides on bacteria, fungi, and parasites to activate complement and phagocytosis. It can also up‐regulate and down‐regulate cytokine production and chemotaxis.

-Haptoglobin reduces oxidative damage associated with hemolysis by binding free hemoglobin. In addition, it has bacteriostatic and immunomodulatory effects.

-Serum amyloid A promotes inflammation; specifically, it enhances chemotaxis of polymorphonuclear cells (especially neutrophils), monocytes, and T cells.

-Major acute‐phase protein (porcine) inhibits trypsin

Question 6

iron regulation during infection

Answer 6

-Iron is important for:
‐ growth of microbes
‐ the host (e.g., component of hemoglobin)

-Therefore, iron regulation during infections affects both.

-The host produces acute phase proteins (e.g., hepcidin,
haptoglobin, etc.) that sequester iron, inhibiting microbial growth.

-Bacteria produce siderophores that steal iron from the host.

-The host can produce proteins (e.g., lipocalin 2) that steal bacterial siderophores.

-Hepcidin binds to iron during recycling of dead or damaged erythrocytes. It also impairs iron absorption in the gut. The result
is reduced synthesis of new red blood cells. Hence, anemia is a
common off‐target effect in chronic infections

Question 7

what is SIRS, what is it caused by, typical signs, cytokines involved, pathogenesis

Answer 7

SIRS = systemic inflammatory response syndrome

caused by a cytokine storm

typical signs:
1. Elevated respiratory rate
2. Fever
3. Leukopenia (loss of white blood cells) or leukocytosis (increased # of white blood cells)
4. Rapid heart rate

-The pathogenesis of the systemic inflammatory response
syndrome. In effect, the syndrome results from over‐expression
of multiple cytokines. These cytokines are toxic in high doses

-IL1 IL6 and TNF-a are involved

Question 8

toxic shock syndrome ; what is it, how it hapens, causes what

Answer 8

• A specific type of SIRS
• The toxin produced by staphylococcal bacteria functions as a “superantigen”
• It non‐specifically crosslinks
  MHC molecules (normally responsible for presenting antigens) to the antigen receptor on T cells
• Because this is non‐specific, it
  results in the inappropriate activation of unusually large #s of T cells
• This causes release of excessive amounts of inflammatory cytokines that cause the syndrome
• The pathogenesis of staphylococcal toxic shock syndrome. The toxic shock syndrome toxin is a potent superantigen that acts as a powerful stimulant of IL‐1 and TNF‐α production

Question 9

protein midfolding diseases; what is incolved, pathogenesis, examples

Answer 9

-The pathogenesis of reactive amyloid fibril deposition. Misfolded proteins aggregate to form insoluble fibrils.

-SAA involved

examples
-Alzheimer`s disease
-Bovine spongiform encephalopathy
(mad cow disease)
-Amyloid A amyloidosis in cheetahs

Question 10

what is the complement system

Answer 10

A group of serum and cell surface proteins activated by factors such as the combination of antigen and antibody and results in the generation of enzyme cascades that have a variety of biological consequences including cell lysis and opsonization

Question 11

triggering the complement cascade; involves what, modes of activation, potential effector outcomes

Answer 11

-A cascade system involving a large # of what are known as complement
proteins

-Three modes of activation:
1. classical (antibody) pathway
2. lectin (collectins)
3. alternative pathway

Common amplification pathway.

Three potential effector outcomes:
1. vascular permeability and
leukocyte attractant (helps effector cells get to sites of danger)
2. cellular uptake via complement
receptor(s) (opsonization; promotion of phagocytosis)
3. MAC (membrane attack complex)
(punches holes in cells, killing them)

Question 12

bone marrow transplantation

Answer 12

-e.g. to treat leukemias

-Mature T cells from donor bone marrow might recognize the recipient’s tissues, leading to graft‐versus‐host disease (GVHD).

-Treat marrow with antibodies that bind only to mature T cells, then add complement proteins to destroy them (i.e., via MAC)

Question 13

cytokines- life span, how they act, regulation, etc

Answer 13

• Short‐lived proteins
• Highly diverse structures and receptors
• Can act locally and/or systemically
• Pleiotropic: affect many different cells
• Redundant: exhibit biologically overlapping functions
• Carefully regulated
• Toxic in high doses (i.e., cytokine storms)

Question 14

triggers of cytokine release; pathways an deetails

Answer 14

Three of the most important pathways that trigger cytokine release are the combination of
antigens with their receptors on T (i.e., TCR) and B (i.e., BCR) cells, the combination of PAMPs with toll‐like receptors (TLRs) on sentinel cells; and the combination of antibodies with Fc
receptors (FcR) on phagocytic cells

Question 15

cytokines and hormones

Answer 15

The distinction among autocrine, paracrine, and endocrine effects. Cytokines differ from hormones in that most of their effects are autocrine or paracrine, whereas hormones usually act on distant cells in an endocrine fashion

Question 16

cytokine signalling

Answer 16

A generic view of signal transduction involving the activation of tyrosine kinases. Although receptor signaling varies in its details and intricacy, the overall process of signal transduction
has some consistent features as shown here

Question 17

three ways to control the effects of a cytokine

Answer 17

1. Alter expression of the receptor
2. Use binding proteins specific for the cytokine (e.g., decoy receptors; secreted, no signaling)
3. Produce cytokines with opposite effects

Question 18

cytokine dysregulation; sepsis –> septic shock

Answer 18

Caused by blood‐borne infection
(bacteremia or viremia)
→ SIRS (systemic inflammatory response syndrome)
→ hypotension due to vasodilaƟon, decreased myocardial activity, endothelial injury & activation
→ systemic leukocyte adhesion
→ disseminated intravascular coagulation (DIC)
→ hypoperfusion
→ multi‐organ failure (death rate ≈ 50%)

Question 19

septic shock fatality

Answer 19

Excessive cytokine responses during immune responses are sometimes the underlying cause of fatalities in cases of serious infectious diseases.

Examples:
→ Severe Acute Respiratory Syndrome (SARS)‐1/2
→ Some influenza outbreaks
→ Ebola hemorrhagic fever
→ Dengue shock syndrome
(high mortalities of some infectious diseases in healthy young adults may be due to cytokine storms)

Question 20

other clinical condition caused by cytokine storm

Answer 20

Another clinical condition caused by a cytokine storm is:
* Graft‐Versus‐Host Disease (GVHD) following transplantation of mismatched bone marrow
* Large #s of effector cells of the donor’s immune system recognize their new host’s cells as dangerous
* The ensuing response is of such magnitude that it results in an overproduction of cytokines that drive this condition