4 - Inflammation - Angyal Flashcards

1
Q

Overall, what is the key result of inflammation?

A

Allows immune cells, defence molecules, coagulation factors to reach site of infection or tissue damage.

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2
Q

More specifically, what are the 4 things that occur during inflammation that allows the body to clear an infection?

A
  • dilation of arterioles, venues, capillaries
  • increased blood flow and permeability
  • immune cell migration into inflammatory sites
  • release of inflammatory mediators once pathogen detected
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3
Q

What are the 5 classic signs of inflammation?

A

redness, pain, swelling, loss of functional, heat

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4
Q

what are the 7 inflammatory mediators that are released once a pathogen has been detected?

A
  • lipid mediators, prostaglandins
  • chemoattractants, fMLP
  • chemokine and cytokines, CXCL8, TNFa
  • complement, C3a/C5a
  • clotting factors
  • small molecules eg ROS, RNS
  • vasoactive amines
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5
Q

Describe the FULL process of extravasation

A

1) cytokines released by cells @ site of infection cause endothelial cells to express adhesion molecules (eg selectins, ICAM-1). Leukocytes also express counter receptors to ICAM1 known as Integrins which form weak interactions.
2) neutrophils are captured by the P/E selectins when glycoproteins (Sialyl Lewis) binds to them. Integrins on neutrophils also bind to ICAM-1/VCAM-1 - adhesion
3) neutrophils can squeeze between endothelial cells through an increasing number of interactions (therefore making them stronger) -> DIAPEDESIS

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6
Q

How can chronic inflammation occur, why is this bad and what are the causes?

A
  • when acute inflammation goes on for too long. inefficient release of anti-inflammatory cytokines and molecules released
  • TB and autoimmune conditions can cause this
  • depletes the body’s resources
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7
Q

What are the 3 systemic actions of cytokines?

A

autocrine - act on themselves eg T cells produce IL2 but also have receptors for IL2
paracrine - act on nearby cells
endocrine - travel in bloodstream to reach a far away target eg IL1 acts on hypothalamus

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8
Q

Is it only immune cells that produce cytokines?

A

no, non immune cells can too

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9
Q

What are cytokines commonly referred to as?

A

hormones of the immune system

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10
Q

Cytokines have pleiotropic effects - what does this mean

A

cells w/ same receptor can be stimulated by same cytokine but may result in different effects

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11
Q

How are cytokines grouped into families?

A

grouped based on structure but may have different functions

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12
Q

Describe the 5 main classes of cytokines

A
  • TNF. Exist as TM proteins, need to be cleaved & act as trimers
  • haemopoietin superfamily eg IL2/4/6. responsible for cell growth and differentiation in bone marrow
  • IFNs - response to viral infection following recognition of viral ssRNA uncapped
  • chemokines - responsible for movement of cells eg IL-8 induces chemotaxis of neutrophils
  • IL-1 family. made as inactive precursor. require activation by inflammasomes (caspase action)
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13
Q

Give 2 examples of cytokines; name the cells that produce them and what their role is

A
  • IL2. Made by T cells. Induce T cell growth and differentiation
  • IL8. Made by macrophages, dendritic cells. Chemotaxis of neutrophils
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14
Q

Give the 2 main ways in cytokine receptors signal

A
  • enzyme coupled receptor dimers (JAK/STAT pathway)

- GPCRs

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15
Q

Give some examples of cytokines secreted in the early induced immune response by macrophages/dendritic cells

A
  • CXCL8. chemotactic factor which recruits neutrophils and T cells to site of infection
  • IL6 - activation of lymphocytes, increased Ab production
  • TNFa - increases permeability of vascular endothelium allowing increased entry of IgG and complement to infection site. also, increased fluid drainage to lymph nodes.
  • both IL6/TNFa give rise to systemic effects eg fever
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16
Q

What is the typical structure of TNFa originally and how does it develop into the active structure?

A

exists as a TM protein that requires proteolysis/cleavage by macrophages. LPS is a potent stimulus. TNF forms trimers

17
Q

Give the name of the TNF receptor family and state briefly that happens upon binding TNFa.

A

TNFR1 family. Binds TNFa as trimer therefore receptor trimerises -> signal. cross linking of 3 receptors

18
Q

What are the local effects of TNFa?

A
  • increased platelet adhesion to endothelial walls and influx of platelets. stops spread of infection through clotting of capillaries
  • microthrombus formation. link between inflammation and coronary thrombosis
  • efflux of fluid from capillaries to lymph nodes. APCs and dendrites can then stimulate the adaptive immune system
  • increase in vascular permeability -> increased migration of lymphocytes / phagocytes to the surround infected tissue
19
Q

What are the systemic effects of TNFa?

A

At less than 1ug/ml, TNFa can stimulate receptors all over the body. Leads to pyrexia (fever) which acts on hypothalamus, increases body temp to 39.5C (compliments the adaptive response), inhibits bacterial/viral replication.
Also causes cachexia (wasting/weight loss). thought to be protective effect against cancer, infection

20
Q

What happens in a systemic infection with a G-ve bacteria?

A

SEPSIS - TNFa conc are > 1ug/ml in blood = dangerous. Exhaustion of clotting factors causes internal bleeding and infection spreading. increase in vascular permeability -> hypotension and reduced blood vol. Disseminated/widespread thrombus formation can lead to cardiac infarction and organ damage.
ALL leads to multiple organ failure and septic shock (80% fatal)

21
Q

When are interferons produced and what do they do?

A

produced upon viral infection and interfere w/ viral replication

22
Q

How can IFN genes be induced?

A

Induced following activation of TLRs (endosomal or cytoplasmic bound), RIG-I (intracellular) which detects viral ssRNA

23
Q

Name the 2 types of IFNs and give examples of each

A

Type I/II
TI - IFNa/B
TII - IFNy

24
Q

How do IFNa/B induce resistance to viral replication in cells?

A

IFNa/B binding - STAT pathway.

  • inducing 2’-5’ linked adenosine oligomers which activate endoribonucleases which degrade viral RNA
  • inducing production of PKR (protein kinase R) which inhibits eIF2 which stops translation initiation
  • production of IFITs. suppress viral RNA translation
  • induce NK cells to kill virally infected cells
  • increase MHC class I expression to express the viral peptides. signal for these cells to be killed
25
Q

How do naive CD4+ T helper cells differentiate into further subsets?

A

presence of specific cytokines in environment influence transcription and therefore differentiation into particular subset

26
Q

Name a cytokine that stimulates differentiation of a naive T cell into a particular T cell subset. Name this T cell and what are its effector function (ie the new cytokines it produces)

A

IL-4 stimulates differentiation of naive T cell -> TH2 cells. produced IL4/5/13 and useful in response to helminth infections