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2021-22 Immunology > Inflammation, Cell Adhesion and Resolution > Flashcards

Inflammation, Cell Adhesion and Resolution Flashcards

1
Q

What is Inflammation?

Can it be sterile?

A
  • Complex, multifactorial response to infection, damage, trauma
  • Beneficial
  • It is NOT synonymous with INFECTION- It can be STERILE
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2
Q

What is inflammation characterised by?

A

–Calor (Heat)

–Dolor (Pain) physiologically important

–Rubor (Redness)

Tumor (Swelling) exudate (that has come out of the blood) flush antigen into secondary lymphoid tissue

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3
Q

What are the characteristics of acute inflammation?

A
  • Local reaction
  • Movement of proteins and cells from blood to tissue
  • Predominantly Neutrophils
  • Clearance of immune challenge
  • Resolution–Poorly studied
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4
Q

Describe the kinetics of acute inflammation

A
  1. Exudation (fluid comes out of the blood and comes into the tissue to cause swelling) after 30 mins
  2. This is followed by neutrophils that start to accumulate in the tissue after about 1 hour
  3. Neutrophils die by apoptosis (peaks about around 24 hours)
  4. Mononuclear cells like monocytes come in, remove the neutrophils and return the tissue to the pre-inflamed state

The bottom of the graph shows the molecular mediators at different time points of inflammation (pro and anti-inflammatory mediators)

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5
Q

What is the resolution of inflammation?

A

•If inflammation gets ‘better’ it RESOLVES through a process that we call RESOLUTION OF INFLAMMATION

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6
Q

What is chronic inflammation?

A
  • Prolonged
  • Non-resolving
  • Leads to loss of function
  • Persistent inflammatory cells and mediators
  • e.g. Rheumatoid arthritis
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7
Q

What regulates an inflammatory response?

A
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8
Q

Name some receptors that recognise pathogens

A
  • Pattern-recognition receptors (PRR)–Receptors for Pathogen-associated molecular patterns (PAMPs)
  • Lectins (bind sugars)–Dectin 1 and Mannose receptor
  • Scavenger receptors e.g SR-A–MARCO–SR-B (e.g. CD36)
  • CR and FcR–Recognise opsonised bacteria. If the bacteria has an antibody bound, it would be recognised by an Fc receptor. If the bacteria was opsonised by complement, it would be recognised by a complement receptor. This enables phagocytosis.
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9
Q

Macrophages have phagocytic receptors that binds microbes and their components

A
  • Mannose receptor
  • Complement receptor
  • Lipid receptor
  • Scavenger receptor
  • Decetin-1 (Beta-glucan receptor)
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10
Q

Bound material is internalized in phagosomes and broken down in

A

phagolysosomes

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11
Q

How does inflection trigger an inflammatory response? (part 1)

A
  1. Bacteria trigger macrophages to release cytokines and chemokines
  2. Vasodilation and increased vascular permeability cause redness, heat, and swelling
  3. Inflammatory cells migrate into tissue, releasing inflammatory mediators that cause pain
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12
Q

How does infection trigger an inflammatory response? (part 2)

A
  1. Cytokines produced by macrophages cause dilation of local and small blood vessels
  2. Leukocytes move to periphery of blood vessel as a result of increased expression of adhesion of molecules by endothelium
  3. Leukocytes extravasate a site of infection
  4. Blood clotting occur in the microvessels
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13
Q

What are TLRs?

A

PPRs

  • Family that recognise a wide range of components of microbes (PAMPs)
  • Recognition in different cellular locations
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14
Q

TLRs sense infection. What are the different TLRs?

A

Surface TLR’s detect extracellular pathogens, intracellular TLR’S detected intracellular pathogens so you get the right response at the right place.

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15
Q

How does TLR dimerization promote cell activation?

A
  1. The convex surfaces of TLR-1 and TLR-2 have binding sites for lipid side chains of triacyl lipopeptides
  2. Binding of each TLR to the same lipopeptide induces dimerization, bringing their cytoplasmic TIR domains into close proximity
  3. LPS has multiple fatty acyl chains liked to a glycan head. Five acyl chains can bind to a pocket within MD-2, but one acyl chain is free
  4. The free acyl chain of an LPS molecule that binds to the outer convex surface of another TLR-4 molecule, including a dimer. An LPS molecule bound to the second TLR-4/MD-2 molecule stabilizes the dimer
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16
Q

Describe inflammatory cytokine production

A
  1. A complex of TLR3, MD2, CD14 and LPS is assembled at the macrophage surface
  2. MyD88 bind TLR4 and activates IRAK4 to phosphorylate TRAF6, which leads to the phosphorylation and activation of IKK
  3. IKK phosphorylates IκB, leading to its degradation and the release of NFκB, which enters the nucleus
  4. NFκB activates transcription of genes for inflammatory cytokines, which are synthesized in the cytoplasm and secreted via the ER
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17
Q

Draw a diagram to show how complement can activate

A
18
Q

Explain how complement can activate inflammation

A
19
Q

Complement can activate inflammation

A
20
Q

Complement receptors facilitate phagocytosis

A
21
Q

Describe small complement components and local responses

A
  • Local inflammatory responses
  • local vascular endothelium changes

Enables EXTRAVASATION of

  • Fluid
  • Proteins
  • cells
22
Q

Show how small complement components contribute to local responses

A
  • Small complement-cleavage products act on blood vessels to increase vascular permeability and cell-cell adhesion molecules
  • Increased permeability allows increased fluid leakage from blood vessels and extravasation of immunoglobulin and complement molecules
  • Migration of macrophages, polymorphonuclear leukocytes (PMNs) and lymphocytes is increased. Microbicidal activity of macrophages ad PMNs is also increased
23
Q

C3a and C5a activate mast cells

A

C3a and C5a are Anaphylatoxins

  • Resident in tissues & sub mucosae
  • Release vasoactive amines
  • Release cytokines e.g. TNF-a

Enables EXTRAVASATION of

  • Fluid
  • Proteins (Ab, complement)
  • Cells
24
Q

Explain this image

A

The main cellular inflammatory mediators are macrophages and neutrophils which lead to an induced innate response.

25
Q

Name some molecular inflammatory mediators

A
  • Cytokines
  • Chemokines
  • Complement
  • Amines
  • Lipid mediators
26
Q

MOLECULAR MEDIATORS OF INFLAMMATION: Name some lipid mediators

What enzymes are they produced from?

A

–Eicosanoids (20 C chain)–Different sub-families with a range of functions

  • Prostaglandins, Prostacyclins, Thromboxanes, Leukotrienes
  • Lipoxins, resolvins, maresins

–Produced from fatty acids (e.g. arachidonic acid) by enzymes…..

•Cyclooxygenase (COX) or lipoxygenase (LOX)

27
Q

During initial phases of inflammation, what are the inflammatory cells?

A

–MØ macrophage

–NØ – neutrophil

–These are INFLAMMATORY CELLS

•Leads to an INDUCED innate response

28
Q

Activated macrophages secrete a range of cytokines: What are the local and systematic effects of IL-1β?

A

Local effects:

  • Activates vascular endothelium
  • Activates lymphocytes
  • Local tissue destruction
  • Increases access of effector cells

Systematic effects

  • Fever
  • Production of IL-6
29
Q

Activated macrophages secrete a range of cytokines: What are the local and systematic effects of TNF-α?

A

Local effects:

  • Activates vascular endothelium and increases vascular permeability, which leads to increased entry of IgG, complement, and cells to tissues and increased fluid drainage to lymph nodes

Systematic effects

  • Fever
  • Mobilization of metabolites
  • Shock
30
Q

Activated macrophages secrete a range of cytokines: What are the local and systematic effects of IL-6?

A

Local effects:

  • Lymphocyte activation increased antibody production

Systematic effects

  • Fever
  • Induces acute-phase
  • Protein production
31
Q

Activated macrophages secrete a range of cytokines: What are the local and systematic effects of IL-6?

A

Local effects:

  • Lymphocyte activation increased antibody production

Systematic effects

  • Fever
  • Induces acute-phase
  • Protein production
32
Q

Activated macrophages secrete a range of cytokines: What are the local effects of CXCL8?

A

Chemotactic factor recruits neutrophils, basophils and T cells to site of infection

33
Q

Activated macrophages secrete a range of cytokines: What are the local effects of IL-12?

A
  • Activates NK cells
  • Induces the differentiation of CD4 T cells into TH1 cells
34
Q

Cell recruitment is adhesion dependent

There are 4 types of adhesion molecule: SELECTINS

A

e.g. L-selectin; P-selectin; E-selectin

Bind to sugars on glycoproteins on other cells (low affinity- rolling adhesion)

35
Q

Cell recruitment is adhesion dependent

There are 4 types of adhesion molecule: INTEGRINS

A

They are heterodimers

e.g. a4b1; a4b7; a6b1

aLb2 (LFA-1); aMb2; axb2

Bind to immunoglobulin superfamily (IgSF) members (firm adhesion phase)

36
Q

Cell recruitment is adhesion dependent

There are 4 types of adhesion molecule: SUGARS on glycoproteins

A

e.g. sLex on GlyCAM-1; CD34

PSGL-1; MAdCAM-1

Bind to selectin (low adhesion)

37
Q

Cell recruitment is adhesion dependent

There are 4 types of adhesion molecule: Immunoglobulin superfamily (IgSF) members

A

e.g. ICAM-1, -2, -3

VCAM-1; LFA-2; LFA-3

38
Q

How Neutrophil extravasate- ‘slow down’

A
  1. Neutrophils slow down using the low affinity interactions between selectins (on the activated endothelium and sugars on the neutrophil surface
  2. Pressure of blood flow means that the low affinity interactions cannot stop the neutrophils altogether
  3. Chemokine CXCL8 binds to CXCL8 receptor, the neutrophil gets activated and it changes the conformation of the integrin LFA-1 (Alpha L beta 2)
  4. LFA-1 can now bind to an ISF member ICAM1. This is a very high affinity interaction. This interaction stops the neutrophil to go through the endothelial cell into the tissue following the concentration of chemokines
39
Q

What of the steps of neutrophil extravasation?

A
  1. Rolling adhesion
  2. Tight binding
  3. Diapedesis
  4. Migration
40
Q

Problems with neutrophil extravasation: Leukocyte adhesion deficiency (LAD)

A

LAD 1

  • Little or no CD18 (b2) (an integrin that mediates a high affinity interaction) Result= Rolling adhesion but no firm adhesion
  • Neutrophilia
  • Large necrotic recurrent infection

LAD 2

  • Poor glycosylation -> no sLeX
  • Neutrophilia / neutrocytosis
  • Defective rolling phase
  • Recurrent bacterial infections

LAD 3

LAD3 is caused by a genetic defect in the FERMT3 gene. This defect leads to abnormal expression of kindlin-3, a protein whose major role is the regulation of integrin activation

41
Q

Kinetics of acute inflammation

A

Neutrophils > > > > Monocytes

NØ first recruited cells

Monocytes follow similar mechanisms, different adhesion molecules e.g. aMb2

42
Q

Why is inflammatory signalling so fast?

A

Due to pre-formed mediators

2021-22 Immunology (4 decks)

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