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MVST1B BOD > L3 - A Kelly - Inflammation > Flashcards

L3 - A Kelly - Inflammation Flashcards

1
Q

what are PRRs

A

receptors expressed by cells which recognise PAMPS and DAMPS

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2
Q

T or F:

Sentinel cells express PRRs

A

Sentinel cells express PRRs

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3
Q

describe PAMPS

A
  • shared by classes of organisms
  • essential for survival of the pathogen
  • highly conserved
  • absent from the vertebrate host
  • allow the innate system to distinguish self from non-self
  • often conponents of cell walls, eg peptidoglycan
  • Some are specific for Gram +ve (lipoteichoic acid) or Gram -ve cells (Lipopolysaccharide LPS)
  • Unmethylated CpG DNA distinguishes the bacterial genome from the mammalian host
  • Mammals have a lower frequency of CpG dinucleotide which are mostly methylated.
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4
Q

are PAMPS on the surface or released?

A

both!

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5
Q

describe PRRs

A
  • detect PAMPs
  • germ-line encoded
  • located where pathogens or their components reside
  • present at the cell surface, in endosomes, in the cytosol and in the circulation
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6
Q

describe the functions of PRRs

A

functions:
- Stimulate ingestion of microbes by phagocytosis
- Act as chemotactic receptors and guide cells to sites of infection
- Produce effector molecules that assist both the innate and adaptive response
Some PRRs are soluble, eg CRP

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7
Q

are TLRs a class of PRR?

A

yep

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8
Q

TLRs function as ____

A

dimers

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9
Q

T or F

TLRs function as dimers and each TLR homodimer or heterodimer pair is specific for a different set of pathogen products

A

T

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10
Q

how many TLRs do humans have?

A

10

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11
Q

which transcription factors do TLRs activate?

A

(eg NF-κB, AP-1 and interferon-regulatory factors IRFs)

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12
Q

bacterial products stimulate which transcription factors?

and viruses?

A
  • bacterial products tend to activate NF-κB and AP-1 and stimulate pro inflammatory cytokine and chemokine production.
  • viral nucleic acids tend to stimulate IRFs which induce antiviral type 1 interferons (IFNα and IFNβ).
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13
Q

are TLRs transmembrane?

A
  • Transmembrane (PM or endosomes) – detect microbes in extracellular spaces + internal
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14
Q

can TLRs recognise hosst DAMPS

A
  • Can also recognise host DAMPs - example high mobility group box-1 (HMGB-1), a host nuclear protein that can induce signalling through TLR2 and TLR4.
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15
Q

T or F

  • In general bacterial products stimulate a pro-inflammatory response (NF-kB/AP-1) and viral products an anti-viral interferon response (IRFs).
A

T

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16
Q

image

A
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17
Q

TLR image

A
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18
Q

as well as TLRs, give some other PRR examples:

A
  • C-type lectin receptors (CLR)- important in fungal infections.
  • RIG-I-like receptors (RLRs)- detect viral RNA in the cytoplasm.
  • Cytosolic NOD-like receptors (NLR)- these cytoplasmic receptors may recognise both PAMPs and DAMPs.
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19
Q
  • Mutations in which PRR are associated with Crohn’s disease, a type of Inflammatory Bowel Disease.
A
  • Mutations in NOD2 are associated with Crohn’s disease, a type of Inflammatory Bowel Disease.
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20
Q

what does NOD2 recognise?

A
  • NOD2 recognises muramyl dipeptide (found in most bacteria)
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21
Q

describe an inflammasome?

A
  • NALP3 or NLRP3 (an NLR - nod like receptor) forms part of a cytosolic inflammasome (detects lots of PAMPs/DAMPs).
  • Linked to disease such as atherosclerosis, gout and Type 2 diabetes
  • Inflammation is induced by caspase 1 activating IL-1.
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22
Q

why is caspase 1 unusual

A

bcasue its also involved in inflammation - all the others are only involed in apoptosis

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23
Q

what are DAMPS

A

usually intracellular molecules that appear in the wrong location.

released from damaged cells - often involved in sterile inflammation from necrosis

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24
Q

examples of DAMPS

A
  • Examples include proteins from chromatin (HMGB-1, high mobility group box-1) and molecules such as ATP, DNA and RNA. Extracellular matrix (ECM) components uncovered by tissue damage can also act as DAMPs as can heat shock proteins.
  • Oxidised LDL which you will see later is involved in atherosclerosis, a chronic inflammation of the arterial wall, is recognised by TLR4/TLR6.
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25
Q

what are the consequences of activated sentinal mast cells and macrophages?

A
  • Degranulate histamine
  • Syntheisze prostaglandins and leukotrienes (slow)
  • Phagocytose microbes
  • Produce cytokines (+ endogenous pyrogens – induce fever)
    o IL-6 – vascular endothelium effects + acute phase protein response
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26
Q

can mast cells be activated by neurogenic inflammation?

A

yep - in response to substance P released from nerve fibres

27
Q

recruitment of inflammatory exudate - 3 main steps

A

o Vasodilation
o Vascular permeability
o Activation of endothelium lining

28
Q

macrophage secreted cytokines:

A
29
Q

effects of IL-1β

A
  • Activates the vascular endothelium
  • activates lymphocytes
  • local tissue destruction
  • increases access of effector cells
30
Q

describe the action of TNF-α

A
  • Activates vascular endothelium
  • increases vascular permeability - leads to increased entry of IgG, complement, and cells to tissues
  • and increased fluid drainage to lymph nodes
31
Q

effects of IL-6

A
  • Lymphocyte activation
  • increased antibody production
32
Q

effects of CXCL8

A

chemotaxic factor recruits neutrophils, basophils, and T cells to sites of infection

33
Q

effects of IL-12

A
  • activates NK cells
  • induced differentiation of CD4 T cells into Th1 cells
34
Q

SYSTEMIC effects of IL-1β

A

fever

production of IL-6

35
Q

SYSTEMIC effects of TNF-α

A
  • fever
  • mobilisation of metabolites
  • shock
36
Q

SYSTEMIC effects of IL-6

A

fever

induced acute phase protein production

37
Q

4 stages of leukocytes leaveing the blood stream

A
  1. rolling (weak tethering)
  2. Tight adhesion
  3. diapedesis
  4. migration
38
Q

describe rolling (weak tethering)

A
  • Thrombin and histamine induce P-selectin expression on endothelial cells
    • P-selectin is released from intracellular stores in endothelial cells (Weibel-Palade bodies)
    • E-selectin appears 1-2 hours later, induced by cytokines (IL-1 and TNF-a) derived from tissue macrophages
  • Selectins bind to glycoprotein ligands present on the neutrophil (Sialyl-Lewis X).
  • These are low affinity interactions that easily break by the force of blood flow resulting in rolling of cells along the endothelium.
39
Q

Describe tight adhesion:

A
  • interaction between integrin family adhesion molecules (LFA-1) binding to Ig superfamily molecules, ICAMs (Intercellular Adhesion Molecules) on the endothelium
  • initially weak, but signallin thorugh chemokine receptors causes conformational changes in LFA-1 that leads to high binding affinity
40
Q

describe diapedesis

A
  • squeeze through the gaps between endothelial cells (extravasation)
  • involves interactions between LFA-1 and CD31 on the endothelial cell
  • neutrophil secretes enzymes (e.g. elastase) that degrade the basement membrane.
41
Q

describe migration

A
  • follow CXCL8 (secreted by activated macrophages) gradient to infection.
42
Q

what is Leukocyte adhesion deficiency (LAD);

A

Leukocyte adhesion deficiency (LAD); a rare immunodeficiency caused by a defect in the recruitment of neutrophils. LAD1 is caused by a defect in CD18, the b-chain subunit of LFA-1. It results in recurrent life-threatening bacterial infection in infants.

43
Q

recruitment of leukocytes picture

A
44
Q

are neutrophils long lived?

A

Neutrophils emigrate 6-24 hours. Die 24-48 hours

so no

45
Q

which is recuited first - neutrophils or monocytes?

A

neutrophils

46
Q

when are monocytes recruited?

A

Monocytes are recruited later because the interaction involving endothelial adhesion molecule (VCAM-1), which binds to monocyte integrins (VLA-4, very late antigen-4) is upregulated more slowly (24 hours).

47
Q

is TNFα good locally?

A

yep - prevent pathogens from entering the blood and spreading.

48
Q

when might TNFα be more systemic?

A

if infection is widespread, as in severe burns where there is loss of skin, infection can spread. Endotoxins such as LPS can provoke widespread TNF-a release.

49
Q

when does sepsis occur?

A

when pathogens enter the blood stream

50
Q

Sepsis occurs when pathogens enter the blood stream. Macrophages in the ____ and ___ secrete -______ into the circulation

A

Sepsis occurs when pathogens enter the blood stream. Macrophages in the liver and spleen secrete TNF-a into the circulation

51
Q

consequnces of wide spread TNF-a in the blood?

A

catastrophic as the vasodilation and movement of fluid into the tissues, triggered in part by TNF-a, contributes to loss of blood pressure, a state that can progress to septic shock and heart failure.

The released TNF-a also triggers blood clotting in the small vessels throughout the body (disseminated intravascular coagulation)

52
Q

septic shock - pictuer

A
53
Q

Septic shock has a high mortality rate.

t or F

A

T

54
Q

How does inflammation resolve?

A
  • Mediators have short half-lives – natural decline in response
  • Neutrophils short lived and die by apoptosis

Switch:

  • Macrophages stop producing inflammatory leukotrienes from arachidonic acid, the lipoxygenase system switches to producing anti-inflammatory lipoxin, a process referred to as lipid mediator class switch.
  • switch to producing anti-inflammatory cytokines such as IL- 10 and TGF-b.
    • The switch is triggered by engulfment of apoptotic neutrophils by macrophages.
55
Q

describe granulation tissue

A

Dead cells replaced with healthy cells

  1. Recruit fibroblasts to lay down extracellular matrix (ECM)
  2. Recruit endothelial cells to form new blood vessels.
  3. Remodel ECM to form strengthened scar tissue
56
Q

describe how macrophages control the repair process (4)

A
  • They phagocytose debris including RBCs, apoptotic neutrophils, dead organisms etc.
  • They recruit fibroblasts (FGF, fibroblast growth factor) which lay down new extracellular matrix (ECM)
  • They recruit endothelial cells (VEGF, vascular endothelial growth factor) to form new blood vessels
  • They secrete metalloproteinases to allow remodelling of ECM
57
Q

how do fibroblasts help in the repair process

A
  • Recruited by cytokines (FGF) produced by macrophages
  • Increase collagen synthesis
  • Produce other ECM proteins – collagen scar
58
Q

describe the process of angiogenesis in inflammation resolution

A
  • Stimulated by cytokines produced by macrophages (VEGF)
  • Drives existing capillaries to grow into damaged area

Endothelial cells:

  • break off from the basement membrane of pre-existing vessels
  • migrate to the site of injury and repair
  • proliferate and then differentiate to form a lumen
  • acquire supporting pericytes and smooth muscle to form the mature vessel.
59
Q

causes of chronic inflammation?

A
  • Injurious agent may be endogenous: e.g. stomach acid (peptic ulcer)
  • Injurious agent may be non-degradable: e.g. silica, dust particles
  • Injurious agent may evade host defences: e.g. tuberculosis
  • Host may attack self components (autoimmunity): e.g. rheumatoid arthritis
60
Q

describe fibrosis

A

Chronically activated macrophages accumulate releasing cytokines that stimulate proliferation of fibroblasts and collagen production. Scar tissue develops, a process termed fibrosis

61
Q

what is a granuloma?

A

If a pathogen cannot be killed (eg mycobacterium) – they can be walled off from the surrounding tissue

  • Core: macrophages surrounded by t cells
  • Macrophages may fuse to become multinucleate giant cells or appear as large epithelioid cells.
  • The central core is often necrotic.
62
Q

how is the adaptive immune system inducted?

A

Dendritic cells take record of organism to lymphodes to engage adaptive immune response.

63
Q

fat

A

mamba

MVST1B BOD (21 decks)

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