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Fundamental Immunology > Granuolyctes - Block C lecture 2 > Flashcards

Granuolyctes - Block C lecture 2 Flashcards

1
Q

when can mast cells have bad effects ?

A

Can have ‘bad effects’ - effector cells are involved in allergy, asthma and hay fever

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2
Q

when can mast cells have protective qualities ?

A

They can be used protective against bacteria and large pathogens e.g. gut helminths

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3
Q

what are mast cells released from ?

A

Released from the bone marrow as undifferentiated cells - human CD34+, KIT+, CD13+ cells. Type of cell surface receptors present are the CD34 e.t.c.

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4
Q

what do these cells differentiate into ?

A

differentiate in tissues e.g. skin, connective tissue, epithelial tissue

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5
Q

what is the mast cell development influenced by ?

A

development influenced by stem cell factor acts on the receptor KIT and cytokines e.g. IL-3 in rodents .

Stem cell factor is an important mast cell growth factor and increased in the intestine during bacterial infection

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6
Q

what are ETS ?

A

Have ability to form ETS (extracellular nets) – made of DNA, histones, tryptase – trap bacteria. These keep the bacteria localised at the site.

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7
Q

on referring to cell size , what is larger a resting mast cell or activate mast cell?

A

Activated mast cells are larger than resting.

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8
Q

are mast cells long or short lived ?

A

involved in allergic responses - long lived up to months-years

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9
Q

role of mast cells in immune response ?

A

can mount an effective inflammatory response at site of infection - very effective defence against bacteria

Show this as mast cell deficient mice are more susceptible to bacterial infections

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10
Q

what are the 2 types of mast cells ?

A
  • ‘mucosal-type’ e.g. gut mucosa - 40 day life span
  • ‘connective-tissue type’ – skin or peritoneal cavity - > 6 month life span

human mast cells: MCT or MCTC based on enzymes present

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11
Q

MCT ?

A

tryptase containing – mainly airway and small bowel submucosa

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12
Q

MCtC ?

A

MCTC - tryptase and chymase – mainly skin and small bowel mucosa

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13
Q

what are their activity regulated by ?

A

activity regulated by cytokines: IL-3, IL-4, IL-5, IL-9, IL-10, GM-CSF receptors present

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14
Q

IFN gamma and mast cells ?

A

reduces mast cell numbers

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15
Q

IL-4 ?

A

IL-4 promotes their proliferation in presence of stem cell factor

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16
Q

What Th response favours the mast cell production ?

A

Th2 response favours the mast cell production

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17
Q

what do mast cells release ?

A

Histamine

Protesases

Proteoglycans

LTB4 and LTC4

PGD2 and PAF

Cytokines

Superoxidase dismutase

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18
Q

mast cells and IgE receptors ?

A

Mast cells contain IgE receptors on their surface , when the IgE binds , cross linking can occur and as a result the mast cell degranulates this occur in seconds and releases products such as histamine, TNF alpha , tryptase , chymase and amines.

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19
Q

eicosanoids release ?

A

this can occur in minutes and eicosanoids are produced such as leukotrienes and prostaglandins.

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20
Q

cytokines , chemokines and growth factor released ?

A

Cytokines , chemokines and growth factors are released in hours and include TNF alpha , IL-4 , IL-5 , IL-6 , IL-13 , IL-17 and VEGF.

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21
Q

what organisms can activate the mast cell and how do they evade detection ?

A

nematodes , salmonella , toxoplasma and commercial bacteria. They can also release products that suppress the mast cell degranulation as a mechanism to evade destruction.

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22
Q

role of tryptase activating ?

A

tryptase is an activating molecule , it acts on mast cells through the use of PAR-2 receptor.

Angiogenesis is the formation of blood cells.

Activates cytokines such as MCP-1 and IL-8 from endothethial cells

Activates nerves and keratinocytes through PAR-2

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23
Q

inhibitory effect of tryptase ?

A

cleavage of eotaxin and RANTES

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24
Q

explain activation of Mast cells through opsonised pathogen ?

A

Antibodies - have a FceR1 for IgE and FcgRIIb (unactivated) and FcgRI (IFN-g activated) for IgG dependent mechanisms

Complement coated pathogens – CR3a and C5a receptors

Mice deficient in C3b receptor have an impaired mast cell activation and neutrophil recruitment which is more susceptible to bacterial infections.

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25
Q

Pathogen recognition receptors ?

A

Lectins on pathogen which bind to mannosylated mast cell receptor, TLR1-7 and TLR9

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26
Q

host molecules ?

A

Host molecules e.g. subfragments of fibrinogen/fibronectin are produced by cleavage of plasmin

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27
Q

what is the action ?

A

Secrete products: influence immune response/cells present locally.

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28
Q

how are these mediators synthesised ?

A

Preformed mediators or synthesised de novo mediators ( make new) - release substances either slowly from granule chambers (piecemeal) or explosively (anaphylactically) - where co-ordinated release

29
Q

cytokines ?

A

TNF-alpha, TGF-beta, IL-1-alpha, IL-1-beta, IL-5, IL-6, IL-13, IL-16, IL-18

30
Q

chemokines ?

A

IL-8 (CXCL8), I-309 (CCL1), MCP-1 (CCL2), MIP-1 alphaS (CCL3), MIP-1-beta (CCL4), MCP-3 (CCL7), RANTES (CCL5), eotaxin (CCL11), MCAF (MCP-1)

31
Q

growth factors

A

CF, M-CSF, GM-CSF, beta FGF, VEGF, NGF, PDGF

32
Q

secreated preformed mediators ?

A

histamine, TNF alpha, beta-glucuronidase, serine proteases, carboxypetidase A, proteoglycans (heparin and chondroitin), acid hydrolases, peroxidase, phospholipases, eosinophilic chemotactic factor, cytokines - Mast cell proteases - 25% of mast cell protein content

33
Q

direct toxicity via granules produced ?

A

TNF alpha is directly toxic to cells/pathogens

34
Q

phagocytosis ?

A

Phagocytosis can occur , it isn’t their most important role but can occur and produce a respiratory burst – number of cells small compared to professional phagocytes - antigen presenting cells - through MHC class I pathway - stimulate Tc cells

35
Q

effector histmaine ?

A

histamine which is a potent vasodilator to increases blood flow and vascular permeability – facilitates arrival of inflammatory cells/antibodies to site of infection - 2.4-7.8pg/106 cell.

36
Q

leukotriene B4 ?

A

leukotriene B4 - chemotactic factor (nanomolar conc) to neutrophils and eosinophils this is shown as leukotriene KO mice more susceptible to bacterial infection

37
Q

tryptase ?

A

Tryptase – function in vivo not defined, can cleave C3 to C3a and activate fibroblasts

38
Q

tryptase and prostaglandin togeher ?

A

tryptase and prostaglandin together D2 – induces neutrophil influx

39
Q

prostaglandins ?

A

tryptase and prostaglandin together D2 – induces neutrophil influx

40
Q

how do they stimulate macrophages ?

A

Stimulate macrophages by producing macrophage inflammatory protein 1 a - (MIP 1 a, MIP 1 b, MIP 2) monocyte chemoattractant protein.

41
Q

TNF alpha ?

A

TNF a - major cytokine produced and is directly toxic it upregulates adhesion molecules and increases bronchoresponsiveness

42
Q

IL-4 ?

A

IL-4 – effects differentiation of Th cells to Th2 cells and this stimulates IgE production involved in helminths protection

43
Q

APC ?

A

antigen presenting cells - through MHC class I pathway - stimulate Tc cells

44
Q

what were the mast cell defiecent mice experiment ?

A

defective c-KIT protein (receptor for stem cell factor) - e.g . one strain called W/Wv mice

infect wild type and W/Wv mice with a gram-negative bacteria

Outcome

wild type 0% mortality

W/Wv mice ( mass cell deficient)80% mortality

Show:

5x less neutrophils in W/Wv mice (KO mice)

Early recruitment of neutrophils is important for bacterial control

Wild type - burst in TNF alpha before neutrophils arrival early on in the control.

45
Q

why is there no effect in WT mcie ?

A

The WT mice already produce TNF alpha so no effect, the KO mice do not produce TNF alpha so injecting will increase their surviva

46
Q

anti TNF ?

A

Anti TNF will decrease survival in WT as mop up TNF produced. However, no effect in KO mice as they don’t produce any so no effect

47
Q

eosinophils ?

A

1-3% of circulating leucocytes

Phagocytic – not main job but can carry it out

preferentially home to gastrointestinal tract during embryonic development

mainly found in the gut and lungs – found in blood but mainly found it tissue

involved in protection against gut/lung infections

can cause adverse effects – e.g. involved in asthma

Can generate a respiratory burst and high levels of NAPDH oxidase at cell surface and produce extracellular superoxide

important in antigen presentation – have MHC Class II molecules and co-stimulatory molecules – present antigen to T helper cells - transfer

Make extracellular traps – explosive - mitochondrial DNA

48
Q

role of eosinophils ?

A

Involved in the developmental functions

Metabolic homeostasis

B cell development/maintenance

Cell to cell interaction involving cytokines

Immune polarisation

Tissue repair/remodelling

49
Q

are eosinophils cytotoxic ?

A

They are cytotoxic as they produce granules that are cytotoxic. They can also trap mitochondrial DNA , produce respiratory bursts , nitric oxide release.

50
Q

are eosinophils inflammatory ?

A

The are pro inflammatory as they attract other cells into the site of infection

51
Q

immunoregulatory ?

A

Immunoregulatory as they act on T cell , B cells and dendritic cells.

52
Q

where do they develop

A

They develop in the bone marrow then enter tissues, after being acted on by chemokines.

53
Q

Eotaxin and adhesion molecules ?

A

Eotaxin is a chemoattractant that pulls it into the tissues. Then the adhesion molecules like ICAM1 , MAdCAM1 and VCAM 1 also aid the tissue migration.

Direct effect

54
Q

direct effect ?

A

Important in defense against gut helminths

Important against viral infection e.g. respiratory syncytial virus

55
Q

indirect effect ?

A

Tissue remodeling

Immunomulation

Defense against reinfection - memory development – present antigen

56
Q

activation through opsonin

A

antibody – receptors for IgG (FcgRII) and IgA (FcaRI) and IgE (FceRI, low)

  • activated cells in vitro by exposure to agarose beads coated with IgG or Ig. IgA being the most potent as more receptors for IgA
57
Q

complement ?

A

eceptors for C3a, C5a, CR1

58
Q

do cytokines activate ?

A

cytokines – receptors for IL-3, IL-5, GM-CSF

59
Q

chemokine ?

A

chemokine receptors

60
Q

Tol like receptor?

A
  1. Toll receptors ( PRR) – express TLR1, TLR4, TLR7, TLR9 and TLR10 – TLR7 and TLR8 may be more impt.
61
Q

4 types of granule product ?

A

crystalloid
primary
small
secretatory

62
Q

crystalloid granule ?

A

Crystalloid granules all the contents are cytotoxic

Core:major basic protein (5-10pg/cell)

63
Q

eosinophil basic ?

A

eosinophil basic protein - causes degranulation of mast cells and basophils – toxic to parasites in vitro e.g. helminths

64
Q

major basic protein ?

A

major basic protein - increases membrane permeability, effects lipid-cell surface bilayer

65
Q

eosinophil cationic protein

A

eosinophil cationic protein – causes formation of selective ion pores – inside leaks out and inside leaks into cell.

66
Q

eosinophil derived neurotoxin

A

directly toxic.

67
Q

eosinophil peroxidase ?

A

eosinophil peroxidase - involved in bacterial killing it catalyses peroxidation of halides to get the formation of acids e.g. hypobromous acid

68
Q

basophils ?

A

Important granulocyte which is present in tissues

69
Q

3 ways to activate complement pathway ?

A

classical , alternative and lectin

Fundamental Immunology (11 decks)

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