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Block 1 Week 5 > Cytokines/Chemokines 1 & 2 > Flashcards

Cytokines/Chemokines 1 & 2 Flashcards

1
Q

3 chemical mediators of inflammation?

A

1) lipid mediators
2) plasma proteins
3) cytokines & chemokines

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2
Q

cytokines

A
  • cyto=cell; kine=movement
  • secreted immunomodulatory proteins
  • carry signals locally between cells, and thus have an immune system effect on other cells
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3
Q

Chemokines

A
  • chemoattractant cytokines
  • are distinct from cytokines in structure & classes of receptors recognizing them
  • play critical role in efficient & target recruitment of specific immune cell populations
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4
Q

cytokines &Chemokines

A
  • have diff structure & classes of receptors that recognize them
  • some functions do overlap though
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5
Q

Chemokines and cytokines functions?

A
  • recruit cells to site of injury/infections
  • activate specific pathway for differnetiation/activation in response to injury/infection
  • help macrophages/dendrites find lymph node
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6
Q

describe the kinetics (timing) of the inflamamtory response to microbial infection?

A
  • inflammation, things happen in specific time zones
  • controlled by specific chemokines & cytokines expressed
  • see inflamm response is a regulated, choreographed dance
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7
Q

What controls what Chemokines and cytokines are expressed?

A
  • the signals sent by PAMPs/DAMPs/other inflamm receptors in respond to cell stress, injury, or pathogen
  • the type of activating event will determine which chemokines & cytokines are released
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8
Q

What are Chemokines?

1) size
2) function

A
  • chemoattractants for specific leukocyte subsets

- very small 8-10KD

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9
Q

Chemokines in healthy homeostasis?

A
  • CCL21 chemokine is heavily expressed in lymph nodes; naive T cells are attracted them
  • this signal retains naive T cells in the lymph node
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10
Q

Chemokines in early innate immune response?

A
  • CCL2 chemokine produced in damaged tissue (receptor= CCR2)
  • recruits macrophages & neutrophils to tissue
  • shows how diff chemokines recruits diff types of cells*
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11
Q

vascular permeability & chemokines?

A
  • chemokines regulate vascular permeability by only attracting specific leukocytes into the tissue
  • if not being signaled, then the cell will not move into the tissue
  • is how make vascular permeability more tightly regulated
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12
Q

autoimmunity & chemokines?

A
  • inappropriate induction of specific chemokines causes inappropriate recruitment of activated immune cells to the site of abnormal chemokines expression
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13
Q

how else can chemokines stimulate specific immune cells?

A
  • in a receptor specific manner

- can lead to proliferation & activation of specific immune cells

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14
Q

How do chemokines act?

A
  • through binding G-protein coupled receptors on leukocytes (very diff than how cytokines act)
  • pathogens that interfere/impair GPCR can effect chemokine signaling
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15
Q

2 ways chemokines bind GPCR

A

1) tethered presentation: bind extracellular matrix of cell that produced it; is anchored to parent cell & then bind GPCR of leukocyte to activate it
2) secreted: are soluble can be secreted by parent cell, diffuse away and bind GPCR of distant leukocyte

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16
Q

tethered presentation of chemokines?

A
  • chemokine receptor expressing cells can be recruited to specific sites by the tethered presentation of the recruiting chemokine to it’s parent cell
  • is how can recruit leukocytes to specific tissue
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17
Q

different classes of chemokines?

A

-target different classes of immune cells & promote different types of inflammatory response

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18
Q

CXC chemokines? what do they target

A
  • alpha chemokines
  • have 1 AA residue separating first two conserved cysteine residues
  • targeted to neutrophils than to other immune cells
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19
Q

number of X’s tell you?

A
  • number of X’s (0-3) tells you how many amino acids away the two conserved cysteines are from eachother
  • have structure-function relationship, CXC’s bind similar receptors & have similar functions; CXXC’s bind similar receptors & have similar functions
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20
Q

exception to CXC family?

A
  • CXCL13
  • this chemokine involved with lymphocyte homing, attracts B cells & makes B cell follicles
  • doesn’t attract not neutrophils
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21
Q

CC chemokines

A
  • Beta chemokines
  • have first two conserved cysteine residues directly adjacent (no amino acids in between)
  • many produced by monocytes
  • not chemoattractant for neutrophils
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22
Q

CCL11 chemokines?

A
  • is Eotaxin

- specifically recruits eosinophils

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23
Q

C chemokines

A
  • Gamma chemokines
  • lack 1st & 3rd cysteines
  • tend to be chemoattractant for specific lymphocyte subsets
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24
Q

CXXXC chemokines?

A

-CX3CL1 is the only member & only example of a chemokine that’s cleaved from the cell surface

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25
Q

What recruits expression of specific chemokine? What happens after?

A
  • PAMPs + DAMPs induce expression of specific chemokines

- the specific chemokines recruit immune cells & cytokines to the vicinity of injury/infection

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26
Q

PAMPs

A
  • anything bacteria has that humans do not
  • have unique PAMP receptor for each one, depending on which is activated, leads to different activations of cytokines
    ex: flagella, proteoglycan etc
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27
Q

DAMPs

A
  • receptors for anything that is chemically abnormal in the host cells
  • ex: high ATP (indicate cell lysis)
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28
Q

do chemokines make covalent bonds with ECM of leukocytes as they are secreted?

A

-no; are not covalent bonds, just stuck on the leukocyte

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29
Q

What is the receptor for CCL2? What does CCL2 and receptor do? Where are they expressed?

A
  • CCL2 is chemokine produced in damaged tissues & expressed on damaged epithelia’s extracellular matrix
  • CCR2 is expressed on monocytes/ other leukocytes
  • attracts them to site of injury/pathogen
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30
Q

Foam cell?

A

macrophage full of phagocytosed debris

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31
Q

Two ways CCL2 chemokine is secreted?

A

1) produced in damaged tissues & expressed on damaged epithelia’s extracellular matrix
2) by activated Foam cells (macrophages that are full of phagocytosed debris)

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32
Q

How is adaptive immune response activated?

A

-coordinated by regulating both expression of chemokines & expression of the chemokine receptors

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33
Q

5 steps in chemokine activation of adaptive immune response

A

1) CCL21 high expressed in lymph node (LN)
2) Naïve T cells express receptor for CCL21 (CCR7); move to LN from thymus
3) Activated dendritic cells carrying antigen express CCR7; run to LN cuz drawn to it’s CCL21 expression
4) Mature (activated) dendritic cells present antigen to naïve T-cells in LN
5) Activated effector T cells down-regulate CCR7 & leave LN cuz they are no longer retained in the lymph node by CCL21

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34
Q

-why can activated effector T cells leave lymph nodes once activated?

A
  • their activation causes a down regulation of CCR7

- without CCR7, they can no longer “see” CCL21 in lymph node so have no reason to stay

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35
Q

How do activated effector T cells get to other tissues after leaving LN?

A

-activation causes other chemokine receptor production which draw them to damaged tisses

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36
Q

What are Naïve T cells?

A

-antigen-inexperienced T cells, have never seen antigen before

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37
Q

CCL21?

A

-chemokine expressed highly in lymph nodes that attracts naive T-cells as well as activated (antigen carrying) dendrites/macrophages

38
Q

CCL21 receptor?

A
  • CCR7

- naive T cells & ctivated (antigen carrying) dendrites/macrophages contain this receptor

39
Q

When do dendrites/macrophages present CCR7 receptor?

A
  • only after their PAMP/DAMP/ other receptors are activating signaling damage or pathogenicity
  • when bind to antigen, is activated & CCR7 can be expressed on surface
40
Q

Inappropriate expression of chemokines and/or receptors leads to?

A
  • associated with specific inflammatory diseases

ex: rheumatoid arthritis, MS

41
Q

Chemokine Receptor Antagonists for therapeutics?

A
  • in current trials as therapies for chronic inflammatory & autoimmune disorders as well as lymphomas
  • no break out chemokine based therapies yet though
42
Q

why no “break-out” chemokine based therapies?

A
  • chemokines participate in a wide variety of functions (from development, normal function, tissue defense & repair)
  • it’s difficult to target a disease’s specific process
43
Q

How are GPCR receptors for chemokines organized?

A
  • by they action/consequence

- ex: inflammatory, homeostatic, atypical, viral

44
Q

What are cytokines?

A
  • cell derived factors
  • small soluble molecules (~25KD); larger than chemokines
  • can exist as monomer or multimer; can function alone or as trimer
45
Q

how are cytokine actions mediated?

A
  • via specific receptors.
  • have both autocrine & paracrine actions
  • have some systemic actions
46
Q

Autocrine actions

A
  • regulating self behavior

- the action is on cell the producing the cytokine

47
Q

Paracrine

A
  • regulating adjacent cells
  • the action is on cells in the vicinity of the cell that is producing the cytokine
  • ex:
48
Q

cytokine systemic actions?

A
  • yes, some

- effects of TNF, IL-6 & IL-1 on liver’s production of chemical mediators of inflammation (CRP etc)

49
Q

What determines which cytokine is made?

A
  • the immune & tissue cells produce cytokines in response to cell damage or the presence of pathogens
  • which cytokine made depends on which receptor was bound & activated, and how much of the signal was received (PAMP, DAMP etc)
50
Q

3 steps of cytokine release & effects on. macrophage?

A

1) Bacteria bind macrophage & triggers to cleanse cytokines& chemokines
2) vasodilation & increased vascular permeability cause redness, heat & swelling
3) inflammatory cells migrate into tissue, releasing inflammatory mediators that cause pain

51
Q

cytokine structure?

A
  • cytokines are structurally diverse (diff than chemokines)

- initially classified into interleukin families (ILs)

52
Q

Cytokines receptors?

A
  • cytokine actions mediated by Jak/Stat receptors
  • NOT GPCR (chemokines use GPCR)
  • cytokine receptors are activated by dimerization
53
Q

Intracellular signaling pathways of cytokines & chemokines?

A
  • they differ
  • chemokines= GPCR
  • cytokines= Jack/Stat
54
Q

Jack/Stat overview?

A

1) cytokine receptor consists of 2 chains; the cytoplasmic domains bind JAK kinase
2) cytokine bind, dimerize receptor, cytoplasmic domains JAK activate eachother & phosphorylate receptor (cross-phosph)
3) Trxn factors (STAT) bind to phosphorylated receptor, are phosph. & activated by JAKs
4) phosph. STAts forom dimers, translocate unit nucleus & imitate new gene trxn

55
Q

Which are easier to therapeutically target; JAK/STAT or GPCR?

A
  • JAK/STAT

- means cytokine pathway is easier to target

56
Q

What are the 3 modes of cytokine action?

A

1) Global
2) Local
3) Final (net) effects)

57
Q

Global cytokine action?

A
  • behavioral responses and systemic immune responses

- have literal effect on our personality/behavior

58
Q

Local actions of cytokines?

A

-regulating differentiation of lymphocytes, antigen- presenting cells and innate immune cells

59
Q

Final (net) effect actions of cytokines?

A
  • Based on the ratio & concentrations of specific cytokines present
  • tell concentration by seeing on how much signal transduction signals are coming from the receptors
  • is how tailer & adapt our immune response
60
Q

What are the 4 cytokines released from an activated macrophage?

A

1) IL-1B
2) TNF-a
4) IL-6
5) IL-12

61
Q

IL-1B local effects? (x4)

A

1) activates vascular endothelium
2) activates lymphocytes
3) local tissue destruction
4) increases access of effector cells

62
Q

IL-1B systemic effects? (x2)

A

1) fever

2) production of IL-6

63
Q

TNF-a local effects? (x3)

A

1) activates vascular endothelium
2) increases vascular permeability, which allows increased IgG entry, increase cells into tissue, increased fluid drainage into lymph nodes
3) activates complement

64
Q

TNF-a systemic effects? (x2)

A

1) fever
2) mobilization of metabolites
3) shock

65
Q

IL-6 local effects? (x2)

A

1) lymphocyte activation

2) increased antibody production

66
Q

IL-6-a systemic effects? (x2)

A

1) fever

2) induces acute-phase protein production

67
Q

IL-12 local effects? (X2)

A

1) activates NK cells

2) induces differentiation of CD4 T cells into TH1 cells

68
Q

cytokines & programmed sickness behavior?

A

-Cytokines shape a coordinated inflammatory response that includes programmed “sickness behavior”

69
Q

what is sickness behavior? what causes it?

A
  • anorexa, lethargy, slow-wave sleep, decreased social behavior, decreased reproductive behavior
  • due to IL-1B, IL-6, TNF-a acting on brain as a result of a pathogen binding a macrophage
70
Q

why is sickness behavior a good thing evolutionarily? From a biology standpoint?

A

1) are weak, don’t want to be around others who can kill you
- isolate self until healed; protecting own gene pool

2) it promotes conservation of resources w/ generation of toxic env for the invading pathogen

71
Q

Why sickness behavior include anorexia?

A

-if don’t eat, blood isn’t full of metabolites for the pathogen, make pathogen work harder for materials

72
Q

Fever importance?

A
  • fever means you’re hot, means metabolism is faster
    & require more energy to do the same work
    -increased protein denaturation/lifespan
    -hopefully both cause death of pathogen
73
Q

side effects of certain cytokine inhibitors?

A

-certain inhibitors can cause depression and other symptoms cuz are blocking the healthy actions of cytokines on the brain

74
Q

IL-1, IL-6, and TNF-a act on what tissues during sickness behavior?

A

1) liver
2) bone marrow epithelium
3) hypothalamus
4) fat/muscle
5) dendrtic cells

75
Q

What determines the final effector function of antigen-activated T cells?

A

-Cytokines produced by antigen-presenting cells
(dendrites, macrophages, B cells)

-all are the same CD4 T cells; depending on PAMP/DAMp determines pathway/end result

76
Q

TGF beta (alone) effect on CD4 T cell?

A
  • made in high levels in brain, ovaries, testes
  • makes Treg cells
  • Treg cells cause increased production of TGF-B as well as IL-10 ( anti-inflamm cytokine)
77
Q

IL-10

A

-anti-inflamm cytokine produced by T reg cell

78
Q

TGF-Beta + IL-6?

A
  • IL-6 made by innate cells, TGF-B in brain, ovaries, testes
  • makes CD4 T cell–> TH-17
  • TH-17 makes IL-6 & IL-17 which both activate more neutrophils
  • indicates in early part of immunity
79
Q

IL-12+ IFN-gamma effect on CD4 T-cell?

A
  • turns it into TH 1 cell
  • TH1 cell releases: IL-2 & IFN-gamma
  • increases T cell proliferation, IFN-super killers, ROS species
80
Q

IL-4 cytokine effect on CD4 T cell?

A
  • makes CD4 into TH2 cells
  • produce IL-4 & IL-5 cytokines
  • both help make antibodies & fight parasites
81
Q

IL-4 & IL-5

A

-help make antibodies & fight parasites

82
Q

How does body determine stage & pathogen specific immune responses?

A
  • cytokines produced vary by the severity and type of infection/tissue damage
  • this help to determine severity- and pathogen- specific immune responses
83
Q

cytokines & innate immune response? good or bad?

A
  • Cytokine expression can amplify innate immune responses

- if amplifies locally this is good; but if causes a systemic amplification is bad & can lead to septic shock

84
Q

How does sepsis happen?

A

-when the inflamm response is worse than the pathogen

85
Q

Explain how an over response of immune system could happen in response to a hand infection to gram - bacteria?

A

1) macrophages activated in liver & spleen to secret TNF-Alpha into bloodstream
2) systemic edema occurs
3) decreased blood volume causes collapse of blood vessels
4) disseminated intravascular coagulation leading to wasting & multiple organ failure
5) death

86
Q

What does systemic edema cause?

A

1) decreased blood volume
2) hyperpoteinemia
3) neutropenia
4) neutrophilia

87
Q

Explain how a correct response of immune system could happen in response to a hand infection to gram - bacteria?

A

1) macrophages activated to secrete TNF-alpha locally in tissue
2) increase: release of plasma protein into tissue. phagocyte & lymphocyte migration into tissue
3) phagocytosis of bacteria; local vessel occlusion, plasma + cells drain to lymph node
4) removal of infection w/ adaptive immunity

88
Q

therapies to block cytokines?

A
  • yes
  • have anti-TNF therapies to treat Rheumatoid arthritis & Psoriasis
  • but are not first line of defense
89
Q

why are anti-TNF not our first line therapies for all chronic inflammatory diseases?

A
  • TNF is required for normal pathogen defense

- w/o TNF you are immunodeficient so on these anti-TNF meds your risk for infection is huge

90
Q

issues with anti-TNF therapies and the brain?

A
  • TNF promotes proliferation of myelinating cells & remyelination during demyelinating diseases (MS)
  • Anti-TNF therapies associated w/ increased demyelination & nerve damage in individuals with diagnosed (and previously undiagnosed) CNS diseases

Block 1 Week 5 (8 decks)

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