First Aid, Chapter 1 Immune Mechanisms, Cytokines, Chemokines, and their receptors Flashcards

1
Q

What is the source of TNF?

A
  • Activated mononuclear phagocytes
  • Antigen-stimulated T cells
  • NK cells
  • Mast cells
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2
Q

What is the stimulus of TNF? What is its synthesis augmented by?

A
  • Most potent stimulus is TLR engagement with LPS and other microbial products
  • Synthesis augmented by IFNγ
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3
Q

What are the receptors of TNF? What does binding to each receptor cause?

A

Two types: Type I TNF and type II TNF

  • Binding to TNF-RII leads to recruitment of TRAFs to cytoplasmic domains, activating transcription factors (NFκB, and AP-1)
  • Binding of TNF-RI leads to apoptosis via caspase 8
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4
Q

What are the actions of TNF?

A
  • Mediates the acute inflammatory response to infectious microbes (ESP gram negative rods)
  • Stimulates the recruitment of neutrophils and monocytes to sites of infection
  • Induces vascular endothelial cells to express adhesion molecules
  • Stimulates endothelial cells and macrophages to induce leukocyte chemotaxis and recruitment
  • Acts on mononuclear phagocytes to stimulate IL-1 secretion
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5
Q

What are the two forms of IL-1?

A

IL1α and IL-1β

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6
Q

What is the source of IL-1?

A
  • Activated mononuclear phagocytes
  • Neutrophils
  • Epithelial cells
  • Endothelial cells
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7
Q

What induces production of IL-1?

A

Production is induced by bacterial products, such as LPS and other cytokines (TNF)

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8
Q

What are the receptors of IL-1 and what does binding to them cause?

A

Binding to type I IL-I R leads to Myd88 recruitment to the TIR domain and protein kinases (IRAK4, IRAK1 and TRAF6), leading to activation of NFκB.

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9
Q

What are the actions of IL-1?

A
  • Low concentrations: Mediates local inflammation and acts on endothelial cells to increase expression of surface molecules that mediate leukocyte adhesion
  • Larger quantities: Induce fever and the synthesis of acute phase reactants by the liver (via IL-6 production), and neutrophil and platelet production by the bone marrow
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10
Q

What is IL-12 made of?

A

Made of p35 and p40 subunits

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11
Q

What is the source of IL-12? What stimulates its production?

A
  • Activated dendritic cells
  • Macrophages
  • Produced in response to TLR signaling induced by many microbial stimuli
  • Stimulated by IFNγ from NK cells or T lymphocytes CD40L/CD40 interaction on macrophages and dendritic cells
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12
Q

What are the receptors for IL-12 and what does binding to them cause?

A

Type I receptor family, composed of β1 and β2 subunits p35 binds to β2 receptor, leading to Jak 2 → STAT4 p40 binds to β1 receptor, leading to Tyk 2 → STAT4

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13
Q

What are the actions of IL-12?

A
  • Stimulates production of IFNγ by NK cells and T lymphocytes
  • Promotes differentiation of CD4 helper T lymphocytes into IFNγ producing TH1 cells
  • Enhances cytotoxicity of NK cells and CD8 cells
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14
Q

What is IL-1B cleaved by?

A

Caspase-1

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15
Q

What does caspase-1 require activation by? What do mutations in this cause?

A

a complex of proteins, including NALP. Gain-offunction mutations of NALP lead to uncontrolled IL-1 production and autoinflammatory syndromes.

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16
Q

What is IL-1ra? What is it made by? What is its commercial name? What is it used for?

A

IL-1ra is a competitive inhibitor of IL-1 made by mononuclear phagocytes. It is available commercially (Anakinra) to treat autoinflammatory syndromes

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17
Q

What do mutations in IL-12B1 cause?

A

Patients with mutations in the IL-12 Rβ1 are susceptible to infections with intracellular bacteria notably Salmonella and atypical mycobacteria.

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18
Q

What does IRAK-4 deficiency cause?

A

IRAK-4 deficiency leads to susceptibility to pyogenic infections, especially with Streptococcus pneumoniae.

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19
Q

What are the sources of type 1 interferons?

A

IFNα: Plasmacytoid dendritic cells and mononuclear phagocytes IFN β: Produced by many cells, including fibroblasts

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20
Q

What stimulates type 1 interferons?

A

Most potent stimulus is viral nucleic acids

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21
Q

What is the receptor for type 1 interferon? What does binding to the receptor cause?

A

Type II cytokine receptor family IFNAR1/Tyk2 and IFNAR2/Jak1, leading to STAT1 and STAT2 phosphorylation and recruitment of IRF9

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22
Q

What are the actions of type 1 interferons?

A
  • Inhibit viral replication, thereby eradicating viral infections
  • Increase expression of class I MHC molecules;
  • Stimulate development of Th1 cells
  • Promote sequestration of lymphocytes in lymph nodes
  • Inhibit proliferation of many cell types
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23
Q

What is the source of IL-10?

A

Macrophages

Regulatory T cells

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24
Q

What is the receptor of IL-10?

A

Type II cytokine receptor family, Jak1 and Tyk2; Janus family kinases, which induce STAT3 signaling molecule

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25
Q

What is the action of IL-10?

A
  • Inhibits production of IL12 by activated macrophages and dendritic cells
  • Inhibits expression on costimulators, and class II molecules on macrophages and dendritic cells
  • Inhibits costimulatory receptors
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26
Q

What is the source of IL-6?

A

Mononuclear phagocytes Vascular endothelial cells Fibroblasts

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27
Q

What stimulates IL-6 production?

A

Produced in response to IL-1 and TNF

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28
Q

What is the receptor for IL-6? What is the signalling pathway?

A

Type I cytokine receptor family Signaling pathway involves Jak1 and STAT3 activation

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29
Q

What are the actions of IL-6?

A
  • Stimulates synthesis of acute phase protein by hepatocytes
  • Stimulates production of neutrophils from bone marrow progenitors
  • Stimulates growth of B lymphocytes that have differentiated into antibody producers
  • Growth factor for neoplastic plasma cells (myelomas)
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30
Q

What is the source of IL-15? In response to what?

A

Mononuclear phagocytes in response to viral infection and LPS

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31
Q

What signalling pathway does IL-15 activate?

A

Activates Jak3, STAT5 and Akt-dependent signaling pathways

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32
Q

What are the actions of IL-15?

A
  • Survival of memory CD8 T lymphocytes, NK cells, and NK-T cells
  • Required for NK cell differentiation and activation
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33
Q

What is the source of IL-18? What is production dependent on?

A

Macrophages
Dendritic cells.

Production is dependent on caspase-1

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34
Q

What is the receptor of IL-18 and what does it signal through?

A

IL-1 or TLR family signals through TIR domain that recruits IRAK and TRAF, leading to activation of NFκB and AP-1 transcription factors

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35
Q

What are the actions of IL-18?

A

Enhances IFNγ production by T lymphocytes Promotes differentiation of IFNγ, producing Th1 CD4 cells

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36
Q

What cytokine is IL-18 synergistic with?

A

IL-12

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37
Q

What are the sources of IL-23? What does production depend on?

A

Macrophages and dendritic cells in response to microbial infection Production depends on caspase-1 (similar to IL-1)

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38
Q

Where is the receptor of IL-23? Describe the receptor.

A

On T lymphocytes and NK cells

IL-23R is a heterodimer of a unique IL-23R chain and the IL12Rβ1 chain

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39
Q

What are the actions of IL-23?

A
  • Contributes to inflammation in autoimmunity
  • Important for resistance to Klebsiella pneumoniae
  • Promotes differentiation and maintenance of T lymphocytes that produce IL-17
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40
Q

What are the sources of IL-27?

A

Macrophages

Dendritic cells

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41
Q

Describe the IL-27 receptor? Where is it expressed?

A
  • IL-27R composed of IL-6 gp30 subunit and a second homologous chain
  • Expressed on resting NK cells and NK-T lymphocytes, effector and memory T lymphocytes, and regulatory T lymphocytes
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42
Q

What are the actions of IL-27?

A
  • Promotes ThI differentiation
  • Promotes IFNγ production by T lymphocytes
  • Role in controlling ongoing Tlymphocyte responses
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43
Q

Which receptors contain γc? What is the clinical significance?

A

Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL21 contain γc, which is affected in X-linked SCID.

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44
Q

Name the cytokines that mediate and regulate innate immunity?

A

TNF, IL-1, IL-12, Type 1 interferons, IL-10, IL-6, IL-15, IL-18, IL-23, IL-27

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45
Q

Name the cytokines that mediate and regulate adaptive immunity?

A

IL-2, IL-4, IL-5, IL-13, IFNγ, TGFβ(1), Lymphotoxin, IL-21, BAFF, APRIL

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46
Q

What is the source of IL-2?

A

Mainly CD4 T lymphocytes (8–12 hr after activation)

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47
Q

Describe the receptor for IL-2? What is the pathway it triggers?

A
  • IL-2R (composed of 3 proteins:IL-2Rα, IL2/15Rβ, γc)

- Engages Jak3-STAT5 signal transduction pathways

48
Q

What are the actions of IL-2?

A
  • Required for survival and function of Treg cells
  • Stimulates the survival, proliferation, and differentiation of antigen-activated T lymphocytes
  • Promotes the proliferation and differentiation of NK cells
  • Induces expression of Bcl-2 (anti-apoptotic protein)
49
Q

What is the source of IL-4?

A

Th2 CD4 T lymphocytes Activated mast cells

50
Q

What is the receptor for IL-4? What is the pathway that it signals through?

A
  • Type I cytokine receptor family

- IL-4Rαγc signals through the Jak-STAT pathway (STAT6).

51
Q

What are the actions of IL-4?

A
  • Th2 differentiation Inhibition of Th1 and Th17 cell development
  • B lymphocyte switching to IgE
  • Acts on macrophages with IL-13 to induce arginase induction, leading to collagen production and increased mannose receptor expression, which promotes phagocytosis of microbes
52
Q

Which cytokines share a common beta chain?

A

The receptors IL-3, IL-5, and granulocyte-monocyte colony-stimulating factor (GMCSF) share a common β chain.

53
Q

What is the source of IL-5?

A

Th2 CD4 T lymphocytes Activated mast cells

54
Q

What are the receptors for IL-5 and what signalling pathway do they induce?

A

IL-5Rα and IL-5Rβc heterodimer induces Jak2 and STAT 3 signaling pathway

55
Q

What are the actions of IL-5?

A
  • Activates immature eosinophils, and stimulates growth and differentiation of eosinophils
  • Stimulates the proliferation of B lymphocytes and production of IgA antibodies
56
Q

What is the source of IL-13?

A

Th2 CD4 T lymphocytes CD8 T lymphocytes
NK T lymphocytes
Basophils
EosinophilS

57
Q

What are the receptors for IL-13?

A

IL-4Rα and IL-13Rα1 heterodimer Binds to IL-4 and IL-13 with high affinity

58
Q

What are the actions of IL-13?

A
  • Promotes fibrosis as part of the tissue repair phase of chronic inflammatory state
  • Stimulates mucus production by lung epithelial cells
  • Induces IgE class switching in B lymphocytes
  • Promotes inflammation by inducing expression of endothelial expression factors and chemokines
59
Q

What is the source of IFNy?

A

NK cells
Th1 CD4 T lymphocytes
CD8 T lymphocytes

60
Q

What is the receptor for IFNy?

A
  • Type II cytokine receptor family, IFNγR1, and IFNγR2 heterodimer
  • IFNγR1 associates with Jak1 kinase and IFNγR2 associates with Jak2 kinase -Leads to STAT1 phosphorylation and dimerization
61
Q

What are the actions of IFNy?

A
  • Promote macrophage rich inflammatory reactions while inhibiting IgEdependent eosinophil rich reactions
  • Activates macrophages to kill phagocytosed microbes -Promotes the differentiation of naïve CD4 T lymphocytes to the Th1 subset (via Tbet)
  • Inhibits the differentiation of TH2 cells;
  • Acts on B lymphocytes to promote switching to certain IgG subclasses
  • Stimulates expression of class I and class II MHC molecules, and costimulators on APCs
62
Q

What is the source of TGFB(1)?

A
  • Antigen-stimulated T lymphocytes

- LPS-activated mononuclear phagocytes

63
Q

What is the receptor of TGFB (1)? What signalling does it trigger?

A
  • Serine or threonine kinase domain that phosphorylates transcription factors of Smads
  • ALK5 phosphorylates Smad2 and Smad3, which, with Smad4, translocates to the nucleus, binds to promoters of target genes, and regulates their transcription
64
Q

What are the actions of TGFB (1)?

A
  • Inhibits the proliferation and effector functions of T lymphocytes, and the activation of macrophages
  • Regulates the differentiation of Tlymphocyte subsets
  • Stimulates the production of IgA antibodies by inducing B lymphocytes to switch to this isotype
  • Regulates tissue repair
65
Q

What is the source of lymphotoxin?

A

T lymphocytes

66
Q

What is the receptor of lymphotoxin?

A

TNF receptors

67
Q

What is the action of lymphotoxin?

A

Activates endothelial cells and neutrophils.

68
Q

What is the source of IL-21?

A

Activated CD4 T lymphocytes

69
Q

What is the receptor for IL-21? What does it activate?

A

Type I family receptor that activates Jak1, Jak2, STAT1, and STAT3.

70
Q

What are the actions of IL-21?

A
  • Stimulation of proliferation and augmentation of effector CD8 T lymphocytes -Enhancement of class switching and Ig production by B lymphocytes
  • Induction of differentiation and enhancement of effector function of NK cells
71
Q

What is the source of BAFF?

A
Neutrophils 
Monocytes 
Macrophages 
Dendritic cells 
Follicular dendritic cells Activated T lymphocytes
72
Q

What are the receptors for BAFF?

A

TACI, BCMA, and BAFF-R

73
Q

What are the actions of BAFF?

A

Up-regulation of antiapoptotic protein Bcl2 activation of NFκB.

74
Q

What are the sources of APRIL?

A

Monocytes
Macrophages
Dendritic cells
Activated T lymphocytes

75
Q

What are the receptors of APRIL?

A

TACI and BCMA

76
Q

What are the actions of APRIL?

A

Up-regulation of antiapoptotic protein Bcl2 activation of NFκB.

77
Q

What are the cytokines that stimulate hematopoiesis?

A
Stem cell factor (c-kit ligand)
IL-7
IL-3
Erythropoietin (Epo)
IL-11
78
Q

What is the Hot T-Bone stEAk menomonic?

A
Hot T-Bone stEAk 
IL-1: fever (Hot) 
IL-2: stimulates T lymphocytes 
IL-3: stimulates Bone marrow 
IL-4: stimulates IgE 
IL-5: stimulates IgA
79
Q

What is the source of Stem cell factor (c-kit ligand)?

A

Stromal cells of the bone marrow

80
Q

What is the receptor of stem cell factor?

A

Act on immature stem cells with c-kit

81
Q

What are the actions of stem cell factor?

A
  • Enhances response to other colony stimulating factors (CSFs)
  • Sustains the viability of T lymphocytes in the thymus
  • Mast cell growth factor
82
Q

What is the source of IL-7?

A

Fibroblasts

Bone marrow stromal cells

83
Q

What is the receptor of IL-7?

A

IL-7Rα chain associated with γc chain

Associated with Jak3 kinase

84
Q

What are the actions of IL-7?

A

Survival of mature, naïve and memory T lymphocytes (especially CD4)

85
Q

What is the source of IL-3?

A

CD4 T lymphocytes

86
Q

What is the receptor of IL-3?

A

Type I cytokine receptor family

Signal transduction involves Jak-STAT

87
Q

What are the actions of IL-3?

A

Promotes the growth and development of mast cells from bone marrow
-Basophil differentiating cytokine

88
Q

What is the source of erythropoietin (Epo)? What is it produced in response to?

A

Produced in the kidney in response to low oxygen tension

89
Q

What is the receptor of erythropoietin?

A

Type I cytokine receptor that signals through Jak2-STAT5 and PI-3 kinase-Akt pathways

90
Q

What is the action of erythropoeitin (Epo)?

A

Promotes production of RBC from committed erythroid progenitors

91
Q

What is the source of IL-11?

A

Bone marrow stromal cells

92
Q

What is the receptor of IL-11?

A

gp130 signaling Jak-STAT

93
Q

What is the action of IL-11?

A

Megakaryocytopoiesis

94
Q

What are the cytokine receptor families?

A
Type I cytokine R (hematopoietin receptors) 
Type II cytokine R 
IL-1 family R
TNFR 
Seven transmembrane α-helical R
95
Q

What pathway does Type I cytokine R (hematopoietin receptors) engage?

A

Engage Jak-STAT signaling pathways

96
Q

What pathway does Type II cytokine R receptors engage?

A

Engage Jak-STAT signaling pathways

97
Q

What pathway does IL-1 family R receptors engage?

A

Share Toll-like/IL-1 receptor (TIR) domain.

98
Q

What pathway does TNFR receptors engage?

A

Intracellular signaling mechanisms induce apoptosis and/or stimulate gene expression

99
Q

What pathway does seven transmembrane alpha-helical R receptors engage?

A

Signaling pathways involve GTP-binding proteins.

100
Q

What are chemokines? How are they grouped into families?

A

Chemokines are a subgroup of cytokines that are divided into four families, based on the number and location of terminal cysteine residue.

101
Q

What is the source of chemokines?

A

Leukocytes, endothelial cells, epithelial cells, and fibroblasts stimulated by microbes via TLR signaling and inflammatory cytokines (TNF and IL-1).

102
Q

What are the receptors of chemokines?

A

Found on leukocytes (greatest number and diversity on T lymphocytes); and G protein-coupled receptors (GPCRs) with seventransmembrane α-helical domains (GTP) modulate cytoskeletal protein configuration and integrin affinity.

103
Q

What are the actions of chemokines?

A

Recruit cells of host defense to sites of infection; induce migration of leukocytes toward the chemical gradient of the cytokine by stimulating alternating polymerization/ depolymerization of actin filaments; regulate the traffic of lymphocytes and other leukocytes through peripheral lymphoid tissues; and promote angiogenesis and wound healing.

104
Q

What disease is associated with defects in CCR5 or CCL3L1 and CXCR4?

A

HIV and/or AIDS

105
Q

What disease is associated with a defect in CXCR4?

A

WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis)

106
Q

What disease is associated with defects in CXCL4?

A

Heparin-induced thrombocytopenia

107
Q

What disease is associated with defects in CX3CR1 and CCL5?

A

Atherosclerosis

108
Q

What disease is associated with defects in CCL2, 5, 7, 11, and CXCL8?

A

Asthma or allergies

109
Q

What disease is associated with defects in CXCL12 or CXCR4?

A

Cancer metastases

110
Q

What disease is associated with defects in CCL25 or CCR9?

A

Crohn’s disease

111
Q

What chemokine defects are associated with HIV and/or AIDS?

A

CCR5 or CCL3L1 and CXCR4

112
Q

What chemokine defect is associated with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis syndrome?

A

CXCR4

113
Q

What chemokine defect is associated with heparin-induced thrombocytopenia?

A

CXCL4

114
Q

What chemokine defects are associated with atherosclerosis?

A

CX3CR1, CCL5

115
Q

What chemokine defects are associated with asthma or allergies?

A

CCL2, 5, 7, 11 and CXCL8

116
Q

What chemokine defects are associated with cancer metastases?

A

CXCL12 or CXCR4

117
Q

What chemokine defects are associated with Crohn’s disease?

A

CCL25 or CCR9