First Aid, Chapter 1 Immune Mechanisms, Cytokines, Chemokines, and their receptors Flashcards
What is the source of TNF?
- Activated mononuclear phagocytes
- Antigen-stimulated T cells
- NK cells
- Mast cells
What is the stimulus of TNF? What is its synthesis augmented by?
- Most potent stimulus is TLR engagement with LPS and other microbial products
- Synthesis augmented by IFNγ
What are the receptors of TNF? What does binding to each receptor cause?
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
What are the actions of TNF?
- 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
What are the two forms of IL-1?
IL1α and IL-1β
What is the source of IL-1?
- Activated mononuclear phagocytes
- Neutrophils
- Epithelial cells
- Endothelial cells
What induces production of IL-1?
Production is induced by bacterial products, such as LPS and other cytokines (TNF)
What are the receptors of IL-1 and what does binding to them cause?
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.
What are the actions of IL-1?
- 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
What is IL-12 made of?
Made of p35 and p40 subunits
What is the source of IL-12? What stimulates its production?
- 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
What are the receptors for IL-12 and what does binding to them cause?
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
What are the actions of IL-12?
- 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
What is IL-1B cleaved by?
Caspase-1
What does caspase-1 require activation by? What do mutations in this cause?
a complex of proteins, including NALP. Gain-offunction mutations of NALP lead to uncontrolled IL-1 production and autoinflammatory syndromes.
What is IL-1ra? What is it made by? What is its commercial name? What is it used for?
IL-1ra is a competitive inhibitor of IL-1 made by mononuclear phagocytes. It is available commercially (Anakinra) to treat autoinflammatory syndromes
What do mutations in IL-12B1 cause?
Patients with mutations in the IL-12 Rβ1 are susceptible to infections with intracellular bacteria notably Salmonella and atypical mycobacteria.
What does IRAK-4 deficiency cause?
IRAK-4 deficiency leads to susceptibility to pyogenic infections, especially with Streptococcus pneumoniae.
What are the sources of type 1 interferons?
IFNα: Plasmacytoid dendritic cells and mononuclear phagocytes IFN β: Produced by many cells, including fibroblasts
What stimulates type 1 interferons?
Most potent stimulus is viral nucleic acids
What is the receptor for type 1 interferon? What does binding to the receptor cause?
Type II cytokine receptor family IFNAR1/Tyk2 and IFNAR2/Jak1, leading to STAT1 and STAT2 phosphorylation and recruitment of IRF9
What are the actions of type 1 interferons?
- 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
What is the source of IL-10?
Macrophages
Regulatory T cells
What is the receptor of IL-10?
Type II cytokine receptor family, Jak1 and Tyk2; Janus family kinases, which induce STAT3 signaling molecule
What is the action of IL-10?
- 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
What is the source of IL-6?
Mononuclear phagocytes Vascular endothelial cells Fibroblasts
What stimulates IL-6 production?
Produced in response to IL-1 and TNF
What is the receptor for IL-6? What is the signalling pathway?
Type I cytokine receptor family Signaling pathway involves Jak1 and STAT3 activation
What are the actions of IL-6?
- 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)
What is the source of IL-15? In response to what?
Mononuclear phagocytes in response to viral infection and LPS
What signalling pathway does IL-15 activate?
Activates Jak3, STAT5 and Akt-dependent signaling pathways
What are the actions of IL-15?
- Survival of memory CD8 T lymphocytes, NK cells, and NK-T cells
- Required for NK cell differentiation and activation
What is the source of IL-18? What is production dependent on?
Macrophages
Dendritic cells.
Production is dependent on caspase-1
What is the receptor of IL-18 and what does it signal through?
IL-1 or TLR family signals through TIR domain that recruits IRAK and TRAF, leading to activation of NFκB and AP-1 transcription factors
What are the actions of IL-18?
Enhances IFNγ production by T lymphocytes Promotes differentiation of IFNγ, producing Th1 CD4 cells
What cytokine is IL-18 synergistic with?
IL-12
What are the sources of IL-23? What does production depend on?
Macrophages and dendritic cells in response to microbial infection Production depends on caspase-1 (similar to IL-1)
Where is the receptor of IL-23? Describe the receptor.
On T lymphocytes and NK cells
IL-23R is a heterodimer of a unique IL-23R chain and the IL12Rβ1 chain
What are the actions of IL-23?
- Contributes to inflammation in autoimmunity
- Important for resistance to Klebsiella pneumoniae
- Promotes differentiation and maintenance of T lymphocytes that produce IL-17
What are the sources of IL-27?
Macrophages
Dendritic cells
Describe the IL-27 receptor? Where is it expressed?
- 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
What are the actions of IL-27?
- Promotes ThI differentiation
- Promotes IFNγ production by T lymphocytes
- Role in controlling ongoing Tlymphocyte responses
Which receptors contain γc? What is the clinical significance?
Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL21 contain γc, which is affected in X-linked SCID.
Name the cytokines that mediate and regulate innate immunity?
TNF, IL-1, IL-12, Type 1 interferons, IL-10, IL-6, IL-15, IL-18, IL-23, IL-27
Name the cytokines that mediate and regulate adaptive immunity?
IL-2, IL-4, IL-5, IL-13, IFNγ, TGFβ(1), Lymphotoxin, IL-21, BAFF, APRIL
What is the source of IL-2?
Mainly CD4 T lymphocytes (8–12 hr after activation)
Describe the receptor for IL-2? What is the pathway it triggers?
- IL-2R (composed of 3 proteins:IL-2Rα, IL2/15Rβ, γc)
- Engages Jak3-STAT5 signal transduction pathways
What are the actions of IL-2?
- 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)
What is the source of IL-4?
Th2 CD4 T lymphocytes Activated mast cells
What is the receptor for IL-4? What is the pathway that it signals through?
- Type I cytokine receptor family
- IL-4Rαγc signals through the Jak-STAT pathway (STAT6).
What are the actions of IL-4?
- 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
Which cytokines share a common beta chain?
The receptors IL-3, IL-5, and granulocyte-monocyte colony-stimulating factor (GMCSF) share a common β chain.
What is the source of IL-5?
Th2 CD4 T lymphocytes Activated mast cells
What are the receptors for IL-5 and what signalling pathway do they induce?
IL-5Rα and IL-5Rβc heterodimer induces Jak2 and STAT 3 signaling pathway
What are the actions of IL-5?
- Activates immature eosinophils, and stimulates growth and differentiation of eosinophils
- Stimulates the proliferation of B lymphocytes and production of IgA antibodies
What is the source of IL-13?
Th2 CD4 T lymphocytes CD8 T lymphocytes
NK T lymphocytes
Basophils
EosinophilS
What are the receptors for IL-13?
IL-4Rα and IL-13Rα1 heterodimer Binds to IL-4 and IL-13 with high affinity
What are the actions of IL-13?
- 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
What is the source of IFNy?
NK cells
Th1 CD4 T lymphocytes
CD8 T lymphocytes
What is the receptor for IFNy?
- 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
What are the actions of IFNy?
- 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
What is the source of TGFB(1)?
- Antigen-stimulated T lymphocytes
- LPS-activated mononuclear phagocytes
What is the receptor of TGFB (1)? What signalling does it trigger?
- 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
What are the actions of TGFB (1)?
- 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
What is the source of lymphotoxin?
T lymphocytes
What is the receptor of lymphotoxin?
TNF receptors
What is the action of lymphotoxin?
Activates endothelial cells and neutrophils.
What is the source of IL-21?
Activated CD4 T lymphocytes
What is the receptor for IL-21? What does it activate?
Type I family receptor that activates Jak1, Jak2, STAT1, and STAT3.
What are the actions of IL-21?
- 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
What is the source of BAFF?
Neutrophils Monocytes Macrophages Dendritic cells Follicular dendritic cells Activated T lymphocytes
What are the receptors for BAFF?
TACI, BCMA, and BAFF-R
What are the actions of BAFF?
Up-regulation of antiapoptotic protein Bcl2 activation of NFκB.
What are the sources of APRIL?
Monocytes
Macrophages
Dendritic cells
Activated T lymphocytes
What are the receptors of APRIL?
TACI and BCMA
What are the actions of APRIL?
Up-regulation of antiapoptotic protein Bcl2 activation of NFκB.
What are the cytokines that stimulate hematopoiesis?
Stem cell factor (c-kit ligand) IL-7 IL-3 Erythropoietin (Epo) IL-11
What is the Hot T-Bone stEAk menomonic?
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
What is the source of Stem cell factor (c-kit ligand)?
Stromal cells of the bone marrow
What is the receptor of stem cell factor?
Act on immature stem cells with c-kit
What are the actions of stem cell factor?
- Enhances response to other colony stimulating factors (CSFs)
- Sustains the viability of T lymphocytes in the thymus
- Mast cell growth factor
What is the source of IL-7?
Fibroblasts
Bone marrow stromal cells
What is the receptor of IL-7?
IL-7Rα chain associated with γc chain
Associated with Jak3 kinase
What are the actions of IL-7?
Survival of mature, naïve and memory T lymphocytes (especially CD4)
What is the source of IL-3?
CD4 T lymphocytes
What is the receptor of IL-3?
Type I cytokine receptor family
Signal transduction involves Jak-STAT
What are the actions of IL-3?
Promotes the growth and development of mast cells from bone marrow
-Basophil differentiating cytokine
What is the source of erythropoietin (Epo)? What is it produced in response to?
Produced in the kidney in response to low oxygen tension
What is the receptor of erythropoietin?
Type I cytokine receptor that signals through Jak2-STAT5 and PI-3 kinase-Akt pathways
What is the action of erythropoeitin (Epo)?
Promotes production of RBC from committed erythroid progenitors
What is the source of IL-11?
Bone marrow stromal cells
What is the receptor of IL-11?
gp130 signaling Jak-STAT
What is the action of IL-11?
Megakaryocytopoiesis
What are the cytokine receptor families?
Type I cytokine R (hematopoietin receptors) Type II cytokine R IL-1 family R TNFR Seven transmembrane α-helical R
What pathway does Type I cytokine R (hematopoietin receptors) engage?
Engage Jak-STAT signaling pathways
What pathway does Type II cytokine R receptors engage?
Engage Jak-STAT signaling pathways
What pathway does IL-1 family R receptors engage?
Share Toll-like/IL-1 receptor (TIR) domain.
What pathway does TNFR receptors engage?
Intracellular signaling mechanisms induce apoptosis and/or stimulate gene expression
What pathway does seven transmembrane alpha-helical R receptors engage?
Signaling pathways involve GTP-binding proteins.
What are chemokines? How are they grouped into families?
Chemokines are a subgroup of cytokines that are divided into four families, based on the number and location of terminal cysteine residue.
What is the source of chemokines?
Leukocytes, endothelial cells, epithelial cells, and fibroblasts stimulated by microbes via TLR signaling and inflammatory cytokines (TNF and IL-1).
What are the receptors of chemokines?
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.
What are the actions of chemokines?
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.
What disease is associated with defects in CCR5 or CCL3L1 and CXCR4?
HIV and/or AIDS
What disease is associated with a defect in CXCR4?
WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis)
What disease is associated with defects in CXCL4?
Heparin-induced thrombocytopenia
What disease is associated with defects in CX3CR1 and CCL5?
Atherosclerosis
What disease is associated with defects in CCL2, 5, 7, 11, and CXCL8?
Asthma or allergies
What disease is associated with defects in CXCL12 or CXCR4?
Cancer metastases
What disease is associated with defects in CCL25 or CCR9?
Crohn’s disease
What chemokine defects are associated with HIV and/or AIDS?
CCR5 or CCL3L1 and CXCR4
What chemokine defect is associated with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis syndrome?
CXCR4
What chemokine defect is associated with heparin-induced thrombocytopenia?
CXCL4
What chemokine defects are associated with atherosclerosis?
CX3CR1, CCL5
What chemokine defects are associated with asthma or allergies?
CCL2, 5, 7, 11 and CXCL8
What chemokine defects are associated with cancer metastases?
CXCL12 or CXCR4
What chemokine defects are associated with Crohn’s disease?
CCL25 or CCR9
