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)
