Cytokines Flashcards
What are cytokines?
Hormone-like, soluble mediators secreted during an immune response
In __________ immunity, microbial and viral products stimulate macrophages and neutrophils to produce cytokines.
Innate
In ____________ immunity, cytokines are secreted by T-cells; they function to regulate T-cell growth and differentiation, as well as regulating the effector functions of T- and B-cells.
Adaptive
True or false: cytokines play a role in haematopoiesis.
True
__________ are highly potent, effective at low concentrations, and only briefly secreted.
Cytokines
What is pleiotropism?
One cytokine having several targets.
What is redundancy?
Many cytokines having the same function
Actions may be local or systemic, with ____________ and endocrine function.
Autocrine
Name three types of cytokine receptors.
General cytokine receptors
Chemokine receptors
TNF receptors
Cytokine receptors are generally not expressed on ___________ cells.
Resting
Once bound, _________ ____________ __________ (JAK) enzymes are activated, transducing the signal to the nucleus.
Protein tyrosine kinase
JAK enzymes activate _____________ _________ called signal transducers and activators (STAT).
Transcription factors
Tumour necrosis factor α (TNF-α) is sourced from ____________ __________, T-cells, mast cells, and NK cells.
Activated macrophages
TNF-α is produced by macrophages upon ligation of ______ by toll-like receptors.
LPS
________ augments TNF-α production.
IFN-γ
TNF-α is synthesised initially as a transmembrane protein, which is then cleaved by a membrane-associated __________________, releasing a 17kD polypeptide.
Metalloproteinase
What does TNF-α stimulate macrophages to secrete?
IL-1
TNF-α Stimulates ______________ actions of neutrophils.
Microbicidal
TNF-α induces vascular endothelial cells to express adhesion molecules, called ____________.
Selectins
List three functions of TNF-α in immunity.
Induces chemotaxis
Induces fever, as an endogenous pyrogen, by prompting the release of prostaglandins from the hypothalamus
Stimulates hepatocytes to increase synthesis of serum proteins, such as serum amyloid A and fibrinogen (acute phase response), causing intravascular thrombosis
Describe four potential adverse effects of TNF-α.
Prolonged production causes tissue wasting, or cachexia, by suppressing appetite
Prolonged production can cause hypotension
High serum levels cause severe metabolic disturbances
High serum levels can also cause septic shock, induced in response to LPS
Cell sources of ___________ include endothelial cells, epithelial cells, fibroblasts, and antigen-stimulated T-cells.
Chemokines
Chemokines are induced by ____________ through TLR, TNF, and IL-1.
Microbes
Chemokines stimulate _____________ movement and migration.
Leucocyte
True or false: some chemokines are produced in response to infection, while others are constitutively produced.
True
What type of receptors do chemokines engage with?
G-protein-coupled receptors, with seven transmembrane domains
Name two chemokine receptors for HIV.
CCR5
CXCR4
List three mechanisms of immunity induced by chemokines.
Increase the affinity of leukocytes for the endothelium
Enhance movement of leukocytes along their chemotactic gradients, by acting on actin filaments
Chemokines are specific to the cell type (e.g., CCL2 attracts monocytes; CCL11 attracts eosinophils)
Chemokines recruit cells to ___________ ____________ organs.
Peripheral lymphoid
True or false: chemokines promote angiogenesis and wound healing.
True
Chemokines promote migration of ___________ and memory T-cells.
Effector
What is interleukin-12?
Principal cytokine in response to intracellular microbes
IL-12 stimulates ________ production by T-cells and NK cells.
IFN-γ
IL-12 drives differentiation of T-cells into the Th1 (IFN-γ secreting) _____________.
Phenotype
IL-12 is produced by dendritic cells and ___________ _______________.
Activated macrophages
What do Type 1 interferons do?
Interfere with viral replication
Name two Type 1 interferons.
IFN-α and IFN-b
Type 1 interferons are secreted by ___________ ____________, dendritic cells and fibroblasts (IFN-b), and virally infected cells.
Mononuclear phagocytes
Production of Type 1 interferons is induced by viral nucleic acids, which bind to ligands and induce activation of __________ ____________ ____________.
Interferon regulatory factor
Receptors TLR3, TLR7, and TLR9 recognise __________ dsRNA .
Viral
State functions of Type 1 interferons.
Promote immunity to intracellular microbes by
Cause cells to synthesise enzymes which interfere with viral replication, e.g., 2’,5’ oligoadenylate synthetase
Induces an anti-viral state in neighbouring healthy cells
Increases expression of MHC class I
Increases CTL activity
Promotes naïve T cell differentiation to Th1 by upregulating IL-12 receptors
IFN-α is used in the treatment of ____________ ____.
Hepatitis C
What is IL-10?
An inhibitor of activated macrophages and dendritic cells, which controls innate immunity
True or false: is a non-covalently linked dimer.
True
Cell sources of ________ include macrophages and T-cells, and non- lymphoid cells (keratinocytes).
IL-10
State four biologic activities of IL-10.
Major anti-inflammatory cytokine
Inhibits IL-12 production and in turn IFN-γ production
Inhibits expression of co-stimulators and class II MHC molecules on macrophages and dendritic cells
Epstein-Barr virus has an IL-10-like gene, important for viral evasion of immunity
In ____________ immunity, cytokines stimulate proliferation, differentiation, and activation of effector T- and B-cells.
Adaptive
IL-2 is produced by activated _____ ___________ ___-________.
CD4+ helper T-cells
Production of IL-2 is described as ____________.
Transient
IL-2 receptor is induced on activation of naïve and memory T-cells, but is always expressed on ____________ T-cells.
Regulatory
________ stimulates survival, proliferation and differentiation of T-cells.
IL-2
IL-2 promotes the proliferation, differentiation and ___________ function of NK cells.
Cytotoxic
IL-2 stimulates __________ production in B-cells.
Antibody
__________ is a major stimulus for antibody production in B-cells.
IL-4
IL-4 promotes development of ________ T-cells into Th2 phenotype (IL-4 producing).
Naïve
What cell type secretes IL-4?
CD4+ T-cells
In synergy with ______, IL-4 activates macrophages.
IL-13
IL-4 induces arginase production, promoting _____________ _____________.
Collagen synthesis
IL-4 increases _________ ___________ expression, promoting phagocytosis.
Mannose receptor
IFN-γ is synonymous with _______ ___ ____________.
Type 2 interferon
______ is the principal macrophage-activating cytokine, essential for immunity to intracellular microbes.
IFN-γ
Describe the structure and production of IFN-γ.
Homodimeric
Produced by CD4+ T-cells, CD8+ T-cells, and NK cells
Produced by T-cells in response to antigen
Production enhanced by IL-12 and IL-18
Delineate some biologic activities of IFN-γ.
Promotes phagocytosis in macrophages
Enhances microbicidal activities of macrophages by promoting reactive oxygen intermediates
Promotes differentiation of naïve cells to Th1 phenotype
Promotes isotype switching to IgG2a in B-cells, indirectly promoting phagocytosis
Stimulates expression of MHC class I and II molecules on APC
List functions of cytokines that are important to health.
Promote the onset of appropriate cellular and humoral immunity
Kick-start inflammation
Regulate haematopoiesis
Control cell proliferation and differentiation
Regulate wound healing and tissue repair
Briefly discuss bronchial asthma.
Inflammatory disease of the upper airways linked with reversible airway obstruction
Increased numbers of T-cells producing exaggerated amounts of IL-4, IL-5, and IL-13 in bronchial biopsies, and these cells are drivers of eosinophil influx and activation
Linked to stimulation of mucus production
Discuss rheumatoid arthritis.
Chronic autoimmune disease presenting with stiffness, pain and synovitis of large joints
Unclear pathophysiology, linked to cross reactivity of T-cells responding to microbial antigens with a self antigen
Triggers an exaggerated cytokine response from macrophages dominated by TNF-a, IL-1, and IL-8
Results in influx of immune cells from the blood (IL-8) facilitated by increased endothelial expression of adhesion molecules, in turn which secrete cytokines damaging local synovium
In chemokine families, how many adjacent cysteine molecules does the CC family have?
Two
In chemokine families, how many separated cysteine molecules does the CXC family have?
Two
In chemokine families, how many cysteine molecules does the C family have?
One
What is the structure of the CX3C chemokine family members?
Two cysteines, separated by three amino acids
Cytokines increase the affinity of __________ for the endothelium.
Leucocytes
Cytokines enhance the movement of leucocytes along their __________ ___________ by acting on actin filaments.
Chemotactic gradients
CCL2 attracts ____________.
Monocytes
CCL11 attracts ____________.
Eosinophils
Cytokines have an __________ effect through stimulating other cells to produce angiogenic factors.
Indirect
Cytokines promote migration of ____________ and memory T-cells.
Effector
Cytokines promote _____________ and wound healing.
Angiogenesis
What is the structure of a T-cell receptor?
Composed of two polypeptide chains, alpha and beta (50 and 39 kDa, respectively)
Each alpha and beta chain is composed of variable (V) and constant (C) regions, joined by _____________ bonds.
Disulphide
___________ regions on both chains are involved in antigenic recognitions.
Hypervariable
__________ hypervariable regions are found on both chains of T-cell receptors.
Three
A smaller group of T-cells express the ___________ _______ TCR.
Gamma delta
CD4 or CD8 ___-__________ are present with T-cell receptors.
Co-receptors
Describe the CD3 complex.
CD3 is stably associated with the TCR
Found on all T-cells
Involved in transducing signals and signalling
Composed of g, d, and e chains are associated with a ζζ homodimer
g, d, and e chains contain an Ig-like domain
Transmembrane aspartic acid binds positive charged residues in the a and b TCR chains
Cytoplasmic domains contain a conserved sequence motif ‘immunoreceptor tyrosine based activation motif’ (ITAM)
List two other T-cell receptor accessory molecules.
CD28
Leucocyte function associated antigen-1
What are accessory molecules?
Several integral membrane proteins involved in functional responses to antigen presentation
Name four accessory molecules.
CTLA-4
CD28
LFA-a1
CD2
State two characteristics of accessory molecules.
Non-polymorphic
Bind ligands on antigen presenting cells (APCs)
Identify four functions of T-cell accessory molecules.
Non-specific recognition of antigen (adhesion)
Transduce biochemical signals (costimulation)
Involved in homing
Useful identification markers on T-cell
All mature T cells arise from naïve T-cell precursors which mature in the thymus, termed Th0; in the _____________, under appropriate stimulation, subsets of CD4+ T-cells (helper) with distinctive patterns of cytokine production develop.
Periphery
Identify three major subpopulations of cytokine secretion.
Th1
Th2
Th17
What do Th1 cells secrete?
IFN-γ
TNF-α
______ cells arise from IFN-γ and IL-12.
Th1
Microbial infection induces secretion of cytokines from ___________, and the cytokines in turn act on naïve T-cells to induce differentiation to Th1 phenotype.
Macrophages
Th1 cells are characterised by expression of __-_____ __________ _________ and by production of IL-2, IFN-γ, TNF-α and lymphotoxin.
T-bet transcription factor
List three ways in which Th1 cells affect the stimulation of macrophages.
Enhancing phagocytic capacity in bacterial infection
Promote macrophage migration and diapedesis
Promote macrophage accumulation at sites of infection
Th1 cells stimulate T-cell _____________ and differentiation.
Proliferation
Th1 cells promote production of ____________-fixing antibodies by B-cells.
Complement
What is the principal function of Th1 cells?
Phagocyte-mediated defence against infection with intracellular microbes, with promotion of neutrophil killing activity
What is delayed-type hypersensitivity?
Unique type of cell-mediated immunity
The name originated from the skin test used in the diagnosis of tuberculosis (the PPD test or the tuberculin test) and denotes cellular infiltrates causing induration and erythema at the skin test site, within 24 to 72 hours
DTH responses can be induced by vaccination or by prior infection
DTH is an example of type IV hypersensitivity
Tissue injury caused by activated Th1 cells and macrophages is known as a DTH reaction, and occurs either as collateral damage after a microbial infection (physiological), or in certain autoimmune reactions (pathological)
Infection or vaccination sensitizes the individual
DTH reaction demonstrated by secondary challenge with the same antigen
Reaction is manifested by redness and swelling which peaks after 48 hours and not at four hours, i.e., ‘delayed’
Outline the sequence of events involved in delayed-type hypersensitivity.
At the local site during the DTH response, CD4+ Th1 cells respond to antigen by secreting cytokines that stimulate inflammation and activate phagocytes
Neutrophils accumulate within four hours
T-cells accumulate within 12 hours
Endothelial cells become leaky
Fibrinogen escapes and becomes fibrin
Tissue swells and becomes firm (known as induration)
Discuss chronic delayed-type hypersensitivity reactions.
Occur if a Th1 response to a microbe fails to eradicate the microbe
Chronically-activated macrophages grow and develop into epithelioid cells which fuse to become multi-nucleate giant cells
Clusters of activated macrophages surround the antigen producing granulomas
Granuloma formation is characteristic of M. tuberculosis infection
Tissue fibrosis accompanies granuloma formation, and normal lung tissue is replaced
_______ cells secrete IL-4, IL-5, IL-13, IL-10.
Th2
Th2 cells arise from _______ secretion.
IL-4
____________ infection and allergens induce chronic activation of cells which is independent of macrophages and is associated with IL-4 secretion; IL-4 in turn acts on naïve T-cells to induce differentiation to a Th2 phenotype.
Helminth
Th2 cells are characterised by expression of _______ and by production of IL-4, -5, -9, -13 and GM-CSF.
GATA3
Th2 cells stimulate ___________ activation in tissue healing and repair.
Macrophage
True or false: Th2 cells contribute significantly to symptoms associated with allergic reactions.
True
Th2 cells cause mast cell ________________.
Degranulation
Th2 cells stimulate activation of ___________ in helminthic infection.
Eosinophils
Th2 cells stimulate production of _____ anti-helminth antibodies.
IgE
IgE-coated helminths are bound by _________ which destroy the helminth.
Eosinophils
True or false: antibodies produced by Th2 cytokines do not promote phagocytosis or complement activation, but can neutralize some toxins.
True
_______ cells secrete IL-6 and IL-17.
Th17
Th17 cells arise from secretion of _______.
IL-23
________ cells are characterised by expression of transcription factor retinoic acid receptor-related orphan receptor γ-t (RORγt), and by secretion of IL-17, IL-22, and GM-CSF.
Th17
Th17 cells play protective roles in host defence against certain bacteria at epithelial and ___________ barriers.
Mucosal
True or false: Th17 are not currently believed to be involved in controlling fungal infection.
False
Dysregulated IL-17 production can result in excessive pro-inflammatory _____________ _____________ and chronic inflammation, which lead to tissue damage and autoimmunity.
Cytokine expression
________ family cytokines have been linked to many autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), inflammatory bowel disease, and psoriasis.
IL-17
