Immune Function Flashcards
What function does MHC-1 have on normal cells?
inhibits apoptosis by NK cells
How can NK cells trigger apoptosis?
1) release perforins - form a pore to allow proteases (granzymes) to enter cell –> cytosolic capsase pathway; 2) Fas-FasLigand pathway on the surface of the cell
What are the 3 types of PAMP (pathogen associated molecular patterns) receptors?
1) Secretory: act as opsonins, binding to microbial cell walls and flagging them for activation of complement and phagocytosis
2) Endocytic receptors: mediate phagocytosis by macrophages;
3) Cell-signaling: activate intracellular pathways that lead to up-regulation of cytokines to trigger an inflammatory cascade
What is the function of toll-like receptors?
specific family of signaling pattern recognition receptors that promote inflammation and the adaptive immune response via the NF-kB cascade
Toll-like receptors are very similar in structure to what interleukin?
IL-1
T/F: The cardinal features of the innate immune system are rapid, non-specific, and has no memory of past events.
TRUE
What are the cardinal features of the adaptive immune system?
specificity, diversity, memory, specialization, self-limitation (return to homeostasis), and non-reactivity to self
What are the components of the innate immune system?
physical barrier, complement, antimicrobial peptides, cytokines, macrophages, neutrophils, NK cells
What are the components of the adaptive immune system?
antigen presenting cells, lymph nodes, T-cells, B-cells
What are the key mediators that link innate and adaptive immunity?
cytokines
Pleiotropy
one cytokine can have a different effect depending on the cell type it binds to
Give an example of how IL-4 exhibits pleiotropy
IL-4 can have both stimulatory and inhibitory effects depending on the target: 1) IL-4 stimulates class switching and IgE production in B cells, growth and differentiation factor for Th2 cells, stimulates expression of adhesion molecules on vascular endothelium, mast cell growth factor; 2) Inhibitory: counter-regulatory to IFN-gamma and down regulates IL-1, IL-6, TNF-alpha secretion by macrophages
Redundancy
multiple cytokines have the same or overlaping biological functions
Give an example of redundancy with B cell proliferation
Multiple cytokines stimulate B cell proliferation (have same function): IL-4, IL-5, IL-13
IL-1 and TNF-alpha both activate macrophages and in high quantities have endocrine effects such as fever and cachexia. Is this an example of Pleiotropy, Redundancy, Synergy, Antagonism, or Cascade Induction?
Redundancy
Synergy
two or more cytokines expressed together have greater than additive effects on a cell
Antagonism
one cytokine inhibits the action of the other
Cascade Induction
cytokine effect on a target cell that induces that cell to produce the same cytokine –> rapidly spreads to adjacent cells that also produce the same or other synergistic cytokines
Interleukins
Cytokines that regulate interactions between lymphocytes and other leukocytes
Interferons
glycoproteins that are synthesized in response to viral infections, immune stimulation or chemical stimulation - inhibit viral replication by interfering with viral RNA and protein synthesis
Tumor necrosis factors
polymeric cytokines derived from macrophages and T cells - involved in immune regulation, inflammation, and programmed cell death of some tumor cells
TNF-alpha, lymphotoxins, fas ligand (CD95L), CD154 (CD40L) and CD30L are all part of what cytokine family?
tumor necrosis factors
Growth factors
also known as colony stimulating factors - stimulate cell growth and proliferation
chemokines
small proteins that act primarily as chemotactic factors or leukocyte activators
Primary cytokines are part of the innate or adaptive immune system?
innate
_____ are cytokines that by themselves initiate all events required to bring about leukocyte infiltration into the tissues.
Primary cytokines
What are examples of primary cytokines?
IL-1, TNF-alpha, TNF-beta, IL-18
_____ are cytokines whose production is induced only after cellular stimulation by a primary cytokine.
Secondary cytokines
What is the main source of TNF-alpha?
activated macrophages
What are the two basic responses in target cells created by TNF-alpha binding?
1) Gene transcription (via NF-kB pathway), 2) Apoptosis
TNF-alpha plays a major role in leukocyte recruitment in what ways?
increased production and secretion of chemokines such as IL-8 and expression of adhesion molecules on the surface of vascular endothelium
Phospholipase A2 is synethesized in response to activation of what pathway?
NF-kB pathway (pro-inflammatory, phospholipase A2 is the enzyme that initiates the arachadonic acid cascade)
In high concentrations, what systemic effects can TNF-alpha have?
1) Fever - through induction of prostaglandin production by the hypothalamus; 2) Induction of hepatocyte-derived plasma proteins, including serum amyloid A, 3) Cachexia - appetite suppression and inhibition of lipoprotein lipase, 4) Growth factor in bone marrow - stimulates production of leukocytes, 5) Decreases myocardial contractility and vascular smooth muscle tone –> hypotension, 6) Intravascular thrombosis due to tissue factors that activate coagulation and inhibit thrombomodulin
What is the principal mechanism by which TNF-alpha can induce apoptosis?
cytoplasmic caspase 8
T/F: NF-kB activation is anti-apoptotic.
True - inhibits caspase-8
T/F: IL-1 and TNF-alpha have the same function and share the same receptors.
False - they do have the same function in that they both stimulate the NF-kB pathway but do NOT share a receptor
IL-1 and TNF-alpha exhibit redundancy in that they both stimulate the NF-kB pathway. What are two things that are different between the two cytokines?
IL-1 does NOT induce apoptosis, IL-1 has three subtypes: IL-1a, IL-1b, and IL-1RA
IL-1a is formed by what cells? Does it require cleavage to be activated?
formed by keratinocytes, does not require cleavage - is formed in its active state
IL-1b is formed through what pathway? Does it require cleavage to be activated?
IL-1b is synthesized in response to NF-kB gene transcription signals; DOES require cleavage to be activated
T/F: IL-1RA does not trigger cell signal when it binds to the IL-1 receptor.
True - it is a competitive inhibitor of IL-1a and IL-1b
What are the three most important cytokines of septic shock?
IL-1, TNF-alpha, IL-6
When a PAMP such as LPS binds to a Toll-like receptor, what cell signal pathway is triggered?
NF-kB pathway, results in gene transcription of TNF-alpha and IL-1
Why does a bad sunburn result in fever and cachexia?
damaged keratinocytes can release IL-1a (constitutively expressed by keratinocytes) –> results in NF-kB signaling –> transcription of TNF-alpha and more IL-1 –> TNF-alpha causes pyrexia in hypothalamus (due to prostaglandin production) and cachexia (due to inhibition of appetite and lipoprotein lipase)
Corticosteroids promote synthesis of what inhibitor of the NF-kB pathway?
IkBalpha –> dimmerizes NF-kB and sequesters it in the cytoplasm, preventing translocation to the nucleus
T/F: Corticosteroids upregulate expression of IL-1RA.
True - IL-1RA is a competitive receptor antagonist for iL-1 in the extracellular space
What are two mechanisms by which corticosteroids can inhibit innate immunity?
1) Inhibit NF-kB signaling through synthesis of IkBalpha (inhibitor of NF-kB), 2) Upregulation of IL-1RA (competitive inhibitor of IL-1a and IL-1b)
IL-2, IL-7, IL-12, IFN-gamma are examples of cytokines associated with what cells of the adaptive immune system?
Th1 helper cells
What is the function of IL-2?
T-cell growth factor - upregulates T cell replication and T-cell function; triggers T-cells to move from G1 to S phase to start mitosis; induces production of Bcl-2, which is anti-apoptotic for the targeted cell; upregulates IL-2 receptors on both the origin T-cell and neighboring T-cells; principle stimulator of IFN-gamma production during responses to viral infections; Increases IgG production when it binds to B-cells; activates and promotes macrophages and NK cells
Is IL-2 involved in the innate or adaptive immune system?
both!
What genetic defect results in Severe Combined Immunodeficiency?
IL-2 receptor defect
What is the function of IL-7?
Is a homologue for IL-2 - does everything that IL-2 does (redundancy)
What is the principal function of IL-12?
promotes cytotoxic death (lethal assassin cytokine)
How does IL-12 induce cytotoxic death?
Stimulates NK cells and CD8+ cytotoxic T cells; upregulates IFN-gamma production for antiviral defense; increases cell sensitivity to IL-2 and suppresses IL-4 (Th1 cytokine profile)
What is the function of IFN-gamma? Is it a Th1 or Th2 cytokine?
Th1 cytokine - important for antiviral activity; enhances cytotoxic T cell mediated apoptosis of infected cells, stimulates phagocytosis by macrophages, upregulates MHC-I expression on T-cells, upregulates MHC-II expression on dendritic cells, promotes B-cell production of antigen-specific IgG; inhibits IL-4 - is a counter-regulator of Th2 lymphocyte responses, activates neutrophils, NK cell stimulator
What are the main Th2 cytokines?
IL-4, IL-5, IL-10, IL-13, IL-31
Functions of IL-4
Promotes IgE class switching, promotes increased IgE production by B cells, mast cell growth factor, stimulates high affinitiy IgE receptor expression on the surface of mast cells, Promotes IL-4 production and favors Th2 polarization, downregulates IL-1, IL-6, TNF-alpha, IFN gamma
Functions of IL-13
IL-4 homologue - EXCEPT does not polarize to TH2
Functions of IL-10
Inhibits IL-12, TNF-alpha, IFN-gamma, and MHC-II costimulation by antigen presenting cells
Functions of IL-5
key growth factor for eosinophils
Functions of IL-31
pruritus – triggers JAK/Stat signaling pathway, present on umyelinated C fibers in the skin; activates eosinophils and macrophages, has pro-inflammatory effects on keratinocytes
What cytokines utilize the Jak/Stat cell signaling pathway?
IFN-alpha/beta/gamma; IL-2, IL-7, IL-9, IL-10, IL-12, IL-15, IL-21, GM-CSF, IL-31
What role does IL-1 play in the innate immune system?
Is produced by keratinocytes (and macrophages) in response to non-specific activation (e.g. injury) – results in cascade induction for local inflammation in response to infection or injury
What role does IL-1 play in the adaptive immune system?
Initiator of contact hypersensitivity and adaptive immune response to antigens exposed across the skin –> stimulates dendtritic cells, triggering them to upregulate sampling of the extracellular space, signaling them to separate from keratinocytes and migrate out of the epidermis
What is the function of IL-6?
support cytokine – enhances the actions of other cytokines present in the milieu; in high concentrations has similar effects to IL-1 and TNF-alpha; also promotes IL-2 production
IL-1 and IL-6 stimulate synthesis of what antibodies by B cells?
IgM
IL-5 and IL-6 stimulate synthesis of what antibodies by B cells?
IgA
What cells are the primary producers of IL-6?
Macrophages - in response to IL-1 or TNF-alpha activation of the NF-kB pathway
What cells produce IL-12?
macrophages and dendritic cells (cells of innate immune system) - in response to activation of NF-kB pathway
Why would a defect in IL-12 or the IL-12 receptor predispose an animal to atopic disease?
IL-12 promotes T-helper cells to produce a Th1 cytokine profile; Without IL-12, are polarized to Th2 and pro-allergic state
T/F: Naïve lymphocytes home to lymph nodes and spleen rather than tissue.
TRUE
What are addressins?
lymphocyte homing receptors expressed in tissue
What is the function of selectins and integrins?
mediate slowing, rolling, and tethering (adhesion) to local capillary epithelium
