Chapter 4 Innate Immunity Flashcards
What are the three essential functions of the innate immune system that protect us against microbes and tissue injury?
1) Innate immunity prevents, controls, or eliminates infection of pathogens
2) Innate immunity has mechanisms to rid the body of damaged tissues and for repair
3) Innate immunity readies the calvary, adaptive immune system.
What are the two major types of responses of the innate immune system that protect against microbes?
1) inflammation 2) antiviral defense
Inflammation
The accumulation of leukocytes and plasma proteins in sites of infection in the tissues which are activated to eliminate offending agents.
Antiviral defense
Changes in the cells that prevent virus replication and increase susceptibility to being killed by lymphocytes, thus eliminating reservoirs of viral infection .
PAMPs
Pathogen associated molecular patterns. Are shared by broad classes of microorganisms. Included LPS, nucleic acids distinct to microbes, ssrna, dsrna, lipoteichoic acids, oligosaccharides w/terminal mannose phosphates, etc.
DAMPs
Damage Associated Molecular Patterns. Endogenous molecules that are produced by or released from damaged and dying cells.
PRRs
Pathogen recognition receptors. Cellular receptors for DAMPS and PAMPs. can be located on the cell surface, in phagocytic vesicles, and in the cytosol of various cell types.
What are the three reasons that the innate immune system does not recognize its own cells as pathogens?
1) Normal cells don’t produce ligands for innate immune receptors 2) Receptors do not interact with, nor are they located near, cells they could recognize; 3) Regulatory proteins expressed by normal cells prevent activation of various components of innate immunity
TLRs
Toll-like receptors (Recognize PAMPs and DAMPs)
What are the two type of DAMPs that TLRs recognize? What types of TLRs recognize them?
HSPs and HMGB1. Activate TLR2 and TLR4 signaling in dendritic cells, macrophages and other cells types.
What is the structural basis of TLR specificity?
Leucine rich modules. LxxLxLxxN. Bind to hydrophobic groups like LPS. TLRs frequently form dimers that cause action
TLR1 (L/F)
Location: Plasma membrane/Function: recognition of bacterial lipopeptides.
TLR2 (L/F)
Location: Plasma membrane/Function: Recognition of Bacterial peptidoglycan
TLR3 (L/F)
Location: Endosomal Membrane/Function: Recognition of viral dsRNA
TLR4 (L/F)
Location: plasma membrane/Function: recognition of LPS ** works in concert w/ MD-2, CD14, and LPS-binding protein
TLR 5 (L/F)
Location: Plasma membrane/ Function: recognition of bacterial flagellin.
TLR6 (L/F)
Location: Plasma membrane/Function: Bacterial lipopeptide recognition
TLR7 (L/F)
Location: Endosomal membrane/Function: recognition of ssRNA
TLR8 (L/F)
Location: Endosomal membrane/Function: recognition of ssRNA
TLR9 (L/F)
Location: Endosomal membrane/Function: recognition of CpG DNA
What are the only two TLRs that do not form homodimers?
TLR1 and TLR 6
What are the only two TLR heterodimers? Do they both recognize the same thing? What do they recognize?
TLR1/TLR2 & TLR2/TLR6. Yes. They both recognize bacterial lipopeptides.
What TLRs are located on the cell surface only?
TLRs 1,2,4,5,6
What TLRs are located on the endosomal membrane only?
TLRs 3,7,8,9
What are the four major pathways activated by TLR signaling?
Nuclear factor kB (NF-kB), Activation protein-1, Interferon response factor 3 (IRF3), and IRF7
What two major TLR pathways lead to the production of the inflammatory response? How?
NF-kB and AP-1. Both stimulate the genes which encode for inflammatory cytokines (TNF & IL-1), chemokines (CCL2 and CXCL8), and endothelial adhesion molecules.
What two major TLR pathways lead to the production of the antiviral state of innate immunity? How?
IRF3 and IRF7. Both promote production of type I interferons (IFN-alpha and IFN-beta)
What is MyD88 and why is it important in the innate immune response?
MyD88 is an signaling adaptor that leads to the activation of NF-kB and is therefore responsible for producing the inflammatory response.
What TLR receptor does not lead to the activation of MyD88?
TLR3
TRIF
TIR domain-containing adaptor inducing IFN-ß. TLR3 signals through TRIF and therefore activates IRF3 and induces expression of type I interferons.
What TLR is capable of activating both MyD88 and TRIF?
TLR4. Endosomal TLRs 7/9 are also capable of activating both MyD88 and TRIF producing an inflammatory and antiviral response. TLRs 7/9 function through a MyD88 dependent and TRIF independent pathway that activates both NF-kB and TRIF.
What are the three major classes of cytosolic receptors?
NOD-like receptors, RIG-like receptors, and cytosolic DNA sensors.
NLR (Broad family definition)
NOD like receptors, are a family of cytosolic proteins, which can recognize PAMPs and DAMPs and recruit other proteins to form signaling complexes to promote inflammation. NOD stands for “nucleotide oligomerization domain-containing protein”
NOD-1
Recognizes DAP from gram negative bacterial peptidoglycan
Inflammasome complex
NLRP3 (sensor) + cytoplasmic adaptor recruits inactive capase-1.
Capase-1
Enzyme that cleaves inactive precursor forms of IL-1ß and IL-18.
How are NLRP-inflammasome responses induced?
reduction in cytoplasmic K+, flagellin, muramyl dipeptide, bacterial and viral RNA, crystals.
RIG-Like Receptors
RLRs, cytosolic sensors of viral RNA that respond to viral nucleic acids by inducing the production of type I interferons.
RIG-1
retinoic acid-inducible gene I, recognizes host RNA from viral DNA. Viral DNA has a 5’ triphosphate moiety, which is not present in mammalian host cell RNA.
MDA5
melanoma differentiation- associated gene 5
RIG-1 and MDA5
The most prevalent RLRs. Both recognize viral components via RNA-helicase domain and a C-terminal domain. Activate IRF3, IRF7, and NF-kB
STING
(Stimulator of IFN genes) DNA induced activation of type I interferon responses.
ILCs
Innate Lymphoid Cells. Bone-marrow derived. Lymphocyte morphology, antimicrobial functions, emerge fully capable of effecting w/o the need for clonal expansion, produce cytokines, does not have TCRs.
NK cells (general)
Type I ILC. Provides defense agains intracellular viruses and bacteria. Innate immune cell. Activated by IL-12 and IL-15.
What are the major functions of NK cells?
1) kill infected cells (Via the release of perforin and granzymes) . 2) produce IFN gamma
Perforin
enzyme contained in the granules of NK cells that cause the formation of pores in target cells.
Granzymes
Cause activation of signaling sequence, which cause the the cell to undergo apoptosis
IFN gamma
Produced by NK cells and CTLs. Increase macrophage ability to kill microbes. Aid in the differentiation of naive T cells into helper t cells.
stochastic
randomly determined; having a random probability distribution or pattern that may be analyzed statistically but may not be predicted precisely.
Activating Receptors
Present on NK cells. Recognize ligands on both normal cells and stress/infected/transformed cells.
KIRs
(Killer Cell Immunoglobulin (Ig) - Like Receptors) Type of activating receptor. (p.66), but largest group of inhibitory receptors, which bind a variety of class I MHC receptor
IgG1/IgG3
Antibodies that associate with infected/stress cells (specifically cells that have antigen present on its cells surface)
CD16
Activating receptor on NK cells which have a low-affinity for IgG antibodies. Binds to Fc region of IgGs, and activates signaling patterns on infected cells. Cause NK cells to kill them.
Antibody-dependent cell mediated cytotoxicity
CD16/NK/IgG1/3 mediated killing of infected cells.
MHC I
Major Histocompatibility Complex I. Molecules which are Cell surface proteins normally expressed on all healthy nucleated cells of the body
What are the functions of MHC I?
NK activation, displaying of microbial proteins on the cell surface for recognition by CD8+. Cells that are not healthy do not display MHC I receptors, which ultimately leads to their death. MHC I gives inhibitory signals to NK cells.
Missing self hypothesis
“Recognition” The ability of NK cells to become activated by host cells that lack class I MHC.
Mast Cells (Location, function)
1) Present in the skin and mucosal epithelium. Express TLRs 2) Secrete pro-inflammatory cytokines and lipid mediators in response to infections and other stimuli. 3) Have granules containing; histamine, proteolytic enzymes, TNF, prostaglandins. 4) Confer resistance against helminths and are the main cells involved in symptoms of allergies.
What is the major response the innate immune system has against viral infection?
The expression of Type I Interferons, which inhibit viral replication.
What are the major sources of IFN-alpha?
Plasmacytoid DCs
Paracrine
The release of molecules by a cell that act on nearby cells
Autocrine
The release of molecules by a cell that act on the cell
What effects do Type I interferons have on lymphocytes?
Type I interferons cause lymphocytes to stay in the lymph nodes, increasing their probability of encountering microbial antigens. CD69 is a molecule on lymphocytes which forms a complex with Type I interferons. This reduces the expression of sphingosine 1-phosphate receptor S1PR1. No binding means no egress from the lymph nodes.
egress
The process of leaving or going out from a place
What effects do Type I interferons have on NK, CTLs, and other T Cells?
Type I interferons increase the cytotoxicity of NK cells, and CD8+ CTLs and promote the differentiation of helper T cells
What role does Type I interferons play in the regulation of MHC I?
Type I interferons upregulate expression of Class I MHC molecules and thereby increase the probability that virally infected cells will be recognized by CD8+ CTLs.
Two signal hypothesis
signal 1 (antigen), signal 2 (molecules generated by the innate immune response) ; works to ensure that immune responses are specific
What are some examples of secondary signals for the two-signal hypothesis?
Co-stimulators for T cells, cytokines for both T and B cells, complement breakdown products for B cells.
IL-12’s Role in adaptive immunity
stimulates differentiation of CD4+ T
IL-15
promotes the survival of memory CD8+ T cells
IL-6 promotes the production of antibodies by activated B cells
promotes the production of antibodies by activating B cells
Adjuvants
substances that need to be administered together with purified protein antigens to elicit maximal T cell dependent immune responses, work by stimulating innate immune responses at the site of antigen exposure.
What is the importance of IL-10 in innate immunity?
IL-10 is produced by dendritic cells and macrophages. Acts on dendritic cells and macrophages to decrease the amount of IL-1,TNF, IL-12. Excellent example of negative feedback.
