Review Flashcards
Pattern Recognition Receptors (PRR’s) are important for recognizing signs of cell damage (DAMPs) or microbial structures (PAMPs). What are the two main types of PRRs, and where are they located (in what cellular compartment)? The cellular compartment affects what exactly they recognize–so describe that.
TLRs: plasma membrane, endosomal vesicles on plasma membrane, TLRs recognize stuff on microbial cell walls: lipids, peptides polysaccharides. TLRs that recognize nucleic acids are in endosomes, into which microbes are ingested and where the microbes are digested and their nucleic acids are released. NLRs: cytosolic, recognize PAMPs and DAMPs.
A 64 year old male presents with pain and swelling in his left big toe joint, and is diagnosed with a gouty flare. An inflammatory reaction occurs when uric acid crystal deposit in joints, leading to cellular necrosis. Inflammatory cells have an inflammasome complex including a cytosolic receptor ______ which recognizes the crystals, subsequently releasing _____ and cleaving ____ to an active form. What is the function of this active form?
Extra Credit: Gout isn’t the only disease associated with the inflammasome. What is the other main disease we talked about in class?
NLR caspase-1 IL-1 IL-1 causes fever, acute inflammation.
activates endothelium to express adhesion molecules. induces chemokine secretion to recruit WBCs.
Atherosclerosis
TLR engagement results in upregulation of two major transcription factors. What are they, and what do they result in?
Gain of function mutations in NLRP-3 result in periodic fever syndromes, which are called _____ syndromes. We can respond to this with what treatment?
autoinflammatory snydromes
IL-1 antagonist
What is the function of Type I interferons? How do they work?
Type I interferons produced in response to viruses act on infected and uninfected cells and activate enzymes that degrade viral nucleic acids and inhibit viral replication, inducing what has been called an antiviral state.
What are two types of blood-circulating phagocytes, and what do they do during times of inflammation? What is the difference?
Neutrophils and monocytes, which go to the site of infection to recognize and ingest microbes for intracellular killing.
Neutrophils only last for a few hours in tissues: first responders, but do not provide prolonged defense.
Monocytes enter extravascular tissues and differentiate into macrophages, which then survive for long periods.
What is the role of li and CLIP? What other protein is required for this to work?
CLIP or Class II-associated invariant chain peptide is the part of the invariant chain (Ii) that binds MHC class II groove and remains there until the MHC receptor is fully assembled. The purpose of CLIP is to prevent the binding of self-peptide fragments prior to MHC II localization within the endo/lysosome.
The antigen is loaded following release of invariant chain in an acidified endosome. Late endosomes/lysosomes also contain a class II MHC like protein called DM, whose function is to exchange CLIP in the class II MHC molecule with other peptides that may be available in this compartment and can bind to the MHC molecule with higher affinity.
List the cell surface proteins on the T cell and what they do.
TCR: binds antigen-MHC complex
CD3: associated with TCR for signal transduction
CD28: costimulator, binds B7 on APC
LFA-1: adhesion molecule, binds ICAM-1 on APC
CXCR4, CCR5: coreceptors for HIV
CD4, CD40 L (on Helper T cells)
CD8, CXCR4, CCR5 (on Cytotoxic T cells)
CD4, CD26 (on Regulatory T cells)
Cyclosporine functions as an immunosuppressant by inhibiting calcineurin. How does this work?
When a T cell receptor binds with an APC, this results in changes in gene transcription via:
TCR has CD3, which has cytoplasmic regions called ITAMs, tyrosine phosphorylation, ZAP-70 -> PLCy, PIP2 -> DAG + IP3, calcium influx from ER< activates calcineurin, cleaves phosphates from NFAT, which then results in transcription of IL-2 (stimulates T cells)
anyway, so if you inhibit calcineurin, you can’t have that IL-2 transcription–> inhibits T cells, = immunosuppressant!
What does IL-2 do? What causes its secretion?
It’s a growth factor for T cells. It causes high affinity Il-2 Receptor (CD25).
When T cell is activated, results in the NFAT activation which then increases expression of IL-2, Il-2r
What is ICOS? What is PD-1?
Inducible T-cell costimulator is an immune checkpoint protein that in humans is encoded by the ICOS gene.
CD278 or ICOS (Inducible T-cell COStimulator) is a CD28-superfamily costimulatory molecule that is expressed on activated T cells. It is thought to be important for Th2 cells in particular.
PD-1: Programmed Death Protein: terminates response of T cells.
What is the key transcription factor required in Th1 differentiation? What about Th2? Th17?
T-bet (Th1)
GATA-3 (Th2)
RORyt (Th17)
chronic mucocutaneous candidiasis, or repeated fungal infections, can be connected with an inherited defect in Th17. Why?
Th17 is induced in response to extracellular bacterial or fungal infections. Release Il-17 and Il-22. Il-17 results in leukocyte recruitment (neutrophils) , Il-22 maintains integrity of mucal barriers. These also stimulate defensin production, which are locally produced endogenous antibiotics.
What is the effect of TGFb on immune responses? how does this change if it’s paired with specific other chemokines (which ones)?
inhibits immune responses
unless with IL-1, Il-6: then results in Th17 production
How are CD8+ T cells activated? What is the role of cross-presentation?
Recognize antigen presented on MHCI. However, there is no costimulation from B7 on APC binding with CD28 equivalent, so this means some APCs present antigens they’d normally put on MHCII’s on MHCI’S instead.
CD4+ T cells help out bc CD40L binds the CD40 on APCs, which makes the APCs better at presenting Ag and costimulation.
This all results in differentiation into active CTL’s and memory cells.
How do CTL’s work?
They secrete cytotoxic proteins into the immune synapse.
Granzyme B: activates caspases for apoptosis
Perforin disrupts target membranes for delivery
Fas ligand on CTLs, Fas (CD95) on target cells –> apoptosis
