Term
| What determines antigen specificity on a B cell? |
|
Definition
|
|
Term
| What determines AG specificity on a T cell? |
|
Definition
|
|
Term
| Is the generation of AG specific receptor on B or T cell AG dependent or independent? |
|
Definition
|
|
Term
| What causes B or T cells to proliferate and differentiate? |
|
Definition
| after the cells mature and are in the periphery, interaction of their receptors and AG causes this |
|
|
Term
| What does differentiation lead to the generation of? |
|
Definition
| memory cells and effector cells |
|
|
Term
| When has to happen to have AG stimulation? |
|
Definition
|
|
Term
| How many ASR have to crosslink to get AG stimulation? |
|
Definition
| exact number isn't known, but more than 2 - like 10-100 |
|
|
Term
| How do B cells and T cells bind AG? |
|
Definition
| B cells bind AG directly, T cells bind to the antigenic peptide-MHC complex |
|
|
Term
| Why don't haptens generate an immune response? |
|
Definition
| there's only 1 binding site, so it can't crosslink receptors |
|
|
Term
| Where do the 2 signals needed for activation come from? |
|
Definition
| the 1st signal is the AG binding to the ASR, the 2nd is from the innate system |
|
|
Term
| The signal in teh 2 signal process that is not AG specific |
|
Definition
| the 2nd signal - it works on lots of T or B cells |
|
|
Term
| If the 2nd signal in the 2 signal activation process is not specific, why doesn't it turn on all T or B cells? |
|
Definition
| B/c only those cells that are already turned on by signal 1 will respond to signal 2 and lead to full activation - signal 2 won't work without signal 1 |
|
|
Term
| In T cell activation, what does the 1st signal do to the TCR complex? |
|
Definition
| when the TCR interacts with the AG and MHC, the tails of CD3 and CD4/CD8 cluster - the CD4/8 bring in Lck, which phosphorylates the ITAMs no the CD3 |
|
|
Term
| What does the phosphorylation of the ITAMs do in a TCR complex? |
|
Definition
| creates a docking station for Zap-70 |
|
|
Term
| What ITAMs are particularly important in the CD3? |
|
Definition
| the ones on the zeta homodimer |
|
|
Term
| What kind of enzyme is Lck? |
|
Definition
|
|
Term
| After Zap-70 binds, what happens to it? |
|
Definition
|
|
Term
| What are the 3 main pathways that can be activated by the phosphorylation of Zap-70? |
|
Definition
| *calcium mediated*PKC mediated*G-protein mediated |
|
|
Term
| What are three things that happen in intracellular signalling events? |
|
Definition
1) phosphorylation/dephosphorylation, which can cause activation and translocation of DNA binding proteins to the nucleus
2) binding of things to a specific promotor site
3) an increase in transcription |
|
|
Term
| What happens when phospholipase C is activated? give intermediates and end results. |
|
Definition
PLC-->generates lipid messengers by hydrolyzing part of the phospholipid cell membrane-->get IP3 and DAG(diacylglycerol)
*IP3 (inositol-3-phosphate)-->causes calcium influx-->adenylate cyclase activation-->cAMP, the calcium released binds to calmodulin-->calmodulin activated-->associates with calcineurin-->calcineurin dephos-->activates NFAT(a transcription factor) that translocates to the nucleus
*DAG causes PKC activation-->phos IkB, which is normally bound to NFkB(transcription factor)-->NFkB gets released, translocates to the nucleus |
|
|
Term
| Describe the overview of the RAS activation pathway and what it results in. |
|
Definition
| Ras-GDP gets phos to RAS-GTP, which activates it-->induces transcription of Fos-->Fos gets phos by MAP kinase and dimerizes with Jun-P, creating a transcription complex AP-1, which causes transcriptional activation of several genes |
|
|
Term
| What purpose does co-stimulation serve? |
|
Definition
| It asks are you sure you want to do this? - it's a double check that you really want to activate the cell and it ensures that cells respond to AG only on professional APCs |
|
|
Term
| What do APCs have to have done in order to provide a 2nd signal to a l'cyte? |
|
Definition
| recognize that there's danger present via pattern recognition (cell damage, inflammation, etc) and have become activated |
|
|
Term
| Is costimulation a single step or a multiple step process? |
|
Definition
| multiple - you have to have enough 2nd signal to make the process work |
|
|
Term
| What happens when a resting APC presents an AG to a t cell? |
|
Definition
| The T cell either has no response or goes into anergy (functional inactivation) b/c it didn't get any costimulation |
|
|
Term
| What happens when an activated APC presents AG to a T cell? |
|
Definition
| The APC puts out B7 which interacts with CD28 on the T cell, providing a 2nd signal - the T cell also releases various cytokines like IL-2 all of which cause the T cell to proliferate and differentiate |
|
|
Term
| What is the most powerful set of costimulators? |
|
Definition
| B7 (from APC) - CD28 (on T cell) |
|
|
Term
| What are the most powerful cytokines released as costimulators and what do they do? |
|
Definition
| IL-1 and IL-6 - they make other cells more sensitive to activating signals either by lowering the requirement for signal or by amplifying the signal - the net result is that you need less AG |
|
|
Term
| What are the 2 types of B7? |
|
Definition
| B7-1 (CD80) and B7-2 (CD-86) |
|
|
Term
| Who expresses B7 and what type? |
|
Definition
| macrophages, B cells and dendritic cells - all of these express both types of B7 |
|
|
Term
| What causes up-regulation of B7 and is there normally a lot on a cell? |
|
Definition
normally not a lot on a cell - upregulation can be caused by
*exposure of the APC to microbial products*signals generated during inflammation*TCR-AG-MHC interaction on the APC - the APC expreses CD40, which induces expression of C40L on the T cell |
|
|
Term
| Explain how CD40 relates to B7 upregulation. |
|
Definition
| TCR-Ag-MHC interaction causes the upregulation of expression of CD40L on the T cell, which interacts with CD40 - this interaction upregulates the expression of B7 on the APC |
|
|
Term
| Is CD28 expressed on all T cells? |
|
Definition
| yes - it's on resting and activated T cells |
|
|
Term
| Is CTLA-4 on all T cells? |
|
Definition
| no - it's only on activated T cells |
|
|
Term
| What is the function of CTLA-4? |
|
Definition
| It acts as a brake (B7-CD28 is the gas for T cell P&D) - it competes for B7 and blocks CD28-B7 binding by competitive inhibition - very important b/c if it wasn't there your T cells would proliferate out of control and your spleen and LN would get massive and you'd eventually die |
|
|
Term
| Explain IL-2 and how it causes proliferation and differentiation. |
|
Definition
| Naive T cells have a low/med affinity IL-2 receptor (beta and gamma chains only) - when the t cell is activated (1st and 2nd signals), this causes the T cell to make the alpha chain, which associates with beta and gamma to make a high affinity IL-2 receptor * the t cell also starts to secrete IL-2, which binds to the high affinity receptor, causing P&D - the IL-2 preferentially binds to and acts on the same T cell, so you get a lot of T cells specific for that particular AG that initiated the 1st signal |
|
|
Term
| What are the relative affinities for IL-2 of the beta-gamma IL-2R, alpha only, and alpha-beta-gamma |
|
Definition
| alpha only has low affinity and is only on activated T cells - b/g has intermediate affinity and is on resting T cells, all three together has high affinity and is only on actvated cells |
|
|
Term
| What is the overall pathway for T cell activation (overall steps)? |
|
Definition
1)AG stimulation
2) costimulation
3)activation-->induction of high affinity IL-2R, secretion of IL-2, IL-2 binds
4)P&D
5) downregulation by CTLA-4-B7 binding |
|
|
Term
|
Definition
| microbial products that bind TCR and MHC-peptide together outside the variable beta region of the TCR |
|
|
Term
|
Definition
| b/c they bind outside the TCR and MHC, they trick the TCR into thinking that it's come in contact with the correct AG-MHC, so this causes the T cell to be activated by all kinds of things that it normally wouldn't |
|
|
Term
| What does the binding of a superAG cause? |
|
Definition
| non-specific activation of T cells |
|
|
Term
| Why do you use superAG in the lab? |
|
Definition
| it lets you turn on lots of T cells independent of the AG specificity of the TCR |
|
|
Term
| What do superAG cause in vivo? |
|
Definition
| systemic inflammation leading to shock - a huge drop in BP b/c all the pipes are leaking - TSS is caused by a superAG |
|
|
Term
| What do adhesion molecules do in the immune synapse? |
|
Definition
| stabilize the interaction of the TCR-MHC/AG and upregulate more adhesion molecules |
|
|
Term
| What are two really important adhesion molecules? |
|
Definition
| LFA-1 (receptor on T cell) - ICAM (ligand on APC) and CD2-LFA-3 |
|
|
Term
| Where is the immune synapse? |
|
Definition
| between a T cell and an APC around the TCR-MHC/AG interaction |
|
|
Term
| How do naive T cells get help finding AG? |
|
Definition
| APCs capture AG and cocentrate it in peripheral lymphoid organs |
|
|
Term
| How does the right type of T cell respond to an AG? |
|
Definition
| CD4/CD8 receptors bring about specificity |
|
|
Term
| What makes sure that T cells respond to microbial AG but not harmless proteins? |
|
Definition
| to be activated you have to have costimulators which are induced by microbes in APC |
|
|
Term
| How do you get a large enough response to an AG for activation? |
|
Definition
| by amplification mechanisms |
|
|
Term
|
Definition
| molecules that affect the function of cells and bind to receptors on target cells |
|
|
Term
| What are some examples of cytokines? |
|
Definition
| interleukins, interferons, colony stimulating factors, growth factors, tumor necrosis factors |
|
|
Term
| What ILs determine what type of Th cell is produced? |
|
Definition
| IL-12 pushes a cell down the Th1 path, IL-4 pushes it down the Th2 path |
|
|
Term
| What do Th1 cells secrete and what does this do? |
|
Definition
| secrete IFN gamma - this activates m'phages to kill microbes, also inhibits Th2 proliferation |
|
|
Term
| What do Th2 cells secrete and what do they do? |
|
Definition
| IL-10 - inhibits the Th1 cells (inhibits production of IFN gamma), and IL-4&5 - activates mast cells, eosinophils, and B cells (IgE AB production) |
|
|
Term
| Are both Th1 and Th2 responses codominant? |
|
Definition
| No - they tend to go in 1 direction or the other - which one depends on which IL is made 1st, wchih is determined by what bugs are there |
|
|
Term
| What "bugs" tend to make a Th1 cell form and how does that happen? |
|
Definition
| small intracellular pathogens (bacteria, viruses, etc) make an APC make IL-12, exposing the T cells to IL-12 which promotes Th1 differentiation - Th1 then makes IFN gamma, whcih activates m'phages and these kill the ingested microbes |
|
|
Term
| What sets off a Th2 differentiation? |
|
Definition
| large extracellular pathogens (helminths, etc) - mast cells make IL-4, which promotes differentiation into Th2 - the Th2 make more IL-4 and IL-5, which promotes IgE (class switching) and eosinophil mediated immunity |
|
|
Term
| Who makes IL-12 and what is it's function? |
|
Definition
| macrophages - promotes Th1 differentiation |
|
|
Term
| IFN gamma - produced by?function? |
|
Definition
| NK and TH1 - inhibits production of IL-4 by Th2, activates macrophages, increases complement binding and opsonizing AB production (these AB bind to Fc receptors on M'phages and activate complement) |
|
|
Term
| IL-4 - produced by? function? |
|
Definition
| mast cells and Th2 - promotes Th2 differentiation by inhibiting IL-12, stimulates B cells favoring class switching to IgE production |
|
|
Term
| IL-10 - made by? function? |
|
Definition
| macrophages and TH2 - inhibits production of IL-12 |
|
|
Term
|
Definition
| CTL induction (TH1 thing) |
|
|
Term
| What types of immunity do TH1 and Th2 favor? |
|
Definition
| TH1 - cell-mediated, Th2 - humoral |
|
|
Term
|
Definition
| TH2 cells, activates eosinophils |
|
|
Term
| What general type of cells make IL-2,4,5,IFN gamma, and TGF-beta? |
|
Definition
| CD4+ - these are Th cells |
|
|
Term
| Who makes IL-2 and what does it do? |
|
Definition
| CD4+ and CD8+, promotes T cell growth and stimulation |
|
|
Term
|
Definition
| inhibits T cell activation |
|
|
Term
| What does autocrine mean? |
|
Definition
| the cytokine made affects the cell that produced it |
|
|
Term
|
Definition
| the cytokine produced affects other cells in relatively close proximity |
|
|
Term
|
Definition
| the cytokine produced passes through circulation to affect other cells farther away |
|
|
Term
| what are the 4 families of cytokines? |
|
Definition
| hemaotpoeitin (class I), interferon (class II), TNF, and chemokine |
|
|
Term
| What are the 5 families of cytokine receptors? |
|
Definition
| hematopoeitin, interferon, TNF, chemokine, Ig superfamily |
|
|
Term
| What is the general structure of the hematopoeitin family? |
|
Definition
| lots of alpha helix, little beta pleated sheet - 2 domains extracellularly- there are 4 conserved cysteine residues in 1 domain and trp-ser-X-trp-ser in the other domain |
|
|
Term
| What are some ligands for Class I cytokine receptors? |
|
Definition
| IL-2 through 9,11,12,13,15, growth hormone, etc |
|
|
Term
| What are is the structure of class II receptors (interferons)? |
|
Definition
| 2 domains - has a conserved cysteine motif |
|
|
Term
| What are common ligands for class II receptors? |
|
Definition
| IFN alpha, beta, gamma, IL-10 |
|
|
Term
| What do TNF receptors look like? |
|
Definition
| 4 domains, all with conserved cysteine motifs |
|
|
Term
| What are the ligands for TNF receptors? |
|
Definition
| TNF alpha, beta, CD40, nerve growth factor, FAS |
|
|
Term
| What do Ig superfamily receptors look like? |
|
Definition
| Ig's - 3 domains, s-s loop |
|
|
Term
| What are common ligands for Ig receptors? |
|
Definition
|
|
Term
| What does a typical chemokine receptor look like? |
|
Definition
| Like a 7 transmembrane receptor |
|
|
Term
| What are common ligands for chemokine receptors? |
|
Definition
|
|
Term
| What are the subfamilies of class I receptors defined by? |
|
Definition
|
|
Term
| what are the 3 subfamilies of class I (hematopoeitin) receptors and what is their common feature? |
|
Definition
| IL-6 (gp 130), GM-CSF (beta chain), IL-2 (gamma subunit) |
|
|
Term
| what is the role of the common chain in cytokine receptors? |
|
Definition
*to increase the affinity of the receptor *signal transduction
**specificity of the receptor is determined by the unique chains in the receptor |
|
|
Term
| What does the presence of a common shared chain result in? |
|
Definition
| An overlap of function and sometimes antagonism - if there are 2 types of alpha chains present that can associate with 1 beta chain, if 1 alpha combines with its cytokine 1st and associates with the beta chains, the other alpha can't bind to its cytokine and associate |
|
|
Term
| What does binding of a cytokine to its receptor trigger (generally)? |
|
Definition
| *brings the units of the receptor together, forming a dimer or trimer, which leads to the activation of intracellular signalling pathways, which turns on gene transcription |
|
|
Term
| In general, what steps does signal transduction in most class I and II receptors involve? |
|
Definition
*different Janus kinases (JAK) associated with the signaling chain
*the binding of cytokine leads to JAK activation (phos of JAK), alpha and beta chains associate
*JAK phos tyrosines on the signaling chain, creating a docking station for STAT
*STAT binds by joining the SH2 domain on STAT with the docking station
*JAK phos STAT, STAT aggregates and forms dimers
*STAT dimers are translocated to the nucleus
*STAT dimers in the nucleus induce the transcription of genes containing regulatory sequences (turns genes on or off) |
|
|
Term
| What is one big promotor that is affected by cytokine binding to a receptor |
|
Definition
|
|
Term
| What does AG stimulation lead to in terms of cytokines? |
|
Definition
| expression of cytokines and cytokine receptors and the ability to respond to signals |
|
|
Term
| Do all cells have cytokine receptors? |
|
Definition
|
|
Term
| In cells with cytokine receptors, what are the responsive genes determined by? |
|
Definition
|
|
Term
| What is pleiotropy and what is an example? |
|
Definition
| 1 cytokine affecting multiple cells - i.e. IL-4 (stim proliferation in B cells, thymocytes, and mast cells) |
|
|
Term
| What is redundancy and what is an example? |
|
Definition
| multiple cytokines affecting one cell - i.e. IL-2,4,5 (stim proliferation in B cells) |
|
|
Term
| what is synergy and what is an example? |
|
Definition
| the sum of 2 cytokines is greater than either one alone - i.e. IL-4 and 5 together induce class switching to IgE better than IL-4 alone |
|
|
Term
| What is antagonism and what is an example? |
|
Definition
| opposite effects - 1 cytokine does one thing another does the opposite thing - i.e. IFN gamma from a T cell blocks IL-4 induced class switching b/c IFN gamma wants to make IgG1 |
|
|
Term
| What does the signal received by a cell depend on? |
|
Definition
| the cytokines in the environment and the receptors that the cell has |
|
|
Term
| What is a useful effect of redundancy? |
|
Definition
|
|
Term
| What can cascades do for signaling? |
|
Definition
| *produce or inhibit responses necessary for the next step in signaling to occur*induce receptor for 2nd cytokine*induce necessary activity |
|
|
Term
| What is the basic pathway of NO production in macrophages? |
|
Definition
| IFN gamma primes m'phages, which induces transcription of the iNOS gene*LPS from the bacteria induces the m'phage to make TNF by binding to its TLR - TNF triggers NO production |
|
|
Term
| What do competitive cytokine inhibitors do? |
|
Definition
| they are antagonists - bind to receptors and do other things |
|
|
Term
| What do soluble receptors do? |
|
Definition
| breaks off the cell and floats around where it binds to cytokine - since it isn't bound to the cell the cytokine won't affect the cell and do its job - this effectively dilutes the cytokine concentration |
|
|
Term
| What do soluble receptors do? |
|
Definition
| breaks off the cell and floats around where it binds to cytokine - since it isn't bound to the cell the cytokine won't affect the cell and do its job - this effectively dilutes the cytokine concentration |
|
|
Term
| What is an opposite effect in terms of cytokines? |
|
Definition
| when you have a 2nd cytokine that can bind and induce an effect opposite to the original one - what effect you get depends on what is present in a higher concentration |
|
|
Term
| What do decoy receptors do? |
|
Definition
| they bind to the cytokine receptor but don't do anything |
|
|
Term
| Where do you typically see soluble cytokine receptors? |
|
Definition
| TNF, IL-6, IL-2, and IFN gamma |
|
|
Term
| How are soluble receptors released? |
|
Definition
| a cell protease chews on the base of the receptor and releases the binding domain |
|
|
Term
| How does a soluble cytokine receptor trigger a response on another cell? |
|
Definition
| the shed receptor associates witha common signaling chain on another cell and triggers a response |
|
|
Term
| Do cytokines usually work alone? |
|
Definition
|
|
Term
| what is the central axis of the cytokine network? |
|
Definition
| te macrophage and the Th cell |
|
|
Term
| What determines the effectors that are ultimately used against a pathogen? |
|
Definition
| depends on the intercommunication of various systems throughout the cytokine network |
|
|
Term
| What is required for cell mediated responses? |
|
Definition
| direct cellular participation |
|
|
Term
| What was originally meant by CM response? |
|
Definition
| a protective response that could not be transferred by serum (AB) alone |
|
|
Term
| How can CMI be transferred? |
|
Definition
|
|
Term
| Can AB be involved in CMI? |
|
Definition
| yes but the cells are required for effector function, not just the production of AB |
|
|
Term
| How is humoral immunity transferred? |
|
Definition
|
|
Term
| Are cells involved in humoral immunity? |
|
Definition
| yes, they are involved in the production of AB, but AB is the key effector |
|
|
Term
| How do you experimentally prove what is the effector in CMI? |
|
Definition
| give an animal listeria and collect the l'cytes - if you mix immune T cells and listeria the cells will kill the listeria (but non-immune cells won't) - serum alone won't kill it - if you mix immune T cells, resting m'phages, activated m'phages, and listeria, you find out that it's actually the activated m'phages that do the killing, not the T cells |
|
|
Term
| What are the 2 roles for immune T cells? |
|
Definition
| Th1 cells secrete cytokines that activate the m'phage and cause it to kill it - they also cause inflammation * CD8+ cells directly kill infected cells |
|
|
Term
| What are the effector cells in CMI? (3 types) |
|
Definition
| lymphoid, MHC-restricted killers - CTL * lymphoid, non-MHC restricted killers - NK, LAK, K cells carrying out ADCC * nonlymphoid killers - m'phages, eosinophils, etc |
|
|
Term
|
Definition
| must recognize AG in association with MHC class I and get IL-2 and co-stimulation |
|
|
Term
| What helps induce CTL and why? |
|
Definition
| Th cells help b/c they can produce IL-2 - most CTL don't make this on their own |
|
|
Term
|
Definition
| no - CD doesn't determine function, it determines MHC restriction - there are CD4+/MHC II CTL, but they aren't common |
|
|
Term
| Describe the process of CTL induction. |
|
Definition
| AG stimulates Th to make costimulatory signals, leads to clonal expansion now in an IL-12 rich, IL-4 low environment, Th1 differentiation takes place - these now produce IL-2 * pre-CTL are activated by AG+MHC I and costimulation * upregulates IL2R, receives IL-2 from Th1 *these now proliferate and become active *when AG has cleared, IL-2 declines, and CTLs and Th1 undergo apoptosis |
|
|
Term
| What is the role of IL2/IL2R interaction in CTL activation? |
|
Definition
| it ensures that only cells with IL2-R will respond to IL2 and become activated - to have IL-2R you have to have been stimulated by an AG, so the net result is that you only get expansion of the cell that is particular for that AG |
|
|
Term
| What is a side effect of CTL and Th1 undergoing apoptosis after AG is cleared? |
|
Definition
| you don't get nonspecific cell damage |
|
|
Term
| In terms of IL-2R, IL-2, proliferation, or effector cytotoxic funcational, what are CTL-P, activated CTL-P, and CTL? |
|
Definition
| CTL-P - nothing, activated CTL-P - IL-2R and IL-2 only (maybe), CTL does all of it, although it may not be strong IL-2 expressor |
|
|
Term
| Describe co-stimulation (how an APC ultimately activates a pre-CTL). |
|
Definition
| APC activates Th1 - the IFN gamma produced and CD40:CD40L interaction causes upregulation of costimulatory and adhesion molecules on APC - the TH1 releases IL-2, which activates pre-CTL |
|
|
Term
| Are pre-CTL and Th1 attached to the same APC? |
|
Definition
| sometimes, or the IL-2 released can affect CTL on different APCs - it's more effective if it's on the same cell b/c the IL-2 won't diffuse and dilute out |
|
|
Term
| What is the difference between naive CTL and memory CTL? |
|
Definition
| memory CTL can make their own IL-2 - sometimes enough to stimulate P&D without Th1 help or other costimulators like C7-CD28 interaction |
|
|
Term
| What 3 things to activated CTL do? |
|
Definition
| *kill the target cell with correct AG in MHC I * secrete large amounts of IFN gamma * increases binding to cellular adhesion molecules |
|
|
Term
| What does IFN gamma that is secreted by CTL do? |
|
Definition
| helps drive the Th1 response |
|
|
Term
| What part of CMI requires costimulation? |
|
Definition
| activation only - effector functions don't require costimulation |
|
|
Term
| Do you have to have B7-CD28 interaction between a CTL and a target cell? |
|
Definition
|
|
Term
| What is on a CTL and a target cell when it's getting ready to kill (molecules)? |
|
Definition
| CTL - TCR, CD8, LFA-1, CD2 * target - MHC+AG, ICAM-1, LFA-3 |
|
|
Term
|
Definition
| tumor cells and virally infected cells |
|
|
Term
| Are NK cells usually AG specific or MHC restricted? |
|
Definition
|
|
Term
| What type of cells are NK cells usually? |
|
Definition
| a large granular lymphocyte |
|
|
Term
| Do NK cells have rearranged genes? |
|
Definition
| no - they haven't rearranged TCR or Ig genes |
|
|
Term
| What is required for NK cells to kill? |
|
Definition
|
|
Term
|
Definition
| it's not phagocytic* they kill similarly to a CTL - the cytoplasm has granules with perforin and granzymes, after the NK cell attaches to the target, degranulation occurs |
|
|
Term
| What increases the number and activity of NK cells? |
|
Definition
|
|
Term
| What do NK cells produce? |
|
Definition
|
|
Term
| Does an NK response generate memory? |
|
Definition
|
|
Term
| What mode is the default in NK cells? |
|
Definition
| kill - the don't kill signal comes from a self-peptide/MHC I interacting with an inhibitory receptor - if it doesn't get that the activating receptor takes over and it kills that cell |
|
|
Term
| What are the 2 types of receptors on NK cells? |
|
Definition
| activating receptors (NCR) and inhibitory receptors |
|
|
Term
| What type of receptors are activating receptors on NK cells? Give examples |
|
Definition
| C type lectins - NKR-P1 and proteins NKp30, 33, and 46, which are part of the Ig superfamily |
|
|
Term
| What types of inhibitory receptors are there? |
|
Definition
| C-type lectins also - NKG2/CD94 and Ig superfamily receptors - KIR (killer cell inhibitory receptors) |
|
|
Term
| What are the most reliable markers for NK cells and why? |
|
Definition
| NCRs - b/c they are selectively expressed by NK cells |
|
|
Term
| What proteins are expressed by all resting and activated NK cells? |
|
Definition
|
|
Term
| What protein is only expressed by activated NK cells? |
|
Definition
|
|
Term
| How can NK cell mediated cytotoxicity be disrupted? |
|
Definition
| by mIg-mediated masking of NCR |
|
|
Term
| What correlates with an NK cell's cytotoxicity? |
|
Definition
| the surface density of NCRs |
|
|
Term
| Structurally, what class do NCRs fall into? |
|
Definition
|
|
Term
| How do NCRs induce killing? |
|
Definition
| when an AG crosslinks NCRs, the NCRs mediate NK cell triggerig, leading to target cell lysis and cytokine production |
|
|
Term
| When is induction of NK cell activation possible? |
|
Definition
| Only when there is no KIR-HLA class I interaction (this is the "don't kill me" signal |
|
|
Term
| What do inhibitory receptors have on them? |
|
Definition
| ITIMS - immunoreceptor tyrosine based inhibitory motifs |
|
|
Term
|
Definition
| a protein that binds to a particular carbohydrate |
|
|
Term
|
Definition
| activating receptor that binds to heat shock proteins on stressed cells - causes activation of NK |
|
|
Term
|
Definition
| on the surface of NK, TCR-1, and TCR-2 T cells |
|
|
Term
| What is NKG2d structurally? |
|
Definition
|
|
Term
| Is binding of HSP to NKG2d enough to kill the cell? |
|
Definition
| sometimes, but sometimes killing requires activation through both NKG2d and NCR |
|
|
Term
|
Definition
| lymphoid activated killer |
|
|
Term
| Are LAKs natural or artificial? |
|
Definition
|
|
Term
|
Definition
| You remove NK cells from the blood and culture them with high concentrations of IL-2 and then infuse them back into the patient with a lot of IL-2 - this is mainly used in cancer therapy, you get really activated NK cells |
|
|
Term
| What are K cells involved in? |
|
Definition
| ADCC - antibody dependent cellular cytotoxicity |
|
|
Term
|
Definition
| AB binds to a target cell - a K cell with an Fc receptor binds to the Fc part of the AB and kills that cell nonphagocytically |
|
|
Term
| What provides the specificity and killing power in ADCC? |
|
Definition
| The cell provides the killing power, the AB provides the specificity |
|
|
Term
| Can cells other than K cells do ADCC? |
|
Definition
| yes - some CTL and NK and other nonlymphoid cells (eosinophils, m'phages, monocytes, neutrophils) |
|
|
Term
| What are the 2 main lymphoid killing mechanisms? |
|
Definition
| granules - perforin, etc, and receptors |
|
|
Term
| Who uses lymphoid killing mechanisms? |
|
Definition
|
|
Term
| Describe granule associate killing |
|
Definition
| When a LK comes into contact with a target, its granules cluster into 1 area of the cell - the cells make contact and the granules are dumped into the interface, which is membrane bounded like a suction cup - perforin monomers insert into the membrane of the target cell polymerize, and make holes in the membrane - granzymes go into the pores created by perforins and activate the caspase cascade, resulting in apoptosis |
|
|
Term
| Why is it important that the granules be dumped into the membrane bound interface? |
|
Definition
| that way, it limits the granule diffusion, which means it's more effective and it limits damage to neighboring cells |
|
|
Term
| What starts the caspase cascade? |
|
Definition
| procaspase being proteolytically cleaved to form caspase |
|
|
Term
| How does receptor mediated killing work? |
|
Definition
| Activated T cells express high levels of Fas and FasL - when they associate, FasL trimerizes Fas, bringing the tails together and triggering the caspase cascade and apoptosis - Fas can be on the T cell itself or on a target cell |
|
|
Term
| What does IFN/TNF do in killing a cell? |
|
Definition
| it slows down protein synthesis and makes other cells more sensitive to TNF - apoptosis requires a lot of protein to make a "don't die" signal, so without adequate anti-apoptotic protein, the die signal overcomes the don't die signal |
|
|
Term
| When FasL and Fas trimerize, what are the signals that take place in the target cell specifically? |
|
Definition
| trimerized Fas binds death domain containing adapter proteins, which recruit and activate caspases, which cleave I-CAD, releasing CAD, which goes to the nucleus and cleaves DNA |
|
|
Term
| What happens in cells during apoptosis? |
|
Definition
| the cell shrinks and breaks apart into apoptotic bodies - no gut release, so no inflammatory response |
|
|
Term
|
Definition
| the killing by a killer cell - the killer comes up, attaches to the target, releases perforin and granzyme, expresses FasL, secretes TNF and leaves |
|
|
Term
| Can killer cells kill more than 1 cell? |
|
Definition
| yes - delivers hit and leaves to kill another cell |
|
|
Term
| Are the processes in a lethal hit separate and distinct? |
|
Definition
| not always - all may function together to bring on cell death |
|
|
Term
| What are the 2 kinds of TNF? |
|
Definition
| TNF beta - lymphotoxin, made by l'cytes, and TNF alpha - made by m'phages and l'cytes |
|
|
Term
| What cytokine do m'phages secrete after encountering an AG? |
|
Definition
| IL-12 - helps push a naive T cell down the Th1 pathway |
|
|
Term
| What does an activated Th1 cell secrete? |
|
Definition
| IFN gamma, which activates the m'phage to kill the microbe |
|
|
Term
| What are the effects of a m'phage encountering an AG (what does it do)? |
|
Definition
1) better AG presentation - upregulates expression of MHC II and B7, increased cytokines
2)upregs ROI and NO (microbicidal paths)
3)becomes tumoricidal
4)kills virally infected cells
5)increases inflammation and fever (nonspecific host defense)
6)secretes actos involved in repairing damage caused by inflammation |
|
|
Term
| What does activation mean for a macrophage? |
|
Definition
| that it does something better than it did before |
|
|
Term
| Is m'phage activation the result of 1 event or multiple events? |
|
Definition
|
|
Term
| Are actvated m'phages short or long lived? |
|
Definition
|
|
Term
| What does prostaglandin do? Why is it made? |
|
Definition
| *made as a result of activation - acts to turn it off *PGE is made - this is a general shutter offer, so the net effect is that the cell is only turned on for a little while |
|
|
Term
| What is an example of the 1st signal of activation? |
|
Definition
| inflammation - gets the m'phage responsive so it puts out receptors to get signals |
|
|
Term
| What's an example of the 2nd signal in m'phage activation? |
|
Definition
| lymphokines, IFN gamma, IL-2, etc - tells the m'phage that it needs to do something |
|
|
Term
| What is the 3rd signal of m'phage activation? |
|
Definition
| a trigger like LPS from bacteria - triggers full blown activation like proteases, ROI, lysosomes, etc |
|
|
Term
| What is delayed type hypersensitivity? |
|
Definition
| a reaction (like a skin reaction) to an AG that the body has seen before |
|
|
Term
| What selectin do naive cells express and what does this do? |
|
Definition
| L selectin - makes them home to the lymph nodes, specifically the high endothelial venules |
|
|
Term
| What selectins do activated T cells express and what do these do? |
|
Definition
| P&E selectins - cause homing to peripheral tissues (sites of infections) and LFA-1 or VLA-4 (interacts with ICAM or VCAM) - stabilizes the cells at sites of infection (peripheral sites) |
|
|
Term
| How to T cells enter sites of infection? |
|
Definition
| through post capillary venules |
|
|
Term
| Can naive T cells get to sites of infection? |
|
Definition
| they can get out, but activated T cells get out more b/c they express more adhesion molecules |
|
|
Term
| Is T cell migration to peripheral sites AG specific? |
|
Definition
| no - the T cell gets out, cruises around, if it finds its AG it P&D, if not it gets back into the blood stream |
|
|
Term
| Is the retention of cells in an area of infection AG specific? |
|
Definition
| yes - it's AG dependent - only those that find their AG will stay and P&D |
|
|
Term
| What is polyinfiltrate and when do you see it? |
|
Definition
| an infiltration into an area that has a lot of neutrophils - see this in early infections (actue inflammation) |
|
|
Term
| What is a mononuclear infiltration and when do you see it? |
|
Definition
| an infiltration into an area that has a lot of monocytes and lymphocytes - see this in chronic inflammation something that's been going on a while |
|
|
Term
| What does a mononuclear infiltration look like? |
|
Definition
|
|
Term
| What does a polyinfiltration look like? |
|
Definition
|
|
Term
| When do you get granuloma formation? |
|
Definition
| after chronic stimulation - this is the body's attempt to wall off an inflammation |
|
|
Term
| What does a granuloma consist of? |
|
Definition
| giant cells (m'phages) and epitheloid cells (also flattened m'phages) |
|
|
Term
| What do you have to have to form a granuloma? |
|
Definition
|
|
Term
| What types of things can cause granulomas? |
|
Definition
| physical irritants like asbestos, mycobacteria |
|
|
Term
| What is the difference between a Th1 response and a Th2 response in fighting a Leishmania infection? |
|
Definition
| Th1 response - you recover, Th2, you get an infection and you can die |
|
|
Term
| What is the difference between a Th1 response and a Th2 response in fighting a Mycobacterium leprae infection? |
|
Definition
| Th1 response - you get tuberculoid leprosy which is a very contained form of the disease, Th2 response - you get lepromatous leprosy which has a lot of lesions and is much more severe |
|
|
Term
| When is a Th1 response preferred over a Th2 response? |
|
Definition
| in fighting intracellular infections |
|
|
Term
| When is a Th2 response preferred over a Th1? |
|
Definition
| When the bacteria or parasite is extracellular (helminths, for example) |
|
|
Term
| When is the killing of an infected cell a bad thing? |
|
Definition
| when it's a cell we don't make more of, like a brain cell |
|
|
Term
| What happens in rheumatoid arthritis? |
|
Definition
| an AG in the joint causes inflammation |
|
|
Term
| What are 2 side effects of chronic inflammation? |
|
Definition
| damage of innocent cells in trying to get the bad guy, granuloma formation |
|
|
Term
| What can excessive release of cytokines cause? |
|
Definition
| shock, circulatory collapse, hemorrhagic necrosis |
|
|
Term
| What is a space occupying lesion? |
|
Definition
| a lesion in a space where you don't want it - like in the middle of a nerve - impinges on the nerve |
|
|
Term
| How does TB testing work - how do you know it's positive? |
|
Definition
| you inject TB AG in the skin - if you've seen TB before you'll get a reaction to it in a few days b/c you have memory cells to it - a hard knot, swelling, the size of the spot tells you how much exposure you've had to it |
|
|
Term
| Can you have a positive TB test from exposure to other mycobacteria? |
|
Definition
| yes - particularly in ones in the soil in the south |
|
|
Term
| Is the hapten or the carrier that is recognized in an immune response? |
|
Definition
|
|
Term
| Describe an experiment with mice and DNP-BSA that shows that both the hapten and carrier are recognized. |
|
Definition
| A group of mice is immunized with DNP-BSA - only the group exposed again to DNP-BSA has a strong reaction - if you give DNP-OA or just BSA you don't get a strong reaction |
|
|
Term
| If you give one mouse DNP-BSA and another mouse BGG, remove the spleen cells from both and inject them into an irradiated syngeneic mouse and give them DNP-BGG, what happens? What does this show? |
|
Definition
| you get a response - it shows that different cells recognize hapten and carrier b/c they came from 2 different original mice |
|
|
Term
| If you have 1 mouse immunized with DNP-BSA and you transfer the spleen cells and give them to an irradiated mouse, then give them DNP-BSA and DNP-OA, what happens? |
|
Definition
| DNP-BSA get a strong response - positive control, DNP-OA - not a strong response - negative control |
|
|
Term
| Give spleen cells from 2 different mice - 1 treated with DNP-BSA and 1 with OA, challenge with DNP-OA - what happens? |
|
Definition
| get a strong response - 2 different cell populations recognizing hapten and carrier |
|
|
Term
| What does x-ray irradiation do? |
|
Definition
| destroys l'cytes, leaves other immune cells intact |
|
|
Term
| How do you show what cells recognize hapten and what cells recognize carrier? How do you show specifically who recognizes carrier? |
|
Definition
immunize 1 mouse with DNP-BSA and a second with BGG - take the spleen cells from the 2nd and treat it with anti-Thy and complement so it kills the T cells - put both cells in an irradiated mouse and treat it with DNP-BGG, you don't get a response, proving that the T cells must be recognizing the carrier and the B cells are recognizing hapten
* if you use anti-CD4, you get no response, but use anti-CD8, you do, proving that anti-CD4 recognize carrier |
|
|
Term
| Can a hapten crosslink a BCR? |
|
Definition
|
|
Term
| What happens when B cells are activated? |
|
Definition
| the receptors are crosslinked, which brings the tails of Ig alpha and beta together, allows phosphorylation of ITAMs by Lck, Fyn, or Blk - this creates a docking station for Syk, and this binds and gets phosphorylated which sets off other stuff |
|
|
Term
| What happens after Syk is phosphorylated in B cell activation? |
|
Definition
| PLC and GTP are activated, leading to transcription of NFAT, NFkB, and AP-1, like in T cells |
|
|
Term
| What is one difference between the activation of B cells and T cells? |
|
Definition
| T cell activation upregulates Il-2R and IL-2, but this doesn't happen in T cells |
|
|
Term
| What are common responses of B cells to Ag and why? (5) |
|
Definition
1)entry into the cell cycle, mitosis - clonal expansion
2) increased expression of B7 - ability to activate Th cells
3)increased expression of cytokine receptors - ability to respond to cytokines put out by Th cells
4)migration out of lymphoid follicles - interaction with Th cells
5) secretion of IgM - early phase of humoral response |
|
|
Term
| Where do T cells activate? |
|
Definition
| in the parafollicular cortex |
|
|
Term
| Where do B cells activate? |
|
Definition
|
|
Term
| Where to activated T cells and B cells interact? |
|
Definition
| In the border between the parafollicular cortex and the lymphoid follicle |
|
|
Term
| How do T cells and B cells interact when a B cell encounters an AG? |
|
Definition
| AG crosslinks mIg on B cell, which generates signal 1, which causes the B cell to increase MHC II and B7 - the B cell internalizes the AG and presents it with MHC II - the T cell recognizes Ag-MHC II and gets costimulation from the B7 and is activated |
|
|
Term
| How does a T cell cause B cell proliferation and differentiation? |
|
Definition
| After the B cell activates the T cell, the T cell expresses Cd40L, which interacts with CD40 on the B cell giving it the 2nd signal and causing it to P&D - the B cell also expresses receptors for cytokines made by T cell, helping stimulate P&D also |
|
|
Term
| What cytokines from the innate system causes proliferation in B cells? |
|
Definition
| Ag and Il-1 from dendritic cells and m'phages and IL-4 from Th |
|
|
Term
| What cytokines cause clonal expansion of B cells? |
|
Definition
| AG and IL-4 and IL-5 and or IL-2 |
|
|
Term
| What cytokines cause differentiation of B cells incluing class switching? |
|
Definition
| IL-4, IFN gamma, IL-5, IL-6, IL-10 |
|
|
Term
| What determines what class a B cell switches to? |
|
Definition
| the ratio of cytokines produced by Th cells |
|
|
Term
| Where does CR2 come into play in B cell activation? |
|
Definition
| CR2 binds to C3d (complement) which is bound to the microbe - crosslinking mIg and CR2 complex brings intracellular domains together - the CD19 part has ITAM, which gets phosphorylated, activating the B cell |
|
|
Term
|
Definition
| increases sensitivity decreasing the concentration of Ag needed for activation |
|
|
Term
| What happens if a B cell reacts to self AG? |
|
Definition
| The B cell will look for a T cell that also reacts to self to provide a 2nd signal so it can P&D, but b/c of the T cell education process, it won't find one, without a 2nd signal, the B cell dies or shuts down (anergy) |
|
|
Term
| Why do B cells form germinal centers? |
|
Definition
| after activation by T cells, the B cells go back into the follicle and form a germinal center - the dividing cells push the other cells out of the way and it gives the appearance of a germinal center b/c the rapidly dividing cells have a lot of cytoplasm |
|
|
Term
| How does soatic point mutation work? |
|
Definition
| When B cells are rapidly dividing, they stop expressing ASR. When they slow down and start reexpressing ASR, regions may mutate so that some B cells express different ASR than the original - mutation is random |
|
|
Term
| Where are most mutations concentrated in B cells? |
|
Definition
|
|
Term
| What is affinity maturation? |
|
Definition
| the making of higher affinity B cells - after they reexpress their ASR, dendritic cells present AG - if the B cell binds strongly, it moves out and proceeds, if it won't bind at all it dies, and if it binds weakly it gets recycled to try and make a B cell with higher affinity |
|
|
Term
| Is affinity maturation dependent on mutation? |
|
Definition
| yes - mutation is how you make higher affinity B cells |
|
|
Term
| What is the end result of affinity maturation? |
|
Definition
| a poopulation of B cells with high affinity for the AG making high affinity AB |
|
|
Term
| Where are cells presented with AG after mutation? |
|
Definition
|
|
Term
| If you measure AB circulation over time, what do you find? |
|
Definition
| a shift to higher affinity AB |
|
|
Term
| If a B cell has high affinity for an AG, what's next? |
|
Definition
| differentiation into effector cells and eventually memory cells |
|
|
Term
| Are there super high affinity B cells? |
|
Definition
| yes - they bind AG better than high affinity B cells |
|
|
Term
| What is the test for affinity? |
|
Definition
| whether a B cell can rip AG off the dendritic cell |
|
|
Term
| When does affinity maturation stop? |
|
Definition
| When the AB concentration is too high or the affinity has reached a maximum |
|
|
Term
| What happens when affinity maturation is ending? |
|
Definition
| AB forming cell differentiation slows and memory B cells are formed |
|
|
Term
| What is peripheral tolerance? |
|
Definition
| a way to check that you don't have self-reactive B cells |
|
|
Term
|
Definition
| The education process in the central lymphoid organs during development that ensures we don't have cells that react to self |
|
|
Term
| What is positive and negative selection in germinal centers for B cells? |
|
Definition
positive - can the B cell bind to AG and CR on a FDC
*negative - can it stimulate Th cells to make cytokines and CD40L so that it gets costimulation
**if it can't do either of these things the B cell undergoes apoptosis |
|
|
Term
| Can naive T cells be used for negative selection of B cells? |
|
Definition
| no - it has to have been previously activated |
|
|
Term
|
Definition
| the end stage in B cell development - it's an AB secreting factory |
|
|
Term
| What type of AB do plasma cells make? |
|
Definition
| secreted (cytoplasmic) - they lose mIg |
|
|
Term
| What do plasma cells lose secretion of? |
|
Definition
|
|
Term
| What do plasma cells express on their surface? |
|
Definition
| PCA-1 - plasma cell antigen 1 - a surface marker |
|
|
Term
| Are plasma cells long or short lived? |
|
Definition
|
|
Term
| What is a lag phase in AB response? |
|
Definition
| the time between AB detection and AG clearance |
|
|
Term
| IN a primary response, what is the lag time? In a secondary? |
|
Definition
| 1 - 5-10 days, 2- 1-3 days - secondary is shorter b/c you have more cells that make AB to that AG |
|
|
Term
| What AB are primary and secondary responses rich in? |
|
Definition
| 1 - IgM, 2 - IgG, sometimes IgA or IgE - class switching induced by affinity maturation |
|
|
Term
| In primary and secondary responses, what is the relative affinity of the AB produced? |
|
Definition
| 1 - lower affinity, really variable 2-higher affinity |
|
|
Term
| What's happening in the decline phase? |
|
Definition
| memory cells are produced that have a high affinity for the AG |
|
|
Term
| What are the properties of the secondary response as a result of having more cells? |
|
Definition
| shorter response time, greater and longer response and some AB that have already class switched |
|
|
Term
| What are the properties of a secondary response as a result of affinity maturation? |
|
Definition
| l'cytes with high affinity receptors-they bind AG longer, get stmulated longer, and make more copies |
|
|
Term
| In terms of stimulation requirements, what's the difference between naive and memory cells? |
|
Definition
| naive cells require a lot of costimulation to get going but memory cells don't - often T-B interaction is sufficient and you don't need as many IL |
|
|
Term
| Why practically are memory cells easier to activate? |
|
Definition
| you want naive cells to be a little hard to start b/c you want to make sure the threat is real and not self-AG, memory cells are already to an AG that we know isn't self |
|
|
Term
| In mice, what pushes class switching to IgG1? |
|
Definition
|
|
Term
| In mice, what pushes the production of IgE? |
|
Definition
|
|
Term
| In humans, what is required for class switching? |
|
Definition
| CD40-CD40L interaction - cell-cell contact |
|
|
Term
| What determines what class of AB is made in humans? |
|
Definition
|
|
Term
| What pushes IgG and IgA production? |
|
Definition
|
|
Term
| What pushes production of IgG4 and IgE in humans? |
|
Definition
|
|
Term
| What is the principle effector function of IgM, IgG1 and 3, IgE and IgA? |
|
Definition
| IgM - complement activation* IgG - Fc receptor dep phagocyte responses, complement activation, neonatal immunity *IgE - immunity against helminths, mast cell degranulation (immediate hypersensitivity)*IgA - mucosal immunity |
|
|
Term
| Are most Ag T dependent or T independent? |
|
Definition
|
|
Term
| What are some characteristics of T dependent AG? |
|
Definition
| *tend to be polymeric (multiple repeats of the same epitope) *tend to be able to activate B cells independent of their ASR (mitogens) |
|
|
Term
| What is the significance of being a polymeric AG? |
|
Definition
| you can crosslink a LOT of receptors so that they get a big initial signal and don't need a lot of costimulation |
|
|
Term
| When are the differences in T dep vs T indep AG detectable? |
|
Definition
| when the responses are generated in vitro - eliminate T cells in vitro or use a nude mouse |
|
|
Term
| Can T indep AG use T dep pathways? |
|
Definition
| yes in the presence of T cells but it won't work the other way around |
|
|
Term
| Do you see a T indep response in real life? |
|
Definition
| no, unless you use a nude mouse - T dep is the path of least resistance |
|
|
Term
| What type of AG do T dep and T indep paths respod to? |
|
Definition
| TD-proteins, TI - polymeric AG, polysaccharides, glycolipids, nucleic acids |
|
|
Term
| TD vs TI - is there class switching? |
|
Definition
| TD-yes, TI - little to none |
|
|
Term
| TD vs TI - affinity maturation? |
|
Definition
|
|
Term
| TD vs TI - secondary response - generation of memory cells |
|
Definition
| TD - yes, TI - only seen with some AG, not usual |
|
|
