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98 Cards in this Set
- Front
- Back
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What are four main ways the immune system can dispose of an antigen?
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Phagocytosis, killing (T-lymphocytes or Abs and complement), neutralization (Abs), inflammation (above w/ cytokines and chemokines).
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What are the main differences between the adaptive and innate immune response?
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The innate immune cells are the first responders and recognize antigenic or non-self associated patterns on microorganisms (these patterns are not specific to one microorganism). The innate immune response eliminates the majority of foreign organisms right away. If a microorganism bypasses the innate immune response, the adaptive response is activated, which in contrast to the innate response takes 3 days to a week but is long lived after the antigen is eliminated. Also the adaptive immune response is antigen specific and requires stimulation besides the microorganism to be activated.
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Are both innate and adaptive immune responses is driven by receptor-ligand activation? If yes, how does receptor production differ?
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1. yes, 2. The adaptive immune cell receptor genes are rearranged in various ways during differentiation in order to yield an enormous variety of receptors with the goal of being able to specifically identify an antigen epitope on any microorganism. Innate immune cell receptor genes are not rearranged and identify patterns common to many antigens.
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How do infecting microorganism direct the innate immune system to induce the most efficient protective adaptive immune mechanism?
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Through the engagement of toll-like receptors (TLR) on innate immune cells, which recognize specific Ag (antigen) patterns and induce the expression of specific gene groups, which encode for the release a specific set of cytokines from the innate cell to activate the adaptive immune cells based on what type of TLR was activated.
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What is the difference between T and B cell epitopes?
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T Cells identify a digested antigen in a MHC-peptide complex where the epitope is usually linear and may be internal to the microorganism, whereas B cells recognize conformational epitopes on the surface of the microorganism.
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Where are MHC molecules found?
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MHC I are found on all nucleated cells in the body. MHC II are generally found on phagocytic antigen-presenting cells.
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What if a nucleated cell does not express MHC I?
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Chances are it has been invaded by a microorganism and will be killed by a natural killer cell.
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What types of peptides do MHC classes bind?
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MHC I generally binds self-antigens. MHC II generally binds foreign antigen.
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What are the different T cell classes?
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CD4+ helper T cells (identify foreign epitopes in MHC II-peptide complexes, activate B cells etc.), CD8+ cytolytic T cells (infected cell expressing MHC I-antigen complex is killed), and NKT cells (kill cells w/ MHC I and lipid antigen).
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What is required for T cell activation?
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TCR bound MHC-peptide complex plus a co-stimulatory signal.
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What is required for B cell activation?
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BCR bound antigen plus a co-stimulatory signal, usually from an activated T cell.
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How are primary and secondary immune responses different?
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The primary immune response takes longer to activate and produces less antibodies than a secondary response. This is because during the primary response memory B cells are made which are able to stimulate clonal expansion and antibody production more rapidly upon secondary exposure.
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What is antiserum?
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Is serum which contains antibodies to a specific antigen; note that this serum may contain multiple types of antibodies which recognize different antigen epitopes (because it is usually produced by B cell activation with an entire antigen).
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What is clonal selection theory?
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This refers to the idea that lymphocytes specific to an observed antigen are selected for clonal expansion into effector lymphocytes, whereas those not specific for an observed antigen are not.
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What is the difference between passive and active immunity?
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Passive immunity refers to when a person is transferred immunity usually through antibodies (occurs during pregnancy between fetus and mother; also can be used as an intervention for Rh- mothers). Active immunity refers to when some antigen triggers an immune response and Ab production through exposure (seen with vaccinations, etc).
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What factors affect immunogenicity?
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In general if the antigen is large, complex, given in intermediate dosage, less soluble, denatured, and very different from self protein it is more likely to be immunogenic.
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Where are some of the locations on the body where microbiota are most abundant? least?
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1. Large intestine, mouth small intestine, scalp/head, 2. Lungs, limbs
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What are 5 main categories of innate immune system soluble mediators?
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Cytokines, chemokines, eicosanoids (prostaglandins, leukotrienes, thromboxanes), acute phase proteins, and antimicrobial peptides.
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After pathogen exposure what is the first step in the innate immune response?
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The pathogen is phagocytosed by macrophages, which in combination with NK cells and others release cytokines like IL-1 and TNF. In addition complement is activated.
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Following macrophage phagocytosis and cytokine release what occurs next in the innate immune response?
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IL-1 and TNF released by macrophages activate endothelial cells to express more integrins and L-selectin to recruit neutrophils. PECAM-1 allows the neutrophil to pass through the endothelial wall. Once in the tissue a chemokine gradient leads neutrophils to the site of invasion. Once there, inflammatory mediators like NO, eicosanoids and reactive oxygen species are produced.
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Which granulocyte is the first to emigrate to the site of inflammation?
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Neutrophils
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What steps occur in phagocytosis?
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Once the phagocyte is recruited to the pathogen it must recognize it through pattern recognition receptors like the mannose receptor, scavenger receptor or TLR. Once recognized it engulfs the microbe into a phagosome which then fuses with a lysosome and is degraded by lysosomal enzymes, NO and reactive oxygen intermediates.
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What is chronic granulomatous disease (CGD)?
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Caused by a deficiency in phagocyte NADPH oxidase, which is required to produce NADPH and subsequently NO and ROIs (needed for microbe digestion following phagocytosis). Clinically recurrent pyogenic infections and neutrophilia are seen.
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What tells a NK cell not to kill an observed cell?
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An inhibitory receptor associated with MHC I-self peptide complex
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What are the two ways that NK cells kill targets?
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1. Kill infected cells, 2. in response to IL-12 released by a macrophage with a phagocytosed microbe it will release IFN-g which stimulates the adaptive immune response and tells the macrophage to kill the microbe inside it.
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What CD do NKT cells express?
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CD3+, CD8-
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What cellular pathways lead to the activation of phagocytes?
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TLRs on the cell surface, in the cytoplasm or in endosomes recognize PAMPs (pathogen associated molecular patterns) and then through intercellular pathways activate NFkB (induce TNF, IL-1, IL-12) or IRF-3 (induce IFN-a/b) transcription factors.
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How can cytokines be autocrine? paracrine? endocrine?
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1. TNF: further activate macrophages, 2. IL-1 and TNF on endothelial cells, 3. TNF with fever.
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What are the main functions of TNF?
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1. Mediator of acute inflammatory response to gram negative bacteria and other microbes, 2. Responsible for systemic effects of infection, 3. Modify gene transcription through NFkB, 4. Muscle, fat catabolism, 5. Apoptosis
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What does Infliximab (Remicade) do? Etanercept (Enbrel)?
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1. a-TNF, 2. IgG that binds to/blocks TNFR
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In moderate concentration (10^-9 to 10^-7) what effects does TNF have? high concentrations?
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1. Induces fever in the brain, release of acute phase proteins from the liver and leukocyte (neutrophils) production in the bone marrow, 2. Septic shock damage liver function
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Which cells primarily produce TNF?
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Macrophages, T cells
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Which cells primarily produce IL-1?
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Macrophages, endothelial cells and some epithelium
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What are the main functions of IL-1?
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1. Activates endothelial cells to promote inflammation and coagulation, 2. Causes fever through the hypothalamus (same as TNF), 3. Promotes liver synthesis of acute phase proteins, 4. Th17 differentiation
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Which cells primarily produce IL-12?
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Dendritic cells and macrophages.
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What are the main functions of IL-12?
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1. Activates NK and T cells to produce IFN-g and increase their cytotoxic activity, 2. Th1 differentiation
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Which cells primarily produce IFN-g?
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NK cells and T cells
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What are the main functions of IFN-g?
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1. Activate macrophages, 2. Stimulate some Ab responses
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Which cells primarily produce IFN-a/b?
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IFN-a: macrophages and dendritic cells; IFN-b: fibroblasts
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What are the main functions of type 1 IFNs (a/b)?
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1. Increase antiviral activity and MHC I expression, 2. Activate NK cells
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Which cells primarily produce IL-10?
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Macrophages, dendritic cells and T cells
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What are the main functions of IL-10?
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1. Inhibit IL-12 production from macrophages and dendritic cells, 2. Reduce expression of MHC II and costimulators.
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Which cells primarily produce IL-6?
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Macrophages, endothelial cells and T cells
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What are the main functions of IL-6?
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1. Stimulate the liver to produce acute phase proteins, 2. Stimulate the B cells to proliferate as Ab producing cells, 3. Th17 differentiation
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What are the main functions of chemokines?
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Stimulate leukocyte integrin affinity, chemotaxis and activation
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What are the main functions of TGF-b?
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1. Inhibit inflammation, 2. Th17 differentiation and T reg differentiation
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What kind of receptors are chemokine receptors?
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G protein coupled receptors
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What is the mechanism of Maraviroc (Selzentry)? Plerixafor (AMD3100)?
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Both act on chemokine receptors, 1. CCR5 antagonist, against HIV entry, 2. CXCR4 antagonist, mobilize stem cells for transplant.
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What are examples of acute phase proteins? what are their functions?
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1. C-reactive protein (CRP), serum amyloid A, 2. bind to microbes to stimulate phagocytosis, also increase recruitment and activation.
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What do defensins do?
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produced by macrophages, cationic peptides that lyse microbes
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What is the function of the B7 receptor?
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Present on macrophages, dendritic cells and binds the CD28 receptor on T cells to provide co-stimulation (cell-mediated immunity).
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How can humoral immunity deal with viruses?
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Abs can only neutralize extracellular viral particles. Cell-mediated immunity is required to dispose of the viral source.
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What kind of peptide is suitable for loading onto MHC I? What protease activity on proteasomes is effective in creating suitable peptides
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1. Peptides that are 8-10 AAs long and have a hydrophobic AA on the 9 position, 2. chymotrypsin-like activity
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what is an immunoproteasome?
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an immunoproteasome has had 3 beta subunits installed called LMPs and MECL, which are better at producing MHC I suitable peptides; this expression (on MHC gene) is induced by IFN-g w/ viral infection
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What is the function/specificity of the TAP transporter?
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The TAP transporter is on the ER and transports proteasome digested peptides between 6-15 AAs into the ER for MHC association. It has a higher affinity for those peptides with a hydrophobic end (match with MHC I). Also it is encoded on MHC.
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What is the function of tapasin?
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Tethers new MHC I in ER to TAP transporter for peptide association.
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What are the 3 main functions of invariant chain?
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1. Stabilize MHC II in a trimer, 2. Barrier for MHC I binding peptides in the ER, 3. Directs MHC II transport to the lysosomal compartment.
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What is CLIP? How is it removed from MHC II?
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1. CLIP is the peptide left in the MHC II complex following lysosomal digestion of invariant chain, 2. MHC II-like HLA-DM bumps the CLIP-MHC II complex or MHC II bound with low affinity to any peptide and knocks it out.
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MHC II and CD1 are expressed in what kind of cells?
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Antigen-presenting cells
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Which cells types are antigen-presenting cells?
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B cells, macrophages, dendritic cells
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What is the function of CD1? What is its structure similar to? How is it different from MHC I/II?
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1. CD1, likely in a way similar to MHC II (with invariant chain) binds lipid antigen and presents them to NKT cells, 2. Like MHC I it has a main alpha chain and smaller beta2-m chain, 3. It is not encoded in the MHC
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Can MHC II present self peptides?
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Yes (i.e. when old RBCs are phagocytosed or in autophagy)
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Describe the structure
of MHC II? |
MHC II is a heterodimer of an alpha and beta chain, binds peptides 10-16 AAs long and like the other MHC requires a peptide to form.
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What factors contribute to the MHC diversity within the population? How do MHC bind almost any antigen?
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1. The fact that MHC/HLA genes are polygenic, co-dominant and polymorphic, 2. The previous factors and because they have few antigen binding limitations
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Is beta2-microglobulin encoded in MHC? Does it have a transmembrane domain? Is it polymorphic?
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No to all three
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What chromosome is MHC on?
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6
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What are the chances that siblings will be HLA matched?
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1 in 4
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Which MHC II chain is more polymorphic?
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beta; this is the chain that is typed for transplant
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Which MHC I domains (alpha 1,2,3 or beta2-m) are most polymorphic?
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Alpha 1 and 2
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What is the function of IL-2?
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T cell activation/proliferation
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What does alloreactivity mean (in regards to TCRs)?
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T cells that bind weakly to self-MHC and are positively selected may bind strongly to non-self MHC (cause graft rejection).
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What does MHC restriction mean?
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It means that allogeneic T cells that may have been specific for an antigen plus self MHC complex will not recognize that same antigen plus an allogeneic MHC; and thus are not protective.
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What are the MHC 1 genes?
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HLA-A,-B,-C
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What motif forms the groove of the MHC binding domain? the bed?
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1. alpha helices, 2. beta sheets
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What is the function of the non-antigen binding components of the antigen receptor complex?
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In T cells CD4 and CD8 bind MHC, while CD3 and zeta chain act in signal transduction. In B cells Ig alpha and beta aid in signal transduction.
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In Abs and TCRs what is the most variable region of hypervariability in antigen binding?
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CDR3
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What is the difference between Ab isotypes, allotypes and idiotypes?
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Isotypes: different heavy chain constant region (IgE vs IgM); allotype: different polymorphic areas in the constant regions; idiotype: different variable region
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In regards to antigen receptors what is allelic exclusion?
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VDJ recombination begins on one parental allele. If successful that parents allele is the only one expressed for that specific chain. If not then go to other parent.
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What is the order of VDJ rearrangement?
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DJ, VDJ, VDJ-C
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What factors lead to antigen receptor diversity?
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multiple variable region genes, recombination, junctional diversity, somatic hypermutation
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What are the steps in B cell development/differentiation?
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Stem cell, Pro-B, Pre-B (recombined surface & cyto. mu heavy chain), immature B (surface BCR, mu heavy chain), mature B (alternate RNA splicing BCR with IgM and IgD)
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D B cells go through selection?
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While less understood it is thought that B cells go through positive and negative selection
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When it comes to recombination which TCR chain is similar to Abs heavy chain?
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The beta chain, because unlike the light/alpha chain it has D gene segments for VDJ recomb.
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How are T cells selected in the thymus?
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T cells go through positive selection via thymic epithelial cells in the cortex and go through negative selection via dendritic cells in the medulla.
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Naive T cells tend to re-circulate from the blood to peripheral immune tissues, while B cells...
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... typically remain in peripheral lymphoid tissue.
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How many TCR receptors need to recognize antigen-MHC complexes for activation?
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At least 2
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What happens to the LFA1:ICAM1 interaction when the T cell is activated?
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Conformational changes that increase the affinity of the interaction.
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How do dendritic cells function?
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Dendritic cells ingest microbes via phagocytosis or macropinocytosis in the tissues mature and migrate to the peripheral lymphoid organs to express potential antigens to T cells.
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How do APCs usually induce B7 expression?
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Through activation of pattern recognition receptors
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How do B cells ingest microbes for antigen presentation?
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Through receptor (BCR) mediated endocytosis.
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What cause T cell integrins (LFA1) to increase their binding affinity for their ligand (ICAM1)?
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TCR signals and chemokines (through receptor) released from APCs
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What happens to a T cell that does not receive a co-stimulatory signal?
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Anergy
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What happens to a T cell that does not receive a co-stimulatory signal?
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Anergy
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How does IL-2 specifically stimulate activated T cells?
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Upon activation T cells express CD25, the alpha subunit of the IL-2 receptor which makes the receptor have a much higher affinity for IL-2.
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What is the function of CD40L?
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It will bind CD40 on APCs and stimulate the maintenance of the immune response.
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Which cytokine(s) stimulate Th1 differentiation? Th2 diff?
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1. Mainly IL-12, 2. Mainly IL-4
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What are the primary cytokine(s) released for Th1 response and what are their functions? Th2?
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1. TNF and IFN-g, which will stimulate Ab production, activate complement and promote co-stimulatory expression, 2. IL-4, IL-5, IL-10, enhance B cell Ab production (eosinophil activation (IL-5)).
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How do CD8+ T cells kill infected cells?
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1. Release perforins (create pore in target cell membrane) and granzymes (go through pores and activate caspases and thus apoptosis) 2. Activate apoptosis through Fas-L.
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