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178 Cards in this Set
- Front
- Back
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What are the three key components of the innate immune system?
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Phagocytes, NK cells, Complement
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What are two phagocytic cells?
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Neutrophils and Monocytes/Macrophages
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What is the difference between a monocyte and a macrophage?
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Monocyte circulates in blood, macrophage is in tissue
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What cells clear dead tissue and initiate tissue repair?
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Monocyte/Macrophage
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What toxic molecules kill microbes in phagocytosis?
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ROS, RNS
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What happens in chronic granulomatous disease?
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Mutation of phagocyte oxidase; microbes can't be killed
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What happens in Chediak-Higashi syndrome?
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lysosomal granules do not form; susceptible to bacterial infection
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What are some examples of PAMPs?
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LPS, Peptidoglycan, bacterial/viral DNA sequences
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Where are PAMPs found?
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On/in pathogen; unique to pathogen (non-human)
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What are some examples of PRRs?
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TLRs (Toll-like receptors), NLRs (NOD-like receptors), scavenger receptors that bind lipid-related ligands on bacterial surfaces
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What types of pathogens do TLRs target?
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extracellular; TLRs are on cell surface
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What types of pathogens do NLRs target?
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viruses/intracellular; NLRs are in cytosol
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Can TLRs bind more than one type of pathogen?
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Yes; location determines what TLR binds to
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Besides PAMPs, how do phagocytic cells recognise pathogens?
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Opsonin binding to antibodies or C3b (indirect recognition; IgG/C3b binding makes pathogen more appealing to macrophage)
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What cytokine activates macrophages?
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IFN-gamma
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Extravasation allows leukocytes to go from where to where?
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Blood circulation into tissue
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What are the two phases of extravasation?
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Margination (adherence to endothelial cells); Diapedesis (transmigration between endothelial cell and through basement membrane)
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What cytokine do NK cells secrete?
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IFN-gamma (activate macrophage)
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How do NK cells actually kill the pathogen?
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Perforins and granzymes
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How do NK cells identify and destroy targets?
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Balance between inhibitory and activating receptors; MHC 1 encourages not to kill, molecules on stressed/infected/damaged cells encourage to kill
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In ADCC, what Ab is involved?
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IgG
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How is the classical complement system activated?
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Ab binds to antigen, Fc region is accessible to complement; C1q begins process of deposition
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In the classical complement system, what fragments make up the C3 convertase?
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C4b2a
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In the classical complement system, what fragments make up the C5 convertase?
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C3b binding to C3 convertase (C4b2a3b)
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How does the MAC work?
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Deposition of C5b, C6-9 in target membrane, structure disrupts osmotic integrity; cell death
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How is the classical complement system controlled?
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C1 inhibitor
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What is hereditary angioedema?
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Deficiency of C1-INH; no classical complement control
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What are lectins?
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Proteins that recognise and bind to specific carbohydrate targets on cell surfaces
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What are the main proteases involved in the MBL complement pathway?
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MASP-1 and -2; similar job to C1r and C1s
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How is the alternative complement pathway initiated?
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Spontaneously
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What stabilises the C3 convertase in the alternative complement pathway?
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Properdin
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What are two complement controlling proteins we have to protect ourselves?
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DAF (Decay Accelerating Factor; breaks down C3 convertase) and CD59 (blocks C9 recruitment)
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What happens in paroxysmal nocturnal hemoglobinuria?
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Lack of DAF, CD59 etc.; lack of host cell protection in complement pathway
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Antigens for T cells are primarily…?
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Proteins
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3 types of APCs?
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DC, macrophage, B cell
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What do the TCRs recognise?
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MHC-antigen complex
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What do functional groups (CD4/CD8) on T cells recognise?
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MHC; CD8-MHC1, CD4-MHC2
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MHC 2 is found only on…?
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APCs
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Where do APCs present to T cells?
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Secondary lymphoid organs
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When/where do DCs mature?
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After picking up antigen, as they travel to lymph nodes through lymph vessels they mature
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What happens in DC maturation?
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Upregulation of MHC molecules and B7
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What genes make up MHC 1? MHC 2?
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MHC 1: HLA-A, -B, -C; MHC 2: HLA-DP, -DQ, -DR
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What are genetic characteristics of MHC?
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Co-dominant expression (both parental alleles expressed), polymorphic (many alleles present in population)
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Which MHC has a larger peptide binding groove?
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MHC 2 (10-30aa, compared to MHC1 which is only 8-11aa)
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How many transmembrane domains does MHC 1 have?
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1 (MHC 2 has 2…easy to remember!)
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What are the structural differences between MHC 1 and 2?
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MHC 1 has 3 alpha domains, 1 beta-2 microglobulin domain; MHC 2 has 2 chains of alpha and beta domains
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What types of antigen can MHC bind?
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ONLY peptides (think: MHC is involved with T cells, and T cells only recognise protein)
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MHC 1 loads _____ peptides
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intracellular
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MHC 2 loads _____ peptides
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extracellular
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Presentation to CD8 cells is generally for ____ pathogens
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intracellular (CD8 responds to MHC 1, which loads intracellular peptides)
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Presentation to CD4 cells is generally for ____ pathogens
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extracellular (CD4 responds to MHC 2, which loads extracellular peptides)
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In the endogenous pathway, how are protein fragments transported into the ER?
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TAP (Transporter Associated with antigen Processing; a specialised transporter protein)
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When is the protein fragment bound to MHC1 to form the MHC1-Ag complex?
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In the ER
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When is the protein fragment bound to MHC2 to form the MHC2-Ag complex?
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In vesicles
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In the exogenous pathway, how are antigen fragments transported to the ER?
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Trick- they never pass through the ER; only MHC 2 is made there, then MHC2 and Ag are complexed in an endosome
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What is CLIP?
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CLass II-associated Invariant chain Peptide; protein that cleaves the invariant chain on MHC 2 in order to bind antigenic peptides
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What portion of an antibody delivers signals to the nucleus?
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IG alpha and beta
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What portion of a TCR delivers signals to the nucleus?
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CD3 complex
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What is the difference in function between membrane-bound and secreted Abs?
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Membrane-bound initiate humoural immune response; secreted are effectors of humoural immunity
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Where does the "mix-and-match" (VDJ somatic recombination) occur?
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Bone marrow
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What portions of the Ab does VDJ recombination affect?
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Variable region (both heavy and light chains)
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What are features of IgG?
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Most versatile and most common; only Ig that crosses the placenta; activates complement; acts as opsonin
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What are features of IgM?
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Pentamer in circulation, monomer when bound; first Ig produced in immune response; potent activator of complement
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When is IgA used?
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Local, mucosal immunity (tears, saliva, colostrum, mucus)
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When is IgE used?
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Allergic/hypersensitivity reactions; parasitic infections (think: Eosinophil for parasites, IgE)
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What is the TCR structure?
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Disulfide-linked heterodimer; alpha and beta chain (rarely delta-gamma chain)
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What are the two main differences between antibodies (BCRs) and TCRs?
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1. TCR are only bound, no secretory form; 2. TCRs are MHC restricted
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Why are CD4 and CD8 known as co-receptors?
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They bind to the same MHC molecule on the APC/target cell as the TCR is engaged with
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When does somatic recombination occur in the life of a lymphocyte?
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During development, before antigen encounter
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What gene segments rearrange to make the Ig heavy chain/TCR beta chain?
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VDJ
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What gene segments rearrange to make the Ig light chain/TCR alpha chain?
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VJ (no D)
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How is a lymphocyte progenitors fate (to become B or T) determined?
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Random recombination of one of each possible V D or J segments
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What proteins are involved in facilitating somatic recombination?
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RAG-1 and RAG-2
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VDJ recombination generally leads to the formation of what isotype of Ab?
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IgM (remember that IgM is first to respond in an immune response, and then class switching occurs afterwards)
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What is junctional diversity?
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Nucleotide sequences are introduced at the junctions of V, D and J segments (additional diversity)
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Where does T cell development and maturation occur?
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Thymus; cortex then medulla
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What is the first type of selection that occurs in T cell maturation?
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Positive selection, for MHC restriction; thymocytes must bind to self-MHC presented by cortical thymic epithelial cells (cTEC)
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How is self-tolerance ensured in T cells?
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Only thymocytes with low affinity receptors to MHC proliferate; those with high affinity apoptose (negative selection)
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Once a T cell is single positive, what happens?
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It goes to the medulla for exposure to AIRE+ (autoimmune regulator) on mTEC for round 2 of negative selection
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What are the "teacher" cells in T cell maturation and selection?
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cTEC and mTEC (cortical and medullar thymal epithelial cells, expressing self MHC proteins, AIRE+, etc.)
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Why are T cells with high affinity binding negatively selected for?
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To avoid T cells attacking the body's own cells; they could bind too tightly to a self cell and incite an immune response against self cells
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Cell-mediated immunity targets _____ microbes.
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intracellular
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Where are the "conference centres", where Ag meets T cell?
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Secondary lymphoid organs: lymph nodes, spleen, MALT
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What three signals do naïve T cells need to become activated?
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1. TCR and Ag engagement; 2. Costimulation; 3. Cytokines
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What is the key protein presented on APCs for costimulation?
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B7
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What is the first signal for T cell activation?
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TCR and CD4/CD8 co-receptor recognise Ag-MHC complex on APC; upregulates adhesion
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What is the point of contact between TCR, accessory molecules, and APC called?
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An immunological synapse
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What is the receptor on a CD4 cell involved in costimulation?
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CD28
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What is the second signal for T cell activation?
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Costimulation; B7 linking with CD28
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Can a T cell in some cases be activated without costimulation?
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No
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What receptor is upregulated in T cells after antigen recognition and costimulation?
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IL-2 receptor
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What is first cytokine produced by naïve T helper cells?
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IL-2
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What does IL-2 do?
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Delivers signal for proliferation or clonal expansion of newly activated T cells
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Why does CD8 activation sometimes require cross-presentation?
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So CD4 helper cells can be activated to produce cytokines (IL-2) to activate CD8 proliferation; also so that extracellular pathogens can activate CD8 activity
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What is a Th cell's role in cell-mediated immunity?
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Activate macrophage to kill phagocytosed microbes
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What is a Th cell's role in humoural immunity?
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Activate B cell to produce antibodies with enhanced abilities to neutralise/eliminate Ag
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How do Th cells respond to antigen? (2 ways)
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Expression of costimulation molecule CD40L; production of cytokines
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What is the difference between CD28 and CD40L?
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CD28 on naïve T cell binds to B7 on APCs as costimulation for T cell proliferation and differentiation (into Th1, Th2, Th17); CD40L on Th binds to CD40 on macrophage/B lymphocyte and causes effector functions
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What are the three subsets of Th cells?
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Th1, Th2, Th17
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What is Th1's role?
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Macrophage activation; IgG production; defense against intracellular microbes
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What cytokine, released by a DC, instructs a CD4 to become Th1?
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IL-12
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What cytokines do Th1 produce?
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IFN-gamma mainly, IL-2, TNF (against intracellular pathogens)
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What is Th2's role?
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Eosinophil/mast cell activation; IgE production; defense against parasites
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What cytokine instructs a CD4 to become Th2?
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IL-4
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What cytokines do Th2 produce?
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IL-4, IL-5, IL-13
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What immune system is promoted by Th1?
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Cell-mediated (intracellular)
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What immune system is promoted by Th2?
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Humoural (extracellular)
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What is Th17's role?
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Inflammation; Chronic autoimmune disorders; Neutrophil/Monocyte inflammation; defense against extracellular bacteria and fungi
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What cytokines, released by a DC, instruct a CD4 to become Th17?
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TGF beta, IL-6
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What cytokines do Th17 produce?
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IL-17, IL-22
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Do effector T cells migrate depending on antigen recognition?
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No; migration is independent of Ag recognition
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What happens if a T cell enters a tissue but is not specific to a microbe?
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It is released back into circulation, and remains naïve
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Do CD4 cells directly kill pathogens?
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No; they only manage immune response by directing other cells to kill ("quarterbacks")
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What response does IFN gamma elicit in macrophages?
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Killing of phagocytosed bacteria (ROS, NO), increased expression of MHC and costimulators, secretion of cytokines (TNF, IL-1, IL-12; IL-12 induces more proliferation of Th1 cells)
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How do CD8 cells kill pathogens?
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Perforins and granzymes; released after TCR-antigen binding
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What do perforins do?
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Protein that forms a pore in the target membrane for delivering granzymes
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What do granzymes do?
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Serine proteases that enter via pores made by perforin and induce apoptosis via caspase enzymes
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What happens in DiGeorge syndrome?
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Incomplete thymus development; failure of T cell maturation
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What happens in bare lymphocyte syndrome (BLS)?
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Failure to express MHC-2; decrease in CD4 cells because of defective activation
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What would some symptoms of bare lymphocyte syndrome be?
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BLS is a failure to express MHC-2; decrease in CD4 cells, therefore you could expect: impaired cell mediated immunity, reduced antibody levels due to impaired T cell help
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What happens in TAP-1 or TAP-2 deficiency (bare lymphocyte syndrome I)?
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Failure to express MHC-1 due to defects in transporter associated with antigen presentation; reduction in functional CD8 cells, increased susceptibility to viral/intracellular bacterial infections
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Is BLS-1 or BLS-2 more severe?
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BLS-2 is more severe; in BLS-1 there is a problem with loading pathogen on MHC 1, but NK cells can be activated to kill when MHC 1 is downregulated
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What cells undergo receptor editing during maturation?
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B cells
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What is receptor editing?
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Additional L chain V-J recombination in B cells, for those that recognised self antigen
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What two antibodies are expressed after maturation?
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IgM and IgD
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How is it possible for both IgM and IgD to be expressed?
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The constant region on the DNA strand contains Cm and Cd exons
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When does co-expression of IgM and IgD occur?
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In the bone marrow, or after B cells leave to enter secondary lymphoid organs
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Is IgM+ IgD+ B cell mature or naïve?
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Mature, but antigen naïve
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Where do B cells live within secondary lymphoid organs?
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In lymphoid follicles
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What is a germinal centre?
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Site of intense B cell proliferation
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What type of pathogens do antibodies target?
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Extracellular
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Are antibodies effective against intracellular organisms?
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No; cell-mediated responses are more effective
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What are the two routes of B cell activation?
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T cell independent and T cell dependent
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What types of antigen activate B cells in the T cell independent pathway?
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Non-protein antigens (polysaccharides, lipids, small chemicals)
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In the T cell independent pathway, how is a B cell initially activated?
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Cross-linking of two or more adjacent receptor molecules with multiple "repeats" on antigen epitope allows for Ig receptor-mediated signal transduction
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What are the two signals required in the T cell indpendent pathway?
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Cross-linking, and complement activation
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In the T cell independent pathway, how is a B cell activated via complement?
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C3d (breakdown of C3b) recognising CR2 receptor on B cell
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What is produced in the T cell independent response?
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Short-lived plasma cells producing IgM
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Do protein antigens cross-link B cell receptors?
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No
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Why do protein antigens elicit weak immune responses without T cell help?
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Protein antigens don't have multiple epitope repeats, so the T cell independent pathway does not work very well
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Where do T and B cells interact?
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Outside follicles in a secondary lymphoid organ
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What is the APC involved in T/B cell interaction?
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The B cell itself is the APC
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What costimulatory molecules are involved in first activating Th cells in B cell activation?
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B7 (B cell) with CD28 (T cell)
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What costimulatory molecules are involved in activating B cells, after Th are activated?
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CD40 (B cell) with CD40L (T cell)
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What three signals are required to stimulate B cell proliferation and synthesis of Abs?
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Antigen presentation on MHC-2 (B cell) to TCR (T cell); CD40 (B cell) with CD40L (T cell); cytokines (T cell) and cytokine receptors (B cell)
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Once activated, where do B cells go?
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Germinal centres
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During B cell proliferation, what is now the role of Th cells?
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Class switching, somatic hypermutation, affinity maturation
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What portion of the antibody is affected in class-switching recombination?
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Constant region of the heavy chain (NOT the variable region)
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What is somatic hypermutation?
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Process where the variable region of heavy and light chains go through increased point mutations (due to rapid proliferation)
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How come some B cells develop a higher affinity to antigen?
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Due to many mutations, some have higher affinity receptors and are rescued to ensure memory cells have a higher capacity for Ag binding
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What mediates class switching?
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CD40L
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What influences the antibody class B cells will switch to?
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Cytokines from T helper cells
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How does CSR contribute to an effective immune response?
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Some antibodies are better suited for different pathogen types, i.e. IgE for parasites
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What cytokine induces CSR from IgM to IgG?
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IFN gamma
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What cytokine induces CSR from IgM to IgE?
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IL-4
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What cytokine induces CSR from IgM to IgA?
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TGF beta
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What happens in X-linked hyper-IgM syndrome?
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Inactivation of CD40L, leading to defective heavy chain class switching, predominantly IgM
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What pathogens are patients with X-linked hyper-IgM syndrome most susceptible to?
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Intracellular microbes; X-linked hyper-IgM syndrome is a defect in CD40L, which is important in CMI
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What region of the antibody is most affected in somatic hypermutation?
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CDR region of heavy and light chains
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At what stage does somatic hypermutation occur in maturation of B cells?
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After VDJ recombination, after class switching (late in maturation)
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How are B cells with higher affinity BCRs selected for?
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They are able to bind to Ag on follicular dendritic cells, and so escape apoptosis
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Affinity maturation occurs in response to _____
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prolonged or repeated antigen exposure
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Where do follicular DCs live?
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Germinal centres
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*Are germinal centres involved with protein antigen, non-protein antigen, or both?
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Protein antigen only, since T helper cells are involved
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What are follicular helper T cells?
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B cells with higher affinity IgG present Ag to follicular Th cells; if they bind, they are selected to survive
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B cells differentiate into _____
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plasma cells
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Does a secondary antibody response require priming?
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No; that has already been done the first time
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What molecule is involved in regulation of the humoural immune response?
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Fc receptor on B cells binds to Fc region on Ab, delivers negative signals to terminate B cell response
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What is the process by which antibody production is inhibited?
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Antibody feedback
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How do antibodies 'neutralise' microbes?
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By blocking penetration through epithelial barrier
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Patients who have undergone splenectomy are highly susceptible to infections by _____
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encapsulated bacteria (spleen is important in phagocytic clearance in Ab-mediated phagocytosis)
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Are antibodies involved in innate immunity?
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Yes; they coat cells for NK cells to destroy
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IgE is involved in what type of response?
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Eosinophil-Mediated ADCC, against helminths
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Where is IgA produced?
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Mucosal lymphoid tissues
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What is passive immunity?
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Like neonatal immunity, when newborns are dependent on their mother's antibodies for protection
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How do newborns acquire their mother's antibodies?
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Through the neonatal Fc receptor (FcRn)
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Oral attenuated vaccines target what type of immune component?
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IgA; mucosal immunity (orally administered)
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What is a conjugate vaccine?
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Microbial polysaccharide antigens chemically coupled to proteins, in order to involve T helper cells and high-affinited antibodies
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