Exam 1 Review *NOTE* This is a study guide for review purposes it is not supposed to be indicative of everything that will

l be on the exam. Study your notes and use your book as a supplement if a concept is not completely clear. Good luck!

CHAPTER 1 -Hallmarks of immunity to infection o Specific recognition (self vs non-self) Presence of PAMPs on microorganisms but not on self cells. PAMPs are recognized by PRRs that are on phagocytic cells. o Effector functions (to eliminate foreign pathogen) Effector B and T cells T cells need APCs(Macrophage, DC, B cell) to present the Ag and provide the co-stimulatory signal Fig. (1.21) APCs- link the innate and adaptive immunity. o Immune regulation (prevent damage to self, autoimmunity) o Immunological memory (basis of vaccination) 3 Levels of Defense o Anatomic + Physiological Barriers Skin, mucous membranes, pH of the stomach, temperature (ex. Fever), lysozyme in saliva/tears o Innate Immunity Non-specific defense barriers Defense system functional at birth Response Time: Hours Specificity: Limited Response to a repeated infection: Same as the first( No memory) Major Components: Barriers, phagocytes, NK Cells, Pattern Recognition Molecules, Complement, Defensins, antimicrobial peptides etc. o Adaptive Immunity Specific- only in higher vertebrates Memory ( ex.why you dont get chicken pox twice) Its acquired as you get exposed to pathogens Response Time: Days Specificity: Diverse: improves during the course of response Response to repeated infection: More rapid than the first Major Components: B Cells, T Cells, MHC molecules, Antibodies

Hematopoeisis: Development of Immune Cells o All cells originate from pluripotent hematopoietic cells (self-renewing) Derived from the Bone Marrow (Also available in umbical cord blood, blood) Myeloid Lineage (know general function of these cells) ex. Neutrophil- more efficient in phagocytosing. First cell to the site of infection Dendritic Cells- more efficient at antigen presentation Macrophages (in tissues)- derived from monocytes (from the blood) Which ones are granulocytes? What are their functions? Dont forget about Mast Cells and Megakaryocytes Lymphoid Lineage B and T cells are part of adaptive immunity NK Cells are part of INNATE Lymphocytes:Part of Adaptive Immunity except NK Cells o Lymphoblasts (activated lymphocytes) o B Cells Humoral Immunity BCR: membrane Ig or soluble Ab Effectors: Plasma cells that secrete antibodies specific to the pathogen o T Cells Cell-mediated Immunity Require MHC molecules for activation: MHC I: present Ag from cytosolic proteins (Fig. 1.29) MHC II: engulfs extracellular peptides to be processed inside the cell Bind Ag fragment that was processed by an APC. Ag is presented on MHC molecule T Helpers (CD4+, requires MHC II)- when presented with antigen from an APC, it secretes cytokines that will activate Cytotoxic T Lymphocytes and B cells. 2 subclasses: Th1 and Th2 T Reg- help regulate the immune response Effectors: Cytotoxic T Lymphocytes(CD8+, requires MHC I)- activated to kill the pathogen. Releases cytotoxic granules. What does the Cd4+/CD8+ do? o Each time a B or T cell is activated, they produce memory cells in addition to their effector cells. Memory Cells are already primed by the antigen (antigen

specific) and therefore provide a quicker response to subsequent infections by the same pathogen. o Unlike Plasma cells, memory cells are long-lived. Inflammation: o Major cells: Neutrophils and Macrophages Typical response during infection: phagocytosis/ release of chemokines and cytokines (Fig. 1.9) o Four Signs of Inflamation: Heat, Pain, Redness, and Swelling Burnetts Clonal Expansion: o A lymphocyte that meets its Ag will differentiate and proliferate into mature lymphocytes. Proliferation generates thousands of copies of the same lymphocyte to ensure the Ag is eliminated. Something to think about: o Clonal Deletion: A lymphocytes antigen specificity is determined before binding the Ag. So why arent they reactive towards our bodys cells? Self- reactive lymphocytes are removed before maturation Four Classes of Pathogen o Extracellular bacteria, fungi, parasites o Intracellular bacteria, fungi, parasites o Intracellular viruses o Extracellular parasitic worms Abs deal with extracellular pathogens Five Classes: IgG, IgA, IgM, IgE, IgD (GAMED) Know each of their functions..What makes them unique from one another? Lymphoid Organs o Primary Organs: ( Where lymphocytes are created)- Bone Marrow and Thymus o Peripheral Lymphoid Organs: (Where lymphocytes meet their Ag)-Lymph nodes, spleen, Mucosal Lymphoid Organs (MALT,GALT,BALT) o What is lymph? Be familiar with structure of lymph node and spleen. Spleen filters Ag in the blood..Lymph nodes filter Ag in the lymph. Primary vs. Secondary Immune Response (works the same for vaccinations) o Primary: 1st encounter with Ag selection of B cell clones clonal expansion Plasma cells secrete IgM- low affinity Memory B Cells Longer lag period o Secondary: 2nd encounter with Ag Activation of Memory B Cells (already primed with Ag) Short lag period

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Plasma cells secrete IgG-high affinity Makes more memory cells

Look at Figures in lecture notes if difficult to understand look to descriptions in the book o Innate Barriers: Skin, saliva, mucus, cilia, stomach acid Microbiota in the gut - benefits of probiotics o Effector molecules of Innate System: Enzymes: Lysozyme-peptide in bodily secretions; Antimicrobial Peptides- found in body fluids: small, cationic, amphiphili Major killing mechanism: through membrane permeabilization Activated by proteolysis Defensins, Cathelicidens, Magainins etc. o Defensins: 3 disulfide bonds o Cathelicidens: lack disulfide bonds that stabilize defensins Amphiphilic hydrophilic nature allows the peptide to bind the surface of microbial target, hydrophobic nature allows the peptide to embed in the membrane of the microbe. LPS-binding by AMPs Other AMP functions Chemotactic, wound healing Complement: plasma proteins, secreted by monocytes/macrophages etc. o Function: Activates a cascade of proteolytic reactions and subsequent protein aggregation on the microbial surface but not on host cell surface -- Host surface has sialic acid which prevents complement from forming. o Opsonization: coats microbes that make them more visible to phagocytic cells. o Forms pores (MAC) that triggers killing o Release small peptides (C5a,C3a,C4a) that contribute to inflammation Inflammation induced by complement. Results in migration of leukocytes , attraction of phagocytes, increased permeability so cells can squeeze through endothelial cells(HEVs) to the sight of infection Can cause anaphylactic shock o Some are zymogens (inactive precursors until cleaved by a protease) o Three Pathways: Lectin pathway: MBL binds carbohydrates(mannose) on microbe surface

Classical pathway: Ab-dependent. Complement (C1q) binds Fc portion of the Antibody. (IgM-is most efficient with complement because its a pentamer) Alternative pathway(more primitive): Spontaneous cleavage of C3 Look at figures and videos to know all three pathways: triggers; binding mechanism; and C3 convertase o All pathways eventually lead to C3 Convertase which cleaves hundreds of C3 molecules resulting in hundreds of C3b on the surface of the microbeopsonization Pore formation (C3b-C9) Look at each figure for more detail Complement receptors: o CR1: C3b receptor on phagocytes, B cells increases phagocytosis o C5a: C5a receptor on endothelial, phagocytes, mast cellsaids inflammatory response, activates phagocytic cells and helps chemotaxis o C3a: C3a receptor. Same function as C5a receptor except not as efficient. Complement Regulators: o Inhibit C3 Convertase formation and promote destruction of C3b o Protectin: on host cells so MAC cant form o Factor 1: cleaves C3b and C4b o C1INH: dissociates C1r and C1s from active C1 complex.

CHAPTER 3 Know functions of phagocytic cells. Difference between monocyte and macrophage. Main cells that participate in Innate Immune Response: Neutrophils, Macrophages, Dendritic Cells, NK Cells o All secrete something that will enhance killing. Can be cytokines, Reactive Oxygen species, defensins etc. Dendritic Cells: o Is derived from both lymphoid and myeloid lineage o Most effective APC o After it meets an Ag, it travels to the lymph nodes to present them to T cells. Pattern Recognition Receptors on phagocytes/epithelial cells: Interact with PAMPs on microbe membrane. Interaction leads to production of antimicrobial peptides. o Specificity: Flawless because the host does not display PAMPs Mannose Binding Lectin: binds mannose on microbe Scavenger receptor: anionic polymers and acetylated lipoproteins. Bind gram +/gram and apoptotic host cells. Complement receptors (under Ch.2)

LPS Binding protein: binds LPS on bacteria TLR: Single-pass transmembrane proteins with extracellular region composed of leucine-rich repeats that form a scaffold for ligand binding. Common Signaling Mechanism o -Ligand binding leads to receptor oligomerization o -Adaptor proteins are assembled - Protein kinases are activated - Ubiquitin ligase enzymes are activated o -NFkB activates gene transcription All TLRs likely have a MyD88 pathway (Except TLR3); TLR4 has a MyD88 independent pathway as well (TRIF) Outcome of TLR Signaling: inflammatory cytokines, chemotactic factors, AMPs, antiviral cytokines. NOD-like receptors(NLR): important in epithelial cells, where TLRs are weakly expressed. Cytosolic and recognize intracellular bacterial products . Function via activation of ser thr kinases NLPRs:sense cellular stress and damage. Form inflammasome complex RLH: detect uncapped viral cytoplasmic RNAs and induce production of inflammatory and antiviral cytokines Chemokine: Small chemoattractant proteins that stimulate migration and activation of lymphocytes and phagocytes. o How do chemokines, cytokines and other molecule affect cell migration (trafficking)? changing their expression of adhesion molecules (Selectins, Integrins, ICAMs) o Understand Leuokocyte Rolling and Extravasation (Fig 3.25) role of selectins; integrins; ICAMs Cytokines: soluble mediators (small proteins) of innate and adaptive immunity and the mechanisms by which leukocytes communicate with one another. o 3 actions: autocrine, paracrine, endocrine o Cytokine receptors are membrane bound. Transduce a signal upon binding a cytokine o Review Fig. 3.26 IL-6: induces synthesis of acute-phase proteins in the liver (C-reactive protein, MBL etc Fig 3.28) TNF-: can cause inflammation (most TNF is from macrophages) Too much can cause septic shock. IFN-/ (Fig. 3.29) NK Cells: Lymphocytes that are derived from the bone marrow. They circulate in the blood and contain cytolytic granules o Important for tumors and virally infected cells.

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Part of the Innate System Do not need to be activated beforehand Recognize cells that have down-regulated MHC I Regulation of NK Cells Activation KAR receptors on NK cells associate with ITAMs: recruit Src family kinase to activate syk and zap70 Inhibition KIR receptors on NK cells associate with ITIMs: recognize MHC class I recruits shp1/2 and dephosphorylates syk and zap70 to inactivate

CHAPTER 4 BCR: (Antibodies aka Immunoglobulin): Made by B Cells. Can be transferred from one person to another. o Membrane and secreted form o Glycoprotein o Binds Ag (two Ag binding sites) o 4 chains: 2HC, 2LC (either or ) HC determines Ig class Isotype: class and subclass (ex. IgG1) o Connected by inter/intra disulfide bonds. o Hinge region gives it flexibility. (IgM and IgE do not have a hinge region) o Variable region (Fab portion=N terminus) binds Ag; Constant Region (Fc portion=C terminus) is the effector function. 3 Hypervariable regions in the variable region o Be familiar with the experiment that led to the determination of the antibody structure. TCR: very similar to BCR, connected by disulfide bonds. o Membrane bound o Binds 1 Ag, must be processed Ag o Short cytoplasmic tail o Mostly chains, some have chains o Two types MHC II: MHC I (1 chain + microglobulin): presents endogenous peptides. On all nucleated cells. Virus encoded Produced by intracellularly replicating microorganisms Enclosed cleft: binds 8 10 aa MHC II (2 chains): presents exogenous peptides. Only on APCs Uptake through phagocytosis and degradation in phagolysosome Open cleft: 13-17 aa

o Anchor residues are amino acid residues that directly interact with MHC. MHC I o Antigen Recognition through TCR Requires Additional Molecules (Fig 4.25) CD4 (on T Cell) interacts with MHC II (on APC) CD8 interacts with MHC I All T-Cells have CD3. Needed for signal transduction. Understand difference between antigenicity and immunogenicity Hapten: small molecules o Not immunogenic alone (needs carrier that is immunogenic) o Antigenic (can bind Abs once formed) o Can serve as known epitopes o When coupled to carrier protein antibodies can be generated, Once antibodies are generated they can recognize and bind to uncoupled hapten. Conformational/Linear epitopes for Antibodies o Non-covalent interactions are responsible for Ag-Ab binding o T cells recognize antigen bound to an MHC molecule