PSC 315 Immunology Review Guide PDF

PSC_315-Immunology Review guide for lectures 1-3; Quiz 1 Lecture 1: Innate immunity-anatomy and antimicrobial peptides 1)​ Differentiate between innate and adaptive immunity. -​ Innate: (not intrinsically affected by prior contact with infectious agent), the body’s i...

PSC_315-Immunology Review guide for lectures 1-3; Quiz 1 Lecture 1: Innate immunity-anatomy and antimicrobial peptides 1)​ Differentiate between innate and adaptive immunity. -​ Innate: (not intrinsically affected by prior contact with infectious agent), the body’s immediate immune response to foreign invaders that is not dependent on prior exposure to the same invader -​ Adaptive: (modified by previous exposure to infectious agents), the response of antigen-specific B and T lymphocytes to antigen, including the development of immunological memory (which takes time to build) 2)​ Compare and contrast the four major classes of infectious agents and their size ranges. -​ Viruses: infectious agents that typically consist of a nucleic acid molecule in a protein coat, is too small to be seen by light microscopy, and is able to multiply only within the living cells of a host (10nm-100nm) -​ 3)​ Explain how pathogens damage our cells and tissues. 4)​ Discuss the first line of defense against pathogens and the anatomical structure of skin and mucosal membranes. 5)​ Be able to describe the interactions between adjacent epithelial cells in the epidermis (junctions). 6)​ Is the skin only a passive barrier to microorganisms? 7)​ Describe, in general, the three major types of initial defense mechanisms (mechanical, chemical and mircrobiological) and examples of each in different parts of the body). 8)​ Describe the characteristics of lysozymes and defensins, including the mechanisms by which they suppress infections. -​ Lysozyme: a peptide which facilitates the hydrolysis of a B-1-4-glycosidic bond between NAG and NAM in bacterial cell walls. It is abundant in a number of secretions, such as tears, saliva human milk and mucus -​ Defensins: two classes (alpha and beta) ​ Alpha: HNP1-3, HNP4, HD5, HD6 ​ Beta: HBD1-3, HBD4 9)​ Describe what mucus is and how it can prevent infections. -​ Mucus: the viscous slippery substance that consists chiefly of mucin, water, cells and inorganic salts and that is secreted as a protective lubricant coating by the cells and glands of the mucous membranes, it helps to protect us against infectious agents, but can be a problem if overproduced which forms a tenacious, congealed mucopurulent material  10)​Describe the characteristics of mucins. Mucins: a visco property of mucus that is derived from major gel-forming glycoprotein components, consists of a peptide backbone containing alternating glycosylated and non-glycosylated domains, with O-linked glycosylated regions comprising 70-80% of the polymer, there are 21 different mucin genes 11)​What does the term “mucosa” mean? Mucosa: 12)​Describe the differences between prokaryote and eukaryote. Prokaryote: no nucleus, 0.1-10micrometers, Eukaryote: has a nucleus, 10-100micrometers Lecture 2: Cells of the immune system 1)​ Explain what “multipotent” or "pluripotent" means. Multipotent: able to give rise to multiple cells Pluripotent: able to give rise to all cell types in an adult 2)​ Describe the process of hematopoiesis, including the three branches and the cells that result from each branch. Hematopoiesis: the generation of blood cells 1.​ Myeloid granulocyte neutrophil, eosinophil, basophil ​ Monocyte macrophage ​ Dendritic cell ​ Mast cell 2.​ Lymphoid common t-cell/ILC precursor common ILC precursor NK cell, ILC1, ILC2, ILC3, LTi ​ Common t-cell/ILC precursor common t-cell precursor CD8 / common CD4 T-cell precursor Treg, TH17, TH2, TH1 ​ B-cell 3.​ Erythroid (megakaryocyte-erythroid precursor cell) erythroblast erythrocyte ​ Megakaryocyte platelets 3)​ Detail the process of phagocytosis.  Phagocytosis: cellular internalization of particulate matter such as bacteria, by means of endocytosis -​ process: chemotaxis → adherence through PAMP recognition → membrane activation through ‘danger’ signal → initiation of phagocytosis → phagosome formation → fusion → killing and digestion → release of degradation products 4)​ Explain what happens to neutrophils after they phagocytose a microorganism. The neutrophils die in the tissue and are then engulfed and degraded by macrophages 5)​ Describe the different types of granules present in neutrophils. -​ non-specific or primary azurophil granules contain myeloperoxidase (causes “green” pus or mucus) uses hydrogen peroxide and chloride to generate hypochlorous acid, a potent bactericidal oxidant, together with most of the non-oxidative antimicrobial effectors including defensins, bactericidal permeability increasing (BP) protein and cathepsin G -​ specific or secondary granules which contain lactoferrin, much of the lysozyme, alkaline phosphatase and membrane bound cytochrome b558 -​ neutrophils contain abundant glycogen stores for glycolysis, enabling the cells to function under anaerobic conditions 6)​ Categorize the salient characteristics of neutrophils, macrophages, monocytes and other cells of the immune system. -​ Neutrophils: have 2-5 nuclear lobes connected by fine filaments of chromatin, cytoplasm is pink to grey because if the neutral staining of specific granules (do not stain), contain abundant glycogen stores for glycolysis, enables the cells to fxn under anaerobic conditions -​ Macrophages: large cell has a lightly stained nucleus that often appears horseshoe or kidney shaped, chromatin appears lacy and nucleoli are usually not apparent, nucleus looks a bit like a “brain”, small dense granules are frequently present even though they are called agranulocytes, derived from monocytes, -​ Monocytes: migrate into connective tissue and become macrophages -​ Eosinophils: killing of antibody-coated parasites through release of granule contents, present in large amounts in intestinal mucosa and lungs, increased in parasitic infections, stimulated in allergic reactions by mast cells -​ Basophils: controlling immune responses to parasites, longest lasting granulocyte, lifespan 2 weeks, contain histamine, leukotrienes, and heparin, involved in hypersensitivity and inflammatory reactions  -​ NK: kills cells infected with certain viruses, contains small granules in their cytoplasm which contain proteins such as perforin and proteases known as granzymes -​ Dendritic cells: activation of t-cells and initiation of adaptive immune responses -​ Mast cells: expulsion of parasites from body through release of granules containing histamine and other active agents 7)​ List the most plentiful to the least plentiful leukocytes in the blood (NLMEB). -​ Neutrophils (polymorphonuclear neutrophils, PMN, polys, segmented neutrophils or segs): 48-78% -​ Lymphocytes (B and T cells and NK cells): 20-40% -​ Monocytes: 2-8% (undifferentiated) -​ Eosinophils: 0-4% -​ Basophils: 0-1% 8)​ How do white blood cell counts compare to RBC counts in the blood (uninfected state). Ratio is 1 WBC to every 600-700 RBCs 9)​ Explain how NK cells “kill” other cells and are able to distinguish abnormal from normal cells. -​ Upon release in close proximity to a cell slated for killing perforin forms pores in the cell membrane of the target cell, creating an aqueous channel through which the granzymes and associated molecules can enter, inducing either apoptosis or osmotic cell lysis, a-defensins are also secreted by NK cells -​ Healthy cells have MHC class 1 so the inhibitor receptor is activated causing no release of granules or perforins -​ An infected cell has no MHC class 1 which means the inhibitor receptor is not activated 10)​Describe “Pathogen-associated molecular patterns” (PAMPs) and Pattern Recognition Receptors (PRRs). -​ PAMPs : recognition of pathogens is achieved, in part by the detection of molecular patterns expressed by pathogens, conserved, shared by a large group of infectious agents (sparing the need for too many receptors), clearly distinguishable from self patterns -​ PRRs: recognize PAMPs on leukocytes, can be found associated to subcellular compartments, such as the cellular and endosomal membranes, the cytosol, as well as extracellularly, in secreted forms present in the bloodstream and interstitial fluids; four major sub-families of PRRs (TLRs, CLRs, NLR, RLR), several PRRs are lectin-like and bing multivalently with considerable specificity to exposed microbial surface sugars with their characteristic rigid three-dimensional geometric configurations.  11)​What are the ideal characteristics of PAMPs from the pathogens’ perspective versus our perspective? conserved, shared by a large group of infectious agents (sparing the need for too many receptors), clearly distinguishable from self patterns 12)​What molecular events follow the activation of PRRs? -​ the engagement of PRRs on the innate immune cells activate microbicidal and pro-inflammatory responses required to eliminate (or at least to contain) infectious agents, including the induction of infected cell death in addition, co-stimulatory signals for the adaptive immune cells are activated -​ When activated, some of these receptors induce phagocytosis while other receptors send signals into the interior of the cell to make and secrete small biologically active proteins called cytokines. the cytokines recruit other immune cells to the infected tissue -​ infection: PAMPs -​ injury: DAMPs Lecture 3: Pattern Recognition Receptors-(PRR): TLRS and NFkB and Cytokines 1)​ Differentiate between gram negative and positive bacteria. Why is this important from a therapeutic perspective? -​ gram negative: have less peptidoglycan, no (lipo)teichoic acid, and an outer membrane made up of lipopolysaccharide (LPS), alcohol dissolves the lipids, forms large pores that leak the dye, leading to loss of dye -​ gram positive: have peptidoglycan and (lipo)teichoic acid. no pores are formed by alcohol and the dye is retained 2)​ Be able to identify the following as gram-negative bacteria: Escherichia coli, Pseudomonas, Haemophilus influenzae. -​ E.coli: bacilli → lactose fermenter → oxidase negative -​ Pseudomonas: bacilli → non-lactose fermenter → oxidase-positive -​ Haemophilus influenzae: bacilli → gram-negative coccobacilli 3)​ Be able to identify the following as gram-positive bacteria: Staphylococci, Streptococci. -​ staphylococci: cocci → clusters -​ streptococci: cocci → chains 4)​ Describe TLRs and their signaling pathway (activation of NFκB) -​ TLRs sense microbial products inside and outside human cells by different TLRs 5)​ Why is the activation of NFκB so important for immunity? What types of genes do they regulate?  -​ NFkB regulates the expression of cytokines, inducible nitric oxide synthase (iNOS), cyclo-oxygenase-2 (COX-2), growth factors, inhibitors of apoptosis -​ genes: -​ cell-cycle: CyclinD1 -​ apoptosis and cell survival: Bcl2, Bcl-xL, SOD, cFLIP, IAPs, IkB, growth factors -​ cell adhesion: VCAM, ICAM, selectins, MMPs -​ inflammation: complement, defensins, COX-2, CRP -​ immunity: B7, IL-2, AgR, MHC, Foxp3, ROR 6)​ What diseases are associated with the dysregulation of NFκB? -​ It is linked to inflammatory diseases such as crohn’s disease and ulcerative colitis. NFkB activation is evident in biopsies of Crohn’s disease and ulcerative colitis patients. TX of patients with steroids decreases NFkB activity in biopsies as well as reducing the clinical symptoms of disease 7)​ Explain what lipopolysaccharide (LPS) is and their relevance for health. -​ LPS is a complex associated w/ the outer membrane of gram-negative bacteria such as E.coli, salmonella, Shigella, Pseudomonas, Haemophilus influenzae, bordetella, pertussis, and Vibrio cholera -​ it os a gram-negative bacterial endotoxin -​ if LPS enters the circulatory system, it causes a toxic reaction, with the sufferer developing a high temp, high respiration rate, and low blood pressure, can lead to endotoxic shock, which can be fatal 8)​ Know what cytokines are and what functions they serve. -​ low molecular weight proteins that act as messenger molecules from one cell to another causing them to stimulate or inhibit differentiation, proliferation or migration or secrete additional cytokines or die -​ unlike endocrine hormones, the majority of cytokines normally act locally in a paracrine or even autocrine fashion -​ some cytokines are proinflammatory while others are anti-inflammatory 9)​ Distinguish the different classes of cytokines and their characteristics. -​ pro-inflammatory: TNFa, IL1, IL6, IL8 -​ anti-inflammatory: IL-1ra, sIL-1R, sTNFR, IL10, IL4, IL11 -​ interleukins: act mostly as communicators between leukocytes. members are diverse, and is based on biological activity rather than sequence or structural homology -​ chemokines: a large family of chemotactic cytokines which stimulates leukocyte movements, can be produced by a variety of cells and can be divided into four families based on the disposition of the first  (N-terminal) two of the four canonical cysteine residues, C chemokines, CC chemokines, CXC chemokines, CX3C chemokines -​ tumor necrosis factors: TNF (TNF-a), lymphotoxin (TNF-B), produced chiefly by activated macrophages, although it can be produced by other cell types as well. the primary role of TNF is in the regulation of immune cells. TNK, being an endogenous pyrogen (induce fever), to induce apoptotic cell death, to induce sepsis (through IL1, and IL6 production), to induce cachexia (wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite), induce inflammation, and to inhibit tumorigenesis and viral replication. dysregulation of TNF production has been implicated in a variety of human diseases, including alzheimer’s disease, cancer, major depression, and inflammatory bowel disease (IBD) -​ colony stimulating factors: stimulate proliferation and differentiation of hematopoietic precursors, G-CSF (gran -​ ulocyte colony-stimulating factor), M-CSF (macrophage colony-stimulating factor), epo (erythropoietin) -​ interferons: broad-spectrum antiviral agents which inhibit viral replication through interactions with PRRs. divided into: -​ interferons 1 (alpha, beta, epsilon, kappa, and omega subtypes) -​ interferons 2 (gamma subtype) -​ interferons 3 (lambda subtypes) They are expressed early on in the host defense mechanism against multiple viruses. interferons exhibit antiviral activity at many stages of the viral replication cycle, including entry, transcription, RNA stability, translation, maturation, and release 10)​Know the meaning of autocrine, paracrine and endocrine. Comparison Summary: Mode Distance Medium Examples Autocrine Acts on the same Local action IL-2 in T-cell cell proliferation Paracrine Acts on nearby Diffuses Cytokines, growth cells locally factors Endocrine Acts on distant Bloodstream Insulin, adrenaline cells Each of these signaling mechanisms is vital for maintaining communication and function across cells and tissues.  11)​Describe the cytokines released by macrophages which have been exposed to pathogens and the functions of these cytokines. 12)​Describe the different types of cytokine receptors and the process of their signaling (memorize cell signaling: JAK-STAT, NFκB activation). Lecture 4: Complement 1)​ Detail the three different pathways of complement activation. -​ alternative pathway: pathogen surface creates local environment conductive to complement activation → first to act → complement activation → cleavage of C3 to C3a and C3b (covalently bound to surface components of pathogen → recruitment of inflammatory cells/opsonization of pathogens facilitating uptake and killing of phagocytes/perforation of pathogen cell membranes → death of pathogen -​ lectin pathway: mannose-binding lectin binds to pathogen surface surface → second to act → complement activation → cleavage of C3 to C3a and C3b (covalently bound to surface components of pathogen → recruitment of inflammatory cells/opsonization of pathogens facilitating uptake and killing of phagocytes/perforation of pathogen cell membranes → death of pathogen -​ classical pathway: c-reactive protein or antibody binds to specific antigen on pathogen surface → third to act → complement activation → cleavage of C3 to C3a and C3b (covalently bound to surface components of pathogen → recruitment of inflammatory cells/opsonization of pathogens facilitating uptake and killing of phagocytes/perforation of pathogen cell membranes → death of pathogen 2)​ Explain how the complement system helps to initiate the innate immunity. -​ one of the first responses to the presence of a foreign organism in the body is the activation of the complement system -​ system of about 30 proteins which along w/ blood clotting, fibrinolysis and kinin formation, forms one of the triggered enzyme systems found in plasma -​ these systems characteristically produce a rapid, highly amplified response to a trigger stimulus mediated by a cascade phenomena where the product of one reaction is the enzymatic catalyst of the next 3)​ Know what opsonization is and its role in immunity. -​ complement proteins are soluble and most are made constitutively in the liver and are present in the blood, lymph, and extracellular fluids -​ activated complement coats the surface of pathogens (this is called opsonization or complement fixation) and makes them more easily phagocytosed 4)​ Understand how complement activation is regulated. What are the functions of DAF, MCP, CD59 proteins? -​ DAF (decay-accerlerating factor) and MCP (membrane cofactor protein) disrupt C3 convertase C3bBb on a human cell surface -​ CD59 proteins bind to the C5b678 complex and prevents recruitment of C9 to form the pore; they also prevent C5bC6C7 complex from completing MAC formation 5)​ How is C-reactive protein (CRP) induced? Where is it made? What does it bind to? How is the detection of CRP used clinically? -​ the classical pathway begins with the cytokines IL-1,IL-6, or TNF-a inducing the synthesis of the acute phase protein, (CRP) → bacteria induce macrophages to produce IL6 which acts on hepatocytes to induce synthesis of acute-phase proteins (CRP) -​ CRP binds to pathogens → binds phosphocholine on bacterial surfaces, acting as an opsonin and as a complement activator -​ 6)​ Know the two types of C3 convertase and how it is assembled. -​ Classical: C4bC2a -​ alternative: C3bBb 7)​ Know what anaphylatoxins are and which components of complement can act as anaphylatoxins and their roles in immunity. -​ the C3a and C5a components are referred to as anaphylatoxins. they cause smooth muscle contraction, histamine release from mast cells, and enhanced vascular permeability. they also mediate chemotaxis, inflammation, and generation of cytotoxic oxygen radicals 8)​ Know what acute phase proteins are and how they are induced. -​ cytokines, IL1, IL6, and TNFa induce the Liver to produce the acute-phase proteins -​ mannose-binding lectin: a protein that binds a carbohydrate, commonly an oligosaccharide, with very high affinity and specificity, mediating cell-cell interactions → pathogens targeted by MBL include certain gram(+) and gram(-) bacteria, yeast, parasites and viruses -​ CRP: a member of the pentraxin family of proteins. it binds to the phosphocholine component of LPS in bacterial and fungal cell walls as well as to a variety of constituents of microorganisms -​ fibrinogen 9)​ Explain the different ways in which the complement system helps us to suppress infection by microorganisms. -​ in addition to improved phagocytosis by opsonization of pathogens, complement can also supress pathogens by a process involving the terminal components of the complement pathway  -​ the terminal process involves the formation of the alternative C5 convertase (C3b2Bb) and C5 activation -​ the terminal complement components form membrane-attack complexes (MAC) which generate pores in the lipid bilayer membrane 10)​What does CRP bind to? (answered above in question 5) 11)​Explain how α-2macroglobulin helps us suppress pathogen infections. -​ pathogens often use proteases to makeit easier to infect us. therefore, we make proteins such as a2-macroglobulin to inactivate their proteases -​ protease cleaves bait region causing conformational change → a2-macroglobulin enshrouds the protease and is covalently bonded to it Lectures 5: Inflammation 1)​ What are the five cardinal signs of inflammation and what causes them? -​ pain: the inflamed area is likely to be painful, especially when touched. chemicals that stimulate nerve endings are released, making the area much more sensitive -​ redness: this is bc the capillaries are filled up with more blood than usual -​ immobility: there may be some loss of fxn -​ swelling: caused by an accumulation of fluid (from blood) -​ heat: as w/ the reason for the redness, more blood in the affected area makes it feel hot to the touch 2)​ Identify the causes of acute inflammation. -​ reactions are triggered by a variety of stimuli -​ infections (bacterial, viral, parasitic) and microbial toxins -​ trauma (blunt and penetrating) -​ physical and chemical agents (thermal injury, burns or frostbite, irradiation, some environmental chemicals) -​ tissue necrosis (from any cause) -​ foreign bodies (splinter, dirt, sutures) -​ immune reactions (also called hypersensitivity reactions) 3)​ Is there only a single type of inflammation? -​ class type ​ ​ ​ ​ ​ -​ acute inflammation w/o neutrophils -​ allergic acute inflammation -​ serous inflammation (in body cavities) -​ catarrhal inflammation (mucous membranes) -​ fibrinous inflammation -​ necrotizing inflammation, hemorrhagic inflammation -​ membranous (pseudomembranous) inflammation  -​ suppurative (purulent) inflammation 4)​ Describe the types of messengers released by mast cells. What causes their release? What are some of their effects? -​ granule release -​ histamine: vasodilation, inc capillary permeability chemokinesis, bronchoconstriction -​ proteoglycan: binds granule protease -​ neutral proteases, B-glucosaminidase: activates C3, splits off glucosamine -​ ECF, NCF: eosinophil chemotaxis, neutrophil chemotaxis -​ platelet activating factor: mediator release -​ IL3-6, GM-CSF, TNF: multiple, including macrophage activation, trigger acute phase proteins etc. -​ lipoxygenase pathway -​ leukotrienes C4, D4 (SRS-A), B4: vasoactive, bronchoconstriction, chemotaxis -​ cyclo-oxygenase pathway -​ prostaglandins, thromboxanes: affect bronchial muscle, platelet aggregation and vasodilation 5)​ Describe the process of extravasation including the four different steps and the major molecules involved in each step. -​ def: a process by which leukocytes such as neutrophils migrate out of the capillaries and into the infected tissue. an important early step in inflammation -​ rolling adhesion: the carbohydrate group: 6-sulfo sLex on the leukocytes bind transmittently to selectin proteins on endothelial cells -​ tight binding: occurs through the interaction of integrins on the surface of leukocytes to adhesion proteins on the endothelial cells. TNF-a induces the expression of LFA-1 and ICAM-1 -​ diapedesis: have to slow down before they can move out of the blood cell -​ migration: towards the pathogens via chemotaxis (movement of a motile cell in a direction corresponding to a gradient of increasing or decreasing conc. of a particular substance 6)​ Why would an inhibitor of extravasation be used as a drug? Which is one way of inhibiting extravasation? -​ natalizumab is used to tx M.S and crohn’s disease -​ MOA: humanized monoclonal antibody → binds to adhesion molecule a4-integrin; prevents adhesion to a4-integrin to endothelial cells -​ pharmacology: prevents migration of autoreactive leukocytes out of blood vessels into target organs  7)​ Be able to describe the resolution stage of acute inflammation. -​ as the injurious agent is eliminated and/or the injury is healed, anti-inflammatory mechanisms become active, the inflammatory process subsides via a process called resolution and the host returns to a normal state of health 8)​ Describe the “stop signals” or “checkpoints” of inflammation and their function. -​ stop signals pave the way for monocyte migration and their differentiation to phagocytosing macrophages, which remove dead cells and then exit the site of inflammation -​ lipoxins -​ resolvins -​ prostaglandins 9)​ Summarize the cyclic pathway from arachidonate to prostaglandins and thromboxanes. the current cyclo-oxygenase (COX) concept (simplified): -​ arachidonic acid -​ cox-1 (constitutive) →(inhibition undesirable) → homeostatic functions: GI tract, renal tract, platelet fxn, macrophage differentiation -​ cox-2 (induced) → (inhibition desirable) → inflammation ​ non-simplified: -​ phospholipid containing arachidonate → phospholipase A2 → arachidonate → cyclooxygenase activity of COX → PGG2 → peroxidase activity → PGH2 → other prostaglandins and thromboxanes 10)​Review the lipoxygenase pathway for the production of leukotrienes and lipoxins. -​ arachidonate -​ lipoxygenase → 12-hydroperoxyeicosateraenoate (12-HPETE) → (multistep) → other leukotrienes -​ lipoxygenase → 5-HPETE → (multistep) → leukotriene A4 → LTC4 → LTD4 11)​How are free radicals created during inflammation (proteins involved and mechanism)? -​ the phagocytes also use free radicals to kill pathogens -​ bacterium is phagocytosed by neutrophils → phagosome fuses w/ azurophilic and specific granules → pH of phagosome rises, antimicrobial response is activated, and bacterium is killed → pH of phagosome dec, fusion w/ lysosomes allows acid hydrolases to degrade the bacterium completely → neutrophil dies by apoptosis and is phagocytosed by macrophages  -​ NADPH oxidase complex contains cytochrome b558, free Fe2+, hydroxyl radical, superoxide ion 12)​Why are free radicals so dangerous? -​ they escape into the cytoplasm and nucleus and can damage macromolecules such as DNA, lipids and proteins -​ can modify nucleotide residues 13)​Describe chronic inflammation. -​ considered to be inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously -​ follows acute inflammation, chronic inflammation frequently begins insidiously, as a low-grade, smoldering, often asymptomatic response. this latter type of chronic inflammation is the cause of tissue damage in some of the most common and disabling human disease such as RA, atherosclerosis, TB, and chronic lung disease -​ persistent infections -​ prolonged exposure to potentially toxic agents, either exogenous or endogenous -​ autoimmunity 14)​What is the difference between acute and chronic inflammation? -​ acute inflammation: manifested by vascular changes, edema, and predominantly neutrophilic infiltration -​ chronic inflammation: infiltration w/ mononuclear cells, which include macrophages, lymphocytes and plasma cells, tissue destruction, induced by the persistent offending agent or by the inflammatory cells, attempts at healing by connective tissue replacement of damaged tissue, accomplished by proliferation of small blood vessels (angiogenesis) and in particular, fibrosis -​ acute -​ short, acute, nonspecific, neutrophils/macrophages, active vasodilation/increased permeability 15)​Summarize the role of macrophages in chronic inflammation. -​ tissue injury: toxic oxygen metabolites, proteases, neutrophil chemotactic factor, coagulation factors, AA metabolites, nitric oxide -​ fibrosis: growth factors (PDGF, FGF, TGFb), fibrogenic cytokines, angiogenesis factors (FGF), “remodeling” collagenesis 16)​Describe the role of COX-1 and COX-2 in inflammation. Differentiate between the two types of enzymes. What cytokines induce Cox-2? 17)​Know what a granuloma is. What is its purpose? -​ a granuloma consists of a microscopic aggregation of macrophages that are transformed into epithelium-like cells surrounded by a collar of  mononuclear leukocytes, principally lymphocytes and occasionally plasma cells 18)​Describe the role of fibroblast in chronic inflammation. -​ inc: proliferation, collagen synthesis, collagenase, protease, PGE synthesis 19)​Read the TIME article (“silent killer”) carefully and discuss the evidence for the role of chronic inflammation in various diseases and the role nutrition plays in inflammation. (content of the TIME article will be tested-please read it multiple times!). Lecture 6: Overview of acquired immunity/lymphoid system and antibodies and immunoglobulin genes. 1) Summarize the relationship between innate and adaptive immunity. -​ (answered in lecture 1 question 1) 2) Describe the primary and secondary lymphoid organs. -​ primary lymphoid organ: education → thymus and bone marrow -​ → secondary lymphoid organ: immune response -​ encapsulated: lymph node (to antigens in tissues), spleen (to antigens in blood) -​ unencapsulated: MALT (mucosa associated lymphoid tissue) (to antigens at mucosal surfaces) 3) Name the major components of the lymphatic system and its function. Does the lymphatic system have a pump? How is lymph circulated? -​ the lymph system is a network of organs, lymph nodes, lymph ducts and lymph vessels that make and move lymph from tissues to the bloodstream. the lymph system is a major part of the body’s immune system -​ lymph: a colorless fluid containing white blood cells, that bathes the tissues and drains through the lymphatic system into the bloodstream -​ the lymphatic system has no pump -​ muscle contraction and movement helps to move the lymph fluid around the lymphatic system -​ lymph nodes: small round stx that act as filters along the lymphatic system. traps pathogens like bacteria, viruses, toxins, as well as cancer cells and ensure that these are removed from the body. there are hundred of lymph nodes located throughout our body -​ the spleen: red pulp where old and damaged red cells are removed from, within white pulp (secondary lymphoid tissue) 4) Explain what “cluster of differentiation” (CD) is. -​ the identity of many cell surface proteins is/was unknown  -​ CD followed by a number is used to identify cell surface proteins, can be used a biomarkers for differentiation of cells, can be expressed in a cell and tissue specific manner 5) Explain how you get so many different BCRs, antibodies and TCRS. -​ BCRs and TCRs are extremely variable and are responsible for the extreme diversity of adaptive immunity -​ BCR (B cell receptor): the antigen binding site is made up of the light chain and the heavy chain -​ TCR (T cell receptor): the antigen binding site is made up of the a and B chains 6) Explain what clonal selection and expansion are and their role in immunity (in a broad sense). -​ adaptive immune response to a pathogen is due to the selection and expansion of the small fraction of B cells and T cells that carry BCR and TCRs respectively, that recognize the infecting pathogen -​ during development, progenitor cells give rise to large numbers of circulating lymphocytes, each having a different form of cell-surface receptor → the receptors of only a few circulating lymphocytes interact with any given pathogen → pathogen-reactive lymphocytes are triggered to divide and proliferate → pathogen-activated lymphocytes differentiate into effector cells that eliminate the pathogen 7) What is the difference between BCRs and antibodies? 8) Define antibody, BCR and describe their structure. What happens to antibodies when you digest it with papain? Lecture 7, Generation of B cell diversity. 1) Describe the process of somatic recombination to create diversity of antibodies, BCR and TCRs (proteins and mechanism). ?? (idk if i answered that correctly) -​ the germline organization of the human immunoglobulin heavy chain (H) and light chain ( or k) loci -​ germline → somatic recombo → DJ joined DNA → somatic recombination → VDJ-joined rearranged DNA 2) Explain how antibodies recognize specific epitopes. -​ immunoglobulins recognize specific epitopes (a localized region on the surface of an antigen that is capable of eliciting an immune reaction) in the antigen that it binds to 3) Describe the Hinge region of antibodies and why they are useful. Which classes of antibodies have it? -​ only in IgG, IgD, and IgA classes 4) Know what hypervariable regions are (HV1-HV3 or CDR1-3) are and why they are important. -​ the recognition of epitope by the antibody is mediated by the antigen binding site of the variable regions of the light and heavy chains. the specificity of epitope recognition is determined by the amino acid sequence in this area, the great diversity in the specificity is part, created by differences in the hypervariable regions 5) Know what RSSs and RAG are and their roles in creating diversity of BCRs, antibodies and TCRs. -​ RSS: recombination signal sequence around each gene segment guide somatic recombination -​ RAG: recombination-activating genes expressed only in B and T cells 6) Describe the process of junctional diversity including the major enzymes involved. Will all junctional diversity events lead to productive BCRs? -​ in addition to the presence of large number of gene segments and somatic recombination, junctional diversity creates further diversity -​ generation of junctional diversity → RAG complex cleaves the heptamer RSSs from the D and J gene segments to yield DNA hairpins → RAG complex opens hairpins by nicking one strand of the DNA, generating palindromic P-nucleotides → n-nucleotide additions by TdT(terminal deoxynucleotidyl transferase) → pairing of strands → unpaired nucleotides are removed by an exonuclease → Gaps are filled by DNA synthesis and ligation to form coding joint 7) Describe mechanisms by which antibodies combat infection. -​ Classical pathway -​ neutralization: ingestion and destruction by phagocyte -​ opsonization: ingestion and destruction by phagocyte 8) Know the characteristics of each type of antibody (IgM, IgD, IgG1-4, IgA1 and IgA2 and IgE) and their roles in immunity. -​ IgG and IgA: further divided into subclasses -​ IgA is found in both monomeric and dimeric forms in the serum, the dimeric form is secreted into mucosal surfaces -​ IgM is found either as a cell surface bound monomer or as a secreted pentamers -​ IgM: neutralization, activation of complement system, transport across epithelium -​ IgG1: neutralization, opsonization, sensitization for killing by NK cells, sensitization of mast cells, activation of complement system, transport across placenta, diffusion into extravascular sites -​ IgG2: neutralization, activation of complement system, transport across placenta, diffusion into extravascular sites  -​ IgG3: neutralization, opsonization, sensitization for killing by NK cells, sensitization of mast cells, activation of complement system, transport across placenta, diffusion into extravascular sites -​ IgG4: neutralization, opsonization, transport across placenta, diffusion into extravascular sites -​ IgA: neutralization, opsonization, activation of complement system, transport across epithelium, diffusion into extravascular sites -​ IgE: sensitization of mast cells, diffusion into extravascular sites 9) Which antibody classes can form multimers? -​ IgM and IgA 10) Explain the process of somatic hypermutation. What is its role in the immune system. When does it occur? -​ occurs after B cell has recombined its immunoglobulin gene and made a fxnal BCR and the B cell activated by an antigen -​ targets the rearranged gene segment encoding the variable region -​ dependent on the enzyme; activation-induced cytidine deaminase (AID) -​ present only in proliferating B cells -​ AID converts cytidine in single-stranded DNA to uridine (uridine then can be converted to any of four nucleotides by DNA repair enzymes 11) How does antibody class switching occur? -​ involves recombination between specific regions -​ IgM and IgD are produced → AID selectively targets the Su and Sy1 switch regions → DNA in the Su and Sy1 switch regions in nicked on both strands → looping out and switch-region recombination → IgG1 produced 12) How does the B-cell make IgM versus IgD? -​ intitially all B cells transcribe both the IgM (Cu) and IgD (Cd) gene segments 13) How does the B cell make BCR versus antibody? -​ alternative splicing determines whether the membrane bound (BCR) or secreted immunoglobulins (antibody) is formed 14) Which stages of antibody production are reversible and which aren’t? event mechanism permanence of change to the B cell’s genome v-region assemble from somatic recombination of irreversible gene fragments genomic DNA generation of junctional imprecision in joining irreversible diversity rearranged DNA segments  adds nongermline nucleotides (P and N) and deletes germline nucleotides assembly of promoter and enhancer irreversible transcriptional controlling are brough closer together elements by V-region assembly transcription activated w/ two patterns of splicing reversible and regulated coexpression of surface and processing RNA are IgM and IgD used synthesis changes from two patterns of splicing reversible and regulated membrane Ig to secreted and processing RNA are antibody used somatic hypermutation point mutation of genomic irreversible DNA isotype switch somatic recombination of irreversible genomic DNA