NOTES Ltt) IMMUNE SYSTEM INTRODUCTION TO THE IMMUNE SYSTEM osms.it/immune-system-introduction + Includes organs, tissues, ells, molecules, + Protects from microorganisms, removes toxins, promotes inflammation, destroys tumor cells, + Two branches Innate, adaptive INNATE IMMUNE RESPONSE. + Nonspecific cells: phagocytes, natural killer (NK) cells; no immunologic memory «+ “Feverishly” fast (minutes to hours) Noncellular components + Physical, chemical barriers e.g. sozymes in tears, cilia in airways) + Infiammation: stops spread of infection, promotes healing » Four cardinal signs: redness, heat, swelling, pain + Complement system: cascade of proteins; ‘riggers inflammation, kills pathogens by tolysis, tags cells for destruction ADAPTIVE IMMUNE RESPONSE + Highly specific calls; immunologic memory, need priming + Significantly slower, esp. initially (weeks) + Clonal expansions: cells replicate + Clonal deletion: cells die off after immune response; some survive as memory cells 372 OSMOSISORG CELLS OF THE IMMUNE SYSTEM Leukocytes (white blood cells) + Formed by hematopoiesis in bone marrow » Starts with multipotent hematopoietic stem cells + Cells develop into myeloid/ymphoid progenitor cells + Myeloid cells: contribute to innate response « Neutrophils: phagocytes, granulocytes, polymorphonuciear cells (nucleus segmented into 3-5 lobes); stain light pinkfeddish-purple; most numerous leukocyte * Eosinophils: phagocytes, granulocytes, polymorphonuciear cells (nucleus Usually bilobed|: stain pink with eosin; larger cells fight parashes + Basophils: nonphagocytes, granulocytes, polymorphonudlear ces {nucleus bilobedisegmented: stain biue- purple with hematoxylin; ad in fighting parasites; granules contain histamine, heparin: involved in inflammatory response; least numerous leukocyte «Mast cells:nonphagocytes, granulocytes; involved in inflammatory response » Monocytes: phagocytes, antigen- presenting cells: release cytokines to recruit other cals; only circulate in bloo differentiate into macrophagesidendritic calls * Dendritic cells: phagocytes, antigen- presenting calls: release cytokines to recruit other cells; circulate in lymph,Chapter 44 Immunology: Immune System blood. tissue: consume large proteins +8 cells: contribute to adaptive response: in interstitial fic; break bloodborne complete development in bone marrow pathogens into small amino acid chains bind to specie antigens (antigen = move to hmph node + present presentation not needed} capable of antigens to T cells phagocytosis, antigen presentation; load + Macrophages: phagocytes, antigen- antigens on major histocompatbilty presenting cells; release cytokines to complex (MHC) Il, display to T cells; feorut other cals stay in connective T-cell activation —B cells mature into tissue, lymphoid organs; nat in blood plasma cells; secrete lts of antibodies! + Lymphoid cels: contribute to the adaptive immunoglobulins (B cell receptors in response (except NK cells) secreted-form, mark pathogens for © NK cells: contribute to innate response; destruction —» “humoral immunity’) ‘complete development in bone marrow: » Feels contribute to adaptive large, contain granules; primarily target response: complete development in infected, cancer celis; kill target cells ‘thymus; responsible for cell-mediated swith ototoxic granules (punch holes immunity; bind to specific antigens in target cell membranes by binding {antigen presentation needed); naive to phospholipids —+ enter cell trigger T cells primed by antigen presenting apoptosis. programmed cell death) cells (usually dendritic cels); generally categorized into CD4", CD8°T cells; CDA" (helper) T cells secrete cytokines ‘to coordinate immune response, only see antigens on MHC Il; CDB* (cytotoxic) T cell kill target cells, cells, with antigens on MHC | rlliptent homatepatc STEM CELL @ ——_ MYELOID LYMPHOID roger eal pragenlr call eo MonocyTE. BCELL WILLERCELL TCELL seinen sr cet eu © © @ @ - @ covpas olvwoRpvonvcLeAR CELLS deatfestin detest ‘GRANULOCYTES, ‘cx § BONE MARROW THYMUS © ote CELL Figure 441 Family tree of immune system cells OSMOSIS.ORG 373ELAESIFICATION OF IMMUNE Granulocytes + Contain granules in cytoplasm + All calls (except mast cells) Phagocytes * Reach around pathogens with cytoplasm, olymerphonvclear swallowing whole (phagosome) ‘Antigen-presenting cells + Destroy some pathogens with cytoplasmic __« Present antigens to T cells granules (phagosomes fuse with granules = phagolysosomes; pH in vesicle drops kiting pathogens) + Continue to swallow pathogens before Tea oxidative burst —+ produces highly reactive oxygen (e. H,0;: destroys proteins, (specie) RECEPTOR nucleic acids, Kling pathogens, phagocyte) ‘ma paTigen sasroctnemsnrry CCONPLEX (Mic) ANTIGEN-PRESENTING cel 2. CYTOPLASMIC GRANULES Figure 44.3 Antigen-presenting cell uncnvenzene (depicted here as dendritic cell presenting an (opposes pepeane) antigen toa T cell CVTOPLASMIC 3. OXIDATIVE BURST 374 OSMOSISORGChapter 44 Immunology: Immune System leat ll Dre Pract) Pores Cred Dan Coat} MACROPHAGES Raa Phagocytes Ciera Granulocytes Antigen-presenting cells VACCINES osms.it/ vaccines + Generate protective adaptive immune response against microbes by exposure tornonpathogenic formsfeomponents of microbes + Differs from passive immunity (body creates own antibodies) + Administration: intramusculary, intradermaly, intranasally, subcutaneously, orally + Immunoglobulin response depends on route, type of vaccine + Intramuscular vaccinations —+ lg + Rotavius vaccine oral — Ig + Four main types of vaccines + Live attenuated, inactivated {whole call vaccines) + Subunit toxoid (fractionated vaccines) LIVE ATTENUATED VACCINES. * Attenuated — pathogen weakened (put stil replicates) + Measles, mumps, rubella, varicella (MMRV); rotavirus; smallpox; yellow fever INACTIVATED VACCINES. + Pathogen killed using heatformalin + Response humoraVantibody-mediated; no cellular immunity + | response + Hepatitis A: polio; rabies: influenza ‘SUBUNIT VACCINES. + Contain immunogenic portions of pathogens {polysaccharidesfroteins) * Combination of proteins from different pathogens ~» conjugate subunit vaccines + Polysaccharide vaccines » T cell independent only respond to protein antigens) * Not effective in children < two years old * Memory B cells never formed — repeated doses needed » Haemophilus infuenzae type B; hepatitis B; HPV: Bordetella pertussis (pertussis); Streptococcus preumoni Neisseria meningitidis; Varicella zoster OSMOSIS.ORG 375376 OSMOSISORG TOXOID VACCINES: + Against specific toxins (main cause of illness) + Toxoid fixedinactivated using formalin + Often combined with subunit vaccines + Tetanus, ciphtheria, and pertussis (Da, diphtheria, tetanus, and pertussis (DTap) vaccine CONTRAINDICATIONS. + Moderate/severe infection * Allergy to eggsiprevious vaccines + Guillain-Barré syndrome (vaccines against influenza, OTaP} * Weakened immune system + Pregnant (lve attenuated vaccines)NOTES Ls INNATE IMMUNITY INNATE IMMUNE SYSTEM + Comprises immune system along with adaptive immunity + Includes barriers to repel pathogens + Chemical barriers:lysozyme (tears) ow stomach pH « Physical barriers: epithelium (skir/gut), iia lining airways Key features + Nonspecific cells do not distinguish invaders + Response occurs within minutes-hours + No memory = Always responds to pathogen in same manner Human microbiome * Included in innate immunity * Bacteria, fungi, viruses in/on humans + May affect host response in own way RESPONSE TO PATHOGENS Phagocyte response to pathogens + Phagocytes eat, kill pathogens + Phagocyte consumes pathagen += Phagocytic pattern recognition receptors (PRRs) on phagocyte identify pathogen-associated molecular patterns (PAMPs} on pathagens (eg. bacterial- wall components} + Phagocyte swallows pathogen, trapsit in phagosome 400 OSMOSISORG + Phagocyte kis pathogen (post- identification) + Phagosome binds with lysosome, forms phagolysosome + Spectic phagolysosome granules (proteases, hyolases}kilinternal microorganisms while decreasing pH + Azurophilic granules (hycrolases, oxidative enzymes) activate in acidic environment -> more microorganisms killed * Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases oxidize oxygen molecules + superoxide fon creation + Superoxide dismutase converts superoxide into hydrogen peroxide, kiling remaining microorganisms Signalling PRRs response to pathogens + Large amount of pathogens enter —+ signalling pattern recognition receptors also activated * Signalling PRRs ~» phagocytes to release cytokines: + Toll-like receptors (TLRs) especially important in signalling PRRs = PAMP activation + TLRs activate transcription factor NF-« —+ proinflammatory cytokines (e.g. TNFa, IL-1, IL-6) secreted — vasodilation, fever, recruiting leukocytes » Intracellular pathogens: interferon alpha, beta may be secreted (prevents pathogen mutiplication)Chapter 47 Immunology: Innate Immunity PHAGOLYSOSOME Ghogosome + lysosome) SPECIFIC. AZUROPHILIC GRANULES GRANULES. ‘SUPEROXIDE, NADPH SUPEROXIDE DISMUTASE ——™~ HYDROGEN. PEROXIDE, Figure 474 Overview ofthe phagocyte response to pathogens 1 The phagocyte's pattern recognition receptors {PRRs} identify pathoger-associated molecular patterns (PAMPs} on the pathogen. 2. The pathogen is phagocytosed and trapped in a phagosome, which then 3. binds with lysosomes, forming a phagolysosom e 3a. Specific granules from the lysosomes act first to kill pathogens and decrease pH. 3b, After the pH is sufficiently lowered, azurophilic granules are activated and kill more pathogens. 4, NADPH oxidases oxidize oxygen molecules to create superoxide ions. The ions are then converted by superoxide dismutase into hydrogen peroxide, which kill the remaining pathogens. OSMOSISORG 401COMPLEMENT SYSTEM * Collection of plasma proteins called complement proteins * Produced in liver, collectively destroy pathogens COMPLEMENT SYSTEM PATHWAYS. + Acts follow one of three pathways += Classical, alternative, lectin Classical pathway + Features C1-C9 proteins scl © Component proteins C1q, Cir, CIs (latter two—serine proteases) C1 PROTEIN enkibdyentigon complex Cty 66 Figure 422 Structure of a C1 protein. Each of the six C1q proteins can bind to an antibody-antigen complex. Calcium ties the protein together + Proteins inactive until “cleaved” (portion of protein breaks off) + Pathway steps = Clq proteins bind to Fe portion of antibody when bound to antigen © Two Clq proteins bind + C1 changes shapes (conformational change} ‘exposing Cir, C1s 402 OSMOSISORG * Circleaves Cis (activating C1 molecule) ++ C1 cleaves Cd into Ca, Cb C4b binds to pathogen *C1 also cleaves C2 into C2a, C2b —> C2a joins Cab on pathogen ~» C4b2a (C3 convertase) formed *C3 convertase cleaves C3 into C3a, C3b * Cb binds to pathogen near CAb2a/ C3 convertase, creates C5 convertase (C4b2036) » C5 convertase cleaves CS into Ca, C5b *C5b binds to C8, C7, C8, many Cs + forms membrane attack complex (MAC) —+ penetrates pathogen cell membrane + Cl consists of six Clg proteins + Binds to six antibody-antigen complexes + Calcium ties together C1 » Lack of calcium —+ lack of C1 Alternative pathway + Factor 8, factor D proteins + C3 cleaved spontaneously [small amounts) + Pathway steps » Cb binds to pathogen —» factor B binds ‘to pathogen ‘Factor D cleaves factor B — forrns Ba, Bb + C3bBb formed (C3 convertase) + Follows classical pathway * Constant activation prevention » C1-inhibitor protein dissociates C3bBb Lectin pathway + Features mannose-binding lectin protein (binds to bacterial mannose} + Pathway steps » Mannose-binding lectin protein acts similar to C1 —» cleaves C4, C2 ‘to eventually establish C4b2a (C3 convertase) » Follows classical pathwayChapter 47 Immunology: Innate Immunity MEMBRANE ATTACK COMPLEX mac) Figure 473 Overview of the classical complement pathway. 1.Ciq binds to an antibody-antigen complex 2. When two Clq proteins are bound, C1 undergoes a conformational change, exposing Cir ‘and Cis. Clr then cleaves Cis to activate C1. 3.C1 cleaves Cé and C2. 4. C4 and C2 bind to the surface of the pathogen, forming C3 convertase. 5. C3 convertase cleaves C3. 6. C3b binds to the pathogen near the C3 convertase, forming C5 convertase. 7.5 convertase cleaves C5. 8 C5b joins C6, C7, C8, and then multiple C9s to form the membrane attack complex, penetrating the pathogen cell membrane, OSMOSISORG 403404 OSMOSISORG ALTERNATIVE PATHWAY FACTOR D oe} “T° Ce, a Oa ‘CONVERTASE cab b v Des wmron Figure 47.4 Overview of the alternative complement pathway. 1. Small amounts of Bare cleaved spontaneously. 2. C3b and factor B bind to the pathogen. 3. Factor D cleaves factor B. 4, C3b and Bb form 2 C3 convertase and cleave more C3 proteins. The rest follows the classical pathway {from step 6 in previous figure). 5. C1-inhibitor Constantly prevents activation of this pathway by dissociating C3bBb. cs a = OPSONIN pathogen joy Moses \ ‘LECTIN PATHWAY NANROSE. ‘Manwose-siNoWNa) VECTIN (ae (Se sa) ane ws ca Figure 4755 Overview of the lectin pathway. Mannose-binding lectin protein binds to ‘mannose on the pathogen, then cleaves C4 and C2. The rest follows the classical pathway (from step 4 in earlier figure). OTHER COMPLEMENT PROTEIN ROLES + In addition to MAC-formation C3b: opsonin ~» opsonizes pathogens, coats them with molecules, encourages phagocytosis » CBa, C3a: chemotaxins —> recruit neutrophils, eosinophils, monocytes, macrophages Ca, C3a: anaphyiatoxins + cause basophil, mast cell degranulation, releases proinflammatory molecules Sa C30 © (7 = cuemovaxins & ANAPHYLATOXINS © osrophis G ‘osophis . rionmetry laces Figure 47.6 Other roles of complement proteins. Cb acts as an opsonin; it coats pathogens to facilitate phagocytosis, C5a and C3a act as chemotaxins; they recruit neutrophils, easinophils, monocytes, and macrophages. C5a and C3a also act as anaphylatoxins; they cause basophils. and mast cells to degranulate.NOTES tts) B& T CELLS ANTIBODY CLASSES + B cel receptor, major component of humoral immunity + Heavy light chain; fragment antigen- binding region; constant region (Fc) +B cell develops into plasma cell -+B cel receptor secreted as antibody + Antibodies: monomers, polymers + Valence: number of antigen-binding fragments FIVE TYPES + Coded by heavy chain genes Immunoglobulin M (IgM) + 1° antibody response + Monomer as B cell receptor (valence: 2} + Pentamer as antibody held together by joining [} chain (valence: 10) + Works against carbohydrate, ipid antigens + Most effective at activating complement pathway Immunoglobulin G (IgG) + Monomer (valence: 2) + Four subclasses +961, Ig62, 1g63, Iga (difer in constant regions) + Serves as opsonin + Activates classical complement pathway Immunoglobulin A (IgA) + Monomer valence: 2) + Serves as opsonin (eosinophils, neutrophils, ‘some macrophages) + Main immunoglobulin in mucosal sites; sometimes occurs as dimer (valence: 4) + Two forms + IgA, lgA2 (differ in constant regions) Immunoglobulin E (IgE) + Monomer (valence: 2) + Production primarily induced by interleukin 4 (hL-4) + Triggers granule release from mast cells, eosinophils, basophils, + Responds to nonpathogenic targets (2g. peanuts} —+ allergies Immunoglobulin D (IgD) + Monomer (valence: 2) + Found alongside IgM antibodies, signals maturation of B cells, Heavy vise sar ne e— | cago BceLL come, ety Figure 454 B cell receptor components. OSMOSIS.ORG 377IgM Ig B CELL RECEPTORS ~ACTMTES 160 HELPS MATURE emeenens CELLS LEAVE ~~ DOESNT REQUIRE ‘the BONE MARROW eee VALENCE: 10, IgG Ig Ig “= HOST ABUNDANT ANTIBODY sh nucosn = ACTS sn OPSONN arom oewmarins SEASONAL ALLERGIES ASTHMA a ~ mEveNTs paTogens Fm ENTEN NG BODY Figure 45.2 Summary of the five classes of antibodies. gM and igD can act as B cell receptors. B CELL ACTIVATION & DIFFERENTIATION Me NCO usta tk UGC Cou * Developing & cell receptor expresses y heavy chain —+ 8 cell receptors IgM + Alternative splicing IgM, IgD expressed fon surface + mature, naive B cell explores lymphatic system — B cells enter Paracortical region of lymph nodes, migrate to cortical region — form primary follicle ACTIVATION + On activation (antigen-binding), 8 cel forms germinal center -» secondary lymphoid folicle + Cross-linkage of two B cell receptors + aipha,Ig-beta, CD19 cluster * Blk, Fyn, Lyn phosphoryiate tyrosine residues on immunoreceptor tyrosine based activation mati TAM] units = transcription factors nuclear factor kappa-light-chain-enhancer of activated 8 cells (NF-KB), nuclear factor of activated T cells (NFAT) -+ gene expression of cytokines, upreguation of antiapoptotic cell surface markers 378 OSMOSISORG DIFFERENTIATION * Bcells stimulated by cluster of differentiation 21 (CD21)/complement receptor Type ll (CR2} (receptor for C3d ‘complement fragment} + Activated B cells differentiate into plasma cells, secrete antibodies » Plasma cells initially secrete IgM, remain mainly in bone marrow, safeguard against future encounters with same antigen Activated CD4* T cell + class switching + B cells: antigen-presenting cells; present antigens on major histocompatiblity complex (MHC) class I! to helper T cells + CD40 ligand on T cell binds to CD40 on B cell+ cytokines instruct 8 cell on type of antibody to produce {by activation-induced cytidine deaminase) F1L-4 IL-5 IgE "Interferon (IFN) gamma — IgGChapter 45 Immunology: B &T Cells, + Activation-induced deaminase removes constant regions during differentiation to leave desired antibody region ANTIGENS SECONDARY LYMPHOID FOLLICLE MU eB CELL gets ACTIVATED. i Forma «GERMINAL CENTER 2.8 CELLS migrate to CORTICAL REGION A.B LT CELLS enter PARACORTICAL REGION Figure 45.3 Mature, naive B cells form a primary folicle in the cortical region of a lymph node. ‘When the 8 cell binds an antigen, it activates and forms a germinal center. The folicle is now called a secondary lymphoid falicle. CC ea cr Peay EXPRESSION Figure 45.4 Series of events following antigen binding that lead to 8 cell activation. g-alpha, Ig- beta, and CD19 are intracellular side chains ofthe B cell receptors that luster when two B cell receptors are cross-linked by an antigen OSMOSIS.ORG 379AcrWATION coat or ORO Figure 45.5 Complement fragment C3d can bind an antigen and then be bound by molecule CD21/CR2 on a B cell. B cells can also be activated when they have a B cell receptor that is bound to an antigen, and a CD21 that's bound to an antigen. CELLS ae coe reeu ‘eset! a acnvareo Bee TEE e erase SS secre ncnvareo Bee EER Figure 45.6 8 cell differentiation. 1: 8 cell presents an antigen to a CD4+ T cell. 2: the T cell activates, it expresses CD40L on its surface, which binds to CD40 on the B cell. 3: CD4QL and CD40 binding causes the B cell to express a cytokine receptor and the T cell to release cytokines, The type of cytokine determines what type of antibody the B cell wil produce. 380 OSMOSISORGChapter 45 Immunology: B &T Cells, B CELL DEVELOPMENT + Lymphopoiesis: development of diverse set of lymphocytes with unique antigen receptors CREATION OF SUITABLE RECEPTOR * B cell receptor contains two chains = Heavy, light + Antigen-binding site made of variable {V), diversity (D}, joining ()) protein segments coded by genes of same name + Heavy chain: all three segments + Light chain: V, J segments, ANTIGEN BINDING SITE. = VARIABLE - DIVERSITY = JOINING. LIGHT CHAIN HEAVY CHAIN z > vw z Figure 45.7 Antigen binding site on heavy chain is composed of V, D, and J segments, \while antigen binding site on light chain has only V and J segments. STAGES OF DEVELOPMENT + Six stages: common lymphoid progenitor cell — early pro-B cell + late pro-B cell + large pre-B cell -+ small pre-B cell > Immature B cell Oud Early pro-B cell + Common lymphoid progenitor cell expresses recombination activating gene (RAG) 1, RAG2 — early pro-B cell Late pro-B cell + Heavy chain D, J gene segments spliced together (allelic exclusion: 1* chromosome to complete splicing suppresses 2) — late pro-B cell Large pre-B cell + Late pro-B-cell attaches D-J gene segment to V gene segment via V(D) recombinase =+ binding site (heavy chain) recombined with mu gene —* large pre-B cell *» Mu gene codes for IgM constant region protein ‘Small pre-B cell + Functionality of heavy chain tested by binding to surrogate light chain (VpreB, lambda 5) ~ if successful, cels proliferate = small pre-B cell Immature B cell + Light chain rearranged — functionality of light chain tested by autoimmune regulator (AIRE), identities self-reactive cells by ‘expressing bodily antigens in lymphoid organs — immature B cell * Central tolerance/negative selection: elimination of self-reactive cells ® Strong binding to self-antigen —+ cell undergoes apoptosis, + Intermediate binding to self-antigen > light chain repeatedly rearranged with kappa gene on 1%, 2 chromosomes, lambda gene 1°, 2~* chromosomes » Failure to eliminate self-reactive cells -+ autoimmunity + Immature 8 cells finaly undergo alternative splicing on constant region —»IgD constant ragion replaces IgM constant region — cells, released into blood OSMOSIS.ORG 381=@ ae med iL crmonosone 2ad conocer viva va YD 02 Dar 3333 26 ML VANS WN 0303 cams mos OOO-0-666 OOOO \ / cian sruceooes 4 sume wava ys wm n3e re co ae NL wor neconeinnse. waazs J vegzaue EEE vorremmmccnent nae es we @ — wet as SURROGATE LIGHT CHAIN ns aves ce. enna, wa Sama, os ss iat @ LIGHT CHAIN ILC) REARRANGEMENT Y settle ree Fa Figure 45.8 8 cell development stages and the changes that move them to the next stage. y @ 382 OSMOSISORGChapter 45 Immunology: B &T Cells, CELL MEDIATED IMMUNITY OF CD4 CELLS osms.it/cell-mediated-immunity-CD4-cells + CDé calls = T helper cells (support other immune cells) + Tells intially naive + In response to antigen, T cell primed —» effector T cell © Two signals: antigen (MHC molecule on antigen-presenting cel), costimulation (CD28 binds to 87 on antigen- presenting cells) + Activated T helper cell IL-2» up- regulates IL-2 alpha receptor + Thelper cell binds to IL-2 (autocrine stimulation) -» clonal expansion FOUR TYPES OF T HELPER CELL + Depends on cytokines in environment Thelper Type | (Thi) + Fights intracellular infections + Macrophages > IL-12, natural killer (NK) cels + IFN-y, infected cells + FNa, IFNB = transcription factors signal transducer and activator of transcription 1 (STATI), STAT2 Thelper Type Il + Fights parasites + Eosinophils, basophils, mast cells — IL-4, IL-4, IL-10 “+ transcription factors STATE, GATA-binding protein 3 (GATA3) T helper Type XVI + Fights fungal, bacterial infections + Fungi, bacteria —+IL1,IL6, 1L23, ‘transforming growth factor (TGF]B + transcription factors ROR-y, STAT T follicular helper (Tfh) + Establishes memory B cells + Antigen-presenting cells -»IL6,1L21, IL27 transcription factors B cell lymphoma protein 5 (BCL-5), cMaf PRIMING REQUIRES 2 SIGNALS: Le AF Figure 45.9 T helper cells require two signals to be primed and become effector T cells: presentation of an antigen and binding of CD28 on T cell to B7 on antigen-presenting cell OSMOSIS.ORG 383CELL MEDIATED IMMUNITY OF NATURAL KILLER & CD8 CELLS osms.it/cell-mediated-immunity-NK-CD8-cells NATURAL KILLER (NK) CELLS. + Identify target cals; deliver perforin, granzymes + Part of innate response -> no need for specific antigen * Activation receptors recognize surface ‘molecules on infected cells: inhibitory receptors recognize molecules (eg. native MHC class | molecules) + Also activated by antibody-dependent cell mediated cytotoxicity += IgG binds to virally-infected cell + CD16 on NK binds to antibody OWNMHC | RHC |ABSENT FOREIGN MHC | 7 & eee 6 ANTIBODY DEPENDENT CELL MEDIATED CYTOTOXICITY (ADCC) \ oN INFECTED CELL Figure 4540 NK cells recognize cell surface ‘molecules like MHC | to determine whether or not to killa cell. They can also kill via ADCC. Inthis process, the NK cellis stimulated by binding to the constant chain of an IgG antibody attached to a virally infected cel. 384 OSMOSISORG CD8 CELLS + CDB cells = cytotoxic T cells + T cells initially naive + In response to antigen, T cell primed —» effector T cell Two signals: antigen (MHC molecule on. antigen-presenting cell, costimulation (CD28 binds to B7 on antigen- presenting cells) * Activated T helper cell —+ IL-2 + up- regulates IL-2 alpha receptor + Thelper cell binds to IL-2 (autocrine stimulation) + clonal expansion + Needs to see antigen in context of MHC | to kill cell (doesn't need CD28) * Binds nonspecifically to multiple cells with. adhesion molecules — fails to bind to MHC | +-disengages + If antigen binds, cytoskeletal rearrangement — forms supramolecular activation cluster (SMAC) + Includes central SMAC (cSMAC) for antigen recognition, peripheral SMAC (pSMAC) * Cytotoxic cell releases granules with perforin, granzymes (caspases —> apoptosis)Chapter 45 Immunology: B &T Cells, INCORRECT ANTIGEN once"! X ‘T CELL DISENGAGES ‘onsen aa CORRECT ANTIGEN ENGAGES MORE smunaty CYTOSKELETAL REARRANGEMENT ‘APOPTOSIS Figure 4511. CD8 cells weakly bind a variety of cells with adhesion molecules. However, they only destroy cells with antigens on their MHC | molecules that alow the CD8 cells to bind tightiy. CYTOKINES Pca ensues + Proteins secreted by all types of cells to communicate (bind to receptors, trigger response) FIVE TYPES Interleukins (ILs) + Act as communication between leukocytes, onleukocytes + Promote development, differentiation of T, Beels + Mostly synthesized by helper T cells Tumor necrosis factors (TNFs) + Bind to cel receptors, cause cells to die {induce apoptosis) + Heavily involved in inflammatory response (up-regulate expression of adhesion ‘molecules, increase vascular permeability, induce fever) Interferons (IFNs) + Type! + Produced by virally infected cells —> affect surrounding cells: degrade messenger RNA (mRNA), inhibit protein synthesis, express MHC * Type ll + Interferon-gamma —+ promotes anti- viral state, activates macrophages, CD4* helper T-cells Colony stimulating factors (CSFs) + Bind to surface receptors on hematopoietic stem cells —» proliferation, differentiation ‘Transforming growth factors (TGFs) * Control proliferation, differentiation of cells MAIN FUNCTIONAL RESPONSES Pro-inflammatory + Enhance innate, adaptive immune responses IL, IL-1, IL-8, TNF, IFNy Parasite/allergy + Help immune system handle large parasites, induce allergic responses + 1L4, ILS, IL-10,1L13 OSMOSIS.ORG 385Regulatory + Immunosuppressive + IL-10, TGF-B Growth and differentiation + Replenish immune cells + Granulacyte-macrophage colony- stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), IL-7 Chemotactic + Help cells move towards site of inflammation sILa7, Le MHC CLASS | & MHC CLASS II MOLECULES alae osms.it/MHC-clas: + Major histocompatibility complex (MHC), ‘AKA “human leukocyte antigen’ += Cell surface proteins, present antigens toT cells MHC CLASS | + Found on all nucleated cells, presents antigens from inside * Bound by CD8 molecules on cytotoxic T cells + Includes HLA~A, HLA-B, HLA-C Structure * Contains alpha, beta-2-microglobulin chains + Alpha chain: peptide binding groove, ‘transmembrane region » Binding groove binds peptides 8-10 amino acids long; hydrophobic peptide residues «+ hydrophilic groove amino acids + Three extracellular domains: alpha-1, alpha-2, alpha-3 MHC CLASS | MOLECULES PEPTIDE BINDING GROOVE ALPHA 2— Figure 4542 Structure of an MHC class | molecule, 386 OSMOSISORG PEPTIDE CHAIN ALPHA 1 BETA-2- MICROGLOBULINFunction + Allows immune cells to sample cellular proteins (via endogenous pathway of antigen presentation) = Marked protein sent to proteasome + Proteasome degrades protein — short Peptide chains + Transporters of antigenic peptides (TAP) Chapter 45 Immunology: B &T Cells, move peptide chains to endoplasmic reticulum, + TAP loads peptide onto MHC class | Using tapasin| * MHC class I loaded into exocytie vesicle, sent to cell surface + Cytotoxic T cells, NK cells interact with Peptide (if necessary) CYTOTOXIC TCELL NATURAL KILLER CELL PROTEIN MARKED ENDOPLASMIC Van Ss TRANSPORTERS of \ ANTIGENIC PEPTIDES ~/| (Tae) eXOCYTIC VESICLE GOLGI APPARATUS Figure 4513 Endogenous pathway of antigen presentation. MHC CLASS II + Found on antigen-presenting cells, presents antigens from outside + Bound by CD4 molecules on helper T cells, + Includes HLA-DP, HLA-DQ, HLA-OR Structure * Contains alpha, beta chains «= Both penetrate cell membrane + Binding groove binds peptides 14-20 amino acids long Function + Engults, destroys pathogens: presents antigens to CD4’ T helper cells (via exogenous pathway of antigen presentation) + Antigen-presenting cel ingests antigen => endosome «= Lysosome + endosome — phagolysosome; degrades protein short peptide chains * MHC class Il binding groove filled temporarily with invariant chain (degrades during vesicular transportation) = Vesicle fuses with phagolysosome + MHC classl binds peptide, sentto cell surface + C4 helper T cells interact with peptide (if necessary) OSMOSIS.ORG 387MIG CLASS II MOLECULE "4-20 nao aco eernve ALPHA Bera onan | J onan renerares LL Renna ALPHA BETA CHAIN \S CHAIN Figure 454 MHC class il molecule structure q __riceursosone _ ‘eD ‘sae an \ co HELPER. Teel Figure 4518 Exogenous pathway of antigen presentation, 388 OSMOSISORGChapter 45 Immunology: B &T Cells, SOMATIC HYPERMUTATION & AFFINITY MATURATION osms.it/somatic-hypermutation-affinity-maturation SOMATIC HYPERMUTATION *» Base excision: uracil-DNA glycosylase + Intentional mutation of antibody genes to removes uracil from uridine —r next create new antigen specificities + stronger, round of replication, random nucleotide more specific response to antigen inserted — mutations + Occurs in activated B cells (germinal + Only some mutations increase affinity centers, spleen) * Low affinity B cells die naturally with + CDAOL on T cell binds to CD40 on B cell -> time Cytokines instruct B cel to produce specific + High affinity B cells live on (affinity type of antibody maturation} + Activation-induced cytidine deaminase {AD} tus evn to une [nc usaly -Y MATURATION found in DNA) — mismatch/base excision AFFINITY MATURATIOI repartee *Mismateh repair potin MSH2, MSH vse ndeasestoremove ie; DNA palmar pices redid + + Process by which B cells increase affinity for antigen during an immune response + Somatic hyperrnutation, clonal selection (only high affinity cells activated — only mutations high affinity cells replicate) SOMATIC HYPERMUTATION AFFINITY MATURATION lowest AFFINITY BCELL STRONGEST Figure 4516 Somatic hypermutation only occurs in B cells which express enzyme AID. AID makes small mutations directly in antigen binding site of B cell receptor, which get expressed in daughter cells of a rapily proliferating cell. These changes in the variable region change affinity (strength) that 8 cell receptor has for its antigen. As antigen becomes limited, B cells with lowest affinity wil die of frst, so only B cells wit strongest affinity for their antigen remain. OSMOSIS.ORG 389T CELL ACTIVATION + Priming: T cell begins differentiation when » Zeta-chain-associated protein kinase 70 exposed to antigen (ZAP-70} phosphorylates LAT, SLP-76 += Two signals: antigen (MHC molecule on = activation of transcription factors antigen-presenting cel, costimulation NF-KB, NFAT —+ gene expression of (CD28 binds to 87 on antigen- cytokines, upreguiation of antiapoptotic presenting cells) cel surface markers + Signal sent to nucleus by CD3 peptide + Activated T cell + IL-2 + up-regulates IL-2 chains alpha receptor + Lymphocyte-spectfic protein tyrosine + Thelper cel binds to IL-2 (autocrine kinase (LCK) phosphorylates tyrosine stimulation) -+cional expansion residues on immunareceptor tyresine based activation motif (TAM) units ® gia —> provuces 2 for CDE T CELLS Niwa 5 maxes sents cuonay RECEPTOR? TTS OWNIL-2 > EXPANSION HELPER T CELL Figure 4547 Summary of T cell activation. T cells need two signals to activate: frst, presentation ofits antigen by MHC class | (cytotoxic C cells) or class Il (helper T cells), and costimulation, which is when CD28 and B7 bind. In helper T cells, this triggers a series of steps that lead to Upregulation of the IL-2 alpha receptor and production of IL-2 for itself, causing clonal expansion, and CDT cells, 390 OSMOSISORGChapter 45 Immunology: B &T Cells, T CELL DEVELOPMENT Ae lel + Lymphopoiesis: hematopoietic stem cell = common lymphoid progenitor cell -» immature B cel (bone marrow} CREATION OF SUITABLE RECEPTOR + T cell receptor contains two chains: alpha, beta += Alpha: comparable to B cell's ight chain = Beta: comparable to B cell's heavy chain + Antigen-binding site: VD, J protein segments coded by genes of same name += Beta chain: all three segments = Alpha chain: VJ segments T CELL RECEPTOR CN ea Gia Caan apoptosis + Negative selection + Autoimmune regulator gene (AIRE): allows primary lymphoid organs to express antigens normally found ‘throughout body, aids in testing self- reactivity * Excessively strong binding to self antigens — apoptosis OSMOSIS.ORG 391comm ‘DN = DOUBLE NEGATIVE CELL (CDS-, CD4., CDE) DP = DOUBLE POSITIVE CELL (CD3», CDM, CDR) '? = SINGLE POSITIVE CELL (CD8+, CD4+/CD3r, CDs) DN IF RAG AAG? pra BETA CHAIN OG O ye ‘Conan 9-5 Seana 66.5-680-4 ‘conse v-0-sSeanenrs EE uncer sno sire 00 CONSTANT REGION | li @ Dna \ \—~DP CELLS ‘1 fosive setecTon 2. Negenve setecTon 3 powiee cu aiON sepyeoa SPOOR TCELL — SPCOE TELL Figure 4549 T cell development summary. 392 OSMOSISORG+ DP cells recognize self-MHC but do not recognize self-antigen presented in MHC molecule -+ downregulate either CD4/CD8 receptor — further development into single positive (SP) cell, «Strong binding to MHC + CD4 downregulated -» SP CD8" T cell = Weak binding to MHC + CD8. downregulated -» SP CD4" T cell Chapter 45 Immunology: B &T Cells, VDT REARRANGEMENT + Mechanism used to generate range of 8, T cel receptors + Antigen-binding sites: V, D.J protein segments coded by genes of same name Each cell inherits multiple V, DJ ‘segments + randomiy recombine > recombinational inaccuracy, random assortment of two chains (heavy! beta chain rearranged first) —+ new specificities + V(D) rearrangement only affects V region (creates variability in hypervariable regions) HYPERVARIABLE REGION COMPLEMENTARITY-DETERMINING REGIONS. ‘ysis secon 6 re aa “eee Tek Figure 45.20 Locations of hypervariable regions on BCRs and TCRs affected by V(ON rearrangement HEAVY/BETA CHAIN REARRANGEMENT + Recombination signal sequence * Heptamer 5'-CACAGTC-3, 12, 23 nucleotides, nonamer S-ACAAAAACC-3' * DNA loops to bring together two recombination signal sequences + RAG1, RAG2 cut DNA at recombination signal sequence + Recombinases (e.g. ku, artemis) reattach, recombine DNA + Error-prone process: » Cut end placed onto terminal deoxynucleotide transferase (TdT) to add random nucleotides —> alters antigen specificity + Functionality of heavy chain tested —» random assortment of chain LIGHT CHAIN REARRANGEMENT + Rearranged into kappalambda light chain (kappa rearranged before lambda) OSMOSIS.ORG 3931, VDT REARRANGEMENT of BETA/HEAVY CHAIN RECOMBINATION Si@NAL SEQUENCE D EXTRACHROMOSOMALL D TCRCULAR DNA [poner SEER ARTEMIS: sal 238 — -a) {eons soe Tat Oe 4 PNA LicaTeD on e e B CELL 2. BINDING TEST 5. PAIRED WITH VARIETY of LIGHT/ALPHA CHAINS | t 4, ALPHA/LIGHT CHAIN ‘3. PROLIFERATION —————> REARRANGEMENT Figure 45.21 Summary of the process by which 8 and T cell receptors are made. 394 OSMOSISORGNOTES Ltt Ata SE REACTIONS —— GENERALLY, WHAT ARE THEY? ——— PATHOLOGY & CAUSES + Exaggerated immune reaction mediated by IgE antibodies (atopy) triggered by harmless antigen (alergens) Sensitization phase + Allergen — antigen presenting cells (APCs) + B-cell, Th2 cells assist in IgE production + bind via Fe region to mast cells —» mast calls sensitized Re-exposureleffector phase + CytotropichgE receptor binding; allergens bind to Fab region of IgE on sensitized cells —+ activates meciator release + Early phase reactions (within minutes) Primary mast cel-rlease of preformed mediators (eg, histamine, proteases, chemotactants); uses vasodilation, capillary leak, increased secretions, bronchial smooth muscle contraction + Late phase reactions (8-12 hours) = Mediators require synthesis (ea, interleukins 4 5, 10; leukotriene increases early downstream effects, prolongs inflammatory response ‘Common Type | hypersensitivity reactions + Ingested allergens * Foods, dander, bee stings, mold, drugs/ medications, pollen, + Other allergens + Latex, lotions, soaps, penicillin + Atopic eczema + Allergic urticaria + Allergic hintis (Hay fever) + Allergic asthma + Anaphylaxis + Eosinophilic esophagitis, CAUSES + Causes of hyperfoveractive re-exposure/ effector phase unclear; environmental exposure (esp. in early childhood), genetic factors: + “Atopic march”: multiple atopic (IgE- mediated) diseases occur over lifetime SIGNS & SYMPTOMS + Range from mild, /ocal (e.g. urticaria, ‘hinorrhea, itching) to life-threatening anaphylactic reaction (.. cardiac ahythmia, shock, bronchospasm, laryngeal obstruction) DIAGNOSIS ‘LAB RESULTS + Skin allergen testing, variable sensitivities + Eosinophilia OTHER DIAGNOSTICS + History of symptoms, frequency, triggers TREATMENT MEDICATIONS + Symptom-based » Antihistamines (eg. HL blockers) corticosteroids, epinephrine OTHER INTERVENTIONS + Hypolde-sensitization + Escalating doses of allergen subcutaneously injected over course of years; variable effectiveness, more severe reactions less responsive OSMOSISORG 219ACUTE RHINITIS + IgE-mediated immune response upon LAB RESULTS re-exposure of airbome allergens to eyes, Skin allergen tests nose » Subdermal introduction of defined + AKA hay fever amount of alergen to volar surtace of + Local mast cells of eye, nose mucosa forearm; observe fr “wheal-and-flare” degranulate, release immediate mediators reaction at specific site (eg. histamine) OTHER DIAGNOSTICS CAUSES * Clinical presentation + Hay, pollen (seasonal due to flowering + History of symptoms, frequency, plants, dust, animal hair, mold spores triggering events SIGNS & SYMPTOMS TREATMENT + Due to increased fiuid in eyes, nasal cavity MEDICATIONS += Conjunctival injection, eyelid edema: * Oral anthistamine (eg, H1 blockers) ‘sneezing; rhinorrhea, nasal obstruction; —_« Nasal corticosteroids ‘edematous bluish-red nasal turbinates OTHER INTERVENTIONS + Nasal irrigation + Environmental control (to avoid antigen) + When severe, hypoldesenstization to allergen 220 OSMOSISORGChapter 36 Type | Hypersensitivity Reactions ANAPHYLAXIS Pou uey ar ets) + Generalized, life-threatening allergic response + Systemic release of large quantities of immune mediators; symptoms most severe at site of greatest mediator concentration Immune mediators * Histamine (ubiquitous systemic concentration) += Vasodilator, immune system modulator © HL receptor —+ tachycardia, pruritus, rhinorrhea, bronchospasm + H2 receptor + flushing, hypotension + Tryptase (high skin concentration) += Activate complement, coagulation pathways, kalkrein-kinin systems © Angioedema, hypotension, disseminated intravascular coagulation (o1c) + Leukotriene C4, prostaglandin D2 fin high lung concentration) + Bronchoconstriction, increased mucus secretion CAUSES + Drugs (eg beta-lactam antbities, insulin) + Foods (e.g. nuts, eggs, seafood) + Proteins (eg, blood transfusions, tetanus antitoxin) + Latex SIGNS & SYMPTOMS * Generalized, mild-moderate » Flushing, feeling of doom, tachycardia, urticaria, incontinence + Generalized, severe + Syncope, shock, hypoxia, cardiorespiratory collapse DIAGNOSIS OTHER DIAGNOSTICS * Clinical presentation » Symptoms indicate allergic reaction TREATMENT MEDICATIONS + Immediate, necessary * Epinephrine intravenously (IV) (1:10,000)/ntramuscularly (M) (1:1,000), repeat every 30 minutes with potential epinephrine infusion after bolus(es) + Agjunct therapy *HL, H2 receptor blockers, IV corticosteroids + IV fluids, 0, supplementation + Critical care * Intubation, vasopressorsif necessary OSMOSIS.ORG 221FOOD ALLERGY CSU Aie ecu T PATHOLOGY & CAUSES + Adverse food reaction; immune response to ingested antigens * Distinct from non-immunologic adverse food reactions += Enzyme deficiency (eg. lactase), toxin ingestions le.g. staphylococcal toxin), intolerance (e.g. caffeine) TYPES: IgE-mediated + Rapid onset (minutes to couple hours after ingestion); immune mediator release from tissue mast cells, circulating basophils; common allergens include peanuts, soy, milk, wheat, fish Non-IgE mediated + Symptoms subacute to chronic in nature; leukocytosis; local, lymphocytic destruction of gastrointestinal (Gil tissue; celiac disease, food protein-induced enterocolitis, syndrome (FPIES) Mixed IgEinon-lg£-mediated + Variable immune response, acute responses involving IgE-mediation, others favoring leukocytes (e.g, eosinophils, iymphocytes); atopic dermatitis, eosinophilic esophagitis, eosinophilic gastroenteritis 222 OSMOSISORG SIGNS & SYMPTOMS + Dermatologic (e.. pruritus, erythema, urticaria), GI (eg, nausea, vomiting, ‘abdominal pain, diarrhea), anaphylactic (egcardiackespiratory reactions) + Non-IgE-mediated food allergies ® Nonspecific, subacuterchronic GI symptoms; distinct dermatologic vesicular, papular eruptions; dermatitis, herpetiformis in celiac disease ‘LAB RESULTS + Skin allergen testing OTHER DIAGNOSTICS ‘+ Food elimination trials TREATMENT MEDICATIONS + Antihistamines * May be of little value unless urticaria, ‘angioedema present OTHER INTERVENTIONS + Elimination of offending food from diet; mild disease may remit with timeNOTES Lt aaa SSA Pitta ik) —— GENERALLY, WHAT ARE THEY? ——— PATHOLOGY & CAUSES + Antibody-mediated hypersensitivity reactions; tissue-specific, broad spectrum of disease manifestations + Disorder due to self-reactiveB cells that produce antibodies (eg. IgM. IgG) that bind antigens on host cells, form antigen- antibody complex at tissue site = Defective central tolerance + autoantibodies against selfintrinsic antigens += Embedded outsidelextrinsic antigens into normal cell surface alter cell antigenicity Common Type il hypersensitivity reactions + Hemolytic disease of the newborn + Autoimmune hemolytic anemia + Immune thrombocytopenic purpura + Bullous pemphigoid + Pemphigus vulgaris + Rheumatic fever + Goodpasture syndrome + Guillain-Barré syndrome + Graves’ disease + Myasthenia gravis + Pemicious anemia TYPES: + Four pathologic mechanisms Activation of complement system + IgMVlgG antibody binds fixed antigen on cell + C1 binds Fe portion of lgMfig + classical pathway C2-C9 cleavage! activation —+ C3a-C5a anaphylatoxin production = Chemoattract promote degranulation ‘of neutrophils, basophils, mast cells (granules of lysosomal contents of leukocytes fuse, degrade target cell + cell death; mast cell degranulation contents include histamine — promote further immune cell response) + Promote macrophage, monocytes pro-inflammatory cytokine release; interleukin (L1), 6 (e.9. Goodpasture's syndrome, antibodies against Type IV collagen in lung, kidney) + Membrane attack complex (MAC) formation (C5b-C9) — insertion into, disruption of cell ‘membrane — impaired osmotic gradient — cell iysis (eg. ABO mismatch in transfusion reaction, hyperacute transplantation reaction) Opsonization, phagocytosis, + Antigen-opsonin C3b/IgG complex circulate To spleen — fixed macrophages recognize IgG-bound antigens ~» phagocytosis »To liver ~+ Kupffer cells recognize C3b-bound antigens ~» phagocytosis (Autoimmune hemolytic anemia (AIHA), ‘ABO, Rh-hemolytic disease of newborn) Antibody-dependent cell-mediated cyto- toxicity (ADC) + Natural killer cells bind Fc portion of antibody-antigen complex —+ release perforins, granzymes, granulysin + ‘apoptotic cell death ‘Antibody-mediated cellular dysfunction (only non-eytotoxic mechanism) + Physical presence of antibody at receptor binding site impairs physiologic function + Activate: thyroid hormone receptor in Graves' disease + Inhibit: acetylcholine receptor in Myasthenia gravis (MG) OSMOSISORG 223224 OSMOSISORG + Acute hemolytic transfusion reactions + Fevers, chills; nausealvomiting; flank, chest pain: dyspnea + Autoimmune hemolytic anemia + Fatigue, jaundice, hepatesplenomegaly (asm + Bullous pemphigotd += Abdominal, groin, extremity blistering + Erythroblastosis felis + Kemicterus, death in fetus + Goodpasture syndrome = Dyspnea, hemoptysis, hematu + Graves’ disease ‘Tremor, insomnia, inability, weight loss, tachycardia + Guilain-Barre syndrome + Ascending paralysis + Idiopathic thrombocytopenic purpura » Petechiae, skin ecchymoses + Myasthenia gravis » Weekness, ptosis, diplopia, dysphagia + Pemphigus vulgaris ® Blstering of oral mucosa + Permicious anemia » Fatigue, lossitis, B., deficiency sequelae + Rheumatic fever © Migratory polyarthritis, fever, ++ cardiac involvement LAB RESULTS + Coombs testing » Direct: detects Fc region of bound antibodies on red biood cells (RBCs) (eg. ABO incompatibility) * Indirect: detects circulating serum antibodies against known antigen (eg. anti-D) + RBC antigen testing + Immunohistochemistry (IHC) + Diffuse radioactive iodine (RA) uptake OTHER DIAGNOSTICS + Clinical presentation of disease-specific symotoms MEDICATIONS * Corticosteroids + Severe reactions may require plasmapheresisimmunosuppressantsChapter 37 Type Il Hypersensitivity Reactions, ae SC Lat SIGNS 8 Og PATHO- Ds Sn TARGET Deg Brin Bd Fever Cd 8 anien vote chet vet th carrera swssvomiong | cnresuooscls | Somsemert | pe ROC ange ey m (RaQ), ‘type screening: Fevgue onsen Porras Pertanian] "eran Pier) Asma. grin, EM oxvemiy storing Feta eric, Sco FETALS vat ne Coord pairs ond ered Eveetrd Ed Sra post Peteciae, sin ecchymoses asin a is Soni, dysohagia Bilstering of al mucosa, may generalize POE Fon cen aw ie “ Migratory ptr, DMCA fever, +/-cordac involvement ABsanedy, ADCS antbody dependent clu medated cto, HSH epatoslenemehy Cea rity OSMOSIS.ORG 225NOTES Ls Ba SS Pita ik) —— GENERALLY, WHAT ARE THEY? ——— ATHOLOGY & CAUSES + Hypersensitivity reaction mediated by immune complexes + Antibodies (IgG) binding to soluble ‘antigens + antigens not bound to cell surfaces, + Formation of immune complexes —+ complement activation (esp. C3a, Ca, C5a) = Anaphylatoxins — increase vascular permeability edema = Chemokins + recruitment of phagocytes, neutrophils, mast ‘cells —+ degranulation of lysosomal enzymes, reactive oxygen species + inflammation, tissue necrosis (ibrinoid necrosis) + May also ect systemic inflammation + Common sites of immune complex accumulation += Blood vessel walls — vasculitis + Kidneys ~+ glomerulonephritis, Joints — arthritis + iftriggered by single exposure to antigen, resolves after catabolism of immune complexes + acute serum sickness + ifrepeatediprolonged exposure —+ chronic serum sickness + Systemic erythematosus lupus (SLE), polyarterts nodosa, poststreptococcal lomerulonephritis, reactive arthritis, ‘Common Type Ill hypersensitivity reactions + Henoch-Schénlein purpura + Hypersensitivity vasculitis + Reactive arthritis + Farmer's lung + Post-streptococcal glomerulonephritis + Serum sickness + Arthus reaction 226 OSMOSISORG + Systemic lupus erythematosus + Subacute bacterial endocarditis + Rheumatoid arthritis SIGNS & SYMPTOMS + Fever, fatigue, weight loss + Skin: rash, urticaria + Kidney: proteinuria + Joints: arthralgias + Mucosa: ulcers + Serosa: pleurtis, pericarditis LAB RESULTS * Antibody testing + Histopathology to observe fibrinoid necrosis # Necrosis of vessel wall with infiltration of neutrophils, eosinophils, complement, plasma proteins; staining pattem reminiscent of fibrin Figure 38.1 A vessel displaying fibrinoid necrosis in Churg-Strauss syndrome, which is atype il hypersensitivity reaction,+ Immunofluorescence microscopy to visualize immune complexes + Complement levels in blood = Track disease progression Chapter 38 Type lll Hypersensitivity Reactions TREATMENT MEDICATIONS + SLE + Administration of ant-infiammatory, corticosteroids, cytotoxic medications to decrease inflammatory activity SERUM SICKNESS PATHOLOGY & CAUSES + Systemic Type Ill hypersensitivity reaction ‘against foreign antibodies in serum + Exposure to foreign serum — triggers B cells to become plasma cells, produce IgS antibodies against foreign antibodies —> immune complexes formed, deposited in basement membrane — complement activation, immune cells recruitment —> lysosomal enzymes, reactive oxygen species, cytokines produced -» local, systemic inflammatory response + Initial exposure © 4-10 days to develop reaction + Second exposure = Faster, more potent reaction + Resolves after withdrawal of culprit agent CAUSES + Medications (e.g. cefaclor, ant-seizure medications) infections (eg. hepatitis B}: SIGNS & SYMPTOMS + Allergy-like response + Present within 1-2 weeks if intial exposure, 12-36 hours if second exposure © General malaise, erythema, itching, arthralgia + Fever > 38.5°C/LOL2°F, rash, lymphadenopathy. polyarthritis, proteinuria ‘LAB RESULTS: * Complete blood count (CBC) Neutropenia, increase in lymphocytes + Elevation of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) + Urinalysis *Mild proteinuria (50%) OTHER DIAGNOSTICS * Clinical presentation; suspected when allergy-like symptoms present after administration of potential responsible agent (e.g. antivenom serum efter bitten by snake) + Testing to exclude infections (e.g, hepatitis 8) TREATMENT MEDICATIONS + Relieve symptoms with antihistamines, analgesics + Glucocorticoids for individuals with severe clinical features (e. very high fever, severe arthritis, extensive rashes) OTHER INTERVENTIONS + Discontinue, avoid offending agent OSMOSISORG 227228 NOTES Ls aaa hae Pita ik) —— GENERALLY, WHAT ARE THEY? ATHOLOGY & CAUSES + Delayed. T cell-mediated (antibody- independent} hypersensitivity reaction + 24-72 hour delayed nature due to stepwise sensitization-response progression + Antigen presentation by antigen presenting cells (APCs) —> naive T-cells recognition + T-cells, macrophages migration, response Role of CD4" (helper) T cells, macrophages * C4" (helper) T cells, ‘+ APC displays antigen on MHC I receptor -+ naive CD4* T cell binds MHC Il via T cell receptor, CD4 coreceptor -» T cell expresses CD28 + binds APC B7 — cobinding stimulates APC cytokine secretion + Interleukin () 12 produced — 2 cell maturation — T,1 secrete IL IFNy — proliferation of T, 1 response, macrophage recruitment. activation =IL-6, TGF-beta produced + 7,17 cell maturation —>T,,17 secrete “17 recruit neutrophils + Macrophages + Secrete TNF-alpha, IL-1, IL-6 = promote inflammation, leaky ‘endothelium —+ edema, fever, secrete lysosomal enzymes, complement, and reactive oxygen species (ROS) — tissue damage + Pathophysiology in inflammatory bowel disease ((8D), multiple sclerosis (MS), rheumatoid arthritis (RA) Role of CD8* (AKA cytotoxic, effector, killer) T cells + Altered host cell MHC I signal -+ CD8*T cell receptor ~» activate CD8* T cells OSMOSISORG + Secrete perforins, granzymes + create ‘membrane pores, induce cellular apoptosis + Pathophysiology in Type | diabetes melitus (OM), against islet cells; Hashimoto's thyfoiitis, against epithelial cells; immune response to some tumor cells ‘Common Type IV hypersensitivity reactions + Allergic contact dermatitis + Mantoux test + Diabetes melitus type | + Hashimoto's thyrocitis + Multiple sclerosis + Coeliac disease + Giant-cell arteritis + Postorgasmic iliness syndrome + Reactive arthritis GVHD + Transfusion-associated graft versus host disease TYPES, Contact hypersensitivity + Molecules covalently alter major histocompatibilty complex (MHC) | receptors to neo-self antigens; nickel, ‘urushiol (poison ivy molecule) Chronic, delayed hypersensitivity + Agents unusvally resistant to elimination by immune system: tuberculosis (TB), leprosy slicosis, sarcoidosis COMPLICATIONS * Granuloma formation in chronic, delayed- type hypersensitivity reactions + Due to hyperactive macrophages, surrounding inflammatory reaction “walls off” offending agent (eg. sarcoidosis, ‘tuberculosis, silicosis)SIGNS & SYMPTOMS + Local inflammatory reaction —» erythema, warmth, edema, fever + Sequelae of organ-specific cell destruction + [slet cell destruction in pancreas insulin-deficient (eg, lethargy, seizure, coma} * Chronic inflammation — granuloma formation —+ organ failure OTHER DIAGNOSTICS + Exposure history of molecule/agent at site of symptoms * Contact hypersensitivity «= Patch test fadhesive-mounted patches ‘with miniscule amounts of allergen imbued in tape} + Evaluate in 48-96 hours for local skin reaction Chapter 39 Type IV Hypersensitivity Reactions + Tuberculosis + Tuberculin skin test (TST}purified protein derivative (PPD) test + Intradermal injection of tuberculin protein -+ pre-sensitized T-cells react ‘to antigen —+ measure induration size at 48-72 hours + Positive test (induration size) inversely related to TB exposure risk of individual TREATMENT MEDICATIONS * Corticosteroids for inflammatory control + Systemic for severe, generalized reactions, otherwise, site-specific (eg. topical for contact dermatitis; inhaled for hypersensitivity pneumonitis) GRAFT-VERSUS-HOST DISEASE (GvHD) COU ucts Cu sees tee PATHOLOGY & CAUSES + Type of transplant rejection caused by immunocompetent, donor T cells reacting against recipient MHC I foreign’ antigens + Variable ime course of symptoms = Common targets: skin iver, intestine epithelial tissue + Donor CD4' T cell + recognize recipient MHC Il as foreign — activated donor CD4+ T cells > cytokine release + recipient macrophage, CD4+ recruitment > exacerbate cytokine response = Tumor necrosis factor (TNF) alpha: possible cause of "metabolic wasting’ + Donor CD8*T cell-+ recognize recipient MHC las foreign -» activated CDB T cells —+ Fas, perforin-mediated cytotoxicity * Majoity of tissue destruction occurs via DB Teells| + Similar graft-versus leukemia reaction (Gvt) beneficial in individuals with leukemia due to ability to help eliminate recipient's hematopoietic cancer cell line RISK FACTORS = Liver, bone marrow transplants (rich in iymphocytes) + T cell immunodeficient individuals, newborns OSMOSIS.ORG 229+ Metabolic wasting/failure to thrive maculopapular rash, jaundice, bloody diarthea, hepatosplenomegaly ‘LAB RESULTS + Histological analysis of easily biopsied tissue in individual with history of transplantation + Liver, skin, gastrointestinal (GI) tract ‘most helpful in chronic, indolent disease OTHER DIAGNOSTICS + Clinical presentation * Constellation of symptoms Figure 394 A CT scanin the coronal plane Of the abdomen of an individual with graft- TREATMENT versus-hast disease. The gastrointestinal MEDICATIONS tract, including the stomach and small bowel, is grossly edematous. + Prophylaxis (¢, cyclosporine, methotrexate) + Site-directed corticosteroids + Topical for primary skin manifestation; nnon-absorbable (eg. budesonide, beclomethasone) for Gl involvement OTHER INTERVENTIONS Prevention + Proper donor, recipient human leukocyte antigen (HLA), MHC, minor histocompatioilty (MiHA) matching, irradiation of transfused blood products Figure 39.4 A colonic biopsy taken from an individual with graft-versus-host disease, ‘Theres florid cryptitis (neutrophils infiltrating the crypt wall) and apoptotic debris at the crypt bases. 230 OSMOSISORG