Inflammation Study Guide Test 1 PDF

Inflammation Study Guide Test 1 Week 1 - The main Immune defense systems are: - Innate immunity - Adaptive immunity - Innate immunity is quick, non-specific, and can be found as physical, chemical, or cellular barrier. - Adaptive immunity is developed from RAG gene, prote...

Inflammation Study Guide Test 1 Week 1 - The main Immune defense systems are: - Innate immunity - Adaptive immunity - Innate immunity is quick, non-specific, and can be found as physical, chemical, or cellular barrier. - Adaptive immunity is developed from RAG gene, protection develops after infection, is slower in response time, antigen specific, and has memory for second responses. - Humoral immunity -- involves combatting pathogens with antibodies - Cell-mediated immunity -- involves pathogen specific T cells to eradicate infections. - Myeloid lineage includes monocytes/macrophages, dendritic cells, neutrophils, eosinophils, and basophils. - Monocytes/macrophages -- specialized in phagocytosis. Can differentiate into dendritic cells and present antigens to T lymphocytes. - Neutrophils -- involved with vasodilation and inflammation. Cause direct harm to pathogens through making digestive enzymes and free radicals. Help neutralize pathogens. - Eosinophils -- vasodilation, basophil degranulation. Anti viral and fight parasitic infections. - Basophils/mast cells -- release histamine for smooth muscle activation. Release heparin to increase blood flow. Involved with allergies. - Lymphoid lineage includes B and T cells. - B lymphtocytes develops in bone marrow, present antigen in secondary response, produces antibodies. - T lymphocytes involves cytotoxi T lympthocytes, T helper cells, T regulatory cells, NKT cells, and memory T cells. T cells develop in thymus. - Prumar lymphoid organs -- where immune cells develop - Secondary lymphoid organs -- where immune response is initiated. Secondary lymphoid organs include lymph nodes, spleen, mucosa-assocaited lymphoid tissues (MALT), and other diffuse and loosly organized areas. - A lymph node is a specialized organ where antigen-specific lymphocytes come in scan for foreight molecules funneled in there. - Dysfuncitons of immune system include allergies, autoimmune disease, and immunodeficiency. - Innate immunity uses microbial non-self and missing slef to recognize pathogens. - Microbial non-self molecules are pPAMPs which are produced by mcirobes but not by the host. - The host has receptors that recognize PAMPs. - The binding of PAMPS to pattern recognition receptor triggers immune response. PAMPs and PRR help link innate to adaptive immunity. - Macrophages link innate to adaptive immunity. - Innate lymphoid cells secrete cytokines that respond wuqickly to pathogenic tissue damage. Link inante and adaptive immntiy. - Missing self natural killer cells. Cytotoxic killing of virus infected or damaged cells. Usea AADC antibodu dependet cell cytotoxicity function to do this. - Inflammation cardinal signs are redness, heat, swelling, pain, loss of function. Week 2 - Adaptive immunity is acquired immunity with antigen specificity. - B and T cells have recetpros specific to a pathogen. - B cells have quartnerary struectures with 2 heavy and two light chains. - All immunoglobulins have light chains of eiehter kappa or lambda. There are then 5 different types of heavy chains which determine what class immunoglobulins are. - An antibody has 2 forms which are membrane bround or secreted. - Antibody either made by B lymphocytes or plasma cells. - BCR has two binding sites to allow cross-linking and proline rich hinge region allows an extension. - There are variable and constant region on antibody. - N terminal on antibody is angiten binding site and has Fab. **N** terminal has antige**n** - C terminal on antigen has Fc = crystallization and mediates biological activities of antibody. Think **C** terminal has F**c**. - Paratope is binding site found on antibodies. - Epitope is binding site found on antigens. - Hypervaraible regions closest contact with antigens. Specificty determined in this area. - Antigen- antibody interacts by non-covalent bonds. - Receptor-lgand interactions -- affinity is sterengh of an indivudal bond. avidity is the combine strength of binding of multipe interactions. - TCR aB recognizes and binds both antigen-deruved peptide and MHC to which peptide is bound. - The T cell receptor complexes with the co-receptor involved in antigen recognition - CD3 contains ITAMs that transmit signals to the cell - CD4 and CD8 function in increasing the avidity of peptide binding by TCR. - CD28 engages CD80 or CD86 on antigen presenting cell to fully activate a naïve T cell Immunoglobulin Shape Role ---------------- ---------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- IgG monomer Found in blood stream and tissue. Crosses placenta, except IgG. 4 different subclasses of IgG. Agglutinates, precipitates, opsonizes -- part of phagocytosis, mediates ADCC -- antibodies help bring microbes to surface of natural killer cell to then be lysed, actives complement, and neutralizes. IgG is primary antibody involved with ADCC in cells. IgA dimer External secretions such as milk, saliva, mucus, sweat, and tears. Absorbed through intestinal lumen when ingested with milk. Agglutinates and neutralizes. Mneumonic = secreted in milk which comes out of two breasts do dimer. IgM pentamer Expressed on the cell surface of early B cells to serve as a B cell receptor. Agglutinates, activates complement, first immunoglobulin produced in an immune response, frist immunoglobulin produced in infants, provide early protection, produced in response to T-indpendent antigens, low affinity, and poor neutralization. IgE monomer H chains have extra domains by which it binds to IgE receptors on basophils and mast cells. Lowest in concentration compared to all other antibodies. It is the allergy antibody. Protection against parasitic infections. Induces degranulation. Binds to IgE Fc receptors on basophils/mast cells and eosinophils. Mneumonic think epinephrine for allergies. IgD monomer Surface bound on mature B cells. Not secreted. Serves as a signal receptor and triggers further differentiation of B lymphocytes. - The five immunoglobulins are IgG, IgA, IgM, IgE, and IgD. Mneumonic is gamed. - IgG and IgM most common antibodies. - Variable and constant region on antibodies. - B cells are able to be diverse thrpugh a few strategies - selection of mnay mini-gene segments - recombination to join the randomly selected mini-genes - addition and deletion of nucleotides during joining of mini-gene segments - association of different light and heavy chains to form binding sites. - Somatic hyper-mutations (B cells only, not T cells) during clonal expansion. Some forms may gain better affinity then the original -- affinity maturation. - VDJ recombination through RAG1/2 recombinase - Junctional diversity thorugh joining of mini DNA semnets. Frameshifts occur. - VDJ rearrangements in heavy chain. VJ rearrangement in light chain. Allelic exclusion only use one per chromosome. Irreversibly nhibit rearrangement of Ig heavy chin locus on other chromosome. - B cells develop in bone marrow. - Elimination fo self-reactive B cells. - In the spleen B cells undergo two stages. T1 is native selection where B cells with receptors that react with self-molecules encounter self-antigens and are deleted. T2 is maturation with IgD where B cells grow to maturity. They end up with high levels of IgD and IgM on their surface. - BAFF is found on B cells and provides a survival signal. - B lymphocytes encounter antigens. B cells can switch to other isotypes during maturation. B cells expressing IgM and IgD may express IgG, IgA, or IgE. - Memory B cell formed within germinal centers following primary infections. - Plasma cells secrete large number of antibody molecule but they lose the cell surface immunoglobulin. - Antibody has two forms either membrane bound or secreted Ig. - T cells arise from precursors in bone marrow and move to thymus. A receptor known as notch commits them to T lineage. - Two types of T cell receptors made - TCRaB and TCRyD. - Tab cells are CD-4 or CD-8 positive and predominate in lymph nodes and spleen. - Tyd are CD-4 or CD-8 negative and predominant in skin and mucosal surfaces. - T cells use same diverse mechanisms as BCR exept somatic hypermuytations to not occur. - T ab cells become double positive and then are selected for affinity to one MHC class and become single positive. - MHC molecyles are self-identiy molecules that have broad binding specificity. - MHC class I foun on almost every cell. CD8 cytotoxic T molcules bind to MHC class I. - MHC class II found on antigen presenting cells. CD4 T helper cells molecules bind to MHC II. - T cells that can't bidn MHC peptides are deleted. - The medullary thymic epithelial cells express and present proteins from all over the body. Autoimmune regulator induces them to express, process, and present many tissue specific proteins. - CD4 and CD8 T cells recognize foreign antigenic peptides presented to them on the MHC molecules. - T cell molecules can bind both self and non self peptides. - Somatic hypermutations do not occur necause after MHC selection, mutations lead to loss of MHC recognition and T cells would not be able to receive signals from antigen presenting cells. - Recognigtion of self-antigens by immautere T cells in thymus may lead to death of cells or development of regulatory T cells that enter peripheral tissue. - Removes autoreactive cells before T cells released into peripheral bloodstteram so body does not attack itself. - Some thymotcutes that see self-antigens in thymus differentiate to CD4+ T reg cells. They leave thymus and inhibit response against self-tissues in periphery. - T cells for lipid antigens -Tyd cells arise from unsuccessful rearrangement of B chain. - TCRyd lymothcytes important in early development to protect young. Protect our barrier from outsie. Join innate immune cells in first line of attack. Does not recognize antigen + MHc. Recognizes protein and nonprotein antigen directly on the surface. - Natural killer cells are a heterogenous group of T cell with TCR assembled with an invariant a chain and a limited number ofB chains. They bind foreign and self lipids and glycol;lipids. They react to lipid antigens presented by CD1, a non-polymorphic MHC class- like angten presenting molecule. - MHC complex called a complex because of genetic locus encoding MHC molecules. Also known as human leukocyte antigen (HLA) in humans. - Hisocompaitvity -- in histological tissue transplant, animals that differ in aray of alleles were rejected. Not rejected if it is self with same MHC molecules -- auto transplant. - Class I and II MHC molecules act on cell surface Bessel for holding or displaung fragments of antigens. Allows TaB cells to engage with his molecule via their Tc cell receptors. - Allelic forms of MHC are inherited in liked groups called haplotypes. - There is genetic polymorphism of MHC in human population -- each molecule is different between people. Can be used for signature/fingerprint molecules or paternity testing. - Polymorphism exhibited in region that binds to peptides. - MHC molecule presents antigens. - Class I MHC molecules - a peptide with 3 domains (a1, a2, and a3) and transmembrane C-terminal + B2-microglobulin. Has broad speicificity. CD8 molecules on T cells bind to the a3 domain. - MHC class I molecules present endogenous (from inside the body) antigens to CD8+ cytotoxic T cells. Week 3 - Once MHC class I molecules present endogenous antigens to CD8+ cells, the CD8+ cells lyse the virus infected cells and eliminate the virus. - MHC class I processing in proteasomes. - MHC class II molecules have a peptide with 2 domains (a1 and a2) and a transmembrane C cerminal and B peptide with 2 odomains (B1 and B2) with a transmembrane C terminal. CD4 binds to B2 domains. - MHC II found on antigen presenting cells and present angitens to CD-4 helper T cells. - Thee are professional antigen preneng cells which always express MHC class II molecule. These are macrophage cells such as Langerhands cells and dendritic cells. - There are occasional antigen presenting cells that express MHC class II molecules when induced. These include cytokines from T cells, keratinocytes, endothelial cells, and epithelial cells. - MHC class II moelcules present exogenous (from outside the body) antigens to CD4+ T helpers. Antigen presenting cells and T cells interact leading to their mutual activation and cytokine production. - MHC class II processing in endosome. - Each individual MHC molecules bind a different panel of antigenic peptides. Therefore we respond to infections/antigens differently. - Diversity at MHC locus imparts an evolutionary survival advangae for a species against mortality from infections diseases. The advanatege is that survival of race, not individuals. The disadvange is certain alleles are associated with diseases. - Presentation of non-peptide antigens CD-1 shares structural similatit t MHC class I but functionally overlaps with class II. Presnetsl lipid-containing antigens. Binding grooves accommodate hydrophobic structes. Presnets lipid containing antigens to NKT cells and Tyd cells. - 3 signas required to activate naïve T cells - 1\. TCR signaling - 2\. Costimulatory interaction - 3.cytokine signaling - TCR signaling through TCRaB peptide/MHC, Cd4or CD8 MHC, adhesion molecules. - Co-stimulatory molecules binding btween CD-80/86 (APC) and CD28(T cells) necessary for activation of T cells. - Co-inhibtors on T cells -- lack of binding between CD-80/86 and CD28 leads to no response, engagement of CD-80/86 and CL-4 leads to no response, and engagement of PD-1 and PDL1/2 leadz to anergy of T cells in periphery. - Cytokines activated different transcription factors that guide the T cells to differentiate T cells into various subsets. - T helper 1 - T helper 2 - T helper 17 - T follicular helpers - T regulatory - Cytokines produced by the APC induce each subset. Which cytokine will the APC produce depend on the infections. - Transcription factors for cytokines - T-bet = Th1 - Gata3=Th2 - RORYt = Th17 - Polarization of response for cytokines -- each T cell subset produces cytokines tha mplify itself byt inhibit the others. So response becomes increasinyl polarized. TH1 Activtates macrophages, stimulates production of IgG to enhance phagocytosis. Produces IFNy, TNFb ------ --------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------- Th2 Effective against worms, mediates antibody class switching to IgE, IgE activates mast cell degraunlation Produces IL-4, IL 5, Il10, and IL 13 Th17 Increase barrier function, such as in the gastrointestinal tract. Critical for ungal and bactieral infections Produces IL-17 and IL-22. Produces pro-inflammatory cytokines such as TNF, Il-1, and IL-6 - IL-4 and IL-13 induce alternative activated macrophages (M2). M2 inhibits inflammation of classically activated marcophages whcb T helpe 1 activated. Promotes tissue repair. - T reg cells -- inhibit profileration and activation of CD4+ and CD8+ cells. Treg consitutively express the co-inhibitory molecules CD8+ cells. - Cytotoxic T lymphocytes -- Th1 cells engage with CTL to provide IL-2 proliferation and differentiation to mature CTL. IL-2 helps with differentaitoon of T cells. - Memory T/B cells -- In the absence of antigen but presences of IL-7 and IL-15 the effector cells become memory cells. Mainetnace of memory cells is dependent on cytokines but does not reuire antigen recognition. - Superantigens -- stimulate T lymphocytes in uncontrolled manner and can cause shock. - Cytokines are proteins that mediate effector functions of immune system. - Cytokines act through - Autocrine action -- released, but bound to receptors on scell that produced them. - Paracrine action -- released to affect nearby cells - Endocrne action -- released into blood stream to affect distant cells. - Cytokines can have pleiotropic activity, redundant activity, synergy effect, antagonistic effect, and casade effect. - Cytokines can both induce and suppress inflmattion Cytokines that induce inflammation Cytokines that suppress inflammatiojn ------------------------------------ --------------------------------------- -- IL-1B, TNFa, and IL-6 TGFB - Chemokines affect lymphocyte movement and induce adhesion moelecules. - Four families of adhesion molecules -- order of adhesion molecules working in the body - Selectins -- bind to carbohydrates and adhere weakly. They mediate the rolling and thumbling. If you select to try you are rolling and thumbling movement and what works gets picked up on the way. - Integrins -- mediate interactions between cells and the extracellular matrix -- arrest and adhesion. Mneumonic is integrins integrate cells and extracellular matrix. - Immunoglobulin-like adhesion molecules -- intercellular adhesion molecule 1 (ICAM-1) on endothelium plays an important role in trans-endothelial migration (extravasion) of leulocutes. Intercellular adhesion molecule helps between cell migration. - Cadherins -- involved on embryonic development, tumor metastasis - Cytokines regulate hematopoiesis -- blood cell production. - IL-2 helps with T cell differentiation. - IFN-antiproliferative and antiviral - IFN-y -- immunostimulatory and antivral - IL-2 immunostimulatory - Erythropoietin -- stimulates erythropoiesis - G-CSF -- stimulates granulocyte and monocyte/macropaheg production. - Monoclonal (Mab)antibodies speicif for cytokines or cytokine receptors in clinical use. - Receptor decoy -- is a drug that mimics natural TNF-a receptor for rheumatoid arthritis. Instead of being functional receptor on cells, it is a fake receptor that floats around the blood stream. It traps TNF-a, the receptor decoy reduces inflammation and helps relieve rheumatoid arthritis. - Complement system functions - Kill microorganisms, including bacteria, viruses, yeasts, and certain cells, directly. - Induce inflammation - Increase phagocytosis by opsonization - Clear insoluble immune complexes. - Activation of complement system is a three stepped process - Recognition - Enzyme activation - Expression of biological activity - Three activation pathway - Classical pathway -- intiated by antigen-antibody complex - Alternate pathway -- activated by cell wall of bacteria and yeats - Lectin pathway -- initated by lectins that bind mannosde - Classical pathway is antibody mediated and is part of adaptive immunity - Consists of 9 proteins - Formation of antigen-antibody complex (aggregates) - C1 complex starts and binding needs two moelcules of IgG or one molecule of IgM. - C1 cleaves c4 and c2 to form C4bC2a which is C3 converatase. - C3 convertase cleaves C3. C3 is the central step in all complement pathways. Is largest amblipifcation step. - C3b and c3a are anaphalytoxins that come off of the complement activation. - C4bC2aC3b forms a complex called C5 convertase. - C5b then intiates the formation of membrane attack complex. - Eventually get to C9. - Kill microorganisms including certain cells, bacteria, viruses, and yeast, directly. - PAMPs can activate complement pathway. - Lectin pathway - Mannose minding lectin binds to carbohydrates on the surface of bacteria nad yeasts. - MBL-associated serine proteases cleaves C4 nd C2. - C3 convertase forms complex on membrane - The rest is similar to the classical pathway. - Altnerate pathway - C3 hydrolyzed by H2O molecules to C3b on activation b pathogens - C3b binds factor B - Factor D cleaves factor B to form C3 convertase. - Properdine binds to form a more stable complex - Amplification loop occurs. - C3bBbP cleaves C5 to form C5b which intiates mebrane attack complex. After that same as in classical pathway and lectin pathway. - Alternate pathway - Factor B: activator of C3 convertase - Factor D: cleaves factor B - Propertine protein: helps in attaching C3b molecule towards cell membrane on pathogrn. - C3 is the largest amplification step in all complement pathways, classical, lectin, and alternate. - The anaphalytoxins broken off in the complement pathways induce inflammation. These molecules are C3a, C4a, c5a. - C-reactive protein used as a marker to test for inflammation. - Anigen antibody complexes get very large. Activate complement cascade. Complex binds to complement receptors. Engance phagocytosis to clear these compelxes. - Deficeny in complement causes diseases. Ex. lupus where there is an inability to clear immune complexes. - Defieciency in alternative pathway -- increased susceptibility to recurrent infection with pyogenic bacteria. - Regulation of complement pathway - Cleavage inhibited by C1 inhibitor for classical pathway - Decay accelerating factor (DAF) -- a protein that binds C4 dissociates C4bC2a -- blocks formation of C3 convertase inhibits classical pathway. - C1 inhibitor can cause antioedema where uncontrolled activation of C cause lips to swell - Alternate pathway -- factor H causes dissociation of C3 convertase. - Alternate pathway -- factor I and membrane cofactor protein cleave C3b forming an inactive C3b. - C59 blocls C9 fbinding and prevent formation of MAC. - Serum carboxypeptidae inactitve anaphalytoxins C3a, C5a, and C4a - NK cells and ILC1s in epithelium act on frontlinke, quickly produing IFNy in response to antigens. - T helper 17 protect against fungal infections. - IgA found in salivary gland and slaiva. - Th2 cells produce IL-5 helps B cells switch to IgA isotypes. - In the intestinal tract, the immune system must hae folerance to normal intestinal flora, yet repond to pathogenic microorganis,s. - TGf-B helps suppress inflammation. - Treg cells also help baalce active immunity versus immunological tolerance in face of diverse antigenic exposures. Week 4 - Hypersensitivity is an over reaction to foreign agents: harmful or benign - 4 categories - Type 1 -- immediate hypersensitivity, mediated by IgE, atopy-allergic reaction due to inhaling of allergy, anaphylaxis -- systemic reaction - Type II -- mediated by soluble antibodies to molecules on cells and tissues - Type III -- mediated by immune complexes rfom chronic exposre to antigens - Type IV = delayed hypersneisitivty, mediated by cells, immunocytss. Only one not mediated by antibodies. - Type I hypersensitivity -- mediated by IgE, mast cells, eosinophils, immediate hypersensitivity, reaction time in minutes. Examples include respiratory tract allergies, skin reactions, GI tract allergies, and anaphylaxis. - Events in type 1 - Sensitization phase -- activation of Th2 cells, production of Il-4, activation of B lymphocytes, production of IgE, generation of memory repsonses - Activation phase -- IgE binds to high affinity IgE specific Fc receptors. Receptors cross linked by allergens. IgE activates basophils and mast cells - Immediate effector phase -- activation of mast cells/nbasophils. Immediate reaction. Degranulation of mast cells. Mast cells release histamine. - Late effector phase -- in 6-24 hours with production of cytokines. Mast cells produce eosinophil chemotactic factor that recrutits eosinophils. Reaction persists for days. - Wheal and flare test for allergies. - Anaphylatic shock is a systemic and violent reaction body has to allergies. - Eosinophils have anti- parasitic activity - Interventions for allergies if environmental avoid exposure. If pharmological can give epinephrine for anaphylaxis. Can also give anti-IgE antibody or anithistamines, or cromolyn to help with response. If immunological can modify allergens, hyposensitiation of t helper cells or IgG. - Type II hypersnsitiivty mediated by soluble IgG and IgM antibodies. - Blood transfusion reaction -IgM - Hemolytic disease of newborn -IgG - For type II, antibody directed against surface molecules on target cells - Interaction with complement. Activation and production of inflammation and tissue destructive mediators. - Type II hypersensitivity is typified by a transfusion reaction in which mismatched red blood cells are rapidly destroyed by specific preformed antibodies (anti-ABO or -Rh) and complement. - Environment carbohydrates induce production of IgM in a T independent manner. - Symptoms include fever, nausea, and vomiting. - Rh factor for mother's Rh being compatible with baby. If incompatible, IgG crosses placenta to destroy red blood cells of rh+ fetus. - Treatment for Rh factor -- give rh immune globulin after delivery to prevent sensitivation. Remove fetal red cells before mother can produce an immune response. - Type III hypersensisitivy mediate by antibody complexes -- antigen and IgG. - For type III hypersensitivity, antigen and IgG complexes form due to chronic infection and activate complement cascade. This allows for mcarophages and neutrophils to be produced which leads to inflammation. - Type III -- Arthus reaction due to repeated injection of antigens. High levels of antibody present. Bind with introduced antigen and form complexes that activate complement system. - Type III -- serum sickness -- injection of serum from horse to fight snake venm. Body reacts because thinks it is harmdul. When complexes become lrge and insoluble they are cleared. Symptoms eventually subside once antibodies cleared and complement not active anymore. - Type IV hypersensitivity -- mediated by Th1 cells. Delayed type hypersensitivity. A reaction occurs 24-48 hours after contact. - Type IV -- antigen presented to CD-4 Th1 cells. Activated produce cytokines, IFNy, TNFB. Th1 cells activate CD-8 CTL. Phagaocytes lead to lesions. - Type Iv types - 1\. Contact dermatitis -- caused by cotact with poison ivy, metals, or cheicals. Infections with viruses such as chickenpox blisters. Presented by Langerhan's and keratinocytes to Th1 cells. - Tuberculin reaction -- skin test. Antigen presentation by dendritic cells and macrophages. - Granulomatas reactions -- walls off bacteria using macrophages. Ex. tuberculosis, visceral leishaniasis, and Hansen disease. - Therapies for hypersensitivity - Block costimulatory molecules CD28: CD80/86 - Block signal transduction - Block cytokines and cytokine receptors - Block adhesion molecules - Immunodiagnosis -- antibodies are used to detect antigens. Antigens are used to detect antibodies. - Agglutination -- particles - Precipitation -- soluble proteins - Passive agglutination -- soluble molecule attached, coating particulate carrier. Coating antigen on surface of carrier molecule used to detect antibodies -- when antibody binds to coated antigen, agglutination takes place on surface of carrier. - Agglutination based assay in test tubes is active. Includes dilute antibody and antigen. - Hemagglutination assay -- report highest dilution of serum that still causes agglutination but beyond which no oagglutination occurs. - Titer -- concentration of substance in a solution. Ex. amount of specific antibody in serum. - Prozone is where antigen is completely covered with antibody molecules (too many) hene cannot crosslink. - There can be false negatives and false postiives for agglutination assay test. - Precitiptation taests -- constant amount of antibody and titrate in variable amount of antigen. - Antibody excess zone- not enough antigen molecules for crss linking to form stable complex -- no \[recipitation. - Equivalent zone: antigen-antibody ratio in good proportion for cross linking to form large aggregates -- precipitation. - At equivalent point, no antigen and antibody molecyles are in slolution, they are completely precipitated out. - Antigen excess zone -- each molecules of antibody is saturated with antigen, insuffiecient cross linking -- no preceipitation. - Immunodiffusion test and radial immunodiffusion can be used. - All the antibody molecules in a monoclonal antibody preparation have same specificity and recognize same epitope. - Monoclonal antibodies are clones of your body\'s antibodies that are made in a laboratory, meant to stimulate your immune system. Monoclonal antibodies as therapies are more targeted than some other types of treatments and have been more successful at treating some types of diseases, including some cancers. - Immunohistochemistry -- antibody conjugated with fluorescent tag. Bind to cells or tissue sections that carry appropriate antigen. - Flow cytometry or FACS -- uses laser eequipment that detcts flourecence on indivudal cells, one by one. Multicolor staining to detect more than pne antigen simultaneously. - ELISA -- enzyme conjugated to secondary antibody. Used in many labs to determine whether a particular antibody is present in patient's blood sample. - Western blotting -- uses gel electrophesis to separate the sample's proteins. Can detect specific protein in sample. - Radioimmunoassay -- label antigen with radioactive compound. Working principle competition for binding. Used to detect subsatnces at low concentrations like IgE. - Complement fixation assays -- The complement fixation assay can detect presence of weither a specifi antibody or antigen in pateitn's serum. Was widely used to diagnose infections. use complement proteins to bind to antigen-antibody complexes and consumption is measured by lysis pof red blood cells. Uses competition for binding as well. - Immunodeficiency -- primary immune deficicny disorders are inherited. - Secondary immune deficiency are comprmised by outside factors such as cancer therapy, immunosuppression for transplant, HIV, malnutrition, stress, strenuous exercise, and trauma. - Primary immune deficiency disorders involve issues with B cells, T cells, phagocytic disfunctions, complement, or leukocyte adhesion molecules. - Immunoficiency disorder present from persistent, recurrent infections, poor response to treatments, delayed or incomplete recovery, certain types of cancers, or certain infections such as fungal and yeast infections. - To test for immunodeficincy disorders -- immunoectrophoresis, low serum antibodies against vaccine, white blood cell count ( B and T cell cpnt), and T cell function -- mixed lympthocyte culture. - B lymphocyte disorders B lymphocyte disorder Defiiciency -------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- X linked infantile **a**gammaglobulinemia (Bruton's disease) no circulation of B cells -- al calles of Ig are absent Transient hypogammaglobulinemia Occurs in premature babies. Temporary where there is a period in eearly life with low levels of antibodies but they eventually outgrow it. Common variable hypogammaglobulinemia B cells fail to mature into plasma cells. Variable results where some patients just have increase in IgG and IgA while others have increase in IgG, IgA, and IgM as well. Selective immunoglobulin deficincy Absent of certain subclass of Ig. Ex. absence of IgA. IgA deficincy Most common of all Ig deficiency. Decreased immune function in mucosal surface in mouth, GI tract, and lungs. Increased risk for repiratory and GI infections. Associated with autoimmune diseases. Can treat with antibitics and anitinflammatories. - Serum immunoelctrophoresis is a lab test that measures proteins called immunoglobulins in the blod. If precipitants do not form in test then you have deficiency of that immunoglobulin class. T lymphocyte disorder Deficincy ------------------------------------------------ ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- DiGeorge syndrome Thymus abnormal so poor T cell development. Parathyroid abnormal -- blood calcium is low in routine blood tests. Infants may be jittery or have seizrures. Treatment give calcium relaplcemnt if T cell function is low but sufficient. Chronicmucocutenous candidiasis -- oral thrush Thrush appears as creamy-white or bluish-white patches on tongue. Caused by T cell deficiency. - Combined T and B lympthocyte disorders Deficiency ------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Ataxia telangiectasia Autosomal recessive chromosomal breage disorder of the ATM protein, an essential enzyme for DNA repair. Progressive decline of motor neurologic functions, wobbly gait, corckscrew shaped blod vessels. Severe combined immunodeficincy disease (SCID) 12 known genetic causes of SCID. Reults from mutations in genes many with adenosine deaminase or with RAG1 and RAG2 deficincy. Severe deficiencies in both T cell and B ell functions. Defects lead to extreme susceptibility to severe infections. Severre infections from organisms that are usually not harmful in children with normal immunity. Suscpetible to vaccines. Fungal (yeast infections complicated to treat, rash from mother's T cells. Most successful treatment is bone marrow transplantation +-----------------------------------+-----------------------------------+ | Phagocytic dysfunctoions | Deficiency | +===================================+===================================+ | Chediak-Higashi syndrome | Neutrophils and macrophages -- | | | ingestion without destruction. | | Mnuemonic think cheat where your | Phagocytosed bacteria not | | body tries to cheat by ingesting | destroyed by lysosome's enzymes. | | but you can't destroy. | Symtoms are parital albinism, | | | platelet dysfunction, and | | | aggressive periodontitis. | +-----------------------------------+-----------------------------------+ | Chronic granulomatous disease | Body's phagocytic cells are | | | unable to make hydrogen peroxide | | Mneumonic -- granulomas can't | and other oxidants needed to kill | | actually destry the | certain microorganisms. Patients | | microorganisms in the gramulomas. | susceptible to infections with | | | bacteria and fungi that usually | | | are of low virulence. Most common | | | in infancy with recurrent, unsual | | | infection with bacteria. May have | | | prolonged drainage, delayed | | | healing,a nd residual scarring. | | | Fungal pneumonia, major risk is | | | handling graden mulch | +-----------------------------------+-----------------------------------+ - Consequences of defincincy in complement cascades areincreased susceptibility to bacterial infections and autoimmune diseases, failure to clear immune complex, deficiencies of later acting compleent proteins, suspetible to bacteira Neisseria, and deficiency in regulators of complement which can result in hereditary angioneurotic cdema that is swelling of lips. - Week 5 - Tumors benign vs malignat - Benign -- unable to invade healthy surrounding tissue, incpable of indefinite growth - Alignant -- becomes progressively more invasice and can metastasize -- invade other distant tissues. - Types of tumors - Leukemia -- early stage development in bone marrow - Lymphoma -- blood cells in later stage of development outside bone marrow - Myeloma -- full differentiated plasma cells that mutated -- produce antibodies -- migrate back to bone marrow and form multiple lesions - Malignant transformations induced by chemical substances, phsycial agents, ionizing radiation, viruses and other infectious agents, ad genetic predispositions. - Inflammatory responses can promote cancer. - Tumor speicifc antigens -unique, new, non-self antigen. - Tumor associated antigens can be normal ceelllar proteins with abnormal expression patterns. - Immune desponse to cancer can both protect against and promote tumor growth. Includes stags elimination, equilibrium, and escape. - Cells to eliminate tumors Cells that help evade tumors -------------------------------- ------------------------------------------------------------------- -- NK cells Treg cells M1 macrophages Type II NKT cells suppress tumor immunity Eosinophils Suppresive macrophages such as laternatively actvated macrophages T cells Tumor-infiltrating lymphocytes B cells - Inhibitory NK receptors that bind to ligand, MHC. - NK cells recognize tumors through activating NK cells with bind to ligand called MICA. - NK and CTL cells work similary. End with apoptosis of cells through either perforin-mediated activation of apoptosis or FasL/Fas pathway activaton of apoptosis. - Perforin-granzymes polymerizes and inserts into the membrane. Forms structureal, functional pores. Perforin and granzyme cooperatively cause target cell apopotosis. - Two subsets of NKT cells that cross-regulate each other - Type I NKT cells promote antitumor immunity - Type II NKT cells suppress tumor immunity Cytokines that fight cancers Soluble factors that suppress immunity and help tumor growth ------------------------------- -------------------------------------------------------------- IFNy TGF-b (transforming growth factors) IL-12 IL-10 TNF-a (tumor necrosis factor) IDO - Tumors evade immunity by co-inhibitory signals. T cell exhaustion from inhibitory signals. Regulatory pathways called chekcpoints. - Antitumor antibodies are not always good as they can bind and block tumor antibody, antibodies may form complexes, can impair antitumor activities of NK cells and macrophages. - Cancer therapies include chemotherapies, hormonal therapies, argeted therapies, and immunotherapies. - Toxin-conjuagted mAb. The monoclonal antibodies direct toxin to tumor cells mAB against Her2 receptor in breast cancer ------------------ ----------------------------------------------- mAb against CD20 B cell marker for non-Hodgkin's lymphoma Anti-idotype mAB For terminal B-cell lymhoma - CAR-T cell therapy no need for antigen to activate T cells. Binding is more efficient. Produced to activate an immune response. - Effect of CAR-tT cell therapy is an overreactive immune response that can lead to excessive inflammation via cytokine release syndrome (cytokine storm) - Immune chekpoint hterpay using Anti-CTLA-4 and Anti-PD-1s. Block tumors from inactivating T cells and prevent T cells from going into energy in process. Side effects relatively mild. - Active protection -- exposure to a disease organism or introduction of killed or weakened form of disease organism through vaccination. Protection is long lasting. - Passive vaccination -- whena. Person is given antibodies to disease rather than producing them through their immune system. Protection is immediate bt only lasts for a few weeks or months. - Seconday responses are faster and have more and better antibodies in circulation. - Vaccines made: - Attenuated -weakened pathogens - Inactivated -killed pathogens - Acellular = components of pathogens. Either recombinant DNA\< conjugated polysaccharide, peptide vaccine, and RNA vaccine. +-----------------------------------+-----------------------------------+ | Name of vaccine | Type of vaccine | +===================================+===================================+ | RotaTeq rotavirus | Attenuated live virus | +-----------------------------------+-----------------------------------+ | Salk's polio vaccine | Inactivated poliovirus (K in Salk | | | for killed virus) | +-----------------------------------+-----------------------------------+ | Sabin's polio vaccine | Attenuated poliovirus | +-----------------------------------+-----------------------------------+ | Hep B vaccine Recombivax HB | Non-infectious protein subunit, | | | portion for HBsAg | +-----------------------------------+-----------------------------------+ | Pneumococal conjuagetd vaccines | Polysacchardige vaccine -- | | | attached to carrier protein | +-----------------------------------+-----------------------------------+ | Meningoccoal vaccine | Polysachharide vaccine | +-----------------------------------+-----------------------------------+ | DTaP vaccine | 3 vaccines combined and is | | | inactive (acellular) -- killed | | | virus | +-----------------------------------+-----------------------------------+ | MMR vaccine | Combined vaccine attenuated | | | weakened live virus | +-----------------------------------+-----------------------------------+ | Covid 19 vaccines | Non-replicating RNA or mRA for | | | Moderna, Pfizer, BioNTech | | | | | | Non-replicating -- DNA in viral | | | vector | | | | | | Protein subunit | | | | | | Inactivated whole virus | +-----------------------------------+-----------------------------------+ - Vaccines very important. We still need them. - Contact immunity -- to polio can occur when attenuated poliovirus derived from the oral polio vaccine is excreted and infects and indirectly vaccinaes unvaccinated individuals. Overcome limits vaccine distribution and immunity. - Thimerosal made with mercury.. even though hypothesis of issues rejected, it has been removed or reduced to small amounts in all vaccines. - Outbreaks occur because some people choose not to immunize out of concern that vaccines cause harm. - Vaccines are much safer than the diseases they prevent. Rare side effect is Gullian-Barre syndrome from vaccines. - Live virus vaccines should not be given to infants with known or suspected weakened immune systems such as kids with SCID. - Two types of RNA vaccines include non-replicating mRNA and self-amplofying mRNA. - Immune stimulations - T follicular cells engage B cells by CD-40-CD-40ligand co stimulatory receptor.  This interaction is essential for **class switching**, **somatic hypermutation**, and the formation of **memory B cells**. It enhances **immunoglobulin (Ig) production**, leading to a stronger adaptive immune response. CD40L also plays role in dendritic cells and macrophages activation through increased expression of MHC-II and costimulatory molecules. - Herd immunity is once enough people are vaccinated spread of contagious didsease contained and disease is unable to perpetuate and spread so it dies out. - Tetanus is only vaccine against a disease not passed from one person to another. - Need vaccines t keep peope safe and ensure that no outbreaks occur.