11Chapter 1 Definition of antigen Antigen (Ag)Substances that combine specifically with a B or T cell’s antigen-binding receptors can then induce an immune response are called antigens.
12Chapter 2 Characteristics of antigen The antigen molecule generally posetwo natures, that is（1）immunogenicity（2）antigenicity
13(1) Antigenic determinants or epitopes Antigenic determinants or epitopes are the immunologically active regions of an immunogen that bind to antigen-specific membrane receptors on lymphocytes (TCR/BCR) or to secreted antibodies.
14Structure of epitopes Inside of the antigen molecule 1 Conformational epitopeNonsequential polypeptides or polysaccharide on the surface of the molecules,Native conformation,2 liner epitopeA sequential amino acid fragment,Linear determinant,Inside of the antigen molecule
15Comparison of epitope of T and B cell T cell epitope B cell epitopeReceptor TCR BCRMHC molecule required to display none requiredprocessed antigencharacter liner peptides natural polypeptide,LPS,polysaccharide,organic compound8 ~12 amino acids (CD8+) ,12 ~17 amino acids (CD4+)5~15 amino acids,5~7 monosaccharideor 5~7 nucleotidesizeEpitope type liner conformational, linerside any on the surface
16(3) hypervarible region (HVR) (complimentarity determining region, CDR) :formation of the Ag binding siteFramework region（ FR ) :maintaining the 3- dimensional configuration(3) hypervarible region (HVR)
27What are cytokines?Cytokines are polypeptides produced by the cells of innate and adaptive immunity in response to microbes and other antigens as a result of cellular activation.Cytokines initiate their actions by binding to specific membrane receptors on target cells.The cellular responses to most cytokines consist of gene activation, resulting in the expression of new functions and sometimes the proliferation of the target cells
28Cytokine actions may be local and systemic Autocrine actionEndocrine actioncirculationact at a distance from the site of infectionParacrine actionact on a nearby cellact on cytokine-producing cell itselfMost cytokines act close to where they are produced, either on cytokine-producing cell itself
29directing migration of leukocytes Chemokines TissuePrimary lymphoid organsSecondary lymphoid organsBloodinflammationStimulate leukocyte movement regulate the migration of leukocytes from the blood to tissuesCellular sourcesto inflammatory sitesinflammatory stimuliConstitutively produced in lymphoid organsPhysiologic traffic of lymphocytes through the organs
30IL-2 a growth factor for antigen-stimulated T lymphocytes responsible for T cell clonal expansion after antigen recognition
31Natural Killer cells (NK cells) A type of cytotoxic lymphocytesThe principal physiologic roleDefense against infections by viruses and some other intracelluarmicrobes2. Rejection of tumors
32The mechanism of effector function PerforinGranzyme
33Pathogen-associated molecular patterns (PAMPs) Small molecular motifs conserved within a class ofmicrobesUsually essential for survival of the microbesRecognized by cells of innate immune systemActivate innate immune response
34Examples of PAMPs PAMPs Source Principle innate immune response LPS Gram-negative bacteria Macrophage activationcell walldsRNAReplicating viruses Type I IFN production byinfected cellsUnmethylated CpG DNABacterial DNA Macrophage activationN-formylmethionineBacteria protein neutrophil and macrophageactivationMannose-richglycansMicrobial glycoproteins phgocytosisor glycolipid opsonizationcomplement activation
35Patterns recognition receptors (PRRs) Proteins expressed by cells of innate immune systemPresent on the cell surface, in endosomal vesicles, andin the cytoplasm
36The subsets of CD4+Th cells How they are induced,What cytokines they produceWhat effector mechanisms they activate
402. BCR coreceptor JBC 2004;279:31973 CD19 B-specific surface marker signal transductionCD21 CR2，receptor for C3d-bound AgCD81 BCR－coreceptor ligationinduce reversible palmitoylation of CD81to stabilize the CD19/CD21/CD81 complexHelp and strengthen the BCR-Ag-signalingJBC 2004;279:31973
41BCR-Iga/Igb coreceptor complex B cell epitopeB cell activation
43Two-signal activation model for T cells naiveco-stimulatory moleculesanergynone
44Two-signal activation model for B cells Signal 1 and signal 2 are not simultaneousBut in two steps, signal 2 from Th cells
45B-1 cells （peritoneal cavity） marginal zone (MZ) B cells （spleen） innate immune functionsB-1 cells （peritoneal cavity）marginal zone (MZ) B cells （spleen）frequent Ag encounter.Secreting essentially germline-encoded, polyreactive natural Abs,respond rapidly and vigorously to pathogensexpress Toll-like receptors (TLR),provide costimulation to GC B cellsimportant link between the innate and adaptive immunity
46B1 B2/FO B location mucosal sites spleen, LN Ig-producing way naturally Ag-inductivespecificity poly-reactive highly specificAg TI Ag TD Ag（polysaccharide）Ig class Ig M IgGaffinity low high
47Significance of humoral immunity eliminate extracellular bacterium and toxineliminate extracellular virus
48Antigen crosslinks mIg(BCR), generating signal 1, which leads to increased expression of class II MHC and costimulatory B7.Antigen–BCR complexes are internalized by receptor-mediated endocytosis and degraded to peptides, which are bound by class II MHC and presented as peptide–MHC complexes.Th cell recognizes Ag–class II MHC and B7-CD28 co-stimulation on B-cell membrane which activates TH cell.Th cell begins to express CD40L.Interaction of CD40 and CD40L provides signal 2.Th cell release large quantities of cytokines(IL-4) signal 3 to support the progression of the B cell replication and differentiation.
49Early events： Late events： follicle（B）-paracortex（T）border, Early and late event in Ab response to TD antigenEarly events：follicle（B）-paracortex（T）border,B activation and T-B activationSmall amounts of Ab productionLate events：At the germinal centerPresence of Ag and ThAffinity maturationIg class switch (IgM IgG)Memory B
50General Features and Mechanisms Immunologically specificCentral tolerance: induced in generative lymphoid organs immature self-reactive lymphocyteThe repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigensThe repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens
51T Lymphocyte Tolerance Central T Cell TolerancePeripheral T cell Tolerance
53Peripheral T cell Tolerance Antigen recognition without adequate costimulationUse CTLA-4 to recognize costimulators on APCsActivation induced cell death (AICD)Regulatory T LymphocytesFactors that determine the tolerogenicity of self antigens
54Tumor Antigen Tumor-specific antigen Antigen that are expressed on tumor cells but not on normal cells were called tumor- specific antigens; some of these antigens are unique to individual tumors, whereas others are shared among tumors of the same type.
55Tumor Antigen Tumor-associated antigen Tumor antigens that are also expressed on normal cells were called tumor-associated antigens; in most cases, these antigens are normal cellular constituents whose expression is aberrant or dysregulated in tumors2 reasons, 1)only one authorized for sale in china, under the special agreement with Peiking University Medical press. 2) An exceptionally lucid guide to the latest immunology concepts. Immunology is not an easy concept to digest at first, but luckily this book explains the difficult topics quite well.
56Evasion of Immune Responses Class I MHC expression may be down-regulated on tumor cells so that they cannot be recognized by CTLs.Tumor lose expression of antigen that elicit immune responses.Tumors may fail to induce CTLs because most tumor cells do not express costimulators or class II MHC molecules.The products of tumor cells may suppress antitumor immune responses.Tumor antigens may induces may induce specific immunologic tolerance.
57Difference between Direct Recognition and Indirect Recognition Allogeneic MHC moleculeIntact allogeneic MHC moleculePeptide of allogeneic MHC moleculeAPCsRecipient APCs are not necessaryRecipient APCsRoles in rejectionAcute rejectionChronic rejectionDegree of rejectionVigorousWeak
58Classification of Allograft Rejection Host versus graft reaction (HVGR)Conventional organ transplantationGraft versus host reaction (GVHR)Bone marrow transplantationImmune cells transplantationAllograft rejection can be classfied into … abbreviation as HVGR
59II.Graft versus host reaction (GVHR) ConditionsEnough immune competent cells in graftsImmunocompromised hostHistocompatability differences between host and graft
60HypersensitivityTissue injury caused by an immune response that is inadequately controlled or inappropriately targeted to host tissues
61Types of hypersensitivity reactions GELL AND COOMB’S CLASSIFICATIONType I: ImmediateType II: CytotoxicType III: Immune complexType IV: cell mediated or delayed