抗原八年制田國寶09212014

1、Antigen (抗 原)Antigen/Antigenic Specificity Epitope/antigenic determinant Antigen categorization ContentsFactors influencing immunogenicity Nonspecific stimulators OUTCOMEUnderstand these concepts antigen (Ag), antigenicity, immunogenicity, immunogen (complete antigen), hapten (incomplete antigen), a

2、llergen, tolerogen, epitope (antigenic determination), TD-Ag, TI-Ag, superantigen, adjuvant, mitogenFactors Influencing ImmunogenicityClassification of antigensAntigen/Antigenic Specificity What is an antigen? Any substance capable of inducing an immune response and binding specifically to compounds

3、 of the immune response, such as lymphocytes and antibodies.Properties of antigenImmunogenicity: ability to generate/stimulate an immune response. Antigenicity: ability to react with antibodies/ primed T cells. immunogen / complete antigen :substance able to induce immune response and bind to Abs/ p

4、rimed T cellshapten/ incomplete antigen : substance without ImmunogenicityHaptenunable to stimulate immune responsebut can bind to Abs/ primed T cellsusually low molecular chemicalsHapten can turn into immunogen Carrier effect: Low molecular weight compounds (hapten) + high molecular weight (carrier

5、) immunogenhapten +carrierantibodyimmunogenCarrier effectSome conceptsAllergen(變應原): Antigens induce anaphylactic reactionsTolerogen(耐受原): Antigens induce immuno-logical toleranceForeignness (抗原異物性) : basic factor for immunogenicity. Foreignness depends on genetic relationshipAntigenic SpecificityAn

6、tigenic Specificity (抗原特異性) 抗原刺激機體產(chǎn)生免疫應答及其與應答產(chǎn)物發(fā)生反應所顯示的專一性：某一特定抗原只能刺激機體產(chǎn)生特異性的抗體或致敏淋巴細胞，且僅能與該抗原或致敏淋巴細胞發(fā)生特異性結合。Epitope/antigenic determinantEpitope(抗原表位)/Antigenic determinants (抗原決定簇): The smallest unit of antigen that is capable of binding specifically with antibodies and/ or TCR. Specific regions o

7、f a given antigen recognized by a lymphocyte Antigenic receptors: Surface of lymphocyte that combines with antigenic determinant epitope /antigenic determinant:Linear/sequential epitope and conformational epitopeB-cell epitope and T-cell epitope: B-cell epitope recognized by BCR, T-cell epitope reco

8、gnized by TCR,T/B-cell epitope and DegradabilityT-cell epitope and B-cell epitopeDegradabilityComparison of T-cell epitope and B-cell epitope（T細胞受體）（B細胞受體）T cells recognize Ag as a small peptide in association with a MHC moleculeAPCAntigen presenting cellTTCRpeptide + MHC(TCR ligand )B細胞的BCR可直接識別抗原，

9、而T細胞需MHC幫助才能識別抗原：抗原被抗原提呈細胞處理-形成抗原肽-MHC復合物-T 細胞的TCR識別該復合物-T細胞活化的第一信號Diversity of antigen receptor decides the recognition specificityHighly specific: TCR and BCRLymphocyte repertoire: 107Recombination: result in diversityAntigenicity and Antigen-binding sitePolyvalency:Antigen-binding sites:Affinity:

10、measures the strength of binding of Ag and Ab (single binding site). Binding site of different Ag receptorsAntigen binding moleculeIg(BCR/Ab)TCRMHCAntigen-binding site3 CDRs(互補決定區(qū)) in VH and VL3 CDRs in V and V, respectivelypeptide-binding grooveBinding Ag propertybiomacromolecule and some low mole-

11、cular chemicalPeptide-MHC compoundpeptidesDeterminant propertyLinear and conforma-tional epitopes of all sorts of agentsPeptide linear epitopes: 2-3 resi-dues of MHC:AgPeptide linear epitopes: only several residuesAffinity Kd 10-7-10-11M, increasing in IrKd 10-5-10-7MKd 10-6MOn-rate and off-rateFast

12、 in combining, dissociating affected by many factorsSlow in combining and dissociatingSlow in combining even slower in dissociating3 CDRs(互補決定區(qū)) in VH and VL Ig(BCR/Ab)TCR/peptide/MHC combiningFactors influencing immunogenicityEffect of chemical group on the specificity of epitope磺酸基胂酸不同化學基團及其位置變化對表

13、位特異性的影響羧基1 表位在外部,容易接近,免疫原性強; 2 表位在內,難接近,免疫原性弱;3 側向空間大,容易接近,免疫原性強Accessibility(易接近性) 免疫原性抗原氨基酸殘基位置和間距與免疫原性的關系heterophil antigen/Forssman antigen(異嗜性抗原) Antigens from different species share with common antigen Cross-reactivity 交叉反應The specificity of antigen recognition by antibody is not absolute.Ant

14、igens may share identical/ similar determinant- common antigenAn antiserum raised against a given antigen can cross-react with a partially related antigen which bears identical/ similar determinant.Specificity and cross-reactionMolecular size: 10,000 kDPhysico-chemical complexity: proteincarbohydrat

15、elipidnucleic acidFactors influencing immunogenicityInoculation rout and dose of the Ag:intradermalsubcutaneousintravenous intraperitoneal; high zone and low zone toleranceHost factors: age, sex, healthy, stress, usage of immunosuppressive drugFactors influencing immunogenicityIntrinsic properties a

16、nd extrinsic factors that affect the immunogenicity of proteinsAntigen categorizationBased on the need of helper T-cellsT-dependent antigen (TD-Ag): an antigen which requires helper T-cells in order to elicit an antibody response.T-independent antigen (TI-Ag): an antigen which is able to elicit an a

17、ntibody response in the absence of helper T-cells.Antigen categorization1212CD40/CD40LB cellB cellT helperTI-1 antigenTD antigen TI- and TD-AgCD4Types of TI-AgPolysaccharidesPropertiesPolymeric structurePolyclonal B cell activationYes -Type 1 (TI-1) No - Type 2 (TI-2)Resistance to degradationExample

18、sPneumococcal polysaccharide, lipopolysaccharideFlagellaTypes of TD-AgProteinsStructureExamplesMicrobial proteinsNon-self or Altered-self proteinsComparison of TD-Ag and TI-AgComparisonTD-AgTI-AgChemical compositionProteins and their compoundspolysaccharidesChemical constitutioncomplicatedsimpleEpit

19、ope Diverse & differentDuplicate Th helpYesNoMHC restrictionYesNoAntibody typeIgM, IgG, IgA Only IgMImmune responseCellular & humoral immunityOnly humoral immunityImmunoligic memoryYesNo Immune toleranceHigh dose induce T & B tolerance; low dose induce T toleranceHigh dose induce B tolerance; low do

20、se does not induce B toleranceBased on chemical property:Protein: antiserum, exotoxin, RhDPolysaccharide: capsular polysaccharide, LPS, peptidoglycan(肽多糖), ABONucleic acid and lipid: haptenLow molecular chemicals: haptenAntigen categorizationBased on relationship with host: heterophil antigen/Forssm

21、an antigen 異嗜性抗原Xenogenic antigen 異種抗原Allogenic antigen 同種異型抗原Autoantigen 自身抗原Idiotype antigen 獨特性抗原Based on synthesizing positionEndogenous antigen (in APC) 內源性抗原Exogenous antigen 外源性抗原Antigen categorizationThe idiotype is based upon the variable region (labeled VL and VH in the diagram.) Nonspecif

22、ic stimulatorsNonspecific stimulatorsSuper antigen(SAg): different from ordinary Ag, it is a potent polyclonal activator which stimulate whole lymphocyte subpopulations sharing the same TCR V independently of antigen specificity.Including: bacterial toxins(SE), viral proteins(MMTV)Action of superant

23、igenSuper antigen(SAg):Conventional AntigenMonoclonal/Oligoclonal T cell response1:104 - 1:106SuperantigenPolyclonal T cell response1:4 - 1:10Comparison of SAg and ordinary AgAdjuvantConcept: any substance which nonspecifically enhances the immunogenicity or change the type of immune response to Ag. Freunds adjuvant:BCG, CP, CKs, PolyI:C, LPS, Cp