抗原八年制田国宝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(变应原): Antigens induce anaphylactic reactionsTolerogen(耐受原): Antigens induce immuno-logical toleranceForeignness (抗原异物性) : basic factor for immunogenicity. Foreignness depends on genetic relationshipAntigenic SpecificityAn

6、tigenic Specificity (抗原特异性) 抗原刺激机体产生免疫应答及其与应答产物发生反应所显示的专一性：某一特定抗原只能刺激机体产生特异性的抗体或致敏淋巴细胞，且仅能与该抗原或致敏淋巴细胞发生特异性结合。Epitope/antigenic determinantEpitope(抗原表位)/Antigenic determinants (抗原决定簇): 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细胞受体）（B细胞受体）T cells recognize Ag as a small peptide in association with a MHC moleculeAPCAntigen presenting cellTTCRpeptide + MHC(TCR ligand )B细胞的BCR可直接识别抗原，

9、而T细胞需MHC帮助才能识别抗原：抗原被抗原提呈细胞处理-形成抗原肽-MHC复合物-T 细胞的TCR识别该复合物-T细胞活化的第一信号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(互补决定区) 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(互补决定区) in VH and VL Ig(BCR/Ab)TCR/peptide/MHC combiningFactors influencing immunogenicityEffect of chemical group on the specificity of epitope磺酸基胂酸不同化学基团及其位置变化对表

13、位特异性的影响羧基1 表位在外部,容易接近,免疫原性强; 2 表位在内,难接近,免疫原性弱;3 侧向空间大,容易接近,免疫原性强Accessibility(易接近性) 免疫原性抗原氨基酸残基位置和间距与免疫原性的关系heterophil antigen/Forssman antigen(异嗜性抗原) Antigens from different species share with common antigen Cross-reactivity 交叉反应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 异嗜性抗原Xenogenic antigen 异种抗原Allogenic antigen 同种异型抗原Autoantigen 自身抗原Idiotype antigen 独特性抗原Based on synthesizing positionEndogenous antigen (in APC) 内源性抗原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