1、Immune SystemOrgans and tissues antibodyCytokinesAntigen MHCComplementCellsMoleculesGranuocytesMonocytesMacrophageDendritic cellsLymphocytesPrimary lymphoid organsSecondary lymphoid organsBone MarrowThymusLymph nodesSpleenMucosa-associated lymphoid tissuesChapter 5 Immune Molecules IImmune SystemOrg

2、ans and tissues CellsMoleculesantibodyCytokinesAntigen MHCComplementAntigenAntibodyVaccine5.1 AntigenAntigen is a substance that stimulates an immune response, especially the production of antibodies. Antigens are usually proteins or polysaccharides, but can be any type of molecule, including small

3、molecules (haptens) coupled to a carrier-protein.5.1.1 Characteristics of AntigenForeignnessSize: High molecular weightChemical ComplexityConformational determinantsSequence determinantsPrimary StructureSecondary StructureTertiary StructureQuarternary Structure5.1.2 Types of antigens Immunogen - Any

4、 substance that provokes the immune response when introduced into the body. An immunogen is always a macromolecule (protein, polysaccharide). Its ability to stimulate the immune reaction depends on its commonness to the host, molecular size, chemical composition and heterogeneity (e.g. similar to am

5、ino acids in a protein). Tolerogen - An antigen that invokes a specific immune non-responsiveness due to its molecular form resulting from a previous exposure to the same antigen . If its molecular form is changed, a tolerogen can e an immunogen. Allergen- An allergen is a substance that causes the

6、allergic reaction. It can be ingested, inhaled, injected or brought into contact with skin5.1.3 Chemical Nature of Immunogens Proteins BSA, Microbial proteins, Non-self or Altered-self proteins Polysaccharides Pneumococcal polysaccharide, lipopolysaccharide Nucleic Acids CpG containing DNA, U-rich s

7、ingle stranded viral RNA Lipids Gram + bacteria, Yeast cell wall components5.1.4 Origin of antigens Exogenous antigens Endogenous antigens Autoantigens Tumor antigens DoseRouteSubcutaneous(皮下) Intravenous (i.v 靜脈) Intraperitoneal （i.p,腹腔) Intragastric(胃腔)Adjuvant(佐劑) Substances that enhance an immun

8、e response to an AgFactors Influencing ImmunogenicityMethod of AdministrationTypes of adjuvantsInorganic adjvants ： Alum precipitate（明礬）Organic adjvants ：Microorganisms and their metabolizing products (toxins and polysaccharides)Synthesized adjvants：BCG (Bacillus Calmette-Guerin)Freunds plete adjvan

9、t： consists of a water-in oil emulsion,液體石蠟與羊毛脂混合Freunds complete adjvant： Freunds plete adjvant and killed Mycobacterium tuberculosis or BCGNew type adjvants： C3d, CpG motif(purine-purine-CpG-pyrimidine-pyrimidine)Immunologic Adjvants5.2 AntibodyAntibodies are soluable glycoproteins.They are found

10、in serum and tissue fluids They can bind to specific antigensImmunoglobulinAntibody (Ab)Immune serum(免疫血清)Ag adsorbed serum12+-albuminglobulinsMobilityAmount of proteinElectrophoretic separation of serum proteinsImmunoglobulins vs AntibodyImmunoglobulin (Ig): A general term for all antibody molecule

11、s including those globulin with the similar structure but with uncertain function. Each Ig unit is made up of two heavy chains and two light chains.All antibodies are Immunoglobulin, but not all Ig are with antibody activities.5.2.1 Structure of AntibodyHypervariable region binding site of the antib

12、ody molecule.Complementarity determining regions (CDRs): the heavy-chain and light-chain CDR regions are located on the loops that connect the strands of the VH and VL domains. CDRs are the antigen-binding regions of antibodies. Structure/Function RelationshipsFab(Fragment antigen binding) Ag bindin

13、gValence = 1Specificity determined by VH and VLPapainFcFabFc (Fragment crystallizable) Effector functionscontain CH2 and CH3 domaincontain the light chain and the VH and CH1 domains (木瓜蛋白酶)Structure/Function RelationshipsFabAg bindingFcEffector functionsF(ab)2divalentPepsinFc PeptidesF(ab)2(胃蛋白酶)Str

14、ucture/Function RelationshipsAg BindingComplement Binding SitePlacental TransferBinding to Fc Receptors5.2.2 Human Immunoglobulin classesIgG - Gamma () heavy chainsIgM - Mu () heavy chainsIgA - Alpha () heavy chainsIgD - Delta ( ) heavy chainsIgE - Epsilon ( ) heavy chainsTypes of antibodiesIgG: Maj

15、or serum Ig; Placental transfer IgA: 2nd highest serum Ig, Major secretory Ig Tears, saliva, gastric and pulmonary secretions IgM: Pentamer, First Ig made by fetus and B cells, Agglutinating IgIgD: B cell surface IgIgE : Allergic reactions, Parasitic infections, C4J ChainThe antigenic determinants,

16、or epitopes, on immunoglobulin molecules fall into three major categories: isotypic, allotypic, and idiotypic determinants.(同種)異型獨(dú)特型同型Types of antibodiesHuman Immunoglobulin Subclasses (類)Based on small differences in the amino acid sequences in the constant region of the heavy chains. IgG Subclasse

17、sIgG1 - Gamma 1 (1) heavy chainsIgG2 - Gamma 2 (2) heavy chainsIgG3 - Gamma 3 (3) heavy chainsIgG4 - Gamma 4 (4) heavy chainsHuman Immunoglobulin Subclasses(亞類)Based on small differences in the amino acid sequences in the constant region of the heavy chains. IgA subclassesIgA1 - Alpha 1 (1) heavy ch

18、ainsIgA2 - Alpha 2 (2) heavy chainsHuman ImmunoglobulinLight Chain Types(型）Immunoglobulins can also be classified by the type of light chain that they have. Light chain types are based on differences in the amino acid sequence in the constant region of the light chain. These differences are detected

19、 by serological means.Kappa () light chains or Lambda () light chainsIgG StructureMonomer (7S)IgG1, IgG2 and IgG4IgG375% of serum Ig is IgG; Major Ig in extravascular (血管外的) spaces is IgG; Only IgG (except IgG2) can cross the placenta (胎盤);Ig G can fixe complement (except IgG4). Not all subclasses f

20、ix equally well IgG3IgG1IgG2; Ig G can bind to Fc receptors (except IgG2, IgG4) to help phagosis (Macrophages, monocytes, PMNs and some lymphocytes ) and opsonization (調(diào)理) such as K cells ADCC（antibody dependent cell-mediated cytotoxiticy) （抗體依賴的細(xì)胞介導(dǎo)的細(xì)胞毒性）IgG PropertiesFixation of C1 by IgG and IgM

21、AbsC1rC1sC1qC1rC1sC1qinactivativeActivativeIgA StructureSerum - monomer(7S)Secretions (sIgA) Dimer (11S)J chainSecretory component (T piece)J ChainSecretory PieceThe secretory piece is made in epithelial cells and is added to the IgA as it passes into the secretions. The secretory piece helps IgA to

22、 be transported across mucosa and also protects it from degradation in the secretions.Origin of Secretory Component of sIgAYYYYYY30% of serum Ig is IgA; 2nd highest serum Ig;80% of secretory Ig IgA; (Mucosal or Local Immunity) tears, saliva(唾液), gastric(胃部的)and pulmonary(肺的) secretions important in

23、local (mucosal) immunity. Ig A can bind to Fc receptors on some cells -PMNs and some lymphocytes.IgA PropertiesIgM StructurePentamer（五聚體）, (19S) Extra domain (CH4)J chainIn the pentameric form of IgM all heavy and light chains are identical. C4J ChainIgM Properties5-10% of serum Ig is IgM; 3rd highe

24、st serum Ig;First Ig made by fetus and B cells;IgM is a good complement fixing Ig. Thus, IgM antibodies are very efficient in leading to the lysis of microorganisms.)Agglutinating IgBinds to Fc receptorsB cell surface Ig_B Cell Receptor (BCR)B Cell Antigen Receptor (BCR)Ig- Ig-Ig- Ig- B-cell recepto

25、r (BCR) is a transmembrane protein posed of mIg and disulfide-linked heterodimers called Iga/Igb. IgD StructureMonomer (7S)Tail pieceTail PieceAbout 1% of serum Ig is IgG; B cell surface Ig: B Cell Receptor (BCR)IgD is primarily found on B cell surfaces where it functions as a receptor for antigen.I

26、gD PropertiesIgE StructureMonomer (7S)Extra domain (CH4)Least common serum Ig;Allergic reactions. IgE can bind to basophils and mast cells and is involved in allergic reactions.Parasitic infections (Helminths). It binds to Fc receptor on eosinophils.Does not fix complementIgE PropertiesC45.2.3 Produ

27、ction of AntibodiesPolyclonal antibodies a mixture of immunoglobulin molecules secreted against a specific antigen, derived from different B-cell lines.Monoclonal antibodies (mAb) Identical immunoglobulin molecule, produced by one type of immune cell and are all clones of a single parent cell.Geneti

28、c engineering Ab Polyclonal antiserumMonoclonal antibodiesProduction of Antibody Class variation: 1o IgM; 2o - IgG, IgA or IgECellular Events in 1o Response to T-dependent AgsLagClonal selectionLogIgMClass switchingStationaryDeclineMemory Cell PoolIgMMemory CellsIgG1o AgLag phaseVirgin cellsMemory c

29、ellsLog phasePool sizeIgG, IgA or IgEStationaryDeclineSustained productionIgMMemory CellsIgGIgGMemory CellsMemory PoolVirgin B cellCellular Events in 2o Response to T-dependent AgsMemory T cellsThMemory CellsThThMemory CellsMemory PoolVirgin cellT CellsVirgin cellsMemory cellsTh cellsCytokinesLong T

30、erm Memory5.2.4 Function of AbsNeutralization Agglutination Activation of complement Activation of effector cellsSpecificity of antigen-antibody binding5.2.5 Immunologic Adjvantsadjuvant : a substance which, when mixed with an immunogen, enhance the immune response against the immunogen.Types of adj

31、uvantsInorganic adjvants eg. Alum precipitate（明礬）Organic adjvants eg. Microorganisms and their metabolizing products (toxins and polysaccharides)Synthesized adjvants eg. BCG (卡介苗 Bacillus Calmette-Guerin)Freunds complete adjvants（弗氏完全佐劑）which consists of a water-in oil emulsion, and killed Mycobacte

32、rium tuberculosis or butyricum.New type adjvants C3d, CpG motif(purine-purine-CpG-pyrimidine-pyrimidine)5.2.6 Detection of Antibody or AntigenEnzyme Linked Immunosorbent Assay ELISA Muromonab (OKT-3) the first FDA-approved therapeutic monoclonal antibody in 1986. It was a murine IgG2a CD3 specific t

33、ransplant rejection drug. 18 FDA-approved therapies 150 therapies undergoing clinical trial, most are concerned with immunological and oncological targets. 5.2.7 Application of AntibodiesMonoclonal antibodies for cancer treatment5.2.8 Nanobodiesa type of single-domain, only 1215 kDa and a few nanome

34、ters in length antibodies derived from camels, and is an antibody fragment consisting of a single monomeric variable antibody domain. After the discovery that camelidea (camels and llamas) possess fully functional antibodies that lack light chains. It is able to bind selectively to a specific antige

35、n.20世紀(jì)獲得諾貝爾醫(yī)學(xué)生理學(xué)獎(jiǎng)的免疫學(xué)家 年代 學(xué)者姓名 國(guó)籍 獲獎(jiǎng)成就 1901 Behring 德國(guó) 發(fā)現(xiàn)抗毒素，開(kāi)創(chuàng)免疫血清療法 1905 Koch 德國(guó) 發(fā)現(xiàn)病原菌 1908 Ehrlich 德國(guó) 提出抗體生成側(cè)鏈學(xué)說(shuō)和體液免疫學(xué)說(shuō) Metchnikoff 俄國(guó) 發(fā)現(xiàn)細(xì)胞吞噬作用，提出細(xì)胞免疫學(xué)說(shuō) 1912 Carrel 法國(guó) 器官移植 1913 Richet 法國(guó) 發(fā)現(xiàn)過(guò)敏現(xiàn)象 1919 Bordet 比利時(shí) 發(fā)現(xiàn)補(bǔ)體 1930 Landsteiner 奧地利 發(fā)現(xiàn)人紅細(xì)胞血型 1951 Theler 南非 發(fā)明黃熱病疫苗 1957 Bovet 意大利 抗組胺藥治療超敏反應(yīng) 19

36、60 Burnet 澳大利亞 提出抗體生成的克隆選擇學(xué)說(shuō) Medawar 英國(guó) 發(fā)現(xiàn)獲得性移植免疫耐受性 20世紀(jì)獲得諾貝爾醫(yī)學(xué)生理學(xué)獎(jiǎng)的免疫學(xué)家 年代 學(xué)者姓名 國(guó)籍 獲獎(jiǎng)成就1972 Edelman 美國(guó) 闡明抗體的化學(xué)結(jié)構(gòu) Porte 英國(guó) 闡明抗體的化學(xué)結(jié)構(gòu)1977 Yallow 美國(guó) 創(chuàng)立放射免疫測(cè)定法1980 Dausset 法國(guó) 發(fā)現(xiàn)人白細(xì)胞抗原 Snell 美國(guó) 發(fā)現(xiàn)小鼠H-2系統(tǒng) Benacerraf 美國(guó) 發(fā)現(xiàn)免疫應(yīng)答的遺傳控制1984 Jerne 丹麥 提出免疫網(wǎng)絡(luò)學(xué)說(shuō) Kohler 德國(guó) 雜交瘤技術(shù)制備單克隆抗體 Milstein 英國(guó) 單克隆抗體技術(shù)及Ig基因表達(dá)的遺

37、傳控制1987 Tonegawa 日本 抗體多樣性的遺傳基礎(chǔ)1990 Marray 美國(guó) 1954年第一例腎移植成功 Thomas 美國(guó) 1950年第一例骨髓移植成功1996 Doherty 美國(guó) 1974年首先提出MHC限制性，即T細(xì)胞 Zinkernagel 瑞士 的雙識(shí)別模式 5.3 Vaccine一般孩子出生之后按照我們國(guó)家常規(guī)的免疫規(guī)劃程序，月齡打第一針，一歲半打第二針，完成國(guó)家規(guī)劃的接種劑次，即可達(dá)到較好的免疫效果。年實(shí)行消除麻疹的目標(biāo)，將麻疹發(fā)病率降到萬(wàn)以下，消除本土麻疹病毒傳播。麻疹強(qiáng)化免疫9月11日起，我國(guó)將對(duì)適齡兒童開(kāi)展大規(guī)模的麻疹疫苗強(qiáng)化免疫。麻疹疫苗系用麻疹病毒減毒株接種雞胚細(xì)胞經(jīng)培養(yǎng)收獲病毒液后凍干制成。Pre- & post-vaccine incidence of common preventable diseases5.3.1 Types of vac