1、第2讲 自然免疫系统 学习目的学习目的z 了解自然免疫系统的基本功能及免疫学基础理论学习要点学习要点z 自然免疫系统对解决工程问题有用的特性，对解决工程问题有用的免疫学理论主要内容主要内容z 2.1免疫系统基本组成z 2.2免疫系统基本功能z 2.3适于工程求解的免疫系统特性z 2.4 免疫学理论2.1 免疫系统基本组成免疫系统基本组成z The immune system is highly complicated z detecting and eliminating infectionsz similar problem:credit card fraud detection6(simp
2、lified view)macrophage2.1 免疫系统基本组成免疫系统基本组成7固有免疫系统固有免疫系统 Innate Immune SystemComposed mainly of phagocytes and the complement system(blood proteins)First line of defense that works rapidlyControls bacterial infectionsRegulates the adaptive immunityImportant for self/non-self discrimination2.1 免疫系统基本组
3、成免疫系统基本组成zThe part of the immune system with which we are bornzDoesnt change or adaptzComplement systemzMacrophageszCytokines,natural killer cellshttp:/www.aids-info.ch/e_te/aas-e-imm.htm2.1 免疫系统基本组成免疫系统基本组成9diversity自适应免疫系统自适应免疫系统 Adaptive Immune SystemComposed mainly of B-cells and T-cellsB-Cells
4、are generated and developed in the Bone MarrowT-Cells are generated in the Bone Marrow and developedin the ThymusGenerate specific antigen receptors on their surface(clonal selection B-Cells and T-Cells)Capable of fine-tuning the cell receptors(maturation B-Cells)Confer resistance against future inf
5、ections(memory B-Cells and T-Cells)memory2.1 免疫系统基本组成免疫系统基本组成The Adaptive Immune Systemz Adapts to recognise specific pathogensz Retains a memory which speeds up future responsesz Consists primarily of lymphocytes which circulate around the body z Distributed detection system without any central con
6、trol 免疫系统基本组成免疫系统基本组成Adaptive Immunityz A detection event occurs when the receptor of a lymphocyte binds to an epitope on a pathogenz Strength of the bond is termed the affinityz Each lymphocyte can have multiple,identical receptorsepitopelymphocyteLow affinityreceptorstructurally similar high affin
7、ity12固有和自适应免疫系统比较固有和自适应免疫系统比较Characteristics CellsMoleculesInnate ImmunityResponds RapidlyPhagocytesNatural killersMast CellsCytokinesComplementAcute Phase ProteinsLow specificityNo memoryAdaptive ImmunitySlow to startT and B-cellsAntibodiesCytokynesHighly SpecificMemory2.1 免疫系统基本组成免疫系统基本组成13Adaptiv
8、e IS:how it works?InvasionDetectionReactionMaturationMemorizing2.1 免疫系统基本组成免疫系统基本组成14Killer T-cells2.1 免疫系统基本组成免疫系统基本组成15How does the immune system kill infected cells?Killer T-cells:mature in the thymustolerated via clonal delectiondo not hypermutate during cloningrecognize only proteins presented
9、by MHC molecules.and kill the respective cells!Killer T-cells2.1 免疫系统基本组成免疫系统基本组成Jon Timmis.Computing Laboratory,University of Kent at Canterbury免疫系统层次免疫系统层次z External surfacesySkinz Chemical and temperature barriersyMucusz Innate immunityyMacrophagesz Acquired(adaptive)immunityyLymphocytes2.1 免疫系统基
10、本组成免疫系统基本组成17DetectionB-Cells Receptors(BCR)T-Cells Receptors(TCR)B-cellBCR or Antibody EpitopesB-cell Receptors(Ab)AntigenT-cellTCR Variable regionVariable regionConstant regionConstant region2.2 免疫系统基本功能免疫系统基本功能Antigen Recognition by B-cell2.2 免疫系统基本功能免疫系统基本功能19Receptors diversityz From Gene Libra
11、ries to a heavy chain of a receptoryGene fragments are concatenated in a strict orderyTranscription joins variable and constant regionsyRNA splicing brings everything together.V V DD J JCGene rearrangementRearranged DNAV D JCTranscriptionRNAV D JCSplicingmRNAV D JCTranslationHeavy chain of an antibo
12、dy2.2 免疫系统基本功能免疫系统基本功能20ReactionClonal Selection Foreign antigens Proliferation Differentiation Plasma Cells Memory Cells Selection M M Antibody Self-antigen Self-antigen Clonal deleti on(negative selection)Clonal deletion (negative selection)(I)(II)(III)(IV)2.2 免疫系统基本功能免疫系统基本功能21Maturation亲和力成熟亲和力成
13、熟Those B-cells that fit the best will be have more affinity and sothey will bind to more pathogens,be activated and clone.B-cells binding to pathogens by using receptors(antibodies)inactivate them ormark them for the innate IScloning subject to Somatic Hypermutation2.2 免疫系统基本功能免疫系统基本功能plasma cellant
14、ibodyHigh affinity selectedmemory cellLow affinity no selectioncell death1.activation2.proliferation3.differentiation2.2 免疫系统基本功能免疫系统基本功能亲和力成熟亲和力成熟23Memorizing Antigen Ag1AntigensAg1,Ag2Primary ResponseSecondary ResponseLagResponseto Ag1Antibody ConcentrationTimeLagResponseto Ag2Responseto Ag1.Cross
15、-ReactiveResponse.AntigenAg1Response toAg1LagSeveral Responses2.2 免疫系统基本功能免疫系统基本功能24Memory(secondary response)After reacting against a pathogen most of the B-cells die,but others adapted B-cells are kept alive and will be usedin the next time the same pathogen invades the organismThe memory is assoc
16、iative:the adapted B-cells are also activated by a similar pathogen(cross-reactive response)Memory2.2 免疫系统基本功能免疫系统基本功能25If the diversity of receptors present is several orders of magnitude less than the diversity of pathogen patterns,how does the immune system detect most pathogens?By using approxim
17、ate binding:each monoclonal lymphocyte can bind to several variants of a pathogen,i.e.it can recognize a similarity subset of patterns.By being very dynamic:lymphocytes are very short-lived(2 to 3 days)and are constantly replaced(100 million new lymphocytes are generated every day).Diversity2.2 免疫系统
18、基本功能免疫系统基本功能Generating Receptor Diversity2.2 免疫系统基本功能免疫系统基本功能27Autoimmune Responses and Tolerance of the SelfHow does the IS ensure tolerance to self?Helper T-cells:T-cells mature in the Thymus where theyare exposed to proteins of the self.If they bind to a selfprotein they are censored(deleted)Clon
19、al DeletionIf not,they mature and can leave the thymus.Selfstrings(S)Repertoire(P)Recognize?RejectAvailablerepertoire(A)NoYes2.2 免疫系统基本功能免疫系统基本功能28T-cells that leave the Thymus will help the B-cells To be stimulatedthe B-cells needto receive twosignals:1-exceed affinitythreshold;2-from helperT-cells
20、Costimulation2.2 免疫系统基本功能免疫系统基本功能Somatic Hypermutationz Mutation rate in proportion to affinityz Very controlled mutation in the natural immune systemz Trade-off between the normalized antibody affinity D*and its mutation rate,00.10.20.30.40.50.60.70.80.9100.10.20.30.40.50.60.70.80.91D*=5 =1 0 =2 02
21、.2 免疫系统基本功能免疫系统基本功能Immune Pattern Recognitionz The immune recognition is based on the complementarity between the binding region of the receptor and a portion of the antigen called epitope.z Antibodies present a single type of receptor,antigens might present several epitopes.y This means that differ
22、ent antibodies can recognize a single antigenB-cellBCR or Antibody Epitopes B-cell Receptors(Ab)Antigen 2.2 免疫系统基本功能免疫系统基本功能Immune Responses Antigen Ag1 Antigens Ag1,Ag2 Primary Response Secondary Response Lag Response to Ag1 Antibody Concentration Time Lag Response to Ag2 Response to Ag1 .Cross-Rea
23、ctive Response.Antigen Ag1+Ag3 Response to Ag1+Ag3 Lag 2.2 免疫系统基本功能免疫系统基本功能Clonal SelectionForeign antigenProliferation(Cloning)DifferentiationPlasma cells Memory cellsSelectionMMAntibody Self-antigenClonal deletion(negative selection)2.2 免疫系统基本功能免疫系统基本功能Self/Non-Self Recognitionz Immune system need
24、s to be able to differentiate between self and non-self cellsz Antigenic encounters may result in cell death,therefore2.2 免疫系统基本功能免疫系统基本功能34uniquenessdistributed detectionimperfect detection(noise tolerance)anomaly detection(non-self)learning and memoryDistiguishing between self and nonself is a har
25、d problem:1016 patterns of the non-self106 patterns of the selfthe body must continue to work properlyShort Summary About the ISdiversity:What is the Immune System?-A lot of things!ClassicalCohenVarelaMatzinger There are many different viewpoints They are not mutually exclusive!AIS can pick and choo
26、se!AIS2.3 适于工程求解的免疫系统特性适于工程求解的免疫系统特性In-vivo IS to In-silico ISzHow do we make the jump?zHistorically,AIS was rooted in real immunologyzNow,there is a tendency to observe-implementz(but lots of simple and effective algorithms developed)2.3 适于工程求解的免疫系统特性适于工程求解的免疫系统特性An Interdisciplinary ApproachMathem
27、atics Computer ScienceEngineeringBiologyAnalysable,validated systems that fully exploit the underlying biology2.3 适于工程求解的免疫系统特性适于工程求解的免疫系统特性From a computational perspective:z Unique to individualsz Distributedz Imperfect Detectionz Anomaly Detectionz Learning/Adaptionz Memoryz Feature Extractionz Di
28、versez.and morez Robustz Scalablez Flexiblez Exhibit graceful degradationz HomeostaticSystems that are:Computational Properties2.3 适于工程求解的免疫系统特性适于工程求解的免疫系统特性04/12/01Dept of Electrical Engineering colloquium series39 Clonal selection Principle Reinforcement learning Immune memory Jernes idiotropic ne
29、twork theory Negative selection Affinity maturation 2.3 适于工程求解的免疫系统特性适于工程求解的免疫系统特性04/12/01Dept of Electrical Engineering colloquium series40免疫系统特性与工程问题对应免疫系统特性与工程问题对应 Genetic mechanisms,clonal selection principle,affinity maturation,content addressable memory,matching mechanisms,and network self org
30、anizing properties.Immune networks Pattern recognition-classification,prediction,diagnosis and data mining Sensor based diagnosis2.3 适于工程求解的免疫系统特性适于工程求解的免疫系统特性04/12/01Dept of Electrical Engineering colloquium series41 Negative selection,self/non self learning Immune network dynamics/negative selecti
31、on principle Negative selection principle Distribution,self organization Anomaly detection-computer security in terms of viruses,unauthorized user detection and elimination Image inspection&image segmentation Novelty detection algorithm for time series data to exhibit the normal behavior of the syst
32、em Agent based approach,Network intrusion detection免疫系统特性与工程问题对应免疫系统特性与工程问题对应2.3 适于工程求解的免疫系统特性适于工程求解的免疫系统特性04/12/01Dept of Electrical Engineering colloquium series42Immune System Property Dynamic decentralized consensus making mechanism,Jernes network,clonal selection algorithm and network dynamics
33、Petri net concepts Immune diversity,network theory and clonal selection principle Cross reactive memory,recruitment mechanismApplication to artificial immune system Robots,Mutual interaction between modules,interaction between robot environments,autonomous agents Adaptive control,identification and
34、synthesis,sequential control Optimization Neural network approaches免疫系统特性与工程问题对应免疫系统特性与工程问题对应2.3 适于工程求解的免疫系统特性适于工程求解的免疫系统特性43z BibliographyyAnabela Simes and Ernesto Costa,An immune system-based genetic algorithm to deal with dynamic environments:diversity and memory,Proc.ICANNGA2003.yLeandro N.Cast
35、ro and Jonathan Thimmis,Artificial Immune Systems:a new computational intelligence approach,Springer-Verlag,2002yhttp:/www.dca.fee.unicamp.br/lnunes/immune.htmlySteven A.Hofmeyr,An Overview of the Immune System,1977yhttp:/www.cs.unm.edu/steveah/inm-html/immune-system.htmlyhttp:/www.msci.memphis.edu/
36、dasgupta/yP.M.Lydyard,A.Whelan and M.W.Fanger,Immunology,Bios,2000.To know moreImmune Network Theoryz Idiotypic network(Jerne,1974)z B cells co-stimulate each otheryTreat each other a bit like antigensz Creates an immunological memory123A gA c tiv a tio nP o s itiv e re s p o n s eS u p p re s s io
37、nN e g a tiv e re s p o n s eA n tib o d yP a ra to p eId io to p e2.4 免疫系统基本理论免疫系统基本理论Varelas Viewz“From the immune systems perspective,it only“knows”itself“(Varela et al 1988).z Sustaining autonomous activity of the network gradually defines the systemz Impacts(without pre-labelling)eitherySmoothl
38、y integrate the system selfyAre rejected from the system non-selfz This is known as self-assertionStewarts Viewz The network provides a cellular communication pathway which allows the system to preserve a perfect integrity and maintain homeostasisz Defensive role of the immune system is secondaryz I
39、mmune system was evolutionary selected as a consequence of its primordial function to provide this pathwayCohens ViewzIS is a cognitive systemzIts role is body maintenancezSignificant departure from self/non-self viewCohens ViewzIS is a cognitive systemzIts role is body maintenancezSignificant depar
40、ture from self/non-self viewzForms an internal historyzSelf-organiseszLearnszMemoryzMakes deterministic decisionsCohens ViewzIS is a cognitive systemzIts role is body maintenancezSignificant departure from self/non-self viewzDetect current state of bodys tissueszElicit an appropriate responseyCo-res
41、pondence and patterns of activityzResponse is result of collaboration of innate and adaptive componentsCohens ViewzIS is a cognitive systemzIts role is body maintenancezSignificant departure from self/non-self viewzDefence against pathogen is just a special case of maintenancezAutoimmunity is required!yBody needs to recognise state of its own tissuesyAntigen receptors exists to achieve thisMore Informationz http:/www.cs.ukc.ac.uk/people/staff/jt6z http:/www.msci.memphis.edu/dasgupta/z http:/www.dcs.kcl.ac.uk/staff/jungwon/z http:/www.dca.fee.unicamp.br/lnunes/z http:/www.cs.unm.edu/forrest/
