固有免疫和适应免疫.pptx

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Innate vs.Acquired Immunity-conceptual and practical difference,The vertebrate“invention”of acquired immunity,How does innate immunity work?(Chapters 1 and 8),Cells,Recognition receptors,Mediators,Lecture 1 Introduction to the Principles of Immunity,The Triumph of Death-Pieter Brueghel the Elder ca.1562,Why the immune system?,What is its function?,How widely is it present in nature?,Why does it affect so many aspects of life?,How can we alter it for improved quality of life?,How does the Immune System(IS)affect your life?,Infectious Diseases:,Almost any deficiency in immunity-you die,Autoimmune diseases:,Graves/hyperthyroidism,Type I diabetes,pernicious anemia,rheumatoid arthritis,thyroiditis,and vitiligo,The incidence of 24 autoimmune diseases is 1/31 Americans.Women are at 2.7x greater risk,Clin Immunol Immunopathol,1997 Sep;84(3):223-43,Cancer:,Evidence in the past year indicates that the immune system does indeed function in tumor surveillance,Hypersensitivity Diseases:,Allergy-Incidence rise from 6%-20%in the past two decades,Asthma-Incidence rise from 3%-8%of the total population in the past two decades,-The hygiene hypothesis-,Heart Disease-The blood vascular system is an integral part of the immune system.It instructs leukocytes to migrate from the blood to a site of infection.New evidence supports that idea that coronary heart disease results from chronic arterial inflammation,Big bugs have little bugsUpon their backs to bite emLittle bugs have littler bugsAnd so on,ad infinitum,-,Ogden Nash,I think,Colonization of large organisms by smaller organisms or viruses is the“,inverse food chain”,Large complex organisms present a source of energy and a habitat for smaller organisms and viruses via colonization,Colonization and defense against colonization is a fundamental principle in biology,The immune system is principally and most importantly evolved to sculpt colonization to benefit the host,Immune Evolution,Dance of the Eons,Virtually every organism faces pressure from viral or microbial colonization and so has evolved strategies to,control,colonization,Likewise,every parasitic organism or piece of selfish DNA has evolved a strategy to mitigate the effects of immunity,This eternal waltz of parasites and their hosts surely began with the origin of life,Corollaries,Just as predator species improve the fitness of their prey,colonial agents select for fitness in their hosts,Just as a host cannot be too permissive for a parasitic agent,the parasitic agent cannot be too effective in killing a host,The more effective the immune system,the more complicated and evolved the parasite,Perhaps we should view the host-parasite interaction as a constantly escalating war or an uneasy(metastable)truce,One view of animal phylogeny,Biological Inventionof Acquired Immunity,Innate vs.Adaptive Immunity,Figure 1.5,Memory,Innate Immunity,All animals have an“innate”immune system,Innate immunity is manifest in many cells of the body.The basis is the recognition of,molecular patterns,that occur in microbes but not animals(e.g.,unmethylated DNA sequences,dsRNA,cell wall components,etc),This is the bedrock of immunity in all organisms-even bacteria have defense mechanisms against bacterial viruses,Innate Immunity,cont,An apparent limitation is that parasitic agents have a generation time orders of magnitude less than that of their hosts,A second limitation is that there is only limited amplification of the response,A third limitation is that there is no memory,Adaptive Immunity,Recognizes any biochemical determinant,Provides a mechanism for immune recognition that can evolve as rapidly as the parasite,(clonal selection),There is rapid amplification of a response,There is memory,To a given organism,other species can represent a source of energy and nutrition:,Food Chain-Large animals eat smaller animals(simplified),Inverse Food Chain:Colonization-Small animals(or microbes and viruses)colonize larger animals that,in turn,provide an environment for replication,All living organisms have a form of immunity to defend against colonization:from bacteria to blue whales to giant sequoia,there are a myriad of mechanisms that have evolved to prevent colonization,Innate vs.Acquired Immunity,The innate immune system of a species detects,molecular patterns,found in other(parasitic)organisms,but not in the species itself.Detection sets up a response that can kill the parasite.,The limitation of the innate immune system is that parasitic microbes have a much shorter generation time than higher animals,and therefore variants can arise to circumvent the recognition or response.,The acquired immune system learns the molecular“self”and anything else is potentially a target for response.The ability to respond to new molecular determinants is on a time-scale similar to the generation time of microbes.,ComponentsPrinciple Functions,Barriers,Epithelial layersPrevent entry,Defensins and CryptidinsMicrobial killing,Circulating and Tissue Effector Cells,NeutrophilsEarly phagocytosis and killing of microbes,Mast CellsRelease of inflammatory granules,MacrophagesEfficient phagocytosis and killing of microbes:cytokines,EosinophilsNasty toxic cells designed to kill helminths(worms),NK cellsLysis of infected cells,activation of macrophages,Circulating Proteins,Complement(C)Killing of microbes,opsonization of microbes,actvn leukocytes,Mannose-binding proteinOpsonization of microbes and activation of C,C-reactive proteinOpsonization of microbes and activation of C,LysozymeBacterial cell wall lysis,Cytokines,TNF,IL-1,6,18Inflammation,IFN,a,b,Resistence to viral infection,IFN,g,Macrophage activation,IL-12IFN,g,production by NK cells,IL-15Proliferation of NK cells,memory T cells,IL-10,TGF,b,Control of Inflammation,Adapted from:Abbas(Saunders),Components of Innate Immunity,Defensins(epithelium),Figure 8.6,Figure 1.4,Figure 8.9,Figure 8.1,Salmonella infection with and without adaptive immunity,Mice deficient for innate immunity(macrophage),WT,T lymphocyte,deficient,What is the basis for innate immunity,and how does is relate to vertebrates?,Drosophila melanogaster,mutants were found that were susceptible to fungal and bacterial infections.,Immunity in Drosophila(Innate),Toll,mutant lacks defense against fungal infections,18 Wheeler,lacks defense against bacteria,This led to the discovery of a family of receptors known as the Toll-related receptors(TLR)present in vertebrates,Innate Immunity Pattern Recognition,Molecular Pattern of Microbe,Source,Pattern Recognition Receptor,Principle Innate Immune Response,dsRNA,Replicating viruses,ds-RNA activated kinase&TLR3,IFNa,b,LPS,Gram-negative bacteria,LBP/CD14/TLR4,Macrophage activation,N-formylmethionyl peptides,Bacterial proteins,NFM receptors,Neutrophil and macrophage act.,Mannose-rich glycans,Microbial glycoproteins,M,F,mannose recptr Plasma mannose lectin,Phagocytosis,Opsonization,C,activation,Phosphorylcholine and related,Microbial membranes,Plasma c-reactive protein,Opsonization,C,activation,CpG,(PuPuCpGPyPy),Bacteria,?TLR9/DNAPK,Macrophage,activation,Other:teichoic acid,Genes to Cells,6,(9),733-742,Kiyoshi Takeda and Shizuo Akira(2001),Activation of the transcription factor:NF,k,B,Toll family of receptors,Toll-like receptors TLR1-10,Recognition alone or in combinations of:,LPS(gram-negative cell wall component),Lipopeptides and peptidoglycan(gram positive cell wall components,Yeast particles,TIR,Domain,Activation of NFkB transcription factor and thus induction of cytokines and other genes that are anti-microbial,Interface between the innate and adaptive immune systems,Unified Immunity Concept,Innate Immunity,molecular pattern recognition,inflammation(alarm and danger),mobilization of many immune components including presentation of foreign agents to the lymphoid system,Adaptive Immunity,clonal recognition of foreign agents by T and B cells followed by selective expansion(production of antibodies,cytokines,and chemokines),+,mechanisms exclusive to adaptive immunity,Progression of Immunity,At least two cell types reside within or beneath the epithelium and induce inflammation in response to trauma or microbial products:Macrophages and Mast Cells,Figure 8.5,Alveolar macrophages(lung),Histiocytes(connective tissue),Kupffer cells(liver),Mesangial cells(kidney),Microglial cells(brain),Tissue macrophage,Figure 1.6ij,Receptors on Macrophages:,LPS receptor-CD14,Toll-like receptors,Fc receptors,Mannose receptor,Complement receptors,IFN,g,receptor,Chemokine receptors,Figure 1.13,Function in disease,not entirely understood,Contains high affinity receptors for IgE,and preformed granules that contain inflammatory mediators including:histamine;heparin;TNF,a,;chondroitin sulfate;neutral proteases;and other.,Mast cells can also secrete:cytokines to induce inflammation;chemokines to induce infiltration by monocytes,and neutrophils,leukotriences to induce muscle contraction and increase vascular permeability,Mast cells are capable of inducing an inflammatory cascade,Figure 1.6gh,Mast cells are also found in the tissues,Mast cells can release histamines which induce inflammation,Redness,swelling,(erythema,edema),Neutrophils and monocytes are recruited,Figure 1.14,TNF,High affinity Fc,e,RI receptor.Effective against worm infections.Granules contain mediators-smooth muscle contraction and worm toxicity,Express some of the same receptors found on macrophages,Figure 1.6ef,LPS receptor:,CD14,toll-like receptor-4,CR3,4:,Complement(C)receptors(C3b),Scavenger receptor:,sialic acid-bearing protein,Mannose receptor:,Binds mannose on bacteria,activates C,Glycan receptor:,Polysaccharides,IN ADDITION:TLRs,Figure 8.8,Figure 1.6ab,Lymphocytes are entirely involved with acquired immunity.,The come in two types:T lymphocytes(T cells)that differentiate in the thymus and B lymphocytes or B cells that differentiate in the bone marrow.,B cells can further differentiate after antigen-activation to plasma cells that produce antibodies,Figure 1.6cd,Nature Killer Cells play several interesting roles in the immune system.One is to monitor cells for identification.If a cell doesnt reveal its identity papers,it is killed.Youll see this later in the course.,Dendritic cells are the most important,antigen presenting cells(APCs),in the immune system,Figure 8.10,*,*The most important inflammatory cytokine(at least in this course),Figure 8.14,Complement facilitates phagocytosis,Figure 1.15,