固有免疫和適應免疫

1、1會計學固有免疫和適應免疫固有免疫和適應免疫Infectious Diseases:Almost any deficiency in immunity-you dieAutoimmune diseases:Graves/hyperthyroidism, Type I diabetes, pernicious anemia, rheumatoid arthritis, thyroiditis, and vitiligoThe incidence of 24 autoimmune diseases is 1/31 Americans. Women are at 2.7x greater risk

2、Clin Immunol Immunopathol 1997 Sep;84(3):223-43Cancer:Evidence in the past year indicates that the immune system does indeed function in tumor surveillanceHypersensitivity Diseases:Allergy-Incidence rise from 6%-20% in the past two decadesAsthma-Incidence rise from 3%-8% of the total population in t

3、he 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 inflammatio

4、n第1頁/共43頁Immune Evolution第2頁/共43頁CorollariesJust as predator species improve the fitness of their prey, colonial agents select for fitness in their hostsJust as a host cannot be too permissive for a parasitic agent, the parasitic agent cannot be too effective in killing a hostThe more effective the

5、immune system, the more complicated and evolved the parasitePerhaps we should view the host-parasite interaction as a constantly escalating war or an uneasy (metastable) truce第3頁/共43頁第4頁/共43頁第5頁/共43頁Figure 1.5Memory第6頁/共43頁第7頁/共43頁第8頁/共43頁第9頁/共43頁To a given organism, other species can represent a so

6、urce of energy and nutrition:1.Food Chain- Large animals eat smaller animals (simplified)2.Inverse Food Chain: Colonization - Small animals (or microbes and viruses) colonize larger animals that, in turn, provide an environment for replicationAll living organisms have a form of immunity to defend ag

7、ainst colonization: from bacteria to blue whales to giant sequoia, there are a myriad of mechanisms that have evolved to prevent colonization第10頁/共43頁The innate immune system of a species detects molecular patterns found in other (parasitic) organisms, but not in the species itself. Detection sets u

8、p 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

9、 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.第11頁/共43頁ComponentsPrinciple FunctionsBarriersEpithelial layersPrevent entryDefensins and Cryptidins Microbial killingCirculating an

10、d Tissue Effector CellsNeutrophilsEarly phagocytosis and killing of microbesMast CellsRelease of inflammatory granulesMacrophagesEfficient phagocytosis and killing of microbes: cytokinesEosinophilsNasty toxic cells designed to kill helminths (worms)NK cellsLysis of infected cells, activation of macr

11、ophagesCirculating ProteinsComplement (C)Killing of microbes, opsonization of microbes, actvn leukocytesMannose-binding proteinOpsonization of microbes and activation of CC-reactive proteinOpsonization of microbes and activation of CLysozymeBacterial cell wall lysisCytokinesTNF, IL-1, 6, 18Inflammat

12、ionIFN a, bResistence to viral infectionIFN gMacrophage activationIL-12IFNg production by NK cellsIL-15Proliferation of NK cells, memory T cellsIL-10, TGF bControl of InflammationAdapted from: Abbas (Saunders)Components of Innate Immunity第12頁/共43頁Defensins (epithelium)Figure 8.6第13頁/共43頁Figure 1.4第1

13、4頁/共43頁Figure 8.9第15頁/共43頁Figure 8.1第16頁/共43頁Salmonella infection with and without adaptive immunityMice deficient for innate immunity (macrophage)WTT lymphocytedeficient第17頁/共43頁What is the basis for innate immunity, and how does is relate to vertebrates? Drosophila melanogaster mutants were found

14、that were susceptible to fungal and bacterial infections. Immunity in Drosophila (Innate)Toll mutant lacks defense against fungal infections18 Wheeler lacks defense against bacteriaThis led to the discovery of a family of receptors known as the Toll-related receptors (TLR) present in vertebrates第18頁

15、/共43頁Molecular Pattern of MicrobeSourcePattern Recognition ReceptorPrinciple Innate Immune ResponsedsRNAReplicating virusesds-RNA activated kinase & TLR3IFNa,bLPSGram-negative bacteriaLBP/CD14/TLR4Macrophage activationN-formylmethionyl peptidesBacterial proteinsNFM receptors Neutrophil and macro

16、phage act.Mannose-rich glycansMicrobial glycoproteinsMF mannose recptr Plasma mannose lectinPhagocytosisOpsonization, C activationPhosphorylcholine and relatedMicrobial membranesPlasma c-reactive proteinOpsonization, C activationCpG(PuPuCpGPyPy)Bacteria? TLR9/DNAPKMacrophageactivationOther: teichoic

17、 acid, 第19頁/共43頁Genes to Cells 6 (9), 733-742 Kiyoshi Takeda and Shizuo Akira (2001)Activation of the transcription factor: NFkB第20頁/共43頁Toll family of receptors第21頁/共43頁Recognition alone or in combinations of: LPS (gram-negative cell wall component) Lipopeptides and peptidoglycan (gram positive cel

18、l wall components Yeast particlesTIRDomainActivation of NFkB transcription factor and thus induction of cytokines and other genes that are anti-microbial第22頁/共43頁Interface between the innate and adaptive immune systems第23頁/共43頁Innate Immunitymolecular pattern recognitioninflammation (alarm and dange

19、r)mobilization of many immune components including presentation of foreign agents to the lymphoid systemAdaptive Immunityclonal recognition of foreign agents by T and B cells followed by selective expansion (production of antibodies, cytokines, and chemokines)+mechanisms exclusive to adaptive immuni

20、ty第24頁/共43頁At least two cell types reside within or beneath the epithelium and induce inflammation in response to trauma or microbial products: Macrophages and Mast CellsFigure 8.5第25頁/共43頁Alveolar macrophages (lung) Histiocytes (connective tissue) Kupffer cells (liver) Mesangial cells (kidney) Micr

21、oglial cells (brain)Tissue macrophage Figure 1.6ij第26頁/共43頁Receptors on Macrophages:LPS receptor-CD14Toll-like receptorsFc receptorsMannose receptorComplement receptorsIFNg receptorChemokine receptorsFigure 1.13第27頁/共43頁Function in disease, not entirely understoodContains high affinity receptors for

22、 IgE, and preformed granules that contain inflammatory mediators including: histamine; heparin; TNFa; 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 ind

23、uce muscle contraction and increase vascular permeabilityMast cells are capable of inducing an inflammatory cascadeFigure 1.6gh第28頁/共43頁Mast cells are also found in the tissuesMast cells can release histamines which induce inflammationRedness, swelling(erythema, edema)Neutrophils and monocytes are r

24、ecruitedFigure 1.14TNF第29頁/共43頁High affinity FceRI receptor. Effective against worm infections. Granules contain mediators-smooth muscle contraction and worm toxicityExpress some of the same receptors found on macrophagesFigure 1.6ef第30頁/共43頁LPS receptor:CD14toll-like receptor-4CR3,4:Complement (C)

25、receptors (C3b)Scavenger receptor:sialic acid-bearing proteinMannose receptor:Binds mannose on bacteria, activates CGlycan receptor:PolysaccharidesIN ADDITION: TLRsFigure 8.8第31頁/共43頁Figure 1.6abLymphocytes are entirely involved with acquired immunity. The come in two types: T lymphocytes (T cells)

26、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第32頁/共43頁Figure 1.6cdNature 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第33頁/共43頁Figure 8.10*The most impo