Immune System Overview
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Immune System Overview
- 1. Immune System Dr Sourav Chowdhury DNB IHTM Apollo Indraprastha
- 2. Definition: The immune system (IS) is complicated, tightly controlled, and includes tissues, organs, cells, and biological mediators that coordinate to defend a host organism against intrusion by a foreign substance or abnormal cells of self-origin. Immune response is collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules of the immune system Immunity refers to the process by which a host organism protects itself from attacks by external and internal agents.
- 3. Classification: Immunity Innate Adaptive Artificial Natural Passive [antibody transfer] Active [immunisation] Passive [Maternal] Active
- 4. Types of Immunity: 1. Innate (non-adaptive) first line of immune response relies on mechanisms that exist before infection 2. Acquired (adaptive) Second line of response (if innate fails) relies on mechanisms that adapt after infection handled by T- and B- lymphocytes one cell determines one antigenic determinant
- 5. Innate immunity: Based on genetic make-up Natural present at birth Relies on already formed components – Physical, Biochemical and Cellular Rapid response: within minutes of infection Non specific Recognizes certain complex repeating patterns Has no memory and does not need any modifications same response after repeated exposure
- 6. Innate immunity: Mechanisms Mechanical barriers / surface secretion skin, acidic pH in stomach, cilia, sweat, tears, mucous etc Humoral mechanisms lysozymes, basic proteins, complement, interferons Cellular defense mechanisms natural killer cells, neutrophils, macrophages, mast cells, basophils, eosinophils Neutrophil NK Cell Monocyte Macrophage Basophils & Mast cells Eosinophils
- 7. Adaptive immunity: Second line of response Based upon resistance acquired during life Relies on genetic events and cellular growth Responds more slowly, over few days Is specific each cell responds to a single epitope on an antigen Has anamnestic memory repeated exposure leads to faster, stronger response Leads to clonal expansion
- 8. Adaptive immunity: Mechanisms Cell-mediated immune response (CMIR) T-lymphocytes Eliminate intracellular microbes that survive within phagocytes or other infected cells Humoral immune response (HIR) B-lymphocytes mediated by antibodies eliminate extra-cellular microbes and their toxins
- 9. Cell-mediated immune response 1. T-cell recognizes peptide antigen on APC in association with major histocompatibility complex (MHC) class identifies molecules on cell surfaces helps body distinguish self from non-self 2. T-cell goes into effectors cells stage that is able to kill infected cells 3. Two Basic forms Delayed type Hypersensitivity Cell Mediated Lysis
- 10. Delayed Type Hypersensitivity Th1 cell binds appropriate pMHC II on APC Tissue APC MHC II peptide complex (pMHC II) Interaction with APC reactivates Th1 cell Reactivated Th1 attracts additional macrophages and activates them
- 11. Specific phase Nonspecifi c phase Encounter microbes at infection site Result Activated Macrophage Macrophage Macrophage not Activated Kill both bystander and microbe reactivated reactivated
- 12. Cell – Mediated Lysis Role of CD8+ T cells Target cell recognition: Like activated CD4 + T cells, activated CD8+ CTLs circulate throughout the body. If the CTL detects this same pMHC I or another pMHC I so similar in structure as to be cross-reactive. It destroys. Target cell destruction: Once attached to a cell that needs to be eliminated, CTLs can use multiple mechanisms to destroy those targeted cells. Release Perforins and Granzyme Finally, CTLs bear molecules (eg. Fas ligand or Fasl) thus activated FAS and induce apotosis in those infected cells Release of perforin creates pores in membrane of targeted cell G ranzymes, released by same CTL, enter target cell through pores induced by perforin Engagement of Fasl on CTL with Fas on target cell initiates apoptosis of targeted cell Granzyme- induced apoptotic death Fas-induced Apoptotic death
- 13. Cell-Mediated Immunity: Components B-cell recognizes soluble Ag in plasma In case the Ag is simple In case the Ag is complex B-cell gets activated and divides Plasma Cell Memory cell Surface IgG, CD19, 20,22 CR CD35, 21 NK cells lack both CD3(Tcell) and surface Ig(Bcell) Targets aberrant host cells Killer Activation Receptors Killer Inhibition receptors CD 56, 16 T-cell never recognizes Ag on its own T-cell receives Ag processed and presented Major function Produce cytokine Kills infected or abnormal cells Types TH Helper cells –TH1 & TH2 CD 4+ CD45, 3 TC Cytotoxic CD 8+ Cd 45, 3
- 14. Antigen Presenting Cells They are Macrophages, Neutrophil, some B-cells and different Dendritic cells APC first phagocytize the Ag Process them internally Present them to TH with help of MHC TH cells recognize them in context of MHC Nucleated cells destroy both self and non-self-tagged with ubiquitin-destruction by proteosome-generates 6to24 AA peptides-load to MHC I (pMHC)-move to Golgi-cell surface-self go unrecognised by CD8+ APC(Dendritic) immature cells phagocytose Ag-by Pattern Recog Receptors and Pathogen Asso. Molecular Patterns-APC move to Lymph nodes-vesicles fuse to Lysosomes-degrades to peptides-fuse with MHC II-cell surface-CD4+ recognition
- 15. Humoral Immune Response: A. Antigen-antibody reactions B. Agglutination C. Neutralization D. Opsonization E. Antibody-dependent cell- mediated cytotoxicity F. Complement activation G. Immediate hypersensitivity Factors affecting Ag-Ab reaction are 1. Distance 2. Ag-Ab ratio 3. pH 4. Temperature 5. valence
- 17. Epitope on Ag Ab against epitopes Fc and Complement receptors act Synergistically Simultaneous use of Fc and Complement increases opsonisation Internalization and degradation Ab Ag C Classical recruitme nt C5 Convertase MAC innitiation
- 18. Immunoglobulin Definition : An immunoglobulin is a specific self-protein produced by the host in response to a specific foreign, non-self protein or rather complex molecule not tolerated by the host.
- 19. Classification Characteristics IgA IgD IgE IgG IgM Heavy Chain Alpha Delta Epsilon Gamma Mu Sedimentation Co. 6.7 19 Molecular Wt. 150 900 Biologic Half-Life 2.3 21 Carbohydrate % 7.5-9 11-12 11-13 2.3-3.5 7-15 Placental Transfer Yes Complement Fix. + +++ Agglutination in Saline + +- +++ % in Total Ig 0.002 80
- 20. Basic Structure of an Immunoglobulin Four polypeptide chains composed of, Two identical light chains Two identical Heavy chains Strong covalent bonds hold light and heavy chains COOH terminal is the constant region in both H & L chains Papain splits one to one Fc and Two Fab fragment at the hinge Fc fragment domains responsible for Complement fixation Monocyte binding Placental transfer Fab fragment has the both H & L variable region for Ag binding NH2 part H & L are known as variable Variability gives specificity to each Ab for specific Ag CR Fc Lc Hc Hinge
- 21. Immunoglobulin Class IgG •Structural difference const. reg. of H •No. of disulphide btw two H •Func. Diff •Complement fixation •Cross placenta IgM •Cell Surface monomer •Secreted pentamer •IgM is the first Ig to be formed •Most Unstimulated Bcell have IgM •Immobilizing Agglutination •Complement activation IgD •Help maturation of B-cell to plasma cell •Helps differentiation of B-cell IgE •Attach to Basophil & Mast •Allergen binding to Fab •Facilitate Histamine release IgA •Monomeric or Polymeric •Acq secr. GlycoPr while pasin thr Mucosal tissue •30% Anti-A,B are IgA class •Severe reaction in IgA deficient •IgG RBC hemolysis
- 22. Variation Isotype Variation- Some Variation of Ig due to the heavy chain variation in a species Allotype Variation- Represent genetically determined differences in Ab between two individual of same species Idiotype Variation- Are Ab that recognizes different species epitopes and the thing that determines the idiotypes is way at the end of the variable region
- 23. Blood Bank Significance: IgG, IgM & IgA are the most significant Ab Most clinically significant Ab react at body temperature IgM most common encountered naturally occurring Ab eg. Anti-ABO Ab IgG is formed in response to non-self Ag in transfused Blood Products Lewis Li P MNS also produce IgM which react at ambient temperature IgM interfere with detection of IgG Ab
- 24. Antibodies of Blood Bank Two types are of concern Naturally occurring as Ag are widely found in nature IgM cold Ab React at ambient temperature May be haemolytic at 37C eg. ABH Li Le MN & P Immune-mediated Transfused Pregnancy Most are IgG React best at 37C Require AHG for detection AlloAb Exposure to genetically different non-self Ag after transfer Not detectable AlloAb is serious problem for BB AutoAb Response to self Ag Cause reaction if transfused blood has that specificity They usually have autoimmune disease They may be Warm or Cold AutoAb Autocontrol or DAT positive By adsorption & elution test Auto Ab can be detected
- 25. Complement Major role: Direct lysis of cells, bacteria, enveloped virus. Assist or act synergistically with Ab in opsonisation Produced peptide fragments(split products) play role in inflammation Pathways: Classical Alternate Lectin
- 26. Pathway Classical Ag binding to Fab allows binding of C1 to Fc of IgM,G1 or G3 For IgG it depends on conc. but IgM large and closer Fc can better activate Alternate Complement activation without Acquired immunity Four important proteins Factor D≈C1, B≈C2, properdin & C3 Alternate pathway require activation by binding of C3 to microbe Lectin Activated by Mannan Binding Lectin (MBL) to Mannose containing GlycoPr. in microbe Subsequent pathway similar to classical pathway
- 28. Trigger Factors Classic Alternate Lectin Ag-Ab Strains of+ve &- ve bacteria IgA, IgE & IgG complexes Mannose Certain bacteria and viruses LPS of Bacteria Cobra venom factor Surface of urate crystals Teichoic acid Anionic polmers eg dextran Myelin Basic Protein Zymosan Pure carbohydrates Fragmented DNA Virus ans infected cells Bacterial Endotoxin Tumor cells Polyanions eg Heparin Tryponosoma
- 29. Blood Bank Importance Except ABO Ab very few Ab activate complements Extravascular haemolysis occurs as a results of Ab coating RBC helped by Complement IgG & complement coated RBC are removed by Complement Receptors CR1(C3B) & Ig Fc receptor in phagocytic cell
- 30. Antigens Antigens are defined as organism, molecule or part of a molecule that is recognised by the immune system. Epitopes – Ag receptors recognize discrete regions of a molecule called Antigenic determinants or epitopes, the smallest part of Ag seen by somatically generated B or T cell receptor B cell recognize specific epitopes whether soluble , surface bound, fragment T cell receptor only bind to epitopes that are small fragments presented by specialized APC Immunogen – contains molecules that both induce an immune response and are the target for that response Innate response – magnitude of response same In contrast adaptive response to same immunogen increases in intensity with each encounter Haptens – are small normally non-immunogenic molecules of non-biologic origin & behave like synthetic Ag They can bind to immune receptor but generate no response But when bound to immunogen or carrier molecule can generate response
- 31. Immunogenicity Size of the molecule eg protein > 10KDa more immunogenic Complexity – complex and diverse protein with diverse epitope induce more response Conformation & accessibility – Ag or epitope should ‘seen’ by immune system Chemical properties – epitopes or Ag should be enzymatically cleavable by phagolysosomes Charge
- 32. Thank You!
Notas del editor
- T-CELLS REQUIRE APC Lymphokines and other effectors play critical role in cellular system by activating and deactivating diff. cells
- Role of CD4 cells Once activated CD$ Th1 leave LN & prowl the body Search MHC II displaying cells Binds with them-access infection site - ↑local vascular permea. Via IL1, IL8 & TNFα CD4 cells activate macro. - ↑phagocytic activity & release enzymes-release cytokines to attract PMN→tissue or microbe destruction
- Even though in Specific phase activation of T-cell is by MHC and epitope specific but the subsequent non-specific(non-epitope specific) activation of macrophage can kill not only the specific pathogen but even others also including host tissue.
- Simple Ag activate and divide – mature to plasma cell & memory B-cell For complex Ag it requires help of t-cells so t-cell dependent Ag T-cell- Cytokines influence various immune function Kills cells that contain foreign Ag
- 6-24 AA – Endopl Reticu, by Transporter Asso c Ag Processing TAP 1&2 TAP heterodimer allows peptide to load to MHC I –move to golgi – by exocytosis to cell surface APC dendritic cells located at microbial portals – immature cells phagocytose large soluble & particulate Ag by Clathrin coated pits by Pattern recog-
- Ag-Ab reaction is one of the special biochemical non-valent reaction Avidity = valence + affinity Ppt\agglutination = Zone of Ag excess Zone of equilibrium Zone of Ab excess Ab can bind and form crosslink and aggregate to have agglutination reaction Entrap microbe in molecular trap Inhibit mobility & susceptible to destruction
- Antigen (Ag)-antibody (Ab) interactions are some of the most specific noncovalent biochemical reactions known The precipitin reaction is the term applied to the i nteraction of soluble antigen with soluble antibody that resu lts in the formation of Ag-Ab complexes (lattices) large enough to precipitate from solution Antibodies can also bind to and cross-link cells or particles, causing an aggregate formation in the agglutination reaction. Entrape microbe & inhibit mobility and make susceptible to destruction Neutralisation is binding of Ab to microbial epitope or toxin in a manner to inhibit these microbe or molecule to bind to host cell IgG & IgA are neutralizing It provides the greatest protection in subsequent infection
- Opsonization- sometimes binding of Ab (IgG 1&3) to microbe surface make them appetizing to phagocytes Upon binding goes conformational change in the Fc region Macroph, PMN through FcR bind to Fc region tagged microbe = destroyed or neutralized Facilitated by simultaneous compliment Receptor C3B are synergestic in Opsonization ADCC – instead engulfing tagged microbe is killed by cytolytic mechanism- NK cells and Eosinophil Compliment Activation by Classical pathway by conformational changes that occur in the Fc potion of Ab on epitope binding IgG IgM facilitate sequential binding of C1 C4 C2 & C3 Release C3b-help in opsonisation Release C3a C4a and C5a – proinflammatory Assemble MAC complex
- Composed of light chain Kappa and Lambda
- Classification according to molecular structure A= alpha D= delta E= epsilon G= gamma M= mu Common light chains Kappa & Lambda Domain on 1 half of Ig VL and CL = light chain VH Number domains decided by isotype Ch1 to Ch3 in IgA,D.G Ch4 in IgE,M Ag binding in variable region of VH & VL
- IgG sublclass diff Structural diff in constant region of H chain No. of disulphide bond between H chains Func diff Compliment fixation Cross placenta= G1 IgA Monomeric or Polymeric Polym acquire secretory glycopr while passing through mucosal pr. Haemolysis imp 30% approx. Anti A&B are IgA Severe reacrtion if transfused in IgA deficient recipient Increase IgG effect on RBC haemolysis IgE monomeric basophil mast cell attaches Fc portion = histamine release on allergen binding to Fab IgD helps maturation of Bcell to plasma cell
- Classical C1 and Fc –C1q which catalyse to activate C1s=serine type protease C2 + C4 – C4b2a- C3 – C3a + C4b -