0
INNATE IMMUNITY      NOBEL PRIZE WINNING TOPIC - 2011                   Dr.T.V.Rao. MDDR.T.V.RAO MD                       ...
2011 NOBEL PRIZE IN PHYSIOLOGY OR              MEDICINE• The 2011 Nobel Prize in Physiology or Medicine was  awarded to Br...
THE NOBEL PRIZE IN PHYSIOLOGY OR                  MEDICINE 2011• The Nobel Prize in  Physiology or Medicine  2011 was divi...
THE IMMUNE SYSTEMInfection of the humanbody by pathogenicmicroorganisms such asbacteria, viruses,parasites or fungi trigge...
OVERVIEW OF THE IMMUNE SYSTEM• We are constantly being  exposed to infectious  agents and yet, in most  cases, we are able...
DR.T.V.RAO MD   6
INNATE IMMUNITY :DEFINITION•    no need for prolonged induction•    no clonal expansion of Ag     specificity•    act quic...
What happens when the physical and   chemical barriers are breached?DR.T.V.RAO MD                          8
Innate Immunity-                  First Line of DefenseCharacteristics:- rapid- does not generate immunologic memory- depe...
Leukocyte Players of     Innate Immune ResponsesDR.T.V.RAO MD                  10
INNATE (NON-SPECIFIC) IMMUNITY• The elements of the innate (non-  specific) immune system include  anatomical barriers, se...
The Innate Immune System              composed of ?- includes physical, chemical, and cellular barriers- physical barriers...
HOW INNATE IMMUNITY PROTECTS•   1. Provides a barrier to prevent the spread of infection     • Mechanical (tight junctions...
HOW INNATE IMMUNITY ELIMINATES               PATHOGENS•     Identifies and eliminates              pathogens    • Non-adap...
INNATE IMMUNITY•   3. Initiates an inflammatory response     • Reaction to injury or infection           • Trauma to tissu...
Macrophage Microbial KillingOnce the PRRs are activated by the PAMPs,phagocytosis is initiatedPhagocytosis is active proce...
INNATE IMMUNITY   • Provides signals to activate and regulate the type of           adaptive immune response generated    ...
FIRST LINE OF DEFENSE -- EPITHELIA • Mechanical                • tight junctions, air/fluid flow, ciliary rejection • Chem...
CELLS OF INNATE IMMUNITY• Neutrophils• Eosinophils• Basophils/Mast Cells• Monocytes• Macrophages• Natural Killer Cells• Pl...
DR.T.V.RAO MD   20
LEUKOCYTE TERMINOLOGY                      TWO SYSTEMS • Nuclear Morphology       • Mononuclear Cells                • Mon...
COMPARATIVE MORPHOLOGY OF                      GRANULOCYTESDR.T.V.RAO MD                               22
Leukocyte Players ofInnate Immune Responses
Innate Immune Receptors   Innate immune receptors are not clonally distributed   Binding of receptors results in rapid r...
Pathogen Recognition   Most microorganisms express repeating patterns of    molecular structures termed Pathogen Associat...
PHAGOCYTOSIS•     Phagocytosis        • Definition: uptake of large particles (>0.5 mm)        • Actin-dependent, clathrin...
MACROPHAGES                                          (MQ)•   Blood - Called monocytes (1-6%    WBC)•   Tissues - Called ma...
NEUTROPHILS                         (PMN)• Present in blood (55-60%  of WBC)• Not normally present in  tissues• Short life...
HUMAN NEUTROPHIL•    Granulocytic Leukocyte•    Most Abundant White Blood Cell                • 2-6 x 103 cells/μL        ...
Human Neutrophil Size• In blood:           • Volume = 300 μm3 sphere (300 fl vs. 90 fl for RBC)           • Diameter = 8.3...
EOSINOPHIL                EM MORPHOLOGYDR.T.V.RAO MD                   31
SIGNAL TRANSDUCTION•    Receptors                 • recognition of                   pathogens                 • chemical ...
G PROTEIN CYCLEDR.T.V.RAO MD     33
Toll-Like Receptors (TLRs)                                                            TNFa                                ...
G PROTEIN-COUPLED RECEPTORS• Largest receptor family appx ~1000 types• Bind proteins, peptides, absorb light• Highly homol...
LL        L                       Receptor - G protein        L            L                L                    Coupling ...
GPCR OF INNATE IMMUNITY•    Peptide receptors                 • fMLF receptor-- chemotaxis toward bacteria                ...
KILLING MECHANISMS•     Phagosome - membrane bounded vesicle that becomes acidified•     Lysozome - granules that contain ...
Activated macrophages secrete proteins that drive                   innate responseCytokines- induce response by binding t...
KILLING MECHANISMS - CONT.•    Respiratory Burst      • Activated following phagocytosis      • Stimulated by PRR      • R...
NADPH OXIDASE                          Mitochondrial-independent                          respiratory burst               ...
ENZYME REACTIONS OF                           RESPIRATORY BURST•      Respiratory Burst        NADPH                      ...
Clinical symptoms of inflammation:   pain, redness, heat, swelling1. Increased vascular diameter, increased blood flow (he...
CHEMOKINES• Infection induces the  release of various  chemokines• Theses substances bind  specific and sometimes  shared ...
DENDRITIC CELLS• DCs link innate and adaptive immunity• DCs are immature as they circulate waiting to encounter  pathogens...
THE CURRENT KNOWLEDGE HELPS FOR            NEWER VACCINE TRENDS• The detailed understanding of the immune  system provided...
FOR FURTHER INFORMATION . . .•   Immunology Project Resources –•   Understanding Autoimmune Disease•   http://www.niaid.ni...
• Programme created by Dr.T.V.Rao MD    for Medical and Paramedical students in             the Developing World          ...
Upcoming SlideShare
Loading in...5
×

Innate immunity- Nobel Prize 2011

2,480

Published on

Innate immunity- Nobel Prize 2011

0 Comments
4 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
2,480
On Slideshare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
229
Comments
0
Likes
4
Embeds 0
No embeds

No notes for slide

Transcript of "Innate immunity- Nobel Prize 2011"

  1. 1. INNATE IMMUNITY NOBEL PRIZE WINNING TOPIC - 2011 Dr.T.V.Rao. MDDR.T.V.RAO MD 1
  2. 2. 2011 NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE• The 2011 Nobel Prize in Physiology or Medicine was awarded to Bruce Beutler at the Scripps Research Institute in California, Jules Hoffmann at the French National Center for Scientific Research and Ralph Steinman at The Rockefeller University in New York City. Beutler and Hoffman helped to elucidate innate immunity, the non-specific array of initial responses by the body’s immune system that can recognize invading microorganisms as being foreign and try to destroy them.DR.T.V.RAO MD 2
  3. 3. THE NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE 2011• The Nobel Prize in Physiology or Medicine 2011 was divided, one half jointly to Bruce A. Beutler and Jules A. Hoffmann "for their discoveries concerning the activation of innate immunity" and the other half to Ralph M. Steinman "for his discovery of the dendritic cell and its role in adaptive immunity".DR.T.V.RAO MD 3
  4. 4. THE IMMUNE SYSTEMInfection of the humanbody by pathogenicmicroorganisms such asbacteria, viruses,parasites or fungi triggersthe immune response. Itoccurs in a two-stepprocess: innate immunityhalts the infection, andadaptive immunitysubsequently clears it.DR.T.V.RAO MD 4
  5. 5. OVERVIEW OF THE IMMUNE SYSTEM• We are constantly being exposed to infectious agents and yet, in most cases, we are able to resist these infections. It is our immune system that enables us to resist infections. The immune system is composed of two major subdivisions, the innate or non-specific immune system and the adaptive or specific immune systemDR.T.V.RAO MD 5
  6. 6. DR.T.V.RAO MD 6
  7. 7. INNATE IMMUNITY :DEFINITION• no need for prolonged induction• no clonal expansion of Ag specificity• act quickly • immediate direct response 0- 4 hrs • rapid induced 4-96 hrs• failure ==> adaptive immune response• dependence on germ line encoded receptors• high discrimination of host and pathogenDR.T.V.RAO MD 7
  8. 8. What happens when the physical and chemical barriers are breached?DR.T.V.RAO MD 8
  9. 9. Innate Immunity- First Line of DefenseCharacteristics:- rapid- does not generate immunologic memory- dependent upon germ line encoded receptors recognizing structures common to many pathogens Innate Immunity DR.T.V.RAO MD 9
  10. 10. Leukocyte Players of Innate Immune ResponsesDR.T.V.RAO MD 10
  11. 11. INNATE (NON-SPECIFIC) IMMUNITY• The elements of the innate (non- specific) immune system include anatomical barriers, secretory molecules and cellular components. Among the mechanical anatomical barriers are the skin and internal epithelial layers, the movement of the intestines and the oscillation of broncho-pulmonary cilia. Associated with these protective surfaces are chemical and biological agents.DR.T.V.RAO MD 11
  12. 12. The Innate Immune System composed of ?- includes physical, chemical, and cellular barriers- physical barriers include skin and mucus membranes- chemical barriers include stomach acidity, secreted anti-microbial peptides- cellular barriers include macrophages, neutrophils- innate immune response activation occurs within minutes of pathogen recognition DR.T.V.RAO MD 12
  13. 13. HOW INNATE IMMUNITY PROTECTS• 1. Provides a barrier to prevent the spread of infection • Mechanical (tight junctions, movement) • Chemical (fatty acids, enzymes, pH, antimicrobial peptides) • Microbiological (normal flora) • Mucosal surfaces • Nasopharyngeal, Oral, Respiratory, Intestinal tract Urogenital tract • Skin (epithelial cells) • Wounds, burns, insect bites DR.T.V.RAO MD 13
  14. 14. HOW INNATE IMMUNITY ELIMINATES PATHOGENS• Identifies and eliminates pathogens • Non-adaptive recognition systems • Activates molecules that target the microbe and aid in it’s identification. • These factors may be expressed at the surface or within cells, released from immune cells or are secreted and present within circulatory systemDR.T.V.RAO MD 14
  15. 15. INNATE IMMUNITY• 3. Initiates an inflammatory response • Reaction to injury or infection • Trauma to tissues or cells • Presence of foreign matter (self vs. non-self) • Infectious agents (viruses, bacteria, fungi) • Delivers effector molecules & immune cells to the site of infection • Components • Leukocytes & secreted factors • Blood vessels • Plasma proteins DR.T.V.RAO MD 15
  16. 16. Macrophage Microbial KillingOnce the PRRs are activated by the PAMPs,phagocytosis is initiatedPhagocytosis is active process:- Internalization of pathogen into phagosome- Acidification of phagosome- Fusion of phagosome with lysosomes that contain anti-microbial compounds (phagolysosome)- This may be sufficient to kill the pathogen- If not, reactive oxygen and nitrogen species may need to be generated
  17. 17. INNATE IMMUNITY • Provides signals to activate and regulate the type of adaptive immune response generated • Stimulation of co-stimulatory molecules • B7 family (CD80/86, PD-L, ICOSL) • TNFR family (OX40L) • Induction of a cytokine/chemokine response • Cytokines: IL-12, IL-23, IL-4 • Chemokines: CXCR1, CXCR2, CCL20 • a variety and depends on stimulusDR.T.V.RAO MD 17
  18. 18. FIRST LINE OF DEFENSE -- EPITHELIA • Mechanical • tight junctions, air/fluid flow, ciliary rejection • Chemical • lysozyme, pH, defensins, surfactant opsonins, TOX(ROX) • Microbiological • normal protective flora competition, antimicrobial colicin • Inductive • receptors that recognize pathogens and signal other innate and adaptive immune responseDR.T.V.RAO MD 18
  19. 19. CELLS OF INNATE IMMUNITY• Neutrophils• Eosinophils• Basophils/Mast Cells• Monocytes• Macrophages• Natural Killer Cells• PlateletsDR.T.V.RAO MD 19
  20. 20. DR.T.V.RAO MD 20
  21. 21. LEUKOCYTE TERMINOLOGY TWO SYSTEMS • Nuclear Morphology • Mononuclear Cells • Monocytes/Macrophages • Lymphocytes • Polymorph nuclear Cells • Polymorphonuclear Leukocytes, PMNLs, PMNs • Granule Morphology • Granulocytes • Neutrophils (neutral), Eosinophils (orange), Basophils (blue) • Agranulocytes • Lymphocytes, Macrophages,DR.T.V.RAO MD 21
  22. 22. COMPARATIVE MORPHOLOGY OF GRANULOCYTESDR.T.V.RAO MD 22
  23. 23. Leukocyte Players ofInnate Immune Responses
  24. 24. Innate Immune Receptors Innate immune receptors are not clonally distributed Binding of receptors results in rapid response Innate immune receptors mediate three functions: - phagocytic receptors to stimulate pathogen uptake - chemotactic receptors that guide phagocytes to site of infection - stimulate production of effector molecules and cytokines that induce innate responses and also influence downstream adaptive immune responses
  25. 25. Pathogen Recognition Most microorganisms express repeating patterns of molecular structures termed Pathogen Associated Molecular Patterns (PAMPs) Innate immune system has evolved mechanisms capable of recognizing these repeating patterns termed Pattern Recognition Receptors (PRRs) Examples of Pattern Recognition Receptors: - Mannose-Binding Lectin (MBL) - Macrophage Mannose Receptor - Scavenger Receptors - Toll-like Receptors (TLRs) - Nod-like Receptors (NLRs) - RNA helicases (RIG-I, MDA-5)
  26. 26. PHAGOCYTOSIS• Phagocytosis • Definition: uptake of large particles (>0.5 mm) • Actin-dependent, clathrin-independent • High rate & efficiency of internalization• Professional phagocytic cells • Macrophages • Neutrophils• These cells have phagocytic receptors • External receptors • FcR, CR3, Mannose receptor • Internal receptors • TLRs DR.T.V.RAO MD 26
  27. 27. MACROPHAGES (MQ)• Blood - Called monocytes (1-6% WBC)• Tissues - Called macrophages • mature form of monocytes • normally found in tissues such as gastrointestinal tract, lung, liver and spleen• Functions: • Phagocytose and kills after bactericidal mechanisms are activated (T cells) • Produce cytokines/chemokines (initiates inflammation) • Is an antigen presenting cell (co-stim. Molecules)DR.T.V.RAO MD 27
  28. 28. NEUTROPHILS (PMN)• Present in blood (55-60% of WBC)• Not normally present in tissues• Short lifespan - 12 hours• Functions: • First at the site of infection/injury• Ingest and kill microbes after bactericidal mechanisms are activated (binding to pathogen)DR.T.V.RAO MD 28
  29. 29. HUMAN NEUTROPHIL• Granulocytic Leukocyte• Most Abundant White Blood Cell • 2-6 x 103 cells/μL • 40 –75 % of leukocytes• Very Short Lifetime • t1/2 = 6 hours• 55 % of Bone Marrow Weight Devoted to Neutrophil Prod uctionDR.T.V.RAO MD 29
  30. 30. Human Neutrophil Size• In blood: • Volume = 300 μm3 sphere (300 fl vs. 90 fl for RBC) • Diameter = 8.3 μm DR.T.V.RAO MD 30
  31. 31. EOSINOPHIL EM MORPHOLOGYDR.T.V.RAO MD 31
  32. 32. SIGNAL TRANSDUCTION• Receptors • recognition of pathogens • chemical signals• Transduction pathways • G proteins, Kinases• Effector activation • gene induction • motility, secretion • adherence, phagocytosisDR.T.V.RAO MD 32
  33. 33. G PROTEIN CYCLEDR.T.V.RAO MD 33
  34. 34. Toll-Like Receptors (TLRs) TNFa IFNabCellular Localization:- Lysosomal localization (i.e. subcellular) of TLR-3 and TLR7-9- TLR-3 and 7-9 recognize viral/bacterial nucleic acids- lysosomal expression isolates pathogen nucleic acid recognition away from potential cross-reaction with host mammalian nucleic acid motifs
  35. 35. G PROTEIN-COUPLED RECEPTORS• Largest receptor family appx ~1000 types• Bind proteins, peptides, absorb light• Highly homologous in structure• Gab protein exchange factors• G protein splitters ==> Ga-GTP & Gb• Primary transducers are Ga-GTP & Gb• Activate membrane phospholipases and cyclases
  36. 36. LL L Receptor - G protein L L L Coupling L L L R R R a a b  a b  GDP L GTP GDP L L L R R PIP2 PIP3 a a a b  P b  GDP GDP GTP P110 L C GTP GDP INTERNALIZED DR.T.V.RAO MD 36
  37. 37. GPCR OF INNATE IMMUNITY• Peptide receptors • fMLF receptor-- chemotaxis toward bacteria • Complement receptors C5a, C3a -- chemotaxis toward sites of complement activation• Lipid receptors • Leukotriene (LTB4), Eiosanoid (LPXA4), PAF, PG• Chemokine receptors • CXC (IL-8), CC (MCP), CXXXC(Fractalkine) • nomenclature from amino terminal cysteines • IL-8, MCP induce extravasation of neuts, M • Fractalkine - monocyte /endothelial adhesionDR.T.V.RAO MD 37
  38. 38. KILLING MECHANISMS• Phagosome - membrane bounded vesicle that becomes acidified• Lysozome - granules that contain products that damage or kill pathogens • Enzymes • Lysozyme - dissolves cell walls of some bacteria • Acid hydrolases - digests bacteria • Proteins • Lactoferrin - binds Fe++ needed for bacterial growth • Vitamin B12-binding protein • Peptides • Defensins and cationic proteins - direct antimicrobials DR.T.V.RAO MD 38
  39. 39. Activated macrophages secrete proteins that drive innate responseCytokines- induce response by binding to specific receptors- can function in autocrine or paracrine manner- cytokines (and their receptors) are clustered according to structural similarities- critical cytokines secreted by macrophages following activation include TNFa, IL-1, IL-6, IL-12 to stimulate inflammation and phagocytosis/killingChemokines- diverse family of chemotactic cytokines, induce directed chemotaxis of cells- all related in amino acid structure- certain chemokines induce cell activation in addition to cell recruitment- promiscuous in receptor usage, each can bind more than one receptor- likewise, receptors are promiscuous
  40. 40. KILLING MECHANISMS - CONT.• Respiratory Burst • Activated following phagocytosis • Stimulated by PRR • Requires increased oxygen consumption • Produces substances that are directly toxic to the bacteria • Oxygen-derived products • O2 -, H2O2 & Myeloperoxidase • Nitrogen-derived products • NO (nitrogen oxide) • Produced by inducible NO synthase (iNOS) enzyme • Enzyme is induced by cytokines (LT, TNFb) DR.T.V.RAO MD 40
  41. 41. NADPH OXIDASE Mitochondrial-independent respiratory burst P47phox & p67phox normally resides in the cytoplasma. P47phox becomes hyperhposphorylated following phagocytosis and binds to p67phox. These components move to the membrane and bind the NADPH complex resulting in an activeDR.T.V.RAO MD complex. 41
  42. 42. ENZYME REACTIONS OF RESPIRATORY BURST• Respiratory Burst NADPH NADP+ Superoxide + dismutase 2 O2 2O - H 2O 2• Myeloperoxidase • Enzyme which is stored in primary granules of PMN & MQ and uses the products of the respiratory burst. - • H2O2 + C1 Chloramines DR.T.V.RAO MD 42
  43. 43. Clinical symptoms of inflammation: pain, redness, heat, swelling1. Increased vascular diameter, increased blood flow (heat, redness)2. Activation of vascular endothelium to express adhesion molecules, increases leukocyte binding3. PMNs are first cell type recruited to site, followed later by monocytes4. Increased vascular permeability results in local swelling and pain Microvascular coagulation helps prevent pathogen spread into bloodstream (physical barrier)
  44. 44. CHEMOKINES• Infection induces the release of various chemokines• Theses substances bind specific and sometimes shared receptors to recruit various types of immune cells to the site of infection
  45. 45. DENDRITIC CELLS• DCs link innate and adaptive immunity• DCs are immature as they circulate waiting to encounter pathogens• At this point, they are highly phagocytic, but not good stimulators of adaptive T cell responses• Once they are activated by pathogens and activation of their PRRs, they secrete cytokines to initiate inflammation and then they migrate to lymph nodes and mature• As mature DCs they are excellent APCs for T cell stimulation DR.T.V.RAO MD 45
  46. 46. THE CURRENT KNOWLEDGE HELPS FOR NEWER VACCINE TRENDS• The detailed understanding of the immune system provided by the new Nobel laureates has given other researchers the ability to improve vaccines and to attempt to stimulate immune reactions to cancer. Their insights also inform efforts to damp down the immune system when it becomes too zealous, which can lead to excessive inflammation and autoimmunity.DR.T.V.RAO MD 46
  47. 47. FOR FURTHER INFORMATION . . .• Immunology Project Resources –• Understanding Autoimmune Disease• http://www.niaid.nih.gov/publications/autoimmune/work.htm• Antibody descriptions [IgG, IgM, IgA]• http://sprojects.mmi.mcgill.ca/immunology/Ig_text.htm• Immunology Hyperlinked History & Molecular Movies• http://www.bio.davidson.edu/courses/Immunology/Bio307.html• Nature Magazine & Immunology• http://www.nature.com/nature/view/030102.html• NCBI Genome• http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1589796• NCBI Genome Base• http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1589796
  48. 48. • Programme created by Dr.T.V.Rao MD for Medical and Paramedical students in the Developing World • Email • doctortvrao@gmail.comDR.T.V.RAO MD 48
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×