Docstoc

Unit 1.ppt

Document Sample
Unit 1.ppt Powered By Docstoc
					Introduction to Immunology
I. General Introduction
              A. Definitions
• Immunity: the state of protection from infectious
  disease involving specific and non-specific
  elements

• Specific immunity (aka aquired immunity)
  employs components of the immune response that
  specifically recognize and selectively eliminate
  microorganisms and molecules perceived as
  foreign by the host
• Nonspecific immunity (aka innate immunity)
  utilizes the basic resistance to disease that a
  species possesses and makes up the first line of
  defense

• Antigen is anything that the adaptive immune
  response (IR) can recognize (antibody generating)
  B. The Origin of Immunology
• Edward Jenner (1796) used the cowpox
  virus (vaccinia) to confer induced protection
  fro human small pox
     • Vaccination – term now used to explain how healthy
       subjects are inoculated with attenuated (weakened)
       strains of pathogens to induce ACQUIRED
       protection (Active immunization)
     • Small pox successfully eradicated in 1979 –
       Announced by the WHO
• Robert Koch (1843-1910) proved that bacteria
  were responsible for causing anthrax and
  tuberculosis.
      • He developed Koch’s postulates
          – A set of criteria to be used when establishing a causative link
            between a particular microorganism and a particular disease
      • Koch’s postulates are still followed today to show that
        pathology (disease) is caused by one of the four major groups
        of pathogens:
          –   Viruses
          –   Bacteria
          –   Pathogenic fungi
          –   Parasites
• Louis Pasteur (1822-1895) – developed vaccines
  against cholera (Vibrio cholerae) and rabies
  (Rhabdovirus –Negribodies – RNA virus)

• Emil von Behring (1845-1917) and Shibasaburo
  Kitasato (1852-1931) – using diphtheria toxin,
  identified that serum of vaccinated individuals
  contained antibodies that specifically interact with
  the immunogen (antisera, passive immunization
  when injected with immune serum)
• Eli Metchnikoff (1845-1916) – reported the
  engulfment and degradation of
  microorganisms by a type of phagocytic cell
  he called macrophages
  – First line of defense
  – Innate (non-adaptive) immunity
  – Receptor-mediated endocytosis/phagocytosis
      C. Major cells of Innate and
      Acquired Immune Responses
• Involve action of white blood cells called leukocytes
  (lymphocytes, polymorphonuclear leukocytes and
  monocytes) and dendritic cells
• Innate immunity
   – Involves mainly granulocytes
       • Granules in cytoplasm
       • Different cell types – many are phagocytic
           – Most are polymorphonuclear leukocytes = neutrophils (multilobed nuclei
             and cytoplasmic granules), eosinophils, basophils, mast cells (PMNLs)
           – Also involves monocytes (mononuclear)  Macrophages in tissues
• Acquired (adaptive) immunity
   – Involves lymphocytes (B cells, T cells, Natural Killer Cells)
   – Lifelong immunity established through generation of memory cells
     (B and T cells have memory)
II.   The Components of the
         Immune System
 A. Hematopoietic Stem Cells Give
 Rise to White and Red Blood Cells
• All circulating blood components originate in the bone
  marrow

• The same precursor cell or progenitor gives rise to all of
  the various lineages = “Pluripotent Hematopoietic Stem
  Cell”
   – Differentiate or mature into two main progenitor populations
       • Lymphoid Lineage [B, T, and NK cells]
       • Myeloid Lineage [PMNL (Basophils, Mast cells, Eosinopils,
         Neutrophils), Monocytes/Macrophages
       • Erythroid Lineage (Megakaryocyte, Platelets and Erythrocytes)
   – Hierarachy of Cell Maturation: Pluripotent Stem Cells 
     Committed Progenitor Cells  Terminally Differentiated Cells
 B. Maturation of Lymphocytes
• Resting B and T cells
  – Small, inactive,
    heterochromatin,scantycytoplasm containing
    few organelles

  – No functional significance
• Receptors to recognize specific antigen
   – B cell receptors
      • Membrane-bound antibody = surface immunoglobulin (Ig)
      • Following B cell activation  Differentiation into plasma cell
         Cytoplasm enlarges, ER expands, active transcription,
        increase in organelles  Antibody secretion
   – T cell receptors
      • Related to Ig but distinctive
      • Following T cell activation (in peripheral lymphoid organ)
          – Cytotoxic T cells (T cyt)  Kill infected target cells
          – Inflammatory (TH1) and Helper (TH2) T cells  Activation of
            other cells (macrophages and B cells, respectively)
• Sites of Maturation  Central/Primary Lymphoid
  Organs
   – B cells mature in the bone marrow (or Bursa of
     Fabricius in birds)
   – T cells mature in the thymus
• After maturation, lymphocytes are transported to
  the bloodstream and then traffic  to the
  Peripheral/Secondary Lymphoid Organs
   – This is where antigen is encountered
   – This is where lymphocytes divide (clonal expansion)
C. Adaptive IRs Occur in Peripheral
          Lymphoid Organs
• Peripheral Lymphoid Organs
   –   Lymph nodes
   –   Spleen
   –   Mucosal associated lymphoid tissue (MALT)
   –   Bronchial associated lymphoid tissue (BALT)
   –   Gut associated lymphoid tissue (GALT)
        •   Tonsils
        •   Adenoids
        •   Appendix
        •   Peyer’s patches
   – Function: to trap antigen from sites of infection and present it to
     circulating, resting lymphocytes to induce adaptive immune
     responses
• Lymph nodes (LN)
  – The afferent lymphatic vessel delivers lymph
    draining the extracellular spaces of the body to
    the L.N. (e.g. in interstitial spaces of tissues)
  – Antigen (Ag) becomes trapped in the L.N.
  – The efferent lymphatic vessel takes lymph
    away from the L.N. medulla region
– Anatomy of a lymph node
   • Post-capillary venules deliver naïve lymphocytes
   • Cortex
       – Outer cortex = B lymphocytes in 1o follicles and 2o follicles
         (germinal centers, where proliferation occurs if B cells are
         responsive to Ag)
       – Paracortex = T lymphocytes and dendritic cells
   • Medulla
       – Medullary cords = macrophages and plasma cells
       – Region where lymph leaves
   • Similar organization in spleen and Peyer’s patches. Important
     for T:B cooperation.
• Spleen (Largest peripheral lymphoid organ)
   – Collects and traps Ag from the blood (via splenic artery)
   – Important for systemic infections
   – Not supplied by afferent lymphatics
   – Final stop for dying (senescent) RBC
   – Red pulp: major area and site of RBC disposal by splenic
     macrophages
   – White pulp forms around a central arteriole:
       • Periarteriolar lymphoid sheath (PALS) = Mainly T cells
       • B Cell corona and germina center
   – Arterioles  vascular sinusoids  splenic vein
   D. Continuous Recirculation of
           Lymphocytes
• Naïve lymphocytes are circulating continuously
  between blood and peripheral lymphoid regions

• Homing to 2o lymphoid tissue
   – Involves binding to adhesion molecules on
     lymphocytes called L-Selectin, to its ligand called
     mucin-like vascular addressin (CD34 + GlyCAM-1 in
     L.N.; MAdCAM-1 in MALT) on high endothelial
     venules (HEV = capillaries delivering cells)
             If Ag IS Encountered
• 1. Ag enters L.N. through the afferent lymph (often via phagocytic
  cells)
• 2. Ag is trapped by professional antigen presenting cells (APC)
• 3. Ag is displayed to naïve lymphocytes
• 4. Lymphocytes, which have a specific cell surface receptor that
  recognizes Ag, remain in peripheral lymphoid organ, proliferate, and
  then differentiate into effector cells
• 5. Effector cells leave L.N. through efferent lymphatic vessel 
  return to blood via thoracic duct
• 6. Emigration of WBC out of the bloodstream to sites of infection
  using adhesion molecules called integrins (extravasation)
    – T cells express increased levels of LFA-1, and begin to express VLA-4
      once activated (binds ICAM-1 and VCAM-1, respectively)
    – Macrophages express MAC-1 (binds ICAM-1)
    If Ag IS NOT Encountered
• Lymphocyte leaves through efferent
  lymphatic vessel of 2o lymphoid

• Returns to bloodstream via thoracic duct
III. Innate versus
  Adaptive Immunity
 A. Distinction Between Innate and
   Adaptive Immune Responses
• Innate immunity is non-adaptive and helps to
  initiate adaptive immune responses (= first line of
  defense – but LIMITED)
   – Immediate (0-4 hours)
• Adaptive immunity provides a more universal line
  of defense and has long-lived memory to provide
  protection upon re-infection
   –   Second line of defense
   –   Generation of Ag-specific effector cells
   –   Early (4-96 hours)
   –   Late (>96 hours)
  B. Innate Immune Responses
• Innate defense is present in al individuals
  and can operate at various locations in the
  body
• Seven types of defensive barriers
• #1 – Anatomical Barriers
   – Skin: epidermis, dermis, keratin, sebum and other
     epithelial surfaces
   – Mucous membrane surfaces: saliva, tears, mucous
     secretions
• #2 – Physiological barriers
   – Temperature, pH, O2 tension, soluble factors
     [lysozyme, interferons, acute phase proteins,
     complement, digestive enzymes, cytokines,
     chemokines, monokines (IL-1, IL-6, TNF alpha)]
  Three Functions of Interferons
• 1. Induce resistance to viral replication by
  activating cellular genes that:
   – Destroy viral mRNA
   – Inhibit translation of viral proteins
• 2. Increase Major Histocompatibility Complex
  (MHC) Class I expression universally
   – Increases level of Ag presentation to Tcyt (CD8+) –
     cytotoxic T cells (aka killer T cells)
   – Increase resistance of uninfected cells to NK cell attack
     (more later)
• 3. Activate NK cells to kill virus-infected cells
Acute Phase Proteins in Humans Act
           as Opsonins
• Hepatocytes in liver produce APP in response to
  IL-1, IL-6 and TNF alpha
• 1. Mannose binding protein (MBP)
   – Binds mannose residues on bacterial cells
   – Acts as an opsonin (enhances receptor mediated
     endocytosis by phagocytes)
   – Activates complement (lectin complement pathway)
   – Mimics activity of antibodies by acting as an opsonin
     and activating complement
• 2. C-Reactive Protein (CRP)
   – Binds bacterial phosphorylcholine
   – Mimics activity of Ab by acting as opsonin and
     activating complement (classical pathway)
• 3. Fibrinogen
   – Also an APP made by hepatocytes

• Definition of opsonization: Alteration of the
  surface of a pathogen enabling its ingestion by
  phagocytic cells (neutrophils and macrophages)
  through RME. Examples: Ab, C’, CRP, MBP
• #3 – Endocytic and Phagocytic Barriers
  – Endocytosis: Pinocytosis or receptor-mediated
    endocytosis or macromolecules (non-specific
    versus specific, respectively), followed by
    fusion with primary lysosomes where they are
    digested and processed (eliminated)
  – Phagocytosis: Ingestions of particulate material
    aided by microfilaments which fuse with
    lysosomes  phagolysosomes
• #4 – Inflammatory Barriers
   – Major events:
      • Vasodilation
      • Increased capillary permeability
      • Influx of phagocytic cells
   – Vasodilation results in reduced blood flow velocity
     allowing leukocytes to move out of capillaries to
     vascular endothelium where they penetrate, resulting in
     accumulation of fluid (swelling, pain)
– Macrophages produce MONOKINES which
  recruit more phagocytic cells and effector
  molecules to site of infection
   • IL-1, IL-6, IL-8, IL-12, TNF-alpha
   • Can also produce harmful, systemic effects
      – Systemic Shock + Disseminated Intravasclar Coagulation
        (DIC)  Organ Failure
   • Have a variety of effects at different locations
            Inflammation – cont.
• Other inflammatory mediators released/generated
  by macrophages and neutrophils include:
   –   Plasminogen activator
   –   Prostaglandins
   –   Phospholipase
   –   Platelet activating factor
   –   Leukotrienes
   –   Respiratory burst molecules: Nitric oxide, hydrogen
       peroxide, superoxide anion (toxic to bacteria, generated
       in phagolysosome)
• Inflammatory mediators induce the expression of
  adhesion molecules that bind monocytes and
  PMNLs and aid in their recruitment to sites of
  infection in tissues  EXRAVASATION (4
  steps)
   –   1.   Rolling adhesion
   –   2.   Tight binding
   –   3.   Diapedesis (crossing the vascular endothelial wall)
   –   4.   Migration
• These 4 steps will now be reviewed.
     Step 1: Rolling Adhesion
• Endothelium is induced by inflammatory
  mediators to express SELECTINS
  – P-selectin induced by leukotriene B4, C5a or histamine
     • Appears immediately
     • Stored in endothelial granules called “Weibel-Palade Bodies”
  – E-selectin induced by TNF-alpha + Lipopolysaccharide
    (LPS)  appears after a few hours
  – Selectin ligand = glycoprotein sialyly-Lewisx on
    monocytes and neutrophils
  – Reversible binding  rolls along endothelium
        Step 2: Tight Binding
• ICAM-1 on endothelium induced by TNF-alpha
• ICAM-1 binds integrins LFA-1 + MAC-1 (CR-3)
• Tight binding induced by IL-8 (or other
  chemokines)  changes conformation of LFA-1 +
  MAC-1
  – Binds better
  – Increases adhesion
  – Rolling stops
         Step 3: Diapedesis
• Crossing of endothelial wall =
  Extravasation (diapedesis)
  – Leukocytes squeeze through
  – Penetration of basement membrane (ECM)
          Step 4: Migration
• Migration through tissues via chemokines
• Recruitment to appropriate location to
  enable phagocytosis/antigen processing
• #5 – Normal Microbiological Flora (Microbiota)
   – Non-pathogenic organisms associated with epithelial
     surfaces compete with invading organisms for
     attachment sites
   – Compete for nutrients
   – Flora can produce anti-microbial substances (e.g.
     colicins made by Escherichia coli, oleic acid made by
     Propionibacterium acnes)
   – Often displaced by antibiotics enabling colonization by
     opportunistic bacteria
• #6 – Alternative pathway of complement
  activation
  – Does not require antibody
  – Acts immediately
  – Activates the terminal complement components which
    destroy bacteria by creating holes (pores) in the
    bacterial membrane  Membrane Attack Complex
  – Opsonization also enhanced (C3b  binds to CR1)
• #7 – Lymphoid lineages involved in non-adaptive
  responses
   – Natural killer (NK) cells (aka large granular
     lymphocytes – LGL)
      •   Defend host against virus-infected cells
      •   Kill sensitized targets
      •   Activated by IL-12, alpha-interferon and beta-interferon
      •   MHC class I involved
            – Present  Negative signal overrides activity of killing
              receptors
– Intraepithelial gamma:delta T cells (gd)
   • A subset of T cells that are produced early during
     embryogenesis in waves
   • Homogeneous T cell receptors within any
     epithelium location
   • Do not recirculate
   • May reorganize alterations on the surfaces of
     epithelial cells as a result of infection
   • Exact function still unclear
– CD5+ B cells (aka B-1 B cells)
   • Also arise early in embryogenesis
   • Limited rearrangement of V genes (ab genes),
     mainly IgM
   • Present as major lymphocyte in the peritoneum
   • Respond t polysaccharide antigens (TI-2 type –
     repeating subunit structure)
   • Exact function still debatable
   • Once IgM is bound, can activate complement
C. Adaptive Immune Responses
• Clonal selection of lymphocytes
   – Lymphocytes express receptors with only one
     specificity
   – The specificity of each lymphocyte is unique
   – The body contains a pool of lymphocytes with a HUGE
     repertoire of different specificities
   – Lymphocytes with useful receptors are selected to
     survive
   – Most lymphocytes with self-reactive receptors are
     deleted (apoptosis) or rendered non-responsive (anergy)
• Clonal expansion of lymphocytes
  – Because of huge variety of different receptors,
    the actual number of lymphocytes that can
    respond to a particular antigen is quite small
  – Lymphocytes will proliferate after activation
    prior to differentiating into effector cells
• Stages of Clonal Expansion
   – Ag trapped in 2o lymphoid tissue is displayed to
     circulating naïve lymphocytes
   – Ag is recognized by a lymphocyte bearing a receptor
     with correct specificity for that Ag
   – Lymphocyte enlarges  Lymphoblast
      •   Chromatin is less dense
      •   Nucleoli appear
      •   Cytoplasm increases
      •   Transcription and translation begin
– Cell division (2-4x every 24 hours for 3-5 days)
– Can get up to 1000 daughter cells from one
  parent cell
– Clones of daughter cells all have the same
  specificity for Ag as original activated cell
– Differentiation into effector cells
   • B cells secrete Antibody (Ab)  Plasma cells
   • T cells destroy infected cells or “help” other cells to
     become activated
– Some effector cells persist and develop into
  memory cells (more rapid 2 o recall responses)
– Lymphocytes with receptors that recognize host
  proteins (self) are deleted early in ontogeny and
  do not appear in the mature lymphocyte
  repertoire = TOLERANCE
• Combinatorial diversity
  – Susumu Tonegawa (1976) demonstrated that Ig
    genes are a set of multiple gene segments that
    together encode the VARIABLE region of the
    antibody molecule (Nobel Price – 1987: Gene
    Rearrangement in Ab Synthesis)
  – Gene segments are joined together differently
    in each cell, generating a unique gene for the
    variable region (same process occurs in T cells)
– Limited number of gene segments can give rise to
  large, diverse sets of products
– Cells express unique Ag-receptors  huge repertoire of
  specificities
– Genomic DNA recombined, changes are permanent 
  Somatic gene rearrangement (all daughter cells will
  have the same rearrangement)
– ~108 different lymphocytes in our bodies each with
  unique specificity
IV. Antigen Presenting Cells
  Types of antigen presenting cells
               (APC)
• Langerhans’ cells of epidermis (in sin and
  squamous epithelia) – Bone Marrow Derived
  – Phagocytic dendritic cells (DC) of tissues
  – Migrate to LN as “veiled” cells via afferent lymph to
    paracortical regions (T rich)  Now referred to as
    Interdigitating Dendritic Cells (ICD)
  – Most potent stimulators of T cell responses
  – MHC class II positive, B7 positive in LN
• Follicular dendritic cells (FDC)
   – Highly branched network in lymphoid follicle stromal
     areas (B rich)
   – Non-migratory, origin uncertain
   – Contain non-endocytic Fc receptors and complement
     receptors that hold Ab:Ag and C’:Ag complexes in
     place for long periods of time (months to years)
   – Play important role in B cell circulation, mortality, and
     memory
   – MHC class II negative
• Germinal Center Dendritic Cells (GCDCs):
   – Migratory, Class II +
   – Interact with T cells in germinal center areas
• Thymic Interdigitating Dendritic Cells (IDCs)
   – Migratory, Class II +
   – Abundant in medulla and at cortico-medullary junction
     of thymus
   – Important in deletion of self-reactive T cells
• Interstitial Dendritic Cells
   – Migratory, Class II +
   – Populate most organs (heart, lung, liver, kidney…)
• B cells as APC
  – MHC class II +
  – Present Ag to T cells (TH2)
  – Use Ig and receptor-mediated endocytosis (very
    effective at low [Ag]).
• Macrophages
  – MHC class II + after stimulated (e.g. infected)
  – Present Ag to TH1
  – Use variety of cell surface receptors for receptor-
    mediated endocytosis (Fc receptor, CR-1)
• Non-professional APCs
  – On-immune, somatic cells
  – Normaly MHC class II negative, but can be
    induced to express class II inappropriately
    (gamma IFN, TNF-alpha)
  – Include keratinocytes, thyroid epithelium,
    endothelium)
  – Ag presentation can result in autoimmunity and
    prolonged (chronic) inflammation
   B. Two Signals Needed for Full
     Activation of Lymphocytes
• B cells usually receive 2 nd signal from T cells
   – 1st signal = binding to Ag using cell-bound Ig
   – Cytokines (e.g. IL-4)
   – Cell surface molecules (CD40) (T cells express
     CD40Ligand – CD40L- when activated)
   – Important in isotype switching
   – Hyper IgM syndrome  CD40L deficiency
      • No help to B cells, Unable to isotype switch, Respond to T-
        independent Ags only
• T cells require 2nd signal from APC
  – 1st signal = recognition of Ag- binding using T
    cell receptor (TCR)
  – 2nd signal = Cytokines (e.g. IL-2 = T cell
    growth factor) (often autocrine effect)
  – 2nd signal = co-stimulatory molecule B7 (binds
    CD28 on T cells)
  V. Recognition and Effector
Mechanisms of Adaptive Immunity
       A. Humoral Immunity
• Antibody-mediated immunity by B cells
  – Involves interaction with innate and adaptive
    mechanisms and complement cascade
  – Five different Ab classes called ISOTYPES
    have different effector functions (IgG, IgA,
    IgM, IgE and IgD) (GAMED)
• Elimination of Ab-coated Ag
  – Cross-linking Ag forms clusters that bind to
    phagocytic cells via Fc receptors =
    OPSONIZATION
  – Coating bacterial toxins or viral particles and
    inhibiting binding to host cell =
    NEUTRALIZATION
  – Activation of COMPLEMENT resulting in
    lysis of invading organism and activation of
    phagocytes
   B. Cell-Mediated Immunity
• Involves the association of T cells with
  APC
• Controls intracellular infections
• Activates B cells or Macrophages, or
  destroys infected, tumor, or transplanted
  cells
• Provides help to B cells (T-dependent B cell
  resonses)(TH2)
• Cytotoxic T cells = Tcyt
  – Recognize virus-infected cells
  – Kill infected cells directly by inducing
    apoptosis (programmed cell death – cell
    suicide)
  – CD8+, MHC class I-restricted
• Inflammatory T cells = TH1
  – Activate macrophages
  – Effective in eradicating bacteria-infected cells
    (e.g. Mycobacterium tuberculosis in
    macrophages)
  – CD4+, MHC class II-restricted
• Helper T cells (TH2)
  – Help to eradicate extracellular pathogens
  – Provide “help” to B cells (2nd signal) (T-
    dependent B cells responses
  – CD4+, MHC class II-restricted
C. T Cells Recognize Ag as Peptide
 Associated with MHC Molecules
• T cells recognize short peptide fragments
  associated with membrane-bound,
  glycoproteins encoded by the Major
  Histocompatibility Complex (MHC)
• MHC/peptide complexes are used by APC
  to present Ag to T cells
   D. The Two Classes Of MHC
           Molecules
• MHC Class I
  – Presents Ag derived from intracellular
    sourc/cytosol
  – CD8+ T cells interact with MHC class I
    (=cytotoxic T cells  kill target)
• MHC Class II
  – Present Ag derived from extracellular or cell-
    bound source
  – CD4+ T cells interact with MHC class II
    (inflammatory T cells and helper T cells)
VI. When Things Go Wrong
 A. Immunodeficiency Diseases
• When some unit or the immune response does not
  function effectively
  – Can be life threatening
  – Often associated with recurrent infections
• Acquired Immune Deficiency Syndrome (AIDS)
  – TH1 and TH2 subsets of T cells destroyed
  – Caused by human immunodeficiency virus (HIV)
  – Individual suffers from multitude of infections,
    including those normally controlled by macrophages
B. Allergies, Autoimmune Diseases
        and Graft Rejection
• Response mounted against Ags in the
  absence of infectious disease
• Allergy: Ag = innocuous foreign substance
  (e.g. pollen)
• Autoimmunity: Ag = self Ag (not tolerant)
• Graft rejection: Ag = foreign cell
• Therapy: Ag-specific suppression and
  general immunosuppression
VII. How to Exploit the Immune
              System
               A. Vaccination
• Adaptive IR is specifically triggered and long
  lasting memory is established
• Examples of successful vaccination programs:
   – Diphtheria, Polio, Tetanus, Pertussis, Measles, Mumps,
     Rubella, Haemophilus influenzae B, Smallpox
• Many diseases for which vaccination does not
  exist or is not effective
   – Malaria, Schistosomiasis, AIDS, Tuberculosis…..
       B. Tumor Surveillance
• Tumor cells express proteins capable of
  inducing immune responses
• Vaccination lends potent cancer prevention
  strategy

				
DOCUMENT INFO