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Introduction to Immunology


... (aka innate immunity) utilizes the basic resistance to disease that a species ... Cells express unique Ag-receptors huge repertoire of specificities ... – PowerPoint PPT presentation

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Title: Introduction to Immunology

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
  • 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 Kochs postulates
  • A set of criteria to be used when establishing a
    causative link between a particular microorganism
    and a particular disease
  • Kochs 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
  • 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
  • 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)

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
  • Lymphoid Lineage B, T, and NK cells
  • Myeloid Lineage PMNL (Basophils, Mast cells,
    Eosinopils, Neutrophils), Monocytes/Macrophages
  • Erythroid Lineage (Megakaryocyte, Platelets and
  • 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
  • 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 (Tcyt) ? Kill infected target
  • Inflammatory (TH1) and Helper (TH2) T cells ?
    Activation of other cells (macrophages and B
    cells, respectively)

  • Sites of Maturation ? Central/Primary Lymphoid
  • 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

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
  • Peyers 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
  • 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
  • Paracortex T lymphocytes and dendritic cells
  • Medulla
  • Medullary cords macrophages and plasma cells
  • Region where lymph leaves
  • Similar organization in spleen and Peyers
    patches. Important for TB cooperation.

  • Spleen (Largest peripheral lymphoid organ)
  • Collects and traps Ag from the blood (via splenic
  • 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
  • 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

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
  • 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

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 (gt96 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
  • 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
  • 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
  • Appears immediately
  • Stored in endothelial granules called
    Weibel-Palade Bodies
  • E-selectin induced by TNF-alpha
    Lipopolysaccharide (LPS) ? appears after a few
  • 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
  • Binds better
  • Increases adhesion
  • Rolling stops

Step 3 Diapedesis
  • Crossing of endothelial wall Extravasation
  • 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
  • Opsonization also enhanced (C3b ? binds to CR1)

  • 7 Lymphoid lineages involved in non-adaptive
  • 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
  • MHC class I involved
  • Present ? Negative signal overrides activity of
    killing receptors

  • Intraepithelial gammadelta 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
  • 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
  • Most lymphocytes with self-reactive receptors are
    deleted (apoptosis) or rendered non-responsive

  • 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
  • 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 2o recall responses)
  • Lymphocytes with receptors that recognize host
    proteins (self) are deleted early in ontogeny and
    do not appear in the mature lymphocyte repertoire

  • 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
  • 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 AbAg and CAg 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,
  • Include keratinocytes, thyroid epithelium,
  • Ag presentation can result in autoimmunity and
    prolonged (chronic) inflammation

B. Two Signals Needed for Full Activation of
  • B cells usually receive 2nd 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

  • 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/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
  • 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
  • Response mounted against Ags in the absence of
    infectious disease
  • Allergy Ag innocuous foreign substance (e.g.
  • Autoimmunity Ag self Ag (not tolerant)
  • Graft rejection Ag foreign cell
  • Therapy Ag-specific suppression and general

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,
  • 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