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Introduction to Immunology
By
Dr. Nabil El Aila
Assistant Professor of Medical Microbiology
Medical Technology Department
Al -Aqsa University
Immunity
1.Immunity: : Meaning the state of protection from infectious disease.
In 430BC, a plaque in Athens, Those who recovered from the plaque would not contact the disease a second time.
2. Agents: microorganisms (viruses, bacteria etc) and their products, foods, chemicals, pollen, tumor cells, etc.
3.Immune system: immune tissues and organs, immune cells, immune molecules
4.Immune response: collective and coordinated response to the introduction of foreign substances.
5.Immunology: study the structure of immune system and its functions.
Immune Response¨ Innate immune response
natural immune response
non-specific immune response¨ Adaptive immune response
acquired immune response
specific immune response
Characteristics Cells Molecules
Innate immunityResponds
rapidly No memoryNo or low
specificity
Physical barriersPhagocytes
(PMNs and macrophages)Natural killer
cells
Humoral factorsComplementAcute phase
ProteinsCytokines
Adaptive immunityResponds
Slowly MemoryHighly specific
T cellsB cellsDendritic cells
AntibodiesCytokinesGranzymes
The innate and adaptive immune response
Adaptive immune response
Innate vs. Adaptive Immune
Innate: structural defenses; responds to nonspecific foreign substances First line: external surface epithelium & membranes Second line: internal defenses: inflammatory processes –
antimicrobial proteins, phagocytes, etc.
Innate vs. Adaptive Immune
Adaptive: responds to specific foreign substances
Innate & adaptive mechanisms work together
Innate, Defenses
Innate, Surface Defenses Skin
physical barrier to microbes Keratin resistant to most bacterial enzymes & toxins secretions are acidic pH 3-5
Mucosa physical barrier & produces a variety of protective
chemicals Gastric mucosa
very acidic & produces proteolytic enzymes Saliva & lacrimal fluid contain lysozyme Mucous
traps bacteria & moves them away from epithelial surface
LACRIMAL APPARATUS.
CILIARY ESCALATOR.
Innate, Defenses
Innate, Internal Defenses Based on recognition of surface carbohydrates
(glycocalyx) Glycocalyx is recognized as “self” or “non-self”
Innate, Internal Defenses
Phagocytes Macrophages: derived from monocytes
Free Macrophages: roam through tissues Fixed Macrophages: Kupffer cells (liver) & microglia
cells (brain)
Ingest cellular debris, foreign material, bacteria, fungi Neutrophils: ingest pathogens Eosinophils: weakly phagocytic of pathogens. Attack
parasites (degranulation) Mast Cells: phagocytic of various bacteria
Innate, Internal Defenses
Phagocytic mechanisms: Adherence: cell binds to invader
Aided by opsonization (a chemical process that enhances binding via complement & antibodies)
Ingestion: formation of phagolysosomes Respiratory Bursts: merge phagosome with lysosome &
flood phagolysosome with free radicals (macrophage) Defensins: proteins that crystallize out of solution &
pierce pathogen membranes (neutrophils)
Mechanism of Phagocytosis
Figure 21.2
Innate, Defenses
Innate, Internal Defenses
Natural Killer Cells: Small population of large granular lymphocytes Non specific for “non-self” Not phagocytic: attack is by release of perforins that
perforate the target cell plasma membrane. Shortly after perforation the target nucleus disintegrates.
Release chemicals that enhance the inflammatory response
Innate, Defenses
Innate, Internal Defenses: Inflammation
tissue response to injury Triggered by injury – trauma, heat, chemical
irritation, infection, etc. Beneficial effects
Prevents spread of injury Disposes of cellular debris & pathogens Promotes repair
Innate, Internal Defenses: Inflammation
cardinal signs of inflammation Redness Heat Swelling Pain (functional impairment Rigon)
Innate, Internal Defenses: Inflammation
Inflammatory response: signs are associated with vasodilation & increased vascular permeabilityDilation: redness, heatPermeability: edema, (increased pressure) painPain also associated with bacterial toxins & some
mediators (kinins, PGs)
Innate, Internal Defenses: Inflammatory Response
Mechanisms causing vasodilation & vascular permeability Injured cells release inflammatory mediators
Histamines Kinins Prostaglandins Complement Cytokines (also activated by receptors on macrophages in
response to microbial glycocalyx)
Innate, Internal Defenses: Inflammatory Response
EdemaDilutes harmful substancesProvides nutrients (& O2) for repairEnhances entry of clotting protein
Epithelial breaches also stimulate b-defensin release from epithelial cells
Events in Inflammation
Figure 21.3
Innate, Internal Defenses: Inflammatory Response
Phagocyte mobilization: infiltration of damaged area by neutrophils & macrophages
Innate, Internal Defenses: Inflammatory Response
Leukocytosis: leukocytosis inducing factors released by injured cells promote rapid release of WBCs from marrow
Margination: increased vascular permeability causes decreased fluid in vessels; blood flow slows & neutrophils are able to move to vessel margins. Here endothelial markers (CAMs) allow neutrophils to cling to vessel walls (pavementing).
Innate, Internal Defenses: Inflammatory Response
Diapedesis: neutrophils migrate through capillary walls
Chemotaxis – inflammatory chemicals attract neutrophils to move up the chemical concentration gradient (neutrophils respond first)
As the process continues, monocytes diapedes into the area & become macrophages. With chronic inflammation, macrophages predominate
Inflammatory Response:Phagocytic Mobilization
Figure 21.4
Innate, Internal Defenses: Inflammatory Response
Macrophages clean up cellular debris & pathogens If pathogens were associated with the injury,
activation of the complement cascade occurs & elements of adaptive immunity join the process
Innate, Internal Defenses
Viral replication – (viruses lack metabolic processes) Viruses release nucleic acid (RNA or DNA) into cytoplasm. The information on the nucleic acid is incorporated into the cell’s DNA. Normal cellular mechanisms then produce viral structural components. Multiple new viral particles are produced & released from the cell (sometimes killing the cell)
Innate, Internal Defenses
Antiviral proteins: interferon & complement Interferon: some cells produce & release interferons
(IFNs) when invaded by virus Released interferons stimulate nearby cells to produce
proteins (PKR) that interfere with viral replication by disrupting protein synthesis & the ribosome
Not virus specific.
Interferon (IFN)
Figure 21.5
Innate, Internal Defenses
Complement – a group of plasma proteins (20) that are activated in the presence of foreign substances
Complement activation enhances & amplifies inflammation
Bacteria & some other cell types are lysed by complement activation
Complement activation enhances both innate & adaptive defenses
Innate, Internal Defenses
Complement activation pathways Classical pathway: requires antibodies
Antibodies bind to target (antigen) Complement protein C1 binds to the antibody-
antigen complex (complement fixation) Alternative pathway: complement factors interact with
microorganism glycocalyx Both pathways lead to a cascade of protein activation,
leading to activation of C3
Innate, Internal Defenses; Complement
Figure 21.6
Innate, Internal Defenses
C-reactive proteins (CRP) produced by the liver in response to inflammatory molecules can activate the classical pathway by binding to membrane & activating C1. Also participates in opsonization.
Fever – a systemic response to infection. Leukocytes & macrophages release pyrogens that raise the hypothalamic “set point” for temperature
ADAPTIVE DEFENSES
ADAPTIVE DEFENSES
Innate & adaptive mechanisms work together in a cohesive fashion
Adaptive Defenses: Characteristics
Specificity: directed at specific targets
Systemic: not restricted to initial site of infection / invasion
Memory: after initial exposure & activation, a more rapid & more vigorous response is made to subsequent exposures to pathogens
(secondary response)
Adaptive Defenses: Components
Humoral Immunity: (antibody mediated immunity) provided by antibodies floating free in body fluids
Cell mediated immunity: lymphocytes directly attack specific invaders by
lysis or indirect attack by initiating inflammation and/or activating other lymphocytes & macrophages
Adaptive, Humoral Immunity
Antigen = any substance that can mobilize the immune system & provoke an immune response*
*Humoral and/or cell mediated
Adaptive, Humoral Immunity
Complete antigens (proteins, nucleic acids, lipids, polysaccharides): Immunogenicity: the ability to stimulate specific
lymphocytes & specific antibodies Reactivity: the ability to react with activated lymphocytes
& antibodies Hapten (an incomplete antigen): a smaller molecule
that is not immunogenic until attached to proteins
Adaptive, Humoral Immunity
Antigenic determinants: sites on an antigenic molecule that are immunogenic Epitope
Major Histocompatibility Complex (MHC): cell surface glycoproteins associated with self recognition
Adaptive Immune System: Cells
LymphocytesT-cellsB-cells
Antigen Presenting Cells (APCs)
Adaptive Immune System: Cells
Lymphocytes: initially uncommitted T-cells: are sorted in the Thymus
Positive selection: recognize MHC survive Negative selection: react against to self-antigens on MHC
killed 2% of initial T-cell precursors T-cells manage the immune response
B-cells: are sorted in the marrow by an incompletely understood process
Adaptive Immune System: Cells
Immunocompetence: as T- or B-cells mature they become immunocompetent, they display receptors on their cell membrane for a specific antigen.
All of the receptors on one cell are identical; immunity depends upon genetic coding for appropriate receptors.
Adaptive Immune System: Cells
Antigen Presenting Cells (APCs) APCs ingest foreign material, then present antigenic
fragments on their cell surface where they are recognized by T-cells T-cells: respond to antigen only if it is displayed on plasma membrane.
APCs: Macrophages & B lymphocytes Interactions between APCs & lymphocytes &
lymphocyte-lymphocyte interactions are critical to immune response
Adaptive, Humoral response
Humoral response (clonal selection) B-cells: Antigen challenge to naïve
immunocompetent B-cell Antigen binds to B-cell receptors & form cross-links
between receptors Cross linked antigen-receptor complex undergoes
endocytosis; B-cell presents to T-cell
Humoral Immunity
Active humoral immunity: B-cells encounter & respond to antigen to produce an
antibody
Passive humoral immunity: Introduced “non-native” antibody
Active Humoral Immunity
Naturally acquired: natural exposure to antigen (i.e. infection) Artificially acquired: vaccines; dead/attenuated or fragmented
pathogen injected to elicit an immune response Bestow immunity without disease; primary response Booster shots (secondary response); intensify response Shortcomings – adverse reactions & the immunity is less
durable (poor memory) & has less cell mediated component
Passive Humoral Immunity
Natural: maternal antibody crosses the placental barrier conferring temporary immunity to the baby (degrades after a few months)
Artificial: antibodies harvested from an outside source given by injection protect from immediate threat but no memory is formed (antitoxins, antivenins , gamma globulin, etc.)
Antibodies
A.K.A Immunoglobulins & gamma globulins Structure
variable hypervariable constant
Antibodies
Constant (C) region defines antibody class determines chemical & cellular interactions determines how class functions to eliminate antigens
Antibody Classes
Antibody Classes: IgM, IgG, IgA, IgD, IgE (Ig = immunoglobulin)
Antibody Classes
IgG: the most abundant circulating Ig. The dominant circulating Ig of the primary & the secondary response. Crosses the placenta. Complement binding (Monomer).
IgA: the Ig of secretions. Helps prevent antigen penetration of membranes (Dimer).
IgD: the Ig of B-cell activation. Found on B-cell
surface (Monomer).
Antibody Classes
IgM: occurs as a monomer & a pentamer
Occurs on the B-cell surface (Monomer).
The Ig of early primary plasma cell response, circulating antibody; a potent agglutinator. Complement binding (Pentamer).
Antibody Classes
IgE: the Ig associated with allergies. Stem binds to mast cells & basophils.Receptor binding results in histamine release &
inflammation.Found mostly in mucosa of respiratory & GI tract
(Monomer).
Antibody Targets & Functions
Immune complex formation = antigen-antibody binding.
All the following events are initiated by antigen-antibody binding.
Complement fixation: Neutralization: Agglutination: Precipitation: Inflammation & phagocytosis prompted by debris
Antibody Targets & Functions
Complement fixation: cells & bacteria. Immune complex formation exposes a complement binding
site on the C region of the Ig. Complement fixation results in cell lysis.
Neutralization: immune complex formation blocks specific sites on virus or toxin & prohibit binding to tissues
Agglutination: cells are crosslinked by immune complexes & clump together
Precipitation: soluble molecules (such as toxins) are crosslinked, become insoluble, & precipitate out of the solution
Inflammation & phagocytosis prompted by debris
Antibody Targets & Functions
Monoclonal antibodies: antibodies produced by descendants of a single cell Pure antibody preparations that are specific for a single
antigenic determinant Research / diagnostic / therapeutic use
Cell Mediated Immune Response
T-cell activation: involves recognition of PM surface antigens only Antigen is combined with MHC & displayed on PM T-cell receptors: bind to the MHC & are stimulated by the
associated antigen The addition of a co-stimulator (cytokines, interleukins,
etc) prompts the T-cell to form a clone In the absence of a co-stimulator the T-cell becomes
tolerant to antigen (anergy)
Cell Mediated: MHC
MHC occurs as two classes MHC I on virtually all tissue cells MHC II only on PM some immune system cells
Cell Mediated: MHC display properties
MHC I on virtually all tissue cells Display only proteins produced inside the cell Endogenous antigens = foreign proteins produced by
the cell (viral / cancer) Stimulate the CD8* cell population
form cytotoxic T-cells (Killer T, TC) *formerly T8 cells
Cell Mediated: MHC display properties
MHC II found only on PM of B-cells, some T-cells & APCs Display proteins derived from a phagocytized target Exogenous antigen: foreign protein from outside the
cell – presented to PM surface Stimulates the CD4* cell population
form Helper T-cells (TH) *formerly T4 cells
Cell Mediated: T-cell roles
Helper T-cells (TH) stimulate B-cells
& other T-cells to
proliferate
Cell Mediated: T-cell roles
Activated TH cells interact with B-cells displaying antigen & produce cytokines that prompt the B-cell to mature & form antibody
Cell Mediated: T-cell roles
TH cells also produce cytokines that promote TC cells
TH cells recruit other WBCs & amplify innate defenses (inflammatory)
Subpopulations of TH cells specialize in specific sets of activations
Cell Mediated: T-cell roles
Cytotoxic T-cells (TC, Killer T): directly attack & kill cells with specific antigen
Activated TC cells are co-stimulated by TH cells
Cell Mediated: T-cell roles
TC mechanism (Cytotoxic T-cells, Killer T) TC binds to cell & releases
perforin & granzymes In the presence of Ca2+
perforin forms pores in target cell PM
Granzymes enter through pores & degrade cellular contents
TC then detaches & moves on
Macrophages clean up
Cells, tissues and organs of the immune system
Immune cells are bone marrow-derived, & distributed through out the body
Primary lymphoid organs: – Thymus: T cell maturation – Bone marrow (bursa of Fabricius in birds): B cell maturation
Secondary lymphoid organs: – Lymph nodes– Spleen– Mucosal lymphoid tissues (lung, gut)
Cells of the Immune system: FORMED ELEMENTS IN BLOOD
Many cells of the immune system derived from the bone marrow
Hematopoetic stem cell differentiation
COMPONENTS OF THE LYMPHATIC SYSTEM.
The bursa of Fabricius in birds
Types of Acquired Immunity
Figure 21.11
Major Types of T Cells
Figure 21.14
T Cell Activation: Step One – Antigen Binding
Figure 21.16
Helper T Cells (TH)
Figure 21.17a
Helper T Cells
Figure 21.17b
Summary of the Primary Immune Response
Figure 21.19