Introduction to Immunology By Dr. Nabil El Aila Assistant Professor of Medical Microbiology Medical Technology Department Al -Aqsa University.

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


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


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


cardinal signs of inflammation Redness Heat Swelling Pain (functional impairment Rigon)


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)


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


Phagocyte mobilization: infiltration of damaged area by neutrophils & macrophages


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).


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


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


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)


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


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


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


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


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


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)


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


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.


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


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


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


Activated TH cells interact with B-cells displaying antigen & produce cytokines that prompt the B-cell to mature & form antibody


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


Cytotoxic T-cells (TC, Killer T): directly attack & kill cells with specific antigen

Activated TC cells are co-stimulated by TH cells


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

Introduction to Immunology By Dr. Nabil El Aila Assistant Professor of Medical Microbiology Medical Technology Department Al -Aqsa University.

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