Transcript The Immune System

The Immune
System
Chapter 21
Immune System

functional system
rather than organ
system
 Hematopoetic
 Vasculature
 Lymphatic
Fig 21.1
Innate vs. Adaptive Immune
System – Introduction

Innate: structural defenses; responds to
nonspecific foreign substances
 First
line: external surface epithelium & membranes
 Second line: inflammatory processes – antimicrobial
proteins, phagocytes, etc.
Fig 21.1
Innate vs. Adaptive Immune
System – Introduction

Adaptive: responds to specific foreign substances
Fig 21.1

Innate & adaptive mechanisms work together
Innate, Surface Defenses

Skin
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Mucosa
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physical barrier & produces a variety of protective chemicals
Gastric mucosa


physical barrier to microbes
Keratin resistant to most bacterial enzymes & toxins
secretions are acidic pH 3-5
very acidic & produces proteolytic enzymes
Saliva & lacrimal fluid contain lysozyme
Mucous

traps bacteria & moves them away from epithelial surface
Innate, Internal Defenses

Based on recognition of surface
carbohydrates (glycocalyx)
 Glycocalyx
is recognized as “self” or “non-self”
Figure 3.3
Innate, Internal Defenses

Phagocytes
 Macrophages:
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derived from monocytes
Free Macrophages: roam through tissues
Fixed Macrophages: Kupffer cells (liver) & microglia (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:

Aided by opsonization (a chemical process that enhances
binding via complement & antibodies)
 Ingestion:
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cell binds to invader
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, 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, 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 Rigor)
 Weapons
of the Spanish Inquisition
Innate, Internal Defenses:
Inflammation

Inflammatory response: signs are
associated with vasodilation & increased
vascular permeability
 Dilation:
redness, heat
 Permeability: edema, (increased pressure)
pain
 Pain also associated with bacterial toxins &
some mediators (kinins, PGs)
Innate, Internal Defenses:
Inflammatory Response

Mechanisms causing vasodilation & vascular
permeability
 Injured
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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


Edema
 Dilutes harmful substances
 Provides nutrients (& O2) for repair
 Enhances 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
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Phagocyte mobilization: infiltration of damaged
area by neutrophils & macrophages
Innate, Internal Defenses:
Inflammatory Response
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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

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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

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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
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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 antibodyantigen 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

C3 is the start of the; Final Common Pathway
 C3 cleaves to form C3a & C3b
 C3a (& C5a) enhance inflammation
by increasing
histamine release, increasing vascular permeability &
stimulating chemotaxis
 C3b coats bacterial membrane supplying adhesion
points (opsonization)
 C3b initiates the cascade forming the membrane
attack complex (MAC)
 The MAC forms a hole in the cell membrane &
enhances Ca2+ influx  cell lysis
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

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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
Figure 21.7

Major Histocompatibility Complex (MHC): cell surface
glycoproteins associated with self recognition
Adaptive Immune System: Cells
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Lymphocytes
 T-cells
 B-cells
Antigen Presenting Cells (APCs)
Adaptive Immune System: Cells
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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
Figure 21.9
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
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Antigen Presenting Cells (APCs)
APCs ingest foreign material, then present
antigenic fragments on their cell surface where
they are recognized by T-cells
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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
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Humoral response (clonal selection)
B-cells: Antigen challenge to naïve
immunocompetent B-cell
Antigen binds to B-cell receptors & form crosslinks 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


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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
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
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
Figure 21.13a
Antibodies
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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
 The
on the B-cell surface (Monomer).
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
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Antibody Targets & Functions
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Complement fixation: cells & bacteria.
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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
Figure 21.14
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
Figure 21.16a

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
Figure 21.16b

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
Figure 21.18
Cell Mediated: T-cell roles

Activated TH cells interact with Bcells displaying antigen & produce
cytokines that prompt the B-cell to
mature & form antibody
Figure 21.18
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

Figure 21.18
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

Figure 21.19a
TC mechanism (Cytotoxic T-cells, Killer T)

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
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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
Cell Mediated: T-cell roles

Other T-cells
 *Regulatory
T-cells (TReg): release inhibitory cytokines
that suppress B-cell & T-cell activity


Help to prevent autoimmune events
*formerly Suppressor T (TS)
 Gamma
Delta T-cells (Tgd): live in the intestine.
Function in surveillance & are triggered much like NK
cells
Organ Transplants/Rejections

Types of Organ Transplants
 Autograft:
tissue graft from one body site to another
(same person)
 Isograft: graft received from a genetically identical
donor (identical twin)
 Allograft: graft received from genetically non-identical
donor (same species)
 Xenograft: graft received from another species of
animal
Organ Transplants/Rejections

Transplant rejection: mediated by the immune
system (especially TC, NK, antibodies)
 Auto/Isograft:
MHC compatible
 Xenograft: most MHC incompatible
 Allograft: attempt to obtain the best MHC match
Organ Transplants/Rejections

Immunosuppressive therapy: used to
delay/prevent rejection
 Corticosteroids:
suppress inflammation
 Antiproliferative: prevent/kill rapidly dividing cells
 Immunosuppressant: prevent/kill rapidly dividing cells
 Side effects tend to be harsh
 Increased risk of infection
Immunologic Dysfunction

Immunodeficiency
 Congenital/Genetic:
varied inborn errors
 Acquired:
Drugs: immunosuppressive / cancer drugs
Radiation therapy – marrow
 Cancer: can be viewed as a failure of immune
surveillance
 Hodgkin’s disease: lymph node cancer
 AIDS/HIV: kills TH cells

Immunologic Dysfunction

Autoimmune disease: production of antibody &
TH against self tissues
 Examples & tissue effected
 Multiple sclerosis: white matter of nervous system
 Graves disease: thyroid
 Type I diabetes mellitus: beta cells of pancreas
 Systemic Lupus Erythrematosis: (anti DNA) kidneys, heart,
lungs & skin
 Rheumatoid Arthritis: destroys joints (cartilage)
 Glomerulonephritis: impaired renal function (may be
secondary to other autoimmune disease)
Immunologic Dysfunction

Mechanisms of immunologic dysfunction
 Failure
of lymphocyte programming
 New self antigens


Gene mutation
Structural change – haptens, infection
 Foreign
antigens that closely resemble self antigen
resulting in cross reactivity.
Immunologic Dysfunction

Hypersensitivities (Allergies): the
immune system responds to a
harmless substance as if it were a
threat.
 Allergen = antigens of an
allergic response
Figure 21.21
Hypersensitivities: Types

Immediate hypersensitivity
(Type I): symptoms within
seconds of exposure to an
allergen
 (requires sensitization =
previous exposure)
Figure 21.21
Hypersensitivities: Type I

Anaphylaxis (IgE mediated; mast / basophils)
 Local:
histamine induced vasodilation & increased
permeability. Watery eyes, runny nose, itching &
redness. Respiratory  allergy induced asthma
 Systemic: anaphylactic shock: associated with
allergens that have systemic distribution. Widespread
vasodilation, airway swelling

Atopy: the tendency to display Type I symptoms
to certain environmental antigens without prior
sensitization
Hypersensitivities: Types II & III

Subacute hypersensitivity (IgG & IgM mediated)
 Cytotoxic
reactions (Type II): antibodies bind to cellular
antigens promoting complement fixation / inflammation /
phagocytosis (transfusion reaction)
 Immune complex h. (Type III): widely distributed antigen
reacts with antibody.

Antigen-antibody complexes cannot be cleared; persistent
inflammation / tissue damage (farmer’s lung; associated with
autoimmune disorders)
Hypersensitivities: Type IV

Delayed hypersensitivity (cell mediated) takes
one to three days to react.
 Involves
TC, TH1 & macrophages.
 Allergic contact dermatitis (poison ivy, heavy metals,
TB tine tests).
 Agents act as haptens & elicit response after binding
to tissue
Developmental Aspects of the
Immune System



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Stem cells arise from embryologic liver & spleen
Self tolerance develops in Thymus (T-cells) &
bone marrow (B-cells)
Immunocompetence: the “library” of receptors is
genetically determined
Immune system degrades with aging
Immunocompetent B or T cells
Key:
Red
bone marrow
= Site of development of immunocompetence
as B or T cells; primary lymphoid organs
= Site of antigen challenge & final
differentiation to activated B & T cells
Immature
lymphocytes
Circulation in
blood
= Site of lymphocyte origin
1
1 Lymphocytes destined to become T
1
Thymus
Bone
marrow
cells migrate to the thymus & develop
immunocompetence there. B cells
develop immunocompetence in red
bone marrow.
2
Immunocompetent,
but still naive,
lymphocyte
migrates via blood
2
2 After leaving the thymus or bone
marrow as naive immunocompetent
cells, lymphocytes “seed” the lymph
nodes, spleen, & other lymphoid
tissues where the antigen challenge
occurs.
Lymph nodes,
spleen, & other
lymphoid tissues
3 Mature (antigen-activated)
3
Activated
immunocompetent
B & T cells
recirculate in blood
& lymph
3
immunocompetent lymphocytes
circulate continuously in the
bloodstream & lymph & throughout
the lymphoid organs of the body.
Figure 21.8
Primary & Secondary Humoral Responses
Figure 21.10
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