Download Defense Lecture Study ppt. part 2 File

Defense Lec Study 2
For Bio 260
Compiled and adapted from Marieb
A&P 8th Edition
Antibodies
• Immunoglobulins—gamma globulin portion of
blood
• Proteins secreted by plasma cells
• Capable of binding specifically with antigen
detected by B cells
Basic Antibody Structure
• T-or Y-shaped monomer of four looping linked
polypeptide chains
• Two identical heavy (H) chains and two
identical light (L) chains
• Variable (V) regions of each arm combine to
form two identical antigen-binding sites
Basic Antibody Structure
• Constant (C) region of stem determines
– The antibody class (IgM, IgA, IgD, IgG, or IgE)
– The cells and chemicals that the antibody can bind
to
– How the antibody class functions in antigen
elimination
Antigen-binding
site
Heavy chain
variable region
Heavy chain
constant region
Light chain
variable region
Light chain
constant region
Disulfide bond
Hinge
region
Stem
region
(a)
Figure 21.14a
Classes of Antibodies
• IgM
– A pentamer; first antibody released
– Potent agglutinating agent
– Readily fixes and activates complement
• IgA (secretory IgA)
– Monomer or dimer; in mucus and other
secretions
– Helps prevent entry of pathogens
Table 21.3
Classes of Antibodies
• IgD
– Monomer attached to the surface of B cells
– Functions as a B cell receptor
• IgG
– Monomer; 75–85% of antibodies in plasma
– From secondary and late primary responses
– Crosses the placental barrier
Classes of Antibodies
• IgE
– Monomer active in some allergies and parasitic
infections
– Causes mast cells and basophils to release
histamine
Table 21.3
Generating Antibody Diversity
• Billions of antibodies result from somatic
recombination of gene segments
• Hypervariable regions of some genes increase
antibody variation through somatic mutations
• Each plasma cell can switch the type of H
chain produced, making an antibody of a
different class
Antibody Targets
• Antibodies inactivate and tag antigens
– Form antigen-antibody (immune) complexes
• Defensive mechanisms used by antibodies
– Neutralization and agglutination (the two most
important)
– Precipitation and complement fixation
Neutralization
• Simplest mechanism
• Antibodies block specific sites on viruses or
bacterial exotoxins
• Prevent these antigens from binding to
receptors on tissue cells
• Antigen-antibody complexes undergo
phagocytosis
Agglutination
• Antibodies bind the same determinant on
more than one cell-bound antigen
• Cross-linked antigen-antibody complexes
agglutinate
– Example: clumping of mismatched blood cells
Precipitation
• Soluble molecules are cross-linked
• Complexes precipitate and are subject to
phagocytosis
Complement Fixation and Activation
• Main antibody defense against cellular
antigens
• Several antibodies bind close together on a
cellular antigen
• Their complement-binding sites trigger
complement fixation into the cell’s surface
• Complement triggers cell lysis
Complement Fixation and Activation
• Activated complement functions
– Amplifies the inflammatory response
– Opsonization
– Enlists more and more defensive elements
Adaptive defenses
Humoral immunity
Antigen
Antigen-antibody
complex
Antibody
Inactivates by
Neutralization
(masks dangerous
parts of bacterial
exotoxins; viruses)
Agglutination
(cell-bound antigens)
Enhances
Phagocytosis
Fixes and activates
Precipitation
(soluble antigens)
Enhances
Complement
Leads to
Inflammation
Cell lysis
Chemotaxis
Histamine
release
Figure 21.15
Monoclonal Antibodies
• Commercially prepared pure antibody
• Produced by hybridomas
– Cell hybrids: fusion of a tumor cell and a B cell
• Proliferate indefinitely and have the ability to
produce a single type of antibody
• Used in research, clinical testing, and cancer
treatment
Cell-Mediated Immune Response
• T cells provide defense against intracellular
antigens
– Two types of surface receptors of T cells
• T cell antigen receptors
• Cell differentiation glycoproteins
– CD4 or CD8
– Play a role in T cell interactions with other cells
Cell-Mediated Immune Response
• Major types of T cells
– CD4 cells become helper T cells (TH) when
activated
– CD8 cells become cytotoxic T cells (TC) that
destroy cells harboring foreign antigens
• Other types of T cells
– Regulatory T cells (TREG)
– Memory T cells
Adaptive defenses
Cellular immunity
Immature
lymphocyte
Red bone marrow
T cell
receptor
Class II MHC
protein
T cell
receptor
Maturation
CD4
cell
Thymus
Activation
APC
(dendritic cell)
Activation
Memory
cells
CD4
Class I MHC
protein
CD8
cell
APC
(dendritic cell)
CD8
Lymphoid
tissues and
organs
Helper T cells
(or regulatory T cells)
Effector
cells
Blood plasma
Cytotoxic T cells
Figure 21.16
Comparison of Humoral and CellMediated Response
• Antibodies of the humoral response
– The simplest ammunition of the immune response
• Targets
– Bacteria and molecules in extracellular
environments (body secretions, tissue fluid, blood,
and lymph)
Comparison of Humoral and CellMediated Response
• T cells of the cell-mediated response
– Recognize and respond only to processed
fragments of antigen displayed on the surface of
body cells
• Targets
– Body cells infected by viruses or bacteria
– Abnormal or cancerous cells
– Cells of infused or transplanted foreign tissue
Antigen Recognition
• Immunocompetent T cells are activated when
their surface receptors bind to a recognized
antigen (nonself)
• T cells must simultaneously recognize
– Nonself (the antigen)
– Self (an MHC protein of a body cell)
MHC Proteins
• Two types of MHC proteins are important to T
cell activation
– Class I MHC proteins - displayed by all cells except
RBCs
– Class II MHC proteins – displayed by APCs
(dendritic cells, macrophages and B cells)
• Both types are synthesized at the ER and bind
to peptide fragments
Class I MHC Proteins
• Bind with fragment of a protein synthesized in
the cell (endogenous antigen)
• Endogenous antigen is a self-antigen in a
normal cell; a nonself antigen in an infected or
abnormal cell
• Informs cytotoxic T cells of the presence of
microorganisms hiding in cells (cytotoxic T
cells ignore displayed self-antigens)
Cytoplasm of any tissue cell
2 Endogenous antigen
1 Endogenous
peptides enter ER via
antigen is degraded
transport protein.
by protease.
Endogenous antigen—
self-protein or foreign
(viral or cancer) protein
Cisternae of
endoplasmic
reticulum (ER)
3 Endogenous
antigen peptide is
loaded onto class
I MHC protein.
4 Loaded MHC protein
migrates in vesicle to
the plasma membrane,
where it displays the
antigenic peptide.
Transport
protein
(ATPase)
Plasma membrane of a tissue cell
Antigenic peptide
Extracellular fluid
(a) Endogenous antigens are processed and displayed on class I MHC of all cells.
Figure 21.17a
Class II MHC Proteins
• Bind with fragments of exogenous antigens
that have been engulfed and broken down in a
phagolysosome
• Recognized by helper T cells
T Cell Activation
•
•
APCs (most often a dendritic cell) migrate to
lymph nodes and other lymphoid tissues to
present their antigens to T cells
T cell activation is a two-step process
1. Antigen binding
2. Co-stimulation
T Cell Activation: Antigen Binding
• CD4 and CD8 cells bind to different classes of
MHC proteins (MHC restriction)
• CD4 cells bind to antigen linked to class II MHC
proteins of APCs
• CD8 cells are activated by antigen fragments
linked to class I MHC of APCs
T Cell Activation: Antigen Binding
• Dendritic cells are able to obtain other cells’
endogenous antigens by
– Engulfing dying virus-infected or tumor cells
– Importing antigens through temporary gap
junctions with infected cells
• Dendritic cells then display the endogenous
antigens on both class I and class II MHCs
T Cell Activation: Antigen Binding
• TCR that recognizes the nonself-self complex
is linked to multiple intracellular signaling
pathways
• Other T cell surface proteins are involved in
antigen binding (e.g., CD4 and CD8 help
maintain coupling during antigen recognition)
• Antigen binding stimulates the T cell, but costimulation is required before proliferation can
occur
Adaptive defenses
Cellular immunity
1 Dendritic cell
Viral antigen
Dendritic
cell
T cell receptor
(TCR)
Clone
formation
Class lI MHC
protein
displaying
processed
viral antigen
CD4 protein
engulfs an
exogenous antigen,
processes it, and
displays its
fragments on class
II MHC protein.
2 Immunocompetent
CD4 cell recognizes
antigen-MHC
complex. Both TCR
and CD4 protein bind
Immunocom- to antigen-MHC
complex.
petent CD4
T cell
3 CD4 cells are
activated,
proliferate (clone),
and become memory
and effector cells.
Helper T
memory cell
Activated
helper
T cells
Figure 21.18
T Cell Activation: Co-Stimulation
• Requires T cell binding to other surface receptors on an
APC
– Dendritic cells and macrophages produce surface B7
proteins when innate defenses are mobilized
– B7 binding with a CD28 receptor on a T cell is a crucial costimulatory signal
• Cytokines (interleukin 1 and 2 from APCs or T cells)
trigger proliferation and differentiation of activated T cell
T Cell Activation: Co-Stimulation
• Without co-stimulation, anergy occurs
– T cells
• Become tolerant to that antigen
• Are unable to divide
• Do not secrete cytokines
T Cell Activation: Co-Stimulation
• T cells that are activated
– Enlarge, proliferate, and form clones
– Differentiate and perform functions according to
their T cell class
T Cell Activation: Co-Stimulation
• Primary T cell response peaks within a week
• T cell apoptosis occurs between days 7 and 30
• Effector activity wanes as the amount of
antigen declines
• Benefit of apoptosis: activated T cells are a
hazard
• Memory T cells remain and mediate
secondary responses
Cytokines
• Mediate cell development, differentiation, and
responses in the immune system
• Include interleukins and interferons
• Interleukin 1 (IL-1) released by macrophages
co-stimulates bound T cells to
– Release interleukin 2 (IL-2)
– Synthesize more IL-2 receptors
Cytokines
• IL-2 is a key growth factor, acting on cells that
release it and other T cells
– Encourages activated T cells to divide rapidly
– Used therapeutically to treat melanoma and
kidney cancers
• Other cytokines amplify and regulate innate
and adaptive responses
Roles of Helper T(TH) Cells
• Play a central role in the adaptive immune response
• Once primed by APC presentation of antigen, they
– Help activate T and B cells
– Induce T and B cell proliferation
– Activate macrophages and recruit other immune cells
• Without TH, there is no immune response
Helper T Cells
• Interact directly with B cells displaying antigen
fragments bound to MHC II receptors
• Stimulate B cells to divide more rapidly and
begin antibody formation
• B cells may be activated without TH cells by
binding to T cell–independent antigens
• Most antigens require TH co-stimulation to
activate B cells
TH cell help in humoral immunity
Activated helper
T cell
1 TH cell binds with the
Helper T cell
CD4 protein
self-nonself complexes of a
B cell that has encountered
its antigen and is displaying
it on MHC II on its surface.
MHC II protein
of B cell displaying
processed antigen
2 TH cell releases
T cell receptor (TCR)
IL- 4 and other
cytokines
interleukins as
co-stimulatory signals to
complete B cell activation.
B cell (being activated)
(a)
Figure 21.19a
Helper T Cells
• Cause dendritic cells to express co-stimulatory
molecules required for CD8 cell activation
TH cell help in cell-mediated immunity
CD4 protein
Helper T cell
1 Previously
activated TH cell
binds dendritic cell.
Class II MHC
protein
APC (dendritic cell)
2 TH cell stimulates
IL-2
dendritic cell to express
co-stimulatory
molecules (not shown)
needed to activate CD8
cell.
3 Dendritic cell can
Class I
MHC protein
(b)
CD8
protein
CD8 T cell
now activate CD8 cell
with the help of
interleukin 2 secreted
by TH cell.
Figure 21.19b
Roles of Cytotoxic T(TC) Cells
• Directly attack and kill other cells
• Activated TC cells circulate in blood and lymph
and lymphoid organs in search of body cells
displaying antigen they recognize
Roles of Cytotoxic T(TC) Cells
• Targets
– Virus-infected cells
– Cells with intracellular bacteria or parasites
– Cancer cells
– Foreign cells (transfusions or transplants)
Cytotoxic T Cells
• Bind to a self-nonself complex
• Can destroy all infected or abnormal cells
Cytotoxic T Cells
• Lethal hit
– Tc cell releases perforins and granzymes by
exocytosis
– Perforins create pores through which granzymes
enter the target cell
– Granzymes stimulate apoptosis
• In some cases, TC cell binds with a Fas
receptor on the target cell, and stimulates
apoptosis
Adaptive defenses
Cytotoxic
T cell (TC)
Cellular immunity
1 TC binds tightly to
the target cell when it
identifies foreign antigen
on MHC I proteins.
granzyme molecules from its
granules by exocytosis.
Granule
Perforin
TC cell
membrane
Target
cell
membrane
Target
cell
2 TC releases perforin and
Perforin
pore
Granzymes
5 The TC detaches and
3 Perforin molecules
insert into the target
cell membrane,
polymerize, and form
transmembrane pores
(cylindrical holes)
similar to those
produced by
complement
activation.
4 Granzymes enter the
target cell via the pores.
Once inside, these
proteases degrade
cellular contents,
stimulating apoptosis.
searches for another prey.
(a) A mechanism of target cell killing by TC cells.
Figure 21.20a
Natural Killer Cells
• Recognize other signs of abnormality
– Lack of class I MHC
– Antibody coating a target cell
– Different surface marker on stressed cells
• Use the same key mechanisms as Tc cells for
killing their target cells
Regulatory T (TReg) Cells
• Dampen the immune response by direct
contact or by inhibitory cytokines
• Important in preventing autoimmune
reactions
Cell-mediated
immunity
Antigen (Ag) intruder
Humoral
immunity
Inhibits
Inhibits
Triggers
Adaptive defenses
Innate defenses
Surface Internal
barriers defenses
Ag-infected
body cell engulfed
by dendritic cell
Becomes
Ag-presenting cell
(APC) presents
self-Ag complex
Activates
Free Ags
may directly
activate B cell
Antigenactivated
B cells
Clone and
give rise to
Activates
Naïve
Naïve
CD8
CD4
T cells
T cells
Activated to clone
Activated to clone
and give rise to Induce and give rise to
co-stimulation
Memory
cytotoxic T cells
Activated
cytotoxic
T cells
Memory
helper T cells
Activated
helper
T cells
Memory
B cells
Plasma cells
(effector B cells)
Secrete
Cytokines stimulate
Together the nonspecific killers
and cytotoxic T cells mount a
physical attack on the Ag
Nonspecific killers
(macrophages and
NK cells of innate
immunity)
Antibodies (Igs)
Circulating lgs along with
complement mount a chemical
attack on the Ag
Figure 21.21
Organ Transplants
• Four varieties
– Autografts: from one body site to another in the
same person
– Isografts: between identical twins
– Allografts: between individuals who are not
identical twins
– Xenografts: from another animal species
Prevention of Rejection
• Depends on the similarity of the tissues
• Patient is treated with immunosuppressive
therapy
– Corticosteroid drugs to suppress inflammation
– Antiproliferative drugs
– Immunosuppressant drugs
• Many of these have severe side effects
Immunodeficiencies
• Congenital and acquired conditions that cause
immune cells, phagocytes, or complement to
behave abnormally
Severe Combined
Immunodeficiency (SCID)
Syndrome
Genetic defect
•
• Marked deficit in B and T cells
• Abnormalities in interleukin receptors
• Defective adenosine deaminase (ADA) enzyme
– Metabolites lethal to T cells accumulate
• SCID is fatal if untreated; treatment is with
bone marrow transplants
Hodgkin’s Disease
• An acquired immunodeficiency
• Cancer of the B cells
• Leads to immunodeficiency by depressing
lymph node cells
Acquired Immune Deficiency
Syndrome (AIDS)
• Cripples the immune system by interfering
with the activity of helper T cells
• Characterized by severe weight loss, night
sweats, and swollen lymph nodes
• Opportunistic infections occur, including
pneumocystis pneumonia and Kaposi’s
sarcoma
Acquired Immune Deficiency
Syndrome (AIDS)
• Caused by human immunodeficiency virus (HIV)
transmitted via body fluids—blood, semen, and vaginal
secretions
• HIV enters the body via
– Blood transfusions
– Blood-contaminated needles
– Sexual intercourse and oral sex
• HIV
– Destroys TH cells
– Depresses cell-mediated immunity
Acquired Immune Deficiency
Syndrome (AIDS)
• HIV multiplies in lymph nodes throughout the
asymptomatic period
• Symptoms appear in a few months to 10 years
• HIV-coated glycoprotein complex attaches to the CD4
receptor
• HIV enters the cell and uses reverse transcriptase to
produce DNA from viral RNA
• The DNA copy (a provirus) directs the host cell to make
viral RNA and proteins, enabling the virus to reproduce
Acquired Immune Deficiency
Syndrome (AIDS)
• HIV reverse transcriptase produces frequent
transcription errors; high mutation rate and
resistance to drugs
• Treatment with antiviral drugs
• Reverse transcriptase inhibitors (AZT)
– Protease inhibitors (saquinavir and ritonavir)
– New Fusion inhibitors that block HIV’s entry to
helper T cells
Autoimmune Diseases
• Immune system loses the ability to distinguish
self from foreign
• Production of autoantibodies and sensitized
TC cells that destroy body tissues
• Examples include multiple sclerosis,
myasthenia gravis, Graves’ disease, type I
diabetes mellitus, systemic lupus
erythematosus (SLE), glomerulonephritis, and
rheumatoid arthritis
Mechanisms of Autoimmune
Diseases
1. Foreign antigens may resemble self-antigens
–
Antibodies against the foreign antigen may cross-react
with self-antigen
2. New self-antigens may appear, generated by
–
–
Gene mutations
Changes in self-antigens by hapten attachment or as a
result of infectious damage
Mechanisms of Autoimmune
Diseases
3. Release of novel self-antigens by trauma of a
barrier (e.g., the blood-brain barrier)
Hypersensitivities
• Immune responses to a perceived (otherwise harmless)
threat
• Causes tissue damage
• Different types are distinguished by
– Their time course
– Whether antibodies or T cells are involved
• Antibodies cause immediate and subacute
hypersensitivities
• T cells cause delayed hypersensitivity
Immediate Hypersensitivity
• Acute (type I) hypersensitivities (allergies)
begin in seconds after contact with allergen
• Initial contact is asymptomatic but sensitizes
the person
• Reaction may be local or systemic
Immediate Hypersensitivity
• The mechanism involves IL-4 secreted by T
cells
• IL-4 stimulates B cells to produce IgE
• IgE binds to mast cells and basophils, resulting
in a flood of histamine release and inducing
the inflammatory response
Anaphylactic Shock
• Systemic response to allergen that directly enters the
blood
• Basophils and mast cells are enlisted throughout the
body
• Systemic histamine releases may cause
– Constriction of bronchioles
– Sudden vasodilation and fluid loss from the bloodstream
– Hypotensive shock and death
• Treatment: epinephrine
Subacute Hypersensitivities
• Caused by IgM and IgG transferred via blood plasma or
serum
• Slow onset (1–3 hours) and long duration (10–15 hours)
• Cytotoxic (type II) reactions
– Antibodies bind to antigens on specific body cells,
stimulating phagocytosis and complement-mediated lysis
of the cellular antigens
– Example: mismatched blood transfusion reaction
Subacute Hypersensitivities
• Immune complex (type III) hypersensitivity
– Antigens are widely distributed through the body
or blood
– Insoluble antigen-antibody complexes form
– Complexes cannot be cleared from a particular
area of the body
– Intense inflammation, local cell lysis, and death
may result
– Example: systemic lupus erythematosus (SLE)
Delayed Hypersensitivities (Type
IV)
• Slow onset (one to three days)
• Mechanism depends on helper T cells
• Cytokine-activated macrophages and cytotoxic
T cells cause damage
• Example: allergic contact dermatitis (e.g.,
poison ivy)
Developmental Aspects
• Immune system stem cells develop in the liver
and spleen by the ninth week
• Bone marrow becomes the primary source of
stem cells
• Lymphocyte development continues in the
bone marrow and thymus
Developmental Aspects
• TH2 lymphocytes predominate in the
newborn, and the TH1 system is educated as
the person encounters antigens
• The immune system is impaired by stress and
depression
• With age, the immune system begins to wane,
and incidence of cancer increases