Download Chapter 51

Chapter 51
The Immune
System
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Introduction
• Body’s defenses are integrated
• Innate
– Recognition of invading pathogens, anything that
looks “nonself”
– Rapid response
– Uses soluble antimicrobial proteins
• Adaptive immunity
– Characterized by genetic rearrangements that
generate a diverse set of molecules to recognize any
invader
– Slower response but highly specific
2
Why have an immune system?
– Come into contact with pathogens constantly
– Everyday!
– Organisms have innate immunity throughout Plant
Kingdom and Animal Kingdom
• Vertebrates exhibit features of adaptive
immune response
– This is beneficial to vertebrates – complex
multicellular organisms, some with long life
spans
Innate immunity
• Skin
• Largest organ of the body
• Provides a nearly impenetrable barrier
• Reinforced with chemical weapons
• Antimicrobial peptides
• Oil and sweat glands give skin a pH of 3–5
• Lysozyme breaks bacterial cell walls
• Also contains many normal flora
• Nonpathogenic microorganisms that out-compete
pathogenic ones
4
Innate immunity
• 3 other potential routes of infection
• Digestive, respiratory, and urogenital tracts
• All 3 lined by epithelial cells
• Cells secrete mucus which traps microbes
• Digestive tract
• Salivary lysozyme; acidic stomach
• Nonpathogenic normal flora
• Respiratory tract
• Ciliary action that pushes microbes away from lower
respiratory system
• Urogenital tract
• Acidic urine, normal flora
5
Innate immunity
• Recognizes molecular patterns
characteristic of invaders (microbes)
– Pathogen-associated molecular patterns
(PAMPs) or microbe-associated molecular
patterns (MAMPs)
• Examples – lipopolysaccharide of gram-negative
bacterial cells, peptidoglycan in bacterial cell walls,
viral DNA and RNA
– Recognized by pattern recognition receptors
(PRRs) that are either soluble or on the
surface of blood cells
6
Innate immunity
• Binding of a pathogen-associated molecule to
any of the innate immune-type receptors
activates signal transduction pathways that lead
to a rapid response against possible pathogen
• Secretion of molecules that signal to other innate cells or to
adaptive cells
• Production of molecules that aid in invader clearance
• Inflammatory response
• complement
7
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction
or display.
Innate immunity
• 3 kinds of defending leukocytes involved
• Macrophages
– Kill microorganisms through phagocytosis
– Monocytes mature into macrophages
• Neutrophils
– Most abundant circulating leukocyte
– Also use phagocytosis
• Natural killer cells
– Do not attack invading cells directly
– Induce apoptosis in target cell
– For instance, if cell is infected with virus, the natural killer cell will
eliminate that infected cell
8
Innate immunity
• Inflammatory response
– Inflammation involves several body systems
– Injured cells release chemical alarms, including histamine and
prostaglandins
– Cause nearby blood vessels to dilate and increase in
permeability
– This is important to bring leukocytes and lymphocytes to
area of injury where pathogens could have entered
– Promote phagocyte accumulation
– Hallmark signs:
– Redness
– Warmth
– swelling (edema)
– pain
10
Innate immunity
• Inflammation is accompanied by an acute
phase response
– One manifestation is fever
• Macrophages release interleukin-1
• Causes hypothalamus to raise body temperature
• Promotes activity of phagocytes, while impeding
microbial growth
• However, very high fevers are hazardous as they
may denature critical enzymes
12
Innate immunity
• Complement system
– Consists of about 30 different proteins that
circulate in the blood in an inactive form
• Becomes activated when invasion occurs
• Proteins aggregate to form a membrane attack
complex (MAC) on surface of pathogen
– Literally pokes holes in membrane of pathogen
– Pathogen swells and bursts
13
Adaptive immunity
• The scientific study of
immunity began with
Edward Jenner in 1796
• Observed that milkmaids
who had cowpox rarely
experienced smallpox
• Inoculated individuals with
fluid from cowpox vesicles
to protect them from
smallpox
• Vaccination
14
Adaptive immunity
• Characterized by
1. Specificity of recognition of antigen
•
Innate immune components recognize markers found
on a variety of “nonself” invaders, adaptive immune
components recognize specific markers
•
For instance, an antibody made by a B cell will
recognize only one epitope found on a particular
bacteria
2. Wide diversity of antigens can be specifically recognized
•
3.
4.
Gene rearrangement in production of antibodies and T cell receptors results in high diversity
Memory, whereby the immune system responds more quickly
to an antigen it encountered previously than one it is meeting
for the first time
Ability to distinguish self-antigens from nonself
15
Adaptive immunity
• An antigen is a molecule that provokes a
specific immune response
– May be components of microorganisms or
proteins/glycoproteins found on surface of red
blood cells or transplanted tissue cells
– A single antigen may many different antigenic
determinants or epitopes
• Each can stimulate a distinct immune
response
16
18
Adaptive immunity
• B lymphocytes or B cells
– Respond to antigens by secreting antibodies
or immunoglobulins (Ig)
– Participate in humoral immunity
• T lymphocytes or T cells
– Regulate other immune cells or directly attack
cells that carry specific antigens
– Participate in cell-mediated immunity
19
Adaptive immunity
• Every B cell produces antibodies that are
specific for a particular antigen and every T cell
produces T cell receptors that are also specific
• When a naive lymphocyte binds a specific
antigen for the first time, it gets activated by
a process called clonal selection
• Produces a clone of cells: some respond
immediately, others are memory cells
20
Adaptive immunity
• Immunity can be acquired in two ways
1. Active immunity results from activation of
an individual’s own lymphocytes
– Pathogen infection or vaccination
2. Passive immunity results from obtaining
another individual’s antibodies
– Transfer of maternal antibodies across
placenta
22
Adaptive immunity
• Organs of the immune system
• Primary lymphoid organs
• Bone marrow and thymus
• Secondary lymphoid organs
• Lymph nodes, spleen, and mucosal-associated lymphoid
tissue (MALT)
23
Adaptive immunity
• Primary Lymphoid Organs
– Bone marrow is site of B cell maturation
– Each B cell has immunoglobulin (Ig)
molecules on its membrane
•
•
•
•
Antibodies
All with the same specificity
All different from cell to cell
Secrete antibodies, also
– Any lymphocytes that are likely to bind to selfantigens undergo apoptosis
– They are “tested” in the bone marrow
25
Adaptive immunity
• Primary Lymphoid Organs
– Thymus is the site of T cell maturation
– Each T cell has T cell receptors (TCR) on its membrane
• All with same specificity
• All different from cell to cell
• Recognize epitopes only if they are combined with major
histocompatibility complex (MHC) peptides
– Lymphocytes that cannot bind MHCs, or that bind self-MHC/selfpeptide too tightly undergo apoptosis
• They are “tested” in thymus
• Killed if they don’t recognize MHC molecule, killed if they
recognize it but won’t let go
26
Adaptive immunity
• Secondary Lymphoid Organs
– Locations of these organs promote the
filtering of antigens that enter any part of an
individual’s body
– Mature but naive B and T cells become
activated in the lymph nodes
– Spleen is site of immune responses to
antigens found mainly in the blood
– Mucosal-associated lymphoid tissue (MALT)
include the tonsils and appendix
28
Cell-mediated immunity
• T lymphocytes are of two types
– Cytotoxic T cells (Tc)
• CD8+ cells
– Helper T cells (TH)
• CD4+ cells
• Distinguished by type of MHC markers
recognized and roles after activation
29
Cell-mediated immunity
• In humans, the MHC complex is also
termed human leukocyte antigens (HLAs)
– As individual as fingerprints
• Self versus nonself recognition
• MHC class I – found on all nucleated cells
– Recognized by Tc cells
• MHC class II – found only on antigenpresenting cells
– Recognized by TH cells
30
Cell-mediated immunity
• Cytotoxic T cells
– Recognize “altered-self” cells, particularly
those that are virally infected or tumor cells
– Example
• If a cell is infected with a virus, it will present some
of the viral antigen on its Class I MHC (which are
found on all cells)
• T cell receptor on cytotoxic T cell recognizes
antigen + MHC, binds, and will eventually lead to
apoptosis of infected cell
– Clonal expansion and differentiation into
activated cells and memory cells
31
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Virus
Dendritic cell
MHC class I
Viral peptide
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
TCR specific for this
MHC–peptide complex
Cytokines
CD8
Cytokines
Naive cytotoxic T cell
Clonal
expansion
Memory cytotoxic T cells Activated cytotoxic T cells
a.
2500×
b.
2500×
a-b: © Dr.Andrejs Liepins/Photo Researchers, Inc.
Destroys
altered cell
Cytotoxic T cells induce apoptosis
of “altered-self” cells. And destroy
tumors
Persists after
alter ed cells
are destroyed
Infected cell
Apoptosis of infected cell
32
Cell-mediated immunity
• Helper T cells
– Secrete cytokines that promote activation or
differentiation of immune system cells
– TH cells respond to exogenous antigen that is
taken up by an antigen presenting cell
• Example:
– Antigen presenting cell engulfs bacteria, breaks it up,
and presents pieces of antigen on its Class II MHC
– T cell receptor on helper T cell recognizes antigen +
MHC, binds, then secretes molecules to activate more
cells in the vicinity to help with infection
– Activated TH cells give rise to effector cells
and memory cells
33
Humoral immunity
• Involves antibodies
• Begins when naive B cells in secondary lymph
organs meet antigens
• B cells are activated when their surface Igs bind
to a specific epitope on an antigen
– TH cytokines may also be required
• Activation results in clonal expansion and
differentiation into plasma and memory cells
• Plasma cells produce soluble antibodies against
the same epitope
34
Humoral immunity
• Antibody consists of
– Two identical short polypeptides – light chains
– Two identical longer polypeptides – heavy
chains
• Four chains are held by disulfide bonds,
forming a Y-shaped molecule
– Fab regions = Two “arms”
– Fc region = “Stem”
35
Humoral immunity
• Each chain has
– Variable region
• Amino acid sequence differs between Igs
• Form antigen-binding site
• Can bind 2 identical epitopes
– form antigen–antibody complexes
– Constant region
• 5 heavy-chain constant regions
• 5 classes of immunoglobulins
– IgM, IgD, IgG, IgA, and IgE
37
39
Humoral immunity
• Human B cells can generate antibodies with over 1010
different antigen-binding sites
• Diversity is generated through a process called DNA
rearrangement
• An Ig protein is encoded by different segments of
DNA
• V (variable), D (diversity), J (joining)
– Which V, which D, and which J are chosen by
any cell appears to be completely random
40
T-Cell Receptors (TCRs)
• Have immunoglobulin domains similar to
antibodies
• TCR diversity is also caused by DNA
rearrangements
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction
or display.
α chain
β chain
Variable region
Immunoglobulin
domains
Constant region
42
Immune Responses
• The first encounter with a foreign antigen is
called the primary immune response
– Only few B or T cells can recognize antigen and
mount response
• Clonal expansion of these B and T cells occur – memory
cells
• Second encounter is called the secondary
immune response
– This time there is a large clone of memory cells that
can recognize the antigen
– Immune response is faster and more effective
43
Autoimmunity
• Immunological tolerance
– Acceptance of self cells
• Autoimmune diseases are caused by the failure
of immune tolerance
• Result in activation of autoreactive T cells, and
production of autoantibodies by B cells
• Cause inflammation and organ damage
• Can be alleviated by corticosteroids and NSAIDs, including
aspirin
45
Allergy
• Refers to a greatly heightened response to
a foreign antigen, or allergen
• Most common type is known as immediate
hypersensitivity
– Results from excessive IgE production
– Seasonal hay fever
– Systemic anaphylaxis – severe and lifethreatening
46
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Initial Exposure
Allergen
Allergen
B cell
Dendritic cell
Memory B cell
Helper T cell
Receptor for IgE
Allergenspecific IgE
Helper T cell
Mast cell
Cytokines (IL-4)
Plasma cell
Subsequent Exposure
Sequence of an
allergic response
Allergen
Histamine and
other mediators
of inflammation
are released
47
Allergy
• Delayed-type hypersensitivity produces
symptoms within about 48 hours of a
second exposure to an allergen
– Mediated by TH cells and macrophages
– Contact dermatitis
• Caused by varied materials, such as poison
ivy, nickel in jewelry, and cosmetics
48
Antibodies in Medicine
• Blood type
– Determined by antigens found on surface of
red blood cells
• ABO blood types – Types A, B, AB, and O
• Rh factor – Rh positive and Rh negative
– Immune system is tolerant of its own RBC
antigens, but makes antibodies that bind to
those that differ (agglutination)
• For example, people with type A blood make
antibodies against the B antigen
49
Antibodies in Medicine
• In blood transfusions, the antigens of the
donor have to be matched to the
antibodies of the recipient
– For instance, a type A person cannot donate
to a type B or type O
– These would have anti-A antibodies
– Blood is typed by agglutination reactions,
using circulating IgM antibodies
50
Monoclonal Antibodies
• Monoclonal antibodies exhibit specificity
for one epitope only
• Animal is immunized with antigen then killed
• B cells are obtained from animal’s spleen
• Fused with a myeloma cell – a B-cell tumor that no
longer produces Igs but will live indefinitely in culture
• A clonal hybrid or hybridoma
• Divides indefinitely and produces monoclonal
antibodies
51
Monoclonal Antibodies
• Availability of large quantities of pure
monoclonal antibodies has allowed the
development of very sensitive clinical tests
• Some pregnancy tests use a monoclonal
antibody against the hormone human
chorionic gonadotropin (hCG)
• Monoclonal antibodies against CD4, a TH
marker, are used to monitor AIDS
53
Evading the Immune System
• Some pathogens can alter their surface antigens
to avoid immune system detection
• Influenza virus expresses 2 surface proteins:
hemaglutinin (HA) and neuraminidase (NA)
– Antigenic drift – point mutations to the HA and NA
genes
– Antigenic shift – sudden appearance of a new virus
subtype where HA and/or NA proteins are completely
different
54
Evading the Immune System
• Salmonella typhimurium
– Can alternate between expression of two
different flagellar proteins
• Mycobacterium tuberculosis
– Once phagocytosed, inhibits fusion of the
phagosome with lysosomes
• Neisseria gonorrhoeae
– Secrete proteases that degrade IgA
antibodies
55
Evading the Immune System
• HIV – human immunodeficiency virus
– Mounts a direct attack on TH cells
– Binds to CD4 proteins and is endocytosed
– An individual is considered to have AIDS
when their TH cell level has dropped
significantly
– Immunosuppression results in an increase in
opportunistic infections and cancers
56
Vaccination
– Point of vaccination is to induce primary response without
causing disease. Therefore, when individual comes across the
pathogen, a secondary response either prevents disease or
lessens effects of disease
– We “vaccinate” ourselves everyday when we come into
contact with microbes on hands, food, etc.
– For some diseases that are very
contagious/deadly/disabling, vaccines have been
developed to go ahead and induce primary response
– Ways to modify pathogens for vaccination:
• Inactivation by heat or chemicals
• Attenuation of virulence by inducing mutations
– Pathogen will grow in individual but not cause disease
• Recombinant DNA technology
• Immunization with antigenic portions of pathogen can result
in immunity
• Vaccination
• Vaccination prevents disease
• Herd immunity
• Some are choosing to not vaccinate children
• Fear of re-emergence of diseases that were disabling
and/or deadly
• LOTS of misinformation about vaccines in the media
causing people to be overly scared of vaccination
• Vaccines Do NOT cause autism; unfortunately, probably
our overexposure in today’s age to an insane amount of
different contaminants could be contributing to autism
spectrum
• It is difficult/timely/costly to develop vaccines
• Have to find right epitope, delivery method, etc in
order to produce effective vaccine that is capable of
inducing secondary response
• That’s why we don’t have vaccines to all diseases – still
more research to be done!