Chapter 21

The Immune System: Innate and Adaptive Body Defenses

Part A

Immunity: Two Intrinsic Defense Systems

• Innate (nonspecific) system responds quickly and consists of:

– First line of defense – intact skin and mucosae prevent entry of
microorganisms
– Second line of defense – antimicrobial proteins, phagocytes, and other
cells
• Inhibit spread of invaders throughout the body
• Inflammation is its hallmark and most important mechanism
• Adaptive (specific) defense system
– Third line of defense – mounts attack against particular foreign substances
• Takes longer to react than the innate system
• Works in conjunction with the innate system

Surface Barriers

• Skin, mucous membranes, and their secretions make up the first line of
defense
• Keratin in the skin:
– Presents a formidable physical barrier to most microorganisms
– Is resistant to weak acids and bases, bacterial enzymes, and toxins
• Mucosae provide similar mechanical barriers

Epithelial Chemical Barriers

• Epithelial membranes produce protective chemicals that destroy

microorganisms
– Skin acidity (pH of 3 to 5) inhibits bacterial growth
– Sebum contains chemicals toxic to bacteria
– Stomach mucosae secrete concentrated HCl and protein-digesting
enzymes
– Saliva and lacrimal fluid contain lysozyme
– Mucus traps microorganisms that enter the digestive and respiratory
systems

Respiratory Tract Mucosae

• Mucus-coated hairs in the nose trap inhaled particles

• Mucosa of the upper respiratory tract is ciliated
– Cilia sweep dust- and bacteria-laden mucus away from lower respiratory
passages

Internal Defenses: Cells and Chemicals

• The body uses nonspecific cellular and chemical devices to protect itself
– Phagocytes and natural killer (NK) cells
– Antimicrobial proteins in blood and tissue fluid
– Inflammatory response enlists macrophages, mast cells, WBCs, and
chemicals
• Harmful substances are identified by surface carbohydrates unique to
infectious organisms

Phagocytes

• Macrophages are the chief phagocytic cells

• Free macrophages wander throughout a region in search of cellular debris
• Kupffer cells (liver) and microglia (brain) are fixed macrophages
• Neutrophils become phagocytic when encountering infectious material
• Eosinophils are weakly phagocytic against parasitic worms
• Mast cells bind and ingest a wide range of bacteria

Mechanism of Phagocytosis

• Microbes adhere to the phagocyte

• Pseudopods engulf the particle (antigen) into a phagosome
• Phagosomes fuse with a lysosome to form a phagolysosome
• Invaders in the phagolysosome are digested by proteolytic enzymes
• Indigestible and residual material is removed by exocytosis
Natural Killer (NK) Cells

• Cells that can lyse and kill cancer cells and virus-infected cells
• Natural killer cells:
– Are a small, distinct group of large granular lymphocytes
– React nonspecifically and eliminate cancerous and virus-infected cells
– Kill their target cells by releasing perforins and other cytolytic chemicals
– Secrete potent chemicals that enhance the inflammatory response

Inflammation: Tissue Response to Injury

• The inflammatory response is triggered whenever body tissues are injured

– Prevents the spread of damaging agents to nearby tissues
– Disposes of cell debris and pathogens
– Sets the stage for repair processes
• The four cardinal signs of acute inflammation are redness, heat, swelling,
and pain

Inflammation Response

• Begins with a flood of inflammatory chemicals released into the

extracellular fluid
• Inflammatory mediators:
– Include kinins, prostaglandins (PGs), complement, and cytokines
– Are released by injured tissue, phagocytes, lymphocytes, and mast cells
– Cause local small blood vessels to dilate, resulting in hyperemia

Toll-like Receptors (TLRs)

• Macrophages and cells lining the gastrointestinal and respiratory tracts

bear TLRs
• TLRs recognize specific classes of infecting microbes
• Activated TLRs trigger the release of cytokines that promote inflammation

Inflammatory Response: Vascular Permeability

• Chemicals liberated by the inflammatory response increase the

permeability of local capillaries
• Exudate (fluid containing proteins, clotting factors, and antibodies):
– Seeps into tissue spaces causing local edema (swelling), which
contributes to the sensation of pain

Inflammatory Response: Edema

• The surge of protein-rich fluids into tissue spaces (edema):

– Helps to dilute harmful substances
– Brings in large quantities of oxygen and nutrients needed for repair
– Allows entry of clotting proteins, which prevents the spread of bacteria

Inflammatory Response: Phagocytic Mobilization

• Occurs in four main phases:

– Leukocytosis – neutrophils are released from the bone marrow in
response to leukocytosis-inducing factors released by injured cells
– Margination – neutrophils cling to the walls of capillaries in the injured area
– Diapedesis – neutrophils squeeze through capillary walls and begin
phagocytosis
– Chemotaxis – inflammatory chemicals attract neutrophils to the injury site

Antimicrobial Proteins

• Enhance the innate defenses by:

– Attacking microorganisms directly
– Hindering microorganisms’ ability to reproduce
• The most important antimicrobial proteins are:
– Interferon
– Complement proteins

Interferon (IFN)

• Genes that synthesize IFN are activated when a host cell is invaded by a
virus
• Interferon molecules leave the infected cell and enter neighboring cells
• Interferon stimulates the neighboring cells to activate genes for PKR (an
antiviral protein)
• PKR nonspecifically blocks viral reproduction in the neighboring cell

Interferon Family

• Interferons are a family of related proteins each with slightly different

physiological effects
• Lymphocytes secrete gamma () interferon, but most other WBCs secrete
alpha () interferon
• Fibroblasts secrete beta () interferon
• Interferons also activate macrophages and mobilize NKs
• FDA-approved alpha IFN is used:
– As an antiviral drug against hepatitis C virus
– To treat genital warts caused by the herpes virus

Complement

• 20 or so proteins that circulate in the blood in an inactive form

• Proteins include C1 through C9, factors B, D, and P, and regulatory
proteins
• Provides a major mechanism for destroying foreign substances in the
body
• Amplifies all aspects of the inflammatory response
• Kills bacteria and certain other cell types (our cells are immune to
complement)
• Enhances the effectiveness of both nonspecific and specific defenses

Complement Pathways

• Complement can be activated by two pathways: classical and alternative

• Classical pathway is linked to the immune system
– Depends on the binding of antibodies to invading organisms
– Subsequent binding of C1 to the antigen-antibody complexes
(complement fixation)
• Alternative pathway is triggered by interaction among factors B, D, and P,
and polysaccharide molecules present on microorganisms
• Each pathway involves a cascade in which complement proteins are
activated in an orderly sequence and where each step catalyzes the next
• Both pathways converge on C3, which cleaves into C3a and C3b
• C3b initiates formation of a membrane attack complex (MAC)
• MAC causes cell lysis by interfering with a cell’s ability to eject Ca2+
• C3b also causes opsonization, and C3a causes inflammation

C-reactive Protein (CRP)

• CRP is produced by the liver in response to inflammatory molecules

• CRP is a clinical marker used to assess for:
– The presence of an acute infection
– An inflammatory condition and its response to treatment

Functions of C-reactive Protein

• Binds to PC receptor of pathogens and exposed self-antigens

• Plays a surveillance role in targeting damaged cells for disposal
• Activates complement

Fever

• Abnormally high body temperature in response to invading

microorganisms
• The body’s thermostat is reset upwards in response to pyrogens,
chemicals secreted by leukocytes and macrophages exposed to bacteria and
other foreign substances
• High fevers are dangerous as they can denature enzymes
• Moderate fever can be beneficial, as it causes:
– The liver and spleen to sequester iron and zinc (needed by
microorganisms)
– An increase in the metabolic rate, which speeds up tissue repair

Adaptive (Specific) Defenses

• The adaptive immune system is a functional system that:

– Recognizes specific foreign substances
– Acts to immobilize, neutralize, or destroy foreign substances
– Amplifies inflammatory response and activates complement

Adaptive Immune Defenses

• The adaptive immune system is antigen-specific, systemic, and has

memory
• It has two separate but overlapping arms
– Humoral, or antibody-mediated immunity
– Cellular, or cell-mediated immunity
Antigens

• Substances that can mobilize the immune system and provoke an immune
response
• The ultimate targets of all immune responses are mostly large, complex
molecules not normally found in the body (nonself)

Complete Antigens

• Important functional properties:

– Immunogenicity – the ability to stimulate proliferation of specific
lymphocytes and antibody production
– Reactivity – the ability to react with the products of the activated
lymphocytes and the antibodies released in response to them
• Complete antigens include foreign protein, nucleic acid, some lipids, and
large polysaccharides

Haptens (Incomplete Antigens)

• Small molecules, such as peptides, nucleotides, and many hormones, that

are not immunogenic but are reactive when attached to protein carriers
• If they link up with the body’s proteins, the adaptive immune system may
recognize them as foreign and mount a harmful attack (allergy)
• Haptens are found in poison ivy, dander, some detergents, and cosmetics

Antigenic Determinants

• Only certain parts of an entire antigen are immunogenic

• Antibodies and activated lymphocytes bind to these antigenic
determinants
• Most naturally occurring antigens have numerous antigenic determinants
that:
– Mobilize several different lymphocyte populations
– Form different kinds of antibodies against it
• Large, chemically simple molecules (e.g., plastics) have little or no
immunogenicity

Self-Antigens: MHC Proteins

• Our cells are dotted with protein molecules (self-antigens) that are not
antigenic to us but are strongly antigenic to others
• One type of these, MHC proteins, mark a cell as self
• The two classes of MHC proteins are:
– Class I MHC proteins – found on virtually all body cells
– Class II MHC proteins – found on certain cells in the immune response

MHC Proteins

• Are coded for by genes of the major histocompatibility complex (MHC) and
are unique to an individual
• Each MHC molecule has a deep groove that displays a peptide, which is a
normal cellular product of protein recycling
• In infected cells, MHC proteins bind to fragments of foreign antigens,
which play a crucial role in mobilizing the immune system

Cells of the Adaptive Immune System

• Two types of lymphocytes

– B lymphocytes – oversee humoral immunity
– T lymphocytes – non-antibody-producing cells that constitute the cell-
mediated arm of immunity
• Antigen-presenting cells (APCs):
– Do not respond to specific antigens
– Play essential auxiliary roles in immunity

Lymphocytes
• Immature lymphocytes released from bone marrow are essentially
identical
• Whether a lymphocyte matures into a B cell or a T cell depends on where
in the body it becomes immunocompetent
– B cells mature in the bone marrow
– T cells mature in the thymus

T Cells

• T cells mature in the thymus under negative and positive selection

pressures
– Negative selection – eliminates T cells that are strongly anti-self
– Positive selection – selects T cells with a weak response to self-antigens,
which thus become both immunocompetent and self-tolerant

B Cells

• B cells become immunocompetent and self-tolerant in bone marrow

• Some self-reactive B cells are inactivated (anergy) while others are killed
• Other B cells undergo receptor editing in which there is a rearrangement
of their receptors

Immunocompetent B or T cells

• Display a unique type of receptor that responds to a distinct antigen

• Become immunocompetent before they encounter antigens they may later
attack
• Are exported to secondary lymphoid tissue where encounters with
antigens occur
• Mature into fully functional antigen-activated cells upon binding with their
recognized antigen
• It is genes, not antigens, that determine which foreign substances our
immune system will recognize and resist

Antigen-Presenting Cells (APCs)

• Major rolls in immunity are:

– To engulf foreign particles
– To present fragments of antigens on their own surfaces, to be recognized
by T cells
• Major APCs are dendritic cells (DCs), macrophages, and activated B cells
• The major initiators of adaptive immunity are DCs, which actively migrate
to the lymph nodes and secondary lymphoid organs and present antigens to T
and B cells

Macrophages and Dendritic Cells

• Secrete soluble proteins that activate T cells

• Activated T cells in turn release chemicals that:
– Rev up the maturation and mobilization of DCs
– Prod macrophages to become activated macrophages, which are
insatiable phagocytes that secrete bactericidal chemicals

Adaptive Immunity: Summary

• Two-fisted defensive system that uses lymphocytes, APCs, and specific

molecules to identify and destroy nonself particles
• Its response depends upon the ability of its cells to:
– Recognize foreign substances (antigens) by binding to them
– Communicate with one another so that the whole system mounts a
response specific to those antigens

Humoral Immunity Response

• Antigen challenge – first encounter between an antigen and a naive

immunocompetent cell
• Takes place in the spleen or other lymphoid organ
• If the lymphocyte is a B cell:
– The challenging antigen provokes a humoral immune response
• Antibodies are produced against the challenger

Clonal Selection

• Stimulated B cell growth forms clones bearing the same antigen-specific

receptors
• A naive, immunocompetent B cell is activated when antigens bind to its
surface receptors and cross-link adjacent receptors
• Antigen binding is followed by receptor-mediated endocytosis of the cross-
linked antigen-receptor complexes
• These activating events, plus T cell interactions, trigger clonal selection

Fate of the Clones

• Most clone cells become antibody-secreting plasma cells

• Plasma cells secrete specific antibody at the rate of 2000 molecules per
second
• Secreted antibodies:
– Bind to free antigens
– Mark the antigens for destruction by specific or nonspecific mechanisms
• Clones that do not become plasma cells become memory cells that can
mount an immediate response to subsequent exposures of the same antigen

Immunological Memory

• Primary immune response – cellular differentiation and proliferation, which

occurs on the first exposure to a specific antigen
– Lag period: 3 to 6 days after antigen challenge
– Peak levels of plasma antibody are achieved in 10 days
– Antibody levels then decline
• Secondary immune response – re-exposure to the same antigen
– Sensitized memory cells respond within hours
– Antibody levels peak in 2 to 3 days at much higher levels than in the
primary response
– Antibodies bind with greater affinity, and their levels in the blood can
remain high for weeks to months

Primary and Secondary Humoral Responses

Active Humoral Immunity

• B cells encounter antigens and produce antibodies against them

– Naturally acquired – response to a bacterial or viral infection
– Artificially acquired – response to a vaccine of dead or attenuated
pathogens
• Vaccines – spare us the symptoms of disease, and their weakened
antigens provide antigenic determinants that are immunogenic and reactive

Passive Humoral Immunity

• Differs from active immunity in the antibody source and the degree of
protection
– B cells are not challenged by antigens
– Immunological memory does not occur
– Protection ends when antigens naturally degrade in the body
• Naturally acquired – from the mother to her fetus via the placenta
• Artificially acquired – from the injection of serum, such as gamma globulin