This document provides an overview of specific immunity and the adaptive immune response. It discusses the third line of defense provided by adaptive immunity and the roles of B cells, T cells, antigens, and antibodies. The four main stages of the specific immune response are described: lymphocyte development, antigen presentation, challenge of lymphocytes by antigens, and the T cell and B cell responses. Key concepts like antigen processing, MHC presentation, and the structures of antibodies are also summarized.

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Chapter 13
Lecture

2. Learning Outcomes Section 13.1
• Describe how the third line of defense is
different from the other two.
• Compare the terms antigen, immunogen, and
epitope.
• List the four stages of a specific immune
response.
• Discuss the role of cell markers in the
immune response.
• Describe the major histocompatibility
complex in two sentences.

3. Specific Immunity: The Third
and Final Line of Defense
• Adaptive immunity acquired only after an
immunizing event such as an infection
• B and T lymphocytes undergo a selective
process that prepares them for reacting
only to one specific antigen or immunogen
• Immunocompetence: the ability of the
body to react with countless foreign
substances

4. Specific Immunity (cont’d)
• Antigens or immunogens: molecules that
stimulate a response by B and T cells
- Protein or polysaccharide molecules on or
inside cells and viruses
- Any exposed or released protein or
polysaccharide is potentially an antigen
- Foreign molecules that stimulate an immune
response
- Unlike PAMPs, antigens are highly individual
and stimulate specific immunity.

5. Specific Immunity (cont’d)
• Two features that characterize the specific
immune response are specificity and
memory:
- Antibodies produced against the chickenpox
virus will not function against the measles
virus.
- Lymphocytes have been programmed to
“recall” their first engagement with an antigen
and rush to the attack once again.

6. Specific Immunity (cont’d)
• Principal stages of immunologic
development and interaction:
- Lymphocyte development and differentiation
- Presentation of antigens
- Challenge of B and T cells by antigens
- T-lymphocyte response: cell-mediated
immunity
- B-lymphocyte response: production and
activities of antibodies

7. A Brief Overview of the Immune
Response: Lymphocyte Development
• All lymphocytes arise from the same basic
stem cell type.
• B cells mature in specialized bone marrow
sites.
• T cells mature in the thymus.
• Both cell types migrate to separate areas of
lymphoid organs.
• B and T cells constantly recirculate through
the circulatory system and lymphatics,
migrating into and out of the lymphoid
organs.

9. Entrance and Presentation of Antigens
and Clonal Selection
• When pathogens carrying antigens cross
the first line of defense:
- Resident macrophages migrate to the site.
- Tissue macrophages ingest the pathogen and
initiate an inflammatory response.
- Dendritic cells ingest the pathogen and
process it to present it to T and B
lymphocytes.
- Gamma-delta cells can be activated by
PAMPs.

10. The Role of Markers and Receptors
in Presentation and Activation
• All cells have a variety of different markers
on their surfaces for:
–Detection
–Recognition
–Cell communication
• These markers play an important role in
activating different components of the
immune system.

11. The Major Histocompatibility
Complex (MHC)
• One set of genes that codes for human
cell markers or receptors:
– Found on all cells except red blood cells
– Also known as the Human Leukocyte Antigen
(HLA) system
– These markers play a vital role in recognition
of self by the immune system and in rejection
of foreign tissue.

12. The Major Histocompatibility
Complex (cont’d)
• Three classes of MHC genes have been
identified:
– Class I genes: code for markers that appear on
all nucleated cells, display unique characteristics
of self, allow for recognition of immune reactions
– Class II genes: also code for immune regulatory
markers found on macrophages, dendritic cells,
and B cells, and are involved in presentation of
antigens to T cells
– Class III genes: encode proteins involved with
the complement system

14. CD Molecules
• CD: “Cluster of Differentiation”
– Over 300 CD molecules have been named
– Many are involved in the immune response
• Most important CDs
– CD3
– CD4
– CD8

15. Lymphocyte Receptors
• Major role is to “accept” or “grasp”
antigens in some form:
– B cells have receptors that bind antigens.
– T cells have receptors that bind antigens that
have been processed and complexed with
MHC molecules on the presenting cell
surface.
– Receptors have the capacity to respond to a
nearly infinite number of unique antigens.

16. Challenging B and T Cells
with Antigen
• When challenged with antigen, both B and
T cells proliferate and differentiate:
– A clone, or group of genetically identical cells,
are created.
– Some clones are memory cells that will
ensure the future reactivity to a specific
antigen.
– B and T cell responses differ.

17. How T Cells Respond to Antigen:
Cell-Mediated Immunity (CMI)
• The three functional types of T cells are as
follows:
- Helper T cells: activate macrophages, assist
B-cell processes, and help activate cytotoxic T
cells
- Regulatory T cells: control the T-cell
response
- Cytotoxic T cells: lead to the destruction of
infected host cells and other “foreign” cells
• T cells secrete cytokines to help destroy
pathogens, but they do not produce
antibodies.

18. How B Cells Respond to Antigen:
Release of Antibodies
• When activated, B cells divide and give
rise to plasma cells.
• Plasma cells release antibodies into the
tissue and the blood.
• Antibodies attach to the antigen for which
they are specific, and the antigen is
marked for destruction or neutralization.

19. Concept Check
B cells mature in the ________ and T
cells mature in the _______. Both cell
types then migrate to the ________ and
________.
A. spleen, lymph nodes; bone marrow, thymus
B. thymus, bone marrow; tonsils, GALT
C. GALT, tonsils; Peyer’s patches, lymph vessels
D. bone marrow, thymus; lymph nodes, spleen
E. thymus, bone marrow; lymph vessels, blood

20. Stage I: The Development of
Lymphocyte Diversity
• Specific events in T-Cell Maturation
- Maturation of T cells and development of their
receptors is directed by the thymus gland and its
hormones.
• CD3 receptors: surround the T-cell receptor and
assist in binding
• CD4 receptors: accessory receptor proteins that
binds to MHC II molecules
• CD8 receptors: found on cytotoxic T cells and
binds to MHC I molecules

21. Stage I: The Development of
Lymphocyte Diversity (cont’d)
• Specific Events in B-cell Maturation:
- First discovered in birds in the bursa
- Occurs in certain bone marrow sites that
harbor stromal cells in humans (Stromal cells
provide chemical signals that initiate B-cell
development.)
- Naïve lymphocytes circulate in the blood,
“homing” to specific sites in the lymph nodes,
spleen, and GALT.

25. The Origin of
Immunologic Diversity
• By the time B and T cells reach lymphoid
tissues, each one is equipped to respond to a
single unique antigen.
• Diversity is generated by rearrangement of gene
segments that code for antigen receptors on T
and B cells:
- Every possible recombination occurs, leading to a
huge assortment of lymphocytes.
- It is estimated that each human produces antibodies
with 10 trillion different specificities.

26. The Specific B-Cell Receptor:
An Immunoglobulin Molecule
• Immunoglobulin (Ig):
- Large glycoprotein molecules that serve as the
antigen receptors of B cells
- When secreted are antibodies
• Immunoglobulin structure:
- Antigen binding sites: pockets in the ends of the forks
of the molecules that can be highly variable in shape
to fit a wide range of antigens
- Variable regions: areas of extreme versatility from
one clone to another
- Light chains, heavy chains, constant regions: amino
content does not vary greatly from one antibody to
another

28. T-Cell Receptors
• Belongs to the same family as the B-cell
receptor
• Similar to B cells:
– Formed by genetic recombination
– Has variable and constant regions
– Inserted into membrane
– Has an antigen binding site
• Relatively small and never secreted

30. Stage II: Presentation of
Antigens – Entrance of Antigens
• Immunogen: synonymous with antigen
– Substances that can elicit an immune response
– Must meet certain requirements in foreignness,
shape, size, and accessibility
– Must not be a normal constituent of the body
• Examples of Immunogens:
– Whole microbes or their parts
– Cells or substances that arise from other
humans, animals, plants, and various molecules
– Complex proteins and protein-containing
molecules are more immunogenic than
repetitious polymers composed of a single type of
unit.

31. Presentation of Antigens (cont’d)
• Most antigens fall into the following
categories:
– Proteins and polypeptide: enzymes, cell
surface structures, and exotoxins
– Lipoproteins: cell membrane
– Glycoproteins: blood cell markers
– Nucleoproteins: DNA complexed to proteins,
but not pure DNA
– Polysaccharides (certain bacterial capsules)
– Lipopolysaccharides

32. Effects of
Molecular Size and Shape
• To initiate an immune response, a
substance must be large enough to “catch
the attention” of surveillance cells:
– Large, complex macromolecules of 100,000
Daltons are the most immunogenic.
– Size alone is not sufficient for antigenicity.
– Highly repetitious structures such as glycogen
are not immunogenic.
– Insulin at 6,000 Daltons is immunogenic.

34. Effects of Molecular
Size and Shape (cont’d)
• Epitope
- The portion of an antigenic molecule to which
a lymphocyte responds
- Primary signal to the immune system that the
molecule is foreign

35. Effects of Molecular
Size and Shape (cont’d)
• Haptens
- Small foreign molecules that are too small by
themselves to elicit an immune response
- If this incomplete molecule is linked to a larger
carrier molecule, the combination develops
immunogenicity.
- The carrier group contributes to the size of the
complex and enhances the proper spatial
orientation of the determinative group.
- The hapten serves as the epitope.

36. Effects of Molecular
Size and Shape (cont’d)
• Examples of haptens:
- Drugs
- Metals
- Ordinarily innocuous household, industrial,
and environmental chemicals
• Many haptens develop antigenicity in the
body by combining with large carrier
molecules such as serum proteins.

38. Effects of Molecular
Size and Shape (cont’d)
• Alloantigens:
- Cell surface markers and molecules that
occur in some members of the same species,
but not in others
- The basis for an individual’s blood group and
major histocompatibility profile
- Responsible for incompatibilities that can
occur in blood transfusion or organ grafting

39. Effects of Molecular
Size and Shape (cont’d)
• Superantigens:
- Bacterial toxins that are potent stimuli for T cells
- Activate T cells at a rate 100 times greater than
ordinary signals
- The result can be an overwhelming release of
cytokines and cell death
- Toxic shock syndrome and certain autoimmune
diseases are associated with superantigens.
• Allergens: antigens that evoke allergic
reactions, discussed in chapter 14

40. Antigen Processing and
Presentation
• In most immune reactions, the antigen must
be further acted upon and formally presented
to lymphocytes by antigen presenting cells
(APCs).
• Examples of APCs:
- Macrophages
- B cells
- Dendritic cells
• After processing is complete, the antigen will
be bound to the MHC receptor and moved to
the surface of the APC so it will be readily
accessible to T lymphocytes.

42. Antigen Processing and
Presentation (cont’d)
• Most antigens must be presented first to
T cells, even though they will eventually
activate both the T-cell and B-cell
systems.
• T-cell-independent antigens: antigens that
can trigger B cells directly without APCs or
T helper cells
– Carbohydrates with many repeating and
invariable determinant groups

43. Concept Check
Which of the following is not an antigen-
presenting cell:
A. Macrophage
B. Dendritic cell
C. T-helper cell
D. B cell
E. All of the choices are antigen presenting
cells.

44. Stages III and IV: T-Cell
Response
• Cell-Mediated Immunity (CMI):
- T-cell reactions are the most complex and diverse
in the immune system and involve several
subsets of T cells.
- Actions of T cells are dictated by the APCs that
activate them.
- Restricted: require some type of MHC (self)
recognition before they can be activated
- All T cells produce cytokines with a spectrum of
biological effects.
- End result of T-cell stimulation is the mobilization
of other T cells, B cells, and phagocytes.

46. T Helper (TH) Cells
• Three types of T helper cells that all bear the
CD4 marker and are critical in regulating
immune reactions to antigens
• Also involved in activating macrophages
- Directly by receptor contact
- Indirectly by releasing cytokines such as interferon
gamma (IFNγ)
• Secrete interleukin 2 (IL-2), which stimulates
primary growth of T cells, including cytotoxic T
cells
• Secrete IL-4, IL-5, and IL-6, which stimulate
B cells
• Make up about 65% of the T-cell population

47. Cytotoxic T (TC) Cells:
Cells that Kill Other Cells
• Target cells that TC cells can destroy
include:
- Virally infected cells: recognize virus peptides
displayed on the cell surface
- Cancer cells: TC constantly survey the tissues
and immediately attack any abnormal cells
they encounter
- Cells from other animals and humans: the
most important factor in graft rejection

48. Gamma-Delta T Cells
• Distinct from other T cells:
– Have T-cell receptors arranged to recognize a
wide range of antigens
– Frequently respond to certain kinds of PAMPs
in the same way as nonspecific WBCs
– Respond more quickly and produce memory
– Particularly responsive to certain types of
phospholipids and react to tumor cells
– Considered the bridge between nonspecific
and specific immune responses

49. Additional Cells with
Orders to Kill
• Natural killer (NK) cells:
- Lack specificity for antigens
- Circulate through the spleen, blood, and lungs
- Probably the first killer cells to attack cancer
cells and virus-infected cells
- Destroy these cells in a similar fashion as TC
cells
- Not part of specific immunity, but sensitive to
IL-12 and interferon

50. Additional Cells with
Orders to Kill (cont’d)
• Natural Killer T (NKT) cells:
- Hybrid cell that is part killer cell and part T cell
- Has T-cell receptors for antigen and the ability
to release large amounts of cytokines very
quickly, leading to cell death
- Another bridge between nonspecific and
specific immunity

52. Concept Check
Cytotoxic T cells are programmed to kill all
of the following except:
A. cancer cells.
B. virus-infected cells.
C. bacteria.
D. foreign cells grafted into the body.
E. None of the choices is correct.

54. Products of B Lymphocytes:
Antibody Structure and Functions
• Symmetrical Y-shaped arrangement
• Antigen-binding fragments (Fabs)
- End of each Fab fragment folds into a groove that can
accommodate an epitope
• Crystallizable fragment (Fc)
• Pair of identical heavy chains (H): bonded
together with disulfide bonds
• Pair of identical light chains (L): one light chain
bonded to one heavy chain with disulfide bonds
• Region between the Fab and Fc regions allows
swiveling of the Fab fragments

56. Antibody-Antigen Interactions
and the Function of the Fab
• Hypervariable region:
- The site on the antibody where the epitope
binds
- Amino acid content of this region is extremely
varied
- Specificity of antigen binding sites for
antigens is very similar to enzymes and
substrates
- Specificity on the two Fab sites is identical, so
an Ig molecule can bind epitope on the same
cell or on two separate cells, and bind them.

58. Functions of the Fc Fragment
• Fc end contains an effector portion that
can bind to receptors on the membranes
of cells, such as macrophages.
• Effect of Fc binding depends on the cell’s
role:
- Opsonization: attachment of antibody to
foreign cells is followed by binding of the Fc
portion to phagocytes
- Fc end of IgE binds to basophils and mast
cells, causing release of allergic mediators

59. The Classes of Immunoglobulins
• Isotypes: structural and functional classes of
immunoglobulins
• IgA:
- Monomer that circulates in small amounts in the
blood
- Dimer that is a significant component of mucous
and serous secretions of the salivary glands,
intestine, nasal membranes, breast, lung, and
genitourinary tract
- Dimer is two monomers held together by a “J”
chain to facilitate transport of IgA across
membranes

60. The Classes of Immunoglobulins
(cont’d)
• IgA (cont’d)
- Coats the surface of mucous membranes
- Suspended in saliva, tears, colostrum, and
mucus
- Provides specific immunity against enteric,
respiratory, and genitourinary pathogens
- Colostrum: earliest secretion of breast milk;
high in IgA that coats the gastrointestinal tract
of a nursing infant

62. Monitoring Antibody Production
Over Time
• Titer: levels of antibodies in the serum over
time
• Memory B and T cells are only created from
clones activated by a specific antigen:
– New research suggests that exposure to a
particular antigen can result in memory cells that
are chemically related to it, even if those antigens
have not been seen by the host.
– Activation of specific memory occurs via
recognition of epitopes.
– May lead to the use of nonpathogenic microbes
in vaccines against more dangerous ones

63. Concept Check:
Match each antibody type with its description.
1. IgG
2. IgA
3. IgM
4. IgD
5. IgE
A. Secreted on mucus
membranes
B. Receptor on B cells
C. Produced in response
to allergies
D. Most prevalent
antibody
E. First antibody
produced

65. Immunization: A Lively History
• First recorded attempt at immunization
occurred in 6th
century China:
- Consisted of drying and grinding up smallpox
scabs and blowing them with a straw into the
nostrils of vulnerable family members
• Variolation in the 10th
century
- Deliberate inoculation of dried pus from smallpox
pustules of one patient into the arm of a healthy
person
- Used in parts of the Far East until Lady Montagu
brought it to England in 1721
- Unfortunately, many recipients and their contacts
still died of smallpox.

66. Immunization: A Lively History
• Edward Jenner: 1796
- Inspired by a dairymaid who had been infected by
cowpox and who was immune to smallpox
- Tested his theory by injecting a young boy with
material from human cowpox lesions, exposed
him to smallpox 2 months later, and was immune
to the disease
- Use of this vaccine was first regarded with
skepticism, but later adopted when it proved
successful
- Vaccination: any immunity obtained by
inoculation with selected antigens

67. Passive Immunization
• First attempts involved the transfusion of horse
serum containing antitoxins to prevent tetanus
and treat diphtheria.
• Antisera from animals has now been replaced
with human products, or genetically engineered
products.
• Gamma globulin:
- Immunoglobulin extracted from the pooled blood of
many human donors
- Used to treat specific infections in high-risk neonates
and other immunocompromised patients
- Useful when there is no effective treatment available
or to treat immune deficiencies

68. Artificial Active Immunity:
Vaccination
• Basic principles behind vaccination:
- Stimulate a primary response and a memory
response
- Prime the immune system for future exposure to
a virulent pathogen
- If the pathogen enters the body, the response will
be immediate, powerful, and sustained
• Vaccines have profoundly reduced the
prevalence and impact of many infectious
diseases that were once common and
deadly.

69. Principles of Vaccine Preparation
• Qualities of an effective vaccine:
- Protect against exposure to natural, wild forms of
the pathogen
- Have a low level of adverse side effects or
toxicity, and not cause harm
- Stimulate both antibody (B-cell) and cell-
mediated (T-cell) response
- Long-term, lasting effects (produce memory)
- Does not require numerous doses or boosters
- Inexpensive, have a relatively long shelf life, and
be easy to administer

70. Principles of Vaccine Preparation
(cont’d)
• Whole cell or virus vaccines:
- Live, attenuated cells or viruses
- Killed cells or inactivated viruses
• Antigenic molecules derived from bacterial cells
or viruses (subunits):
- Subunits derived from cultures of cells or viruses
- Subunits synthesized to mimic natural molecules
- Subunits manufactured via genetic engineering
- Conjugated vaccines: subunits conjugated with
proteins to make them more immunogenic

72. Development of New Vaccines
• Dozens of bacterial, viral, protozoan, and fungal
diseases remain without a functional vaccine:
- Malaria, HIV/AIDS, diarrheal diseases, respiratory
diseases, and worm infections that affect over 200
million people per year
• Even vaccines that are available are out of reach
for much of the world’s population.
• Difficult-to-design vaccines for latent or persistent
viral infections:
- Herpesviruses and cytomegaloviruses
- Since the host’s natural immunity cannot clear the
virus, the artificial immunity must outperform the
host’s natural response.

73. Development of New Vaccines
• Dozens of bacterial, viral, protozoan, and fungal
diseases remain without a functional vaccine:
- Malaria, HIV/AIDS, diarrheal diseases, respiratory
diseases, and worm infections that affect over 200
million people per year
• Even vaccines that are available are out of reach
for much of the world’s population.
• Difficult-to-design vaccines for latent or persistent
viral infections:
- Herpesviruses and cytomegaloviruses
- Since the host’s natural immunity cannot clear the
virus, the artificial immunity must outperform the
host’s natural response.

75. Route of Administration and
Side Effects of Vaccines
• Most vaccines are administered via the routes
below:
- Subcutaneous
- Intramuscular
- Intradermal
• Nasal and oral vaccines:
- Available for only a few diseases
- Stimulates IgA protection on mucous membranes
- Easier to give than injections
- More readily accepted and well tolerated

76. Vaccine Administration (cont’d)
• Adjuvant: special binding substance required
by some vaccines
- Enhances immunogenicity
- Prolongs antigen retention at the injection site
- Precipitates the antigen and holds it in the tissues
so that it will be released gradually
- Facilitates contact with antigen-presenting cells
and lymphocytes
- Most common adjuvant: alum (aluminum
hydroxide salts)

77. Vaccine Side Effects
• Vaccines must go through years of trials in
experimental animals and human
volunteers before they are licensed for
general use.
• Still some complications occur:
- Local reactions at the injection site
- Fever
- Allergies
- Other adverse reactions

78. Vaccine Side Effects (cont’d)
• Rare reactions:
- Panencephalitis (measles vaccine)
- Back-mutation to a virulent strain (polio
vaccine)
- Disease due to contamination with dangerous
viruses or chemicals
- Neurological effects of unknown cause
(pertussis and swine flu vaccines)
- Allergic reactions to the medium rather than
vaccine antigens (egg or tissue culture)

79. Vaccine Side Effects (cont’d)
• No link between autism and MMR vaccine:
– 1998 paper linking autism to MMR was
entirely discredited and the principal author’s
medical license was revoked.
– Scores of studies have studied these
negative associations and found they
are unsupportable.
– 2011: Institute of Medicine stated
unequivocally that MMR vaccine does not
cause autism.

80. Vaccine Side Effects (cont’d)
• Price of not vaccinating:
- Outbreaks of measles, mumps, diphtheria, polio,
typhoid fever, and whooping cough
- Decrease in the level of herd immunity, a
phenomenon in which a certain percentage of the
population is vaccinated, making it impossible for the
microbe to circulate
• Getting vaccinated serves the common good, as
well as the individual good.
• Many young parents have no memory of the pre-
vaccination era and don’t appreciate the greater
risk of not vaccinating their children.

81. Vaccine Side Effects (cont’d)
• In the decade before the measles vaccine
was available:
- 3 – 4 million cases of measles per year
- 300 – 400 children died annually
- 1000 more chronically disabled due to measles
encephalitis
• Childhood vaccines save the lives of 2.5
million children a year worldwide (UNICEF).
• Risks from infectious disease almost always
outweigh the chance of an adverse vaccine
reaction.

82. Vaccination:
For Whom and When?
• Caution must be exercised in giving live
vaccines to immunocompromised or pregnant
patients.
• Recommendation has been vaccination for all
typical childhood diseases for which a vaccine
is available:
- Adults, only in certain circumstances: health
workers, travelers, military personnel
• Revised recommendation: vaccination in adults
to “boost” older immunizations, protect against
adult infections, and to provide special
protection in people with certain medical
conditions

83. Concept Check
Determine which of the statements below
describes active or passive immunity:
A. Infusion of gamma globulin
B. Recovery from influenza
C. Receipt of the influenza vaccination
D. Antibodies passed from mother to infant
through breastfeeding