College: COLLEGE OF VETERINARY MEDICINE

Campus : Bayombong Campus

DEGREE PROGRAM BAS-DVM COURSE NO. VMIC 4

SPECIALIZATION COURSE TITLE Fundamentals of Immunology

YEAR LEVEL BAS-DVM 3 TIME FRAME WK NO. 1 IM NO. 01

I. UNIT TITLE/CHAPTER TITLE

Chapter I

II. LESSON TITLE

Introduction to Immunology

III. LESSON OVERVIEW

This chapter will help the students to define and appreciate the significance/ importance of Immunology. The
basic terms that are used in this subject will be introduced to the students. Important people who contributed to the
field of immunology are acknowledged. The concept of immunity is introduced into this topic.

IV. DESIRED LEARNING OUTCOMES

At the end of this chapter, the students will be able to define and appreciate the significance of Immunology.
They will be able to distinguish and familiarize themselves with the terms used in this subject. They will be able to
recognize the contributions of scientists involved in this field. They will be able to understand the basic concepts of
immunity
V. LESSON CONTENT

What is Immunology?
 Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all
organisms.
 It deals with:
 physiological functioning of the immune system in states of both health and disease
 malfunctions of the immune system in immunological disorders (autoimmune diseases, hypersensitivities, immune
deficiency, transplant rejection)
 the physical, chemical and physiological characteristics of the components of the immune system in vitro, in situ, and
in vivo Divisions/ Fields
◦ Histological examination of the immune system- histological characterization of different organs of the lymphoid system
◦ Classical immunology- ties in with the fields of epidemiology and medicine. It studies the relationship between the body
systems, pathogens and immunity
◦ Developmental immunology- concerns the immunological state of neonates
◦ Immunotherapy-The use of immune system components to treat a disease or disorder
◦ Diagnostic immunology- use of antigen and antibody as a tool in diagnostic techniques
◦ Reproductive immunology-devoted to the study of immunological aspects of the reproductive process including fetus
acceptance
◦ Clinical immunology- study of diseases caused by disorders of the immune system (failure, aberrant action, and
malignant growth of the cellular elements of the system). It also involves diseases of other systems, where immune
reactions play a part in the pathology and clinical features.
◦ Ecoimmunology, or ecological immunology, explores the relationship between the immune system of an
organism and its social, biotic and abiotic environment. More recent ecoimmunological research has focused on
host pathogen defences traditionally considered "non-immunological", such as pathogen avoidance, self-
medication, symbiont-mediated defenses, and fecundity trade-offs.
Behavioural immunity, a phrase coined by Mark Schaller, specifically refers to psychological pathogen avoidance
drivers, such as disgust aroused by stimuli encountered around pathogen-infected individuals, such as the smell of
vomit.] More broadly, "behavioural" ecological immunity has been demonstrated in multiple species.
 History of Veterinary Immunology

◦ 1549 – The earliest account of inoculation of smallpox (variolation) occurs in Wan Quan's
◦ 1718 – Smallpox inoculation in Ottoman Empire realized by West. Lady Mary Wortley Montagu, the wife of the
British ambassador to Constantinople, observed the positive effects of variolation on the native population and had
the technique performed on her own children.
◦ 1796 – First demonstration of smallpox vaccination (Edward Jenner- Father of immunology)
◦ 1808 – 1813 - First experimental demonstration of the germ theory of disease by Agostino Bassi though he does not
formally propose the theory until 1844
◦ 1837 – Description of the role of microbes in putrefaction and fermentation (Theodore Schwann)
◦ 1850 – Demonstration of the contagious nature of puerperal fever (childbed fever) (Ignaz Semmelweis)
◦ 1857–1870 – Confirmation of the role of microbes in fermentation (Louis Pasteur)
◦ 1862 – Observation of Phagocytosis (Ernst Haeckel)
◦ 1867 – Aseptic practice in surgery using carbolic acid (Joseph Lister)
◦ 1876 – Demonstration that microbes can cause disease-anthrax (Robert Koch)
◦ 1877 –Discovery of Mast cells (Paul Ehrlich)
◦ 1878 – Confirmation and popularization of the germ theory of disease (Louis Pasteur)
◦ 1880 – 1881 -Theory that bacterial virulence could be attenuated by culture in vitro and used as vaccines. Proposed
that live attenuated microbes produced immunity by depleting host of vital trace nutrients. Used to make chicken
cholera and anthrax "vaccines" (Louis Pasteur)
◦ 1883 – 1905 – Cellular theory of immunity via phagocytosis by macrophages and microphages (polymorhonuclear
leukocytes) (Elie Metchnikoff)
◦ 1885 – Introduction of concept of a "therapeutic vaccination". Report of a live "attenuated" vaccine for rabies (Louis
Pasteur and Pierre Paul Émile Roux).
◦ 1888 – Identification of bacterial toxins (diphtheria bacillus) (Pierre Roux and Alexandre Yersin)
◦ 1888 – Bactericidal action of blood (George Nuttall)
◦ 1890 – Demonstration of antibody activity against diphtheria and tetanus toxins. Beginning of humoral theory of
immunity. (Emil von Behring) and (Kitasato Shibasaburō)
◦ 1891 – Demonstration of cutaneous (delayed type) hypersensitivity (Robert Koch)
◦ 1893 – Use of live bacteria and bacterial lysates to treat tumors-"Coley's Toxins" (William B. Coley) ◦ 1894 –
Bacteriolysis (Richard Pfeiffer)
◦ 1896 – An antibacterial, heat-labile serum component (complement) is described (Jules Bordet)
◦ 1900 – Antibody formation theory (Paul Ehrlich)
◦ 1901 – Blood groups (Karl Landsteiner)
◦ 1902 – Immediate hypersensitivity anaphylaxis (Paul Portier) and (Charles Richet)
◦ 1903 – Intermediate hypersensitivity, the "Arthus reaction" (Maurice Arthus)
◦ 1903 – elucidation of the mechanism of Opsonization
◦ 1905 – "Serum sickness" allergy (Clemens von Pirquet and (Bela Schick)
◦ 1909 – Paul Ehrlich proposes "immune surveillance" hypothesis of tumor recognition and eradication
◦ 1911 – 2nd demonstration of filterable agent that caused tumors (Peyton Rous)
◦ 1917 – Discovery of the Hapten (Karl Landsteiner)
◦ 1921 – Cutaneous allergic reactions (Otto Prausnitz and Heinz Küstner)
◦ 1924 – Discovery of the Reticuloendothelial system
◦ 1938 – Antigen-Antibody binding hypothesis (John Marrack)
◦ 1940 – Identification of the Rh antigens (Karl Landsteiner and Alexander Weiner)
◦ 1942 – Anaphylaxis (Karl Landsteiner and Merill Chase)
◦ 1942 – Adjuvants (Jules Freund and Katherine McDermott)
◦ 1944 – hypothesis of allograft rejection
◦ 1945 – Coombs test a.k.a. antiglobulin test (AGT)
◦ 1946 – Identification of mouse MHC (H2) by George Snell and Peter A. Gorer
◦ 1948 – Antibody production in plasma B cells
◦ 1949 – Growth of polio virus in tissue culture, neutralization with immune sera, and demonstration of attenuation of
neurovirulence with repetitive passage (John Enders) and (Thomas Weller) and (Frederick Robbins)
◦ 1951 – vaccine against yellow fever
◦ 1953 – Graft-versus-host disease
◦ 1953 – Validation of immunological tolerance hypothesis
◦ 1957 – Clonal selection theory (Frank Macfarlane Burnet)
◦ 1957 – Discovery of interferon by Alick Isaacs and Jean Lindenmann
◦ 1958–1962 – Discovery of human leukocyte antigens (Jean Dausset and others)
◦ 1959–1962 – Discovery of antibody structure (independently elucidated by Gerald Edelman and
Rodney Porter)
◦ 1959 – Discovery of lymphocyte circulation (James Gowans)
◦ 1960 – Discovery of lymphocyte "blastogenic transformation" and proliferation in response to mitogenic lectins-
phytohemagglutinin (PHA) (Peter Nowell)
◦ 1961–1962 Discovery of thymus involvement in cellular immunity (Jacques Miller)
◦ 1960 – Radioimmunoassay – (Rosalyn Sussman Yalow)
◦ 1961 – Demonstration that glucocorticoids inhibit PHA-induced lymphocyte proliferation (Peter Nowell)
◦ 1963 – Development of the plaque assay for the enumeration of antibody-forming cells in vitro by Niels Jerne and
Albert Nordin
◦ 1963 – Gell and Coombs classification of hypersensitivity
◦ 1964–1968 – T and B cell cooperation in immune response
◦ 1965 – Discovery of lymphocyte mitogenic activity, "blastogenic factor" (Shinpei Kamakura) and (Louis Lowenstein) (J.
Gordon) and (L.D. MacLean)
◦ 1965 – Discovery of "immune interferon" (gamma interferon) (E.F. Wheelock)
◦ 1965 – Secretory immunoglobulins
◦ 1967 – Identification of IgE as the reaginic antibody (Kimishige Ishizaka)
◦ 1968 – Passenger leukocytes identified as significant immunogens in allograft rejection (William L. Elkins and
Ronald D. Guttmann)
◦ 1969 – The lymphocyte cytolysis Cr51 release assay (Theodore Brunner) and (Jean-Charles Cerottini)
◦ 1971 – Peter Perlmann and Eva Engvall at Stockholm University invented ELISA
◦ 1972 – Structure of the antibody molecule
◦ 1973 – Dendritic Cells first described by Ralph M. Steinman
◦ 1974 – Immune Network Hypothesis (Niels Jerne)
◦ 1974 – T-cell restriction to MHC (Rolf Zinkernagel and (Peter C. Doherty)
◦ 1975 – Generation of monoclonal antibodies (Georges Köhler) and (César Milstein)[4]
◦ 1975 – Discovery of Natural Killer cells (Rolf Kiessling, Eva Klein, Hans Wigzell)
◦ 1976 – Identification of somatic recombination of immunoglobulin genes (Susumu Tonegawa)
◦ 1980–1983 – Discovery and characterization of interleukins, 1 and 2 IL-1 IL-2 (Robert Gallo, Kendall A. Smith,
Tadatsugu Taniguchi)
◦ 1983 – Discovery of the T cell antigen receptor TCR (Ellis Reinherz) (Philippa Marrack) and (John Kappler)[5]
(James Allison)
◦ 1983 – Discovery of HIV (Luc Montagnier) (Françoise Barré-Sinoussi) (Robert Gallo)
◦ 1985–1987 – Identification of genes for the T cell receptor
◦ 1986 – Hepatitis B vaccine produced by genetic engineering
◦ 1986 – Th1 vs Th2 model of T helper cell function (Timothy Mosmann)
◦ 1988 – Discovery of biochemical initiators of T-cell activation: CD4- and CD8-p56lck complexes (Christopher E.
Rudd)
◦ 1990 – Gene therapy for SCID
◦ 1991 – Role of peptide for MHC Class II structure
◦ 1992 – Discovery of transitional B cells (David Allman & Michael Cancro)
◦ 1994 – 'Danger' model of immunological tolerance (Polly Matzinger)
◦ 1995 – James P. Allison describes the function of CTLA-4
◦ 1995 – Regulatory T cells (Shimon Sakaguchi)
◦ 1995 – First Dendritic cell vaccine trial reported by Mukherji et al.
◦ 1996 – 1998 – Identification of Toll-like receptors
◦ 1997 – Discovery of the autoimmune regulator and the AIRE (autimmune regulator) gene.
◦ 2000 – Characterization of M1 and M2 macrophage subsets by Charles Mills
◦ 2001 – Discovery of FOXP3 – the gene directing regulatory T cell development
◦ 2005 – Development of human papillomavirus vaccine (Ian Frazer)
◦ 2006 – Antigen-specific NK cell memory first reported by Ulrich von Andrian's group after discovery by
Mahmoud Goodarzi
◦ 2010 – The first autologous cell-based cancer vaccine, PROVENGE, is approved by the FDA for the
treatment of metastatic, asymptomatic stage IV prostate cancer. The treatment is marketed at a cost of
$93,000 and imparts, on average, only an extra four months of life expectancy. The manufacturer,
Dendreon Inc, declares bankruptcy in 2014.
◦ 2010 – First immune checkpoint inhibitor, ipilimumab (anti-CTLA-4), is approved by the FDA for
treatment of stage IV melanoma
◦ 2011 – Carl H. June reports first successful use of CAR T-cells expressing the 4-1BB costimulatory
signaling domain for the treatment of CD19+ malignancies
◦ 2014 – A second class of immune checkpoint inhibitor (anti-PD-1) is approved by the FDA for the
treatment of melanoma. Two different drugs, pembrolizumab and nivolumab are approved within
months of each other.
◦ 2016 – Halpert and Konduri first characterize the role of dendritic cell CTLA-4 in Th immune
polarization
◦ 2016 – A third class of immune checkpoint inhibitor, anti-PD-L1 (atezolizumab), is approved for the
treatment of bladder cancer
 ◦ 2017 – The first autologous CAR T-cell therapy tisagenlecleucel also known as Kymriah is approved for
the treatment of pediatric B-ALL. Marketed at a cost of $475,000, the treatment provides an 83% rate of
durable remission among poor prognosis patients for whom a bad outcome would otherwise be
expected. A second autologous CAR T-cell therapy axicabtagene ciloleucel (Yescarta) is approved
months later.
◦ 2020 - The first modified mRNA vaccine is developed for the prevention of SARS-CoV-2 infection. This
breakthrough technology allowed design, testing, and potential approvalof a prophylactic vaccine in
under one year.
◦ 2020- Phase 3 of the clinical trial of the COVID vaccine from Pfizer was found to have 90% efficacy.

VI. LEARNING ACTIVITIES

VII. ASSIGNMENT

VIII. EVALUATION (Note: Not to be included in the student’s copy of the IM) Quiz
1 (Chapter 1)
1. This division of Immunology involves the use of immune system components to treat a disease or
disorder (1 point)
a. Reproductive immunology c. Clinical immunology
b. Immunotherapy d. Classical immunology
2. Give the name of 4 scientist/s and his/her discovery/contribution to the field of immunology (4 points)

IX. REFERENCES
 College: COLLEGE OF VETERINARY MEDICINE
Campus : Bayombong Campus

DEGREE BAS-DVM COURSE VMIC 4

PROGRAM NO.
SPECIALIZATION COURSE Fundamentals of Immunology
TITLE
YEAR LEVEL BAS-DVM 3 TIME WK 2 IM 02
FRAME NO. NO.

I. UNIT TITLE/CHAPTER TITLE

Chapter 2

II. LESSON TITLE

The phenomenon of Immunity

VI. III. LESSON OVERVIEW

This chapter will introduce the basic concepts on the phenomenon of immunity with emphasis on
the different mechanisms employed by the body to protect against infection.

VII. IV. DESIRED LEARNING OUTCOMES

At the end of this chapter, the students will be able to able to understand the general concepts of immune
response of the body towards antigens.
VIII. V. LESSON CONTENT

The Phenomenon of Immunity

 In order to survive, an animal depends on a successful defense against microbial invasion

 To be effective, the body needs multiple defense systems
 Some will act at the body surface to exclude invaders
 Others will act deep within the body to destroy organisms that breached the outer body
 Some will act against bacterial invaders, some against viruses and even large invaders such as parasitic worms and insects

The Body’s Defenses

1. Physical barriers
2. Innate immunity
3. Acquired immunity

Physical barriers -The first layer of defense

1. Skin
2. self- cleaning mechanism
-coughing
- sneezing
-mucus flow in the respiratory tract,
-vomiting
-diarrhea

Innate Immunity -2nd layer of defense

- consists of chemical and cellular defense mechanisms collectively known as the innate immune system
- relies on the fact that invading microorganisms are chemically different from normal body components
- key aspect of innate response is inflammation (increase in blood flow and local accumulation of cells that attack
and destroy invaders.

Acquired immunity
- is a complex and sophisticated system that provides the ultimate defense of the body
- acquired immune system recognize and destroy foreign invaders and retain the memory of the encounter
 - Has 2 categories- the humoral immune response and the cell mediated immune response

Humoral and Cell Mediated Immunity

- Humoral immune response is mediated by antibodies and is directed against the extracellular or exogenous
invaders.
- Antibodies are found on body fluids or humors
- Cell mediated immune response is directed against the intracellular or endogenous invaders that cause cellular
abnormalities
- specialized cytotoxic cells destroy these abnormal cells.

HUMORAL IMMUNE RESPONSE

- Also called antibody-mediated immune response
- Humoral Immunity- Results in production of proteins called “immunoglobulins” or “antibodies”.
- Body exposed to “foreign” material termed “antigen” which may be harmful to body: virus, bacteria, etc. -
Antigen has bypassed other protective mechanisms, ie, first and second line of defense.

IX. Antibody
- also called immunoglobulin, a protective protein produced by the immune system in response to the presence of a
foreign substance, called an antigen. Antibodies recognize and latch onto antigens in order to remove them from the
body.

Fig. 1 Illustration of an antibody

Dynamics of Antibody Production

Fig. 2 Illustration of the antibody production to antigen exposure

 Primary immune response

◦ Latent period
◦ Gradual rise in antibody production taking days to weeks
◦ Plateau reached
◦ Antibody level declines
 Antibody production
◦ Initial antibody produced in IgM
◦ Lasts 10-12 days
◦ Followed by production of IgG
◦ Lasts 4-5 days
◦ Without continued antigenic challenge antibody levels drop off, although IgG may continue to be produced.
 Secondary Response
- Second exposure to SAME antigen.
- Memory cells are produced.
 - Recognition of antigen is immediate.
- Results in immediate production of protective antibody, mainly IgG but may see some IgM

Fig. 2 Illustration of the antibody production to antigen exposure

Cellular Events in antibody production

- Antigen is “processed” by T lymphocytes and macrophages. - Possess special receptors on surface.
- Termed “antigen presenter cell” APC.
- Antigen presented to B cell
Plasma cells are specialized B lymphocytes (called B cells as they develop in the bone marrow) that secrete a
large number of antibodies during a selective immune response. Since they are a cell that produces and secretes a
large number of antibodies (proteins), they contain an extensive amount of rER, ribosomes and mitochondria (for
energy).
 The active B-cells begin to clone themselves (by mitosis) producing cloned plasma B cells that produce antibodies
and memory cells. The generation of large numbers of plasma cells that produce one specific antibody type is known
as clonal selection. Memory cells remain in the blood in case a second infection occurs to provide long term protection
and a quick response to the new infection. The plasma cells created produce and release mass amounts of antibodies
into the bloodstream. These antibodies surround and bind to the antigens on the foreign pathogens. Through a variety
of different methods, the pathogens are destroyed by the antibodies and other white blood cells.

VI. LEARNING ACTIVITIES

X. VII. ASSIGNMENT

VIII. EVALUATION (Note: Not to be included in the student’s copy of the IM) Quiz 2
(Chapter 2)
1. Give 2 examples of body’s defenses? (2 points)
2. Differentiate primary from secondary immune response. (4 points)
3. True or False. Memory cells come from T-lymphocytes (1 point)
4. Explain how antibodies are produced (3 points)

XI. IX. REFERENCES

Tizard, Ian R. 2000. Veterinary Immunology: An Introduction

Wise, DJ. And Carter GR. 2001. Immunology. A comprehensive review. Blackwell, Ames Iowa
https://www.britannica.com/science/antibody
https://www.mrgscience.com/topic-111-antibody-production-and-vaccination.html
 XII. College: COLLEGE OF VETERINARY MEDICINE
Campus : Bayombong Campus

DEGREE PROGRAM BAS-DVM COURSE NO. VMIC 4

SPECIALIZATION COURSE TITLE Fundamentals of Immunology

YEAR LEVEL BAS-DVM 3 TIME FRAME WK NO. 2 IM NO. 02b

I. UNIT TITLE/CHAPTER TITLE

Chapter 2b

II. LESSON TITLE

Antigens

III. LESSON OVERVIEW

XIII. IV. LESSON CONTENT

• An antigen is a substance/molecule that, when introduced into the body, triggers the production of an antibody
by the immune system.
• The term is derived from the generation of antibodies to such substances.
• Often antigens are foreign proteins (or parts of them) that enter the body via an infection.
• Sometimes, however, the body's own proteins, expressed in an inappropriate manner (where or when they
are not usually seen), are treated like antigens by the immune system.
 • It is important to recognize that bacteria or viruses are not themselves antigens but they contain antigens both
on their surface and inside them.
• Some components are better able to stimulate the immune response than others.
• These components are said to be more “antigenic”.

Types of antigens
MICROBIAL ANTIGENS
 Bacterial antigens
 Viral antigens
 Other microbial antigens
NON-MICROBIAL ANTIGENS
 Cell surface antigens
 autoantigens

BACTERIAL ANTIGENS
- Bacteria are either ovoid or spherical
- Cytoplasm is surrounded by a cell membrane
- Other bacterial antigens are porins (proteins that form pores on surface of Gram-negative bacteria; heat shock
proteins (produced when bacteria is stressed), and exotoxins
- Exotoxins are immunogenic and stimulate production of antibodies known as “antitoxins”
- Exotoxins that are modified to lose toxicity by retain immunogenicity are called “toxoids” (ex. Tetanus toxoid from
Clostridium tetani ). Viral antigens
- Viruses are small obligate intracellular parasites that consist of a nucleic acid core surrounded by a layer of protein
subunits.
- Protein layer is called capsid and the subunits are called capsomeres
- Capsid proteins are good antigens
- Viruses incorporate their nucleic acid in the cell’s genome and start producing new proteins which are then displayed
on the surface of the cell
- Viral proteins that are synthesized are called “endogenous antigens”
- Antigens that come from the outside are called “exogenous antigens” Other microbial antigens
 Fungi
 Protozoan parasites
 Parasitic worms
- Consists of proteins, carbohydrates, lipids, and nucleic acids
- Nonmicrobial antigens
- Food may contain foreign molecules that may trigger an immune response
- Dust may contain pollens grains or fungal spores
- Mosquito or snake bites can introduce foreign molecules (saliva and venom) - Organ grafts
- Cell-surface antigens
- Proteins that are found on cell surfaces
- These can cause an immune response when injected into another species of animal
- Blood-group antigens are antigens found on the surface of RBCs
- MHCs (Major Histocompatibility Complex) molecules are group of molecules which trigger Graft rejection
autoantigens
- An autoantigen is usually a normal protein or complex of proteins (and sometimes DNA or RNA) that is recognized by
the immune system of patients suffering from a specific autoimmune disease
- These antigens should, under normal conditions, not be the target of the immune system, but, due to mainly genetic
and environmental factors, the normal immunological tolerance for such an antigen has been lost in these patients

What are the characteristics of a good antigen?

- Size- should be more than 1000 daltons
- Complexity- the more complex, the better
- Stability- should have structural stability
- Foreignness- the greater the difference from the self components, the greater the immune response
 Epitope- The distinct molecular surface features of an antigen capable of being bound by an antibody (a.k.a. antigenic
determinant).
 Antigenic molecules, normally being "large" biological polymers, usually present several surface features that can act
as points of interaction for specific antibodies.
 Any such distinct molecular feature constitutes an epitope. Therefore, most antigens have the potential to be bound
by several distinct antibodies, each of which is specific to a particular epitope.
  Using the "lock and key" metaphor, the antigen itself can be seen as a string of keys - any epitope being a "key" - each
of which can match a different lock. Different antibody idiotypes, each having distinctly formed complementarity
determining regions, correspond to the various "locks" that can match "the keys" (epitopes) presented on the antigen
molecule.
 Allergen - A substance capable of causing an allergic reaction. The (detrimental) reaction may result after exposure
via ingestion, inhalation, injection, or contact with skin.
 Superantigen - A class of antigens that cause non-specific activation of T-cells, resulting in polyclonal T cell activation
and massive cytokine release.
 Tolerogen - A substance that invokes a specific immune non-responsiveness due to its molecular form. If its molecular
form is changed, a tolerogen can become an immunogen.
 Immunoglobulin binding protein - These proteins are capable of binding to antibodies at positions outside of the
antigen-binding site. That is, whereas antigens are the "target" of antibodies, immunoglobulin-binding proteins "attack"
antibodies. Protein A, protein G, and protein L are examples of proteins that strongly bind to various antibody isotypes.
 Hapten – a small molecule than can function as an epitope when bond to other larger molecules
- Haptens are less than 1000 daltons
- The molecules in which haptens attach to become antigenic is called a “carrier”
- Examples of haptens: penicillin which becomes antigenic when it reacts with albumin
- Urushiol which is a component of poison ivy

XIV. V. DESIRED LEARNING OUTCOMES

At the end of this chapter, the students will be able to :

1. Define antigen and immunogen.
2. State what antigens are composed of chemically.
3. List 3 characteristics an antigen must have to be immunogenic.
4. Define epitope.
5. Briefly describe how the body recognizes an antigen as foreign.
6. Compare B-cell receptors and T-cell receptors in terms of how they recognize epitopes.
7. In terms of infectious diseases, list 2 categories of microbial materials that may act as an antigen.
 XV. College: COLLEGE OF VETERINARY MEDICINE
Campus : Bayombong Campus

DEGREE PROGRAM BAS-DVM COURSE NO. VMIC 4

SPECIALIZATION COURSE TITLE Fundamentals of Immunology

YEAR LEVEL BAS-DVM 3 TIME FRAME WK NO. 2 IM NO. 02c

I. UNIT TITLE/CHAPTER TITLE

Chapter 2c

II. LESSON TITLE

Immune Tolerance

III. LESSON OVERVIEW

XVI. IV. LESSON CONTENT

TOLERANCE
Some Definitions

1. unprimed (= "virgin") (= "naive") (= "inexperienced")

 These are cells (both T and B) that have generated an antigen receptor (TCR for T cells, BCR for B cells) of a
particular specificity, but have never encountered that antigen. There is some evidence that if they do encounter the
antigen but fail to receive a "second signal", they self-destruct by apoptosis.

2. primed (= "experienced")

Both T cells and B cells that have encountered the antigen for which they are specific. If they receive a second,
costimulatory signal, they become

3. activated T (or B) cells.

Having received a second signal from an antigen-presenting cell, they become metabolically more active and begin
rounds of mitosis (= clonal expansion).

4. antigen-presenting cells (APCs).

If activated, "professional" APCs can always provide the second signal for T cells. Dendritic cells are professional
APCs, and sometimes macrophages may be.

Nonprofessional APCs can present antigen but not the second signal. B cells are nonprofessional — they present
antigen to T-helper cells, but these must already be activated by an earlier encounter with professionals.

5. effector cells. o B cells that have differentiated into antibody-secreting plasma cells.
o T cells that have differentiated into
 CD8+ cytotoxic T lymphocytes (CTL)
 CD4+ T cells (Th1) that release cytokines producing a cell-mediated immune response 
CD4+ Th2 helper cells which promote the synthesis of IgE by B cells.
 Tfh cells which also stimulate B cells to develop into antibody-secreting plasma cells. 
Th17 cells which promote inflammation.
6. memory cells.
 Experienced T (or B) cells that have returned to — or remained in — a quiescent state.
Immunological tolerance is the process by which the immune system does not attack an antigen 
Can be natural/self-tolerance or induced
  3 forms
-central
-peripheral
-acquired
Natural tolerance -The body does not mount an immune response to self antigens
Induced tolerance -Tolerance to external antigens can be created by manipulating the immune system
Central Tolerance
- Occurs during lymphocyte development and operates in the thymus and bone marrow
- T and B lymphocytes that recognize self antigens are deleted before they develop into fully immunocompetent
cells, preventing autoimmunity
- This process is most active in fetal life, but continues throughout life as immature lymphocytes are generated
- In mammals the process occurs in the thymus (T cells) and bone marrow (B
cells), when maturing lymphocytes are exposed to self antigens.
Positive selection occurs first when naive T-cells are exposed to antigens in the thymus.
T-cells which have receptors with sufficient affinity for self-MHC molecules are selected. Other cells that do
not show sufficient affinity to self-antigens will undergo a deletion process known as death by neglect which
involves apoptosis of the cells. The positive selection is a classical example of the importance of some
degree of autorreactiveness. This does not occur in B-cells.
Negative selection of T-cells with a very high affinity of self-MHC molecules are induced to anergy, or
lineage divergence to form T-regulatory cells.
Peripheral Tolerance
Immunological tolerance developed after T and B cells mature and enter the “periphery”
Occurs in the secondary lymphoid organs or the peripheral circulation.
Acquired Tolerance
Acquired or induced tolerance refers to the immune system's adaptation to external antigens characterized
by a specific non-reactivity of the lymphoid tissues to a given antigen that in other circumstances would
likely induce cell-mediated or humoral immunity
One of the most important natural kinds of acquired tolerance is immune tolerance in pregnancy , where the
fetus and the placenta must be tolerated by the maternal immune system.
In adults, tolerance may be induced by repeated administration of very large doses of antigen, or of small
doses that are below the threshold required for stimulation of an immune response
 Another example of acquired tolerance is during organ transplant. Immuno-suppression and a variety of
medicine are used to produce acquired tolerance and to prevent rejection.

XVII. V. DESIRED LEARNING OUTCOMES

At the end of this chapter, the students will be able to :

1. Differentiate the different types of tolerance
2. Explain the role of tolerance during pregnancy and organ transplantation.

VI. LEARNING ACTIVITIES

VII. ASSIGNMENT

VIII. EVALUATION (Note: Not to be included in the student’s copy of the IM)

XVIII. IX. REFERENCES

Tizard, Ian R. 2000. Veterinary Immunology: An Introduction

Wise, DJ. And Carter GR. 2001. Immunology. A comprehensive review. Blackwell, Ames Iowa
http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit6/antigens/u3fg2.html
https://bio.libretexts.org/Bookshelves/Microbiology/Book%3A_Microbiology_(Kaiser)/Unit_6%3A_Adapti
ve_Immunity/12%3A_Introduction_to_Adaptive_Immunity/12.2%3A_Antigens_and_Epitopes

Rahman MS, Rahman MK, Saha S, Kaykobad M, Rahman MS. Antigenic: An improved prediction model of
protective antigens. Artif Intell Med. 2019 Mar;94:28-41. doi: 10.1016/j.artmed.2018.12.010. Epub 2019 Jan 3.
PMID: 30871681.
An Immunology lecture prepared by V. A
l
Antibodies, also called “immunoglobulins”, are
one of two important protein molecules of the
immune system that engage in the recognition
of pathogens or other foreign material
It is produced by B-lymphocytes (soluble
form)
It is also found on the surfaces of B
lymphocytes and called B cell receptors
(BCR)
Immunoglobulin’s function is the recognition of
a specific antigen
based on chemical and structural differences
are classified in five distinct classes of
 molecules called isotypes that are named IgM,
IgG, IgA, IgD, and IgE.

 Each immunoglobulin has two small chains (molecular

weight of 22 kD) termed light chains (LCs) and two
more chains (55 kD) called heavy chains (HCs).
 Each IgG molecule is composed of two identical LCs and
two identical HCs which form a Y-shaped structure
 Antibody is made up of four polypeptides or 2 pairs of
"chains“. The heavy chain (H chain) and the light chain
(L chain).
 The heavy and light chains are folded into domains and
are held together by disulphide bonds.
 Once the heavy and light chains are assembled, they
form regions:
-Fab (antigen binding fragment) region and the Fc
(constant fragment) region.
 
The antigen binding region (Fab) is the recognition region of the
antibody.
 It has great diversity so that antibodies can be made to recognize
any and every antigen the body encounters.
 The Fc region is responsible for the effector function of the
antibody (such as opsonization or Complement activation) and also
defines the class of antibody (IgG versus IgA for example).
 The lower stem of the molecule displays an effector function and
interacts with other components of the immune system such as
complement and cell receptors specific for this part of the
molecule, which is referred to as the crystallizable fragment (Fc)
 Another fragment of immunoglobulin, referred to as the Fv
fragment, retains the complete antibody-binding sites and consists
of the variable regions of both heavy and light chains containing the
N-terminal half of the Fab. These fragment have been generated
from the use of a DNA recombinant expression system and are used
clinically, for example, when treating cancer patients with mouse
monoclonal antibodies specific for tumor antigens. However, the
efficacy of these monoclonal fragments is diminished since they lack
the constant regions essential for many of the effector functions.
 
Both light and heavy chains of the immunoglobulin molecule are
further divided into regions referred to as variable (V) and constant
(C) regions (Figure 1B)
 The variable region is responsible for the highly specific
antigenrecognition function of an individual antibody molecule for its
antigen
 The variable and the constant regions are are joined by a hinge (J
chain)
 LCs contain two domains, i.e., the variable light (VL) and the
constant light (CL); the heavy chains contain one variable heavy (VH)
domain and either three or four constant CH domains depending on
the immunoglobulin isotype.
 The constant region of the IgG, IgA, and IgD HCs contain three
domains and the constant regions of IgM and IgE have an extra
domain resulting in four domains.
 In the Y-shaped immunoglobulin molecule is a proline-rich region
between the first (CH1) and second (CH2) domains of the HC called
the hinge region. This region contains cysteine residues that allow
linkage of the HC polypeptides to each other by S-S bonds.
 
 This region confers flexibility to the molecule by providing mobility
of the two upper arms of the molecule, thus enhancing their
antigenbinding potential.
Two immunoglobulin isotypes, IgM and IgE, do not have hinge
regions; however, their CH2 regions perform a hinge-like function.
 Immunoglobulin isotypes are named by their HCs (γ, α, μ, δ, and ɛ )
and contain two types of LCs.
 There are two different types of LCs in each of the isotypes, kappa
(κ) and lambda (λ).
 In contrast to the kappa isotype, which is of only one type, there
are four slightly different constant region sequences of the lambda
LC, forming four subclasses (subtypes).
A schematic representation of the IgG molecule showing the two light
chains and the two heavy chains and the location of interchain disulfide
bonds in the hinge region. The amino terminal end is at the top and the
carboxyl terminal end is on the bottom. Panel B: The variable regions of
the light and heavy chains (i.e., VL and VH, respectively, crosshatched)
that, together with the constant regions of the light (CL) and the heavy
(CH1), make up the antigen-binding region (Fab) of the molecule. Panel C:
The binding of antigen with the antigen-binding region (Fab).
 Immunoglobulins can either be found as transmembrane
proteins on the surface of the B cell or they can be secreted
by the terminal cell of B cell differentiation, i.e., the plasma
cell.
 Immunoglobulins function as antibodies and have the property
to combine with the antigen (i.e., immunogen) that triggered
their production.
 This unique property of recognition, referred to as specificity,
is controlled by an amazing assortment of genes that regulate
the production of individual parts of the immunoglobulin
molecule by determining the primary amino acid sequence of
these components.
 Immunoglobulins are specialized molecules that basically provide
two functions:
 (1) an antigen-recognition function, which is carried out by one end
of the molecule that binds to antigen, i.e., the two Fab’s
 (2) and an effector function, which is performed by the other end of
the molecule by interaction with phagocytic cells, other effector
cells and mediator molecules (for example, complement), i.e., the Fc
end
 Both these functions are extremely important during the
immune response
 The antigen-recognition property of the immunoglobulin molecule
confers its exquisite specificity to react with different molecular
structures: epitopes which are either linear or more often of a
conformational configuration, i.e., antigen
 For example, antibodies directed against the influenza virus recognize
neuraminidase (N) and hemagglutinin (H), viral components whose
 neutralization prevents the virus from adhering to respiratory
epithelial cells, thereby destroying the infectivity of the virus.
 This is achieved by producing two separate sets of antibodies, one
directed at the N and the other at the H, with different amino acid
sequences, each recognizing one of the two unrelated target antigens.
 Antigen recognition by the B cell occurs both at its cell surface
through the BCR and by its secreted immunoglobulin product; in
contrast, antigen recognition by the T cell occurs only through its
surface receptor, i.e., the TCR
 During the course of an immune response to an immunogen specific
classes of antibodies are generated at temporally different time
periods
 For example, IgM antibody is synthesized early and IgG later by a
process referred to as immunoglobulin class switching or isotype
switching.
 The genetic mechanism by which this class switching
occurs is referred to as somatic recombination or V(D)J
recombination
 The effector function of an immunoglobulin is related to
the specific isotype produced.
 For example, IgM antibodies synthesized early in the
immune response because of their large molecular size
are found and function best within the vascular system.
 Other immunoglobulins of lower molecular weight, e.g., the
IgG antibodies, produced later in the immune response
can readily diffuse between the intravascular and
interstitial tissues where they function most effectively.
 Still other antibody molecules, i.e., the secretory IgA, are
found at mucosal surfaces where they are produced and
function as first lines of defense against pathogens that
enter through the mucosal route, as exemplified by
influenza, rhinoviruses, and HIV.
IgA is most abundant and most active in
secretions at mucosal surfaces where it
appears as a dimeric protein.
The dimeric IgA provides the primary defense
at mucosal surfaces such as bronchioles, nasal
mucosa, prostate, vagina, and intestine. IgA is
also abundant in saliva, tears and breast milk,
especially colostrum.
The blood concentration of this antibody is
normally very low as most IgE is tightly bound
to its Fc receptors (Fc_R) on mast cells and
basophils.
The production of IgE is controlled by
specific cytokines.
This class of antibody is responsible for Type
I hypersensitivity reactions (allergy, asthma
and anaphylaxis).
 IgE is increased greatly in response to
helminth (worm) parasite infection.

 It can be found as "surface antibody" on the

surface membrane of B cells or as a 5-subunit
macromolecule secreted into the blood by
activated B cells and plasma cells.
 Secreted IgM is found as a "pentameric" molecule
in blood at moderate levels (1-3g/l in adults)
 The five IgM subunits are held together by a
polypeptide (Jchain, for joining)
 Because of its pentameric configuration, IgM is
particularly good at activating Complement, via its
 Fc regions, and causing agglutination but it is very
poor at opsonization.
 IgM is the first antibody to be produced in
response to infection since it does not require
"class switch" to another antibody class.
 IgM is the largest of the immunoglobulin molecules, present in the
serum as a pentamer with ten antigen-binding sites and, because of
its large size, is restricted almost entirely to the intravascular
space.
 These macromolecules are highly efficient agglutinators of
particulate antigens, e.g., bacteria and red blood cells, and they
activate complement through the classical pathway with a high
degree of efficiency.
 This class of immunoglobulin appears to be of greatest importance
early in the primary immune response.
 When a foreign antigen is introduced into a host for the first time,
the rapid synthesis of IgM antibodies ensures protection before
IgG are produced.
 The transition from the production of IgM to IgG and the other isotypes
occurs through a ‘‘class switch mechanism’’ involving the interaction of a
cascading set of hypermutational events
 The duration of IgM synthesis peaks within a few days and the level of
specific serum IgM declines more rapidly than the level of IgG antibodies.
 In one of the primary immune deficiencies, hyperimmunoglobulinemia M
syndrome (HIGM), the congenital absence of the CD40 ligand on T cells or of
the CD40 molecule on B cells results in the failure of the switch from IgM to
IgG, causing the hyperproduction of IgM antibody with diminished production
of IgG and the other isotypes, resulting in susceptibility to recurrent
bacterial infection
 It is the most abundant class of antibody in the blood
(serum concentration is 8-16 g/l).
 They are and they usually have a very high affinity for
antigen.
 Unlike IgM, IgG is able to rapidly leave the blood
stream and enter tissues, especially at sites of
inflammation.
 IgG is also the only class of antibody to be actively
transported across the placental barrier. Therefore
IgG provides the only antibody protection for newborns
until their own immune system begins to produce
antibodies in response to antigen.
 IgG is very good at activating Complement, and is the
best antibody for opsonization using Fc receptors on
phagocytes.
 IgG also plays an important role in neutralizing toxins
produced by pathogens in the blood and tissues.
 The IgG are the most abundant of the immunoglobulins and
achieve significant concentrations in both the vascular and
extravascular spaces.
 They have a relatively long half-life (t1/2) of ~23 days, cross
the placenta, and are able to activate complement through
the classical pathway
 This class of immunoglobulin, through its antigen-recognition
function, is thought to contribute to protective immunity
against many infectious agents, including bacteria, viruses,
parasites, and some fungi.
 In addition to its role in the blood, IgG also provides antibody
activity in tissues by exerting its effector function.
 In the human, receptors for the Fc region exist on several types of
phagocytic cells, including monocytes, macrophages, dendritic cells,
neutrophils, and some lymphocyte subsets, such as NK cells (i.e.,
lymphocytes that carry out ADCC) (Table 2).
 Target cells coated with IgG antibodies directed against cell surface
antigens may be eliminated through this ADCC mechanism.
 This occurs through the action of cytotoxic NK cells, which bind to
the surface-coated IgG antibodies through their Fc receptor, thus
allowing these cells to come into close contact with and kill the target
cells by apoptosis.
This type of antibody is found on the surface
of most B lymphocytes just like sIgM.
The exact function of this antibody is
unknown but it appears that it acts as an
antigen receptor and that it is needed for B
cell activation.
A very small amount of IgD is secreted, and
its functions as a secreted antibody are
unclear.
Receptor Principal Affinity for Cell distribution Effect(s) following binding to
name antibody ligand antibody
ligand

FcγRI IgG1 and High (Kd ~ Macrophages Phagocytosis

(CD64) IgG3 10 −9 M)
Neutrophils Cell activation
Eosinophils Activation of respiratory burst

Dendritic cells Induction of microbe killing

FcγRIIA IgG Low (Kd > Macrophages Phagocytosis
(CD32) 10 −7 M)
Neutrophils Degranulation (eosinophils)
Eosinophils
Platelets
 Langerhans cells
FcγRIIB1 IgG Low B Cells No phagocytosis
(CD32) (Kd
>
10
−7
M)
Mast cells Inhibition of cell activity
FcγRIIB2 IgG Low Macrophages Phagocytosis
(CD32) (Kd
>
10
−7
M)
Neutrophils Inhibition of cell activity
Eosinophils
FcγRIIIA IgG Low NK cells Induction of antibody-
(CD16a) (Kd dependent cell-mediated
> cytotoxicity (ADCC)
10
−6
M)
Macrophages Induction of cytokine release
(certain tissues) by macrophages
 Lifespan of a B cell may be divided in an antigen-independent and an
antigendependent phase.
 In the antigen-independent phase, a hematopoietic stem cell undergoes a
series of divisions, giving rise to the generation of a large and diverse
repertoire of daughter clones of B cells of increasing maturity, i.e., pro-B
cell, pre-B cell, and immature B cell, characterized by the acquisition of
certain surface markers, e.g., CD19 and BCR.
 The genes responsible for immunoglobulin synthesis are rearranged during
the antigen-independent phase . This process continues during the
antigendependent phase, when antigen is encountered and during which
immunoglobulin genes undergo additional genetic modifications (somatic
mutation and isotype switching).
 During this antigen-independent phase, the genes encoding for the heavy and
light chains (V, D, and J) are cut and joined by DNA recombination, known as
somatic recombination (Figure 2).
 The recombination of V, D, and J gene segments is carried out by a process called
variable (diversity) joining [V(D)J] recombination and is directed by a set of enzymes
called recombination activating gene-1, recombination activating gene2 (RAG-1 and
RAG-2)
 RAG-1 and RAG-2 recognize sequences called recombination signal sequences (RSSs)
that flank the 3′ side of V segment, both sides of the D segment, and the 5′ side of
the J segment.
 A successful heavy-chain gene rearrangement resulting in the synthesis of a functional
pre-BCR stops VH to DJH rearrangement, and the pre-B cell begins to divide into a
clone of cells, all expressing the same H chain.
 Schematic representation of the chromosomal locations of genetic loci, which control
immunoglobulin synthesis together with the progressive steps of gene rearrangement,
transcription, and translation involved in the synthesis and assembly of the various parts of an
immunoglobulin molecule. The loci for light chains are found on chromosome 2 (kappa) and
chromosome 22 (lambda) and for the heavy chain on chromosome 14. [Reproduced with
permission from Bellanti, JA (Ed). Immunology IV: Clinical Applications in Health and Disease. I
Care Press, Bethesda, MD, 2012].

Recombinases are again re-expressed and the

cells randomly join V and J gene segments on the
kappa chain locus. After LC expression with the
H chain signals the B cell to stop expressing
recombinase; at this stage it is called an
immature B cell and has expressed IgM on its
membrane.
The random events occurring during rearrangement
and assembling of the BCR may, some times, lead to
 the production of autoreactive B cells responsible
for autoimmune disease.
Elimination of these potentially damaging
specificities (negative selection) is ensured by two
mechanisms known as clonal deletion and receptor
editing.

As the B cells enter the lymph nodes via the T

cell areas, they encounter antigen, which binds
to their BCR and stimulates the B cell to begin
proliferating.
Some B cells at this stage become short-lived IgM
secreting plasma cells. Most B cells endocytose their
antigen-BCR complexes, process the antigen, and
present it on their membranes in combination with
MHC-II.
Protein antigens require the participation of Th2 cells,
whereas nonprotein antigens activate B lymphocytes
without the contribution of CD4+.
 Several elements contribute to the variability of the repertoire,
including the large number of V, D, and J genes, their random
rearrangement, the additional sequences created by the DNA repair
mechanisms, and finally the combination of HC and LC.
 During the immune response, few B cells reacting to the antigen will
start to proliferate in the germinal centers. At this time, the
introduction of random mutations into the variable region of Ig genes
(somatic hypermutation, SHM) results in the generation of B cells
 carrying a new BCR, which may have a lower or higher affinity for the
antigen or have acquired self-reactivity.
 The interaction with the antigen on the surface of follicular dendritic
cells, selects the cells with the highest affinity, useful to the ongoing
immune reaction and which will generate plasma cells producing high
affinity antibodies first of IgM and later of switched isotypes. This
process is known as affinity maturation.
 Memory B cells carrying mutated and selected Ig genes will remain in
the organism for a long time to prevent reinfection with the same
pathogen.
Isotype class switching, begins with the binding of
antigen to the surface IgM receptor, followed by
signaling through a cascading set of transcription
factors which then activate the expression of gene
transcripts through DNA interactions to begin the
synthesis of H chains on chromosome 14 and L chains
 on chromosomes 2 and 22 and final assembly and
release of the component parts of the molecule into a
complete immunoglobulin.
When antigen interacts with a B cell without Th2 cell
help, a continued synthesis of IgM alone occurs with no
isotype switching, in contrast to that which occurs
when B2 cells receive signals through Th2 help, where
the subsequent IgG, IgA IgE progression is seen.

 Immediately after the initial introduction of the immunogen, little or no antibody is

detected in the serum. This period is referred to as the inductive or latent period.
 The processed antigen is presented to appropriate T cells for interaction with T or B
cells for subsequent cell-mediated or humoral antibody production.
 The earliest primary response to most immunogens is characterized by the predominance
of IgM antibody; the IgG class of antibody appears somewhat later and is followed even
 later still by the production of IgA and IgE. IgM antibody production is usually
transient, and within two weeks after the initiation of the immune response,
IgG antibody predominates.
 The IgM antibody formed early during the immune response has a low affinity,
in contrast to the IgG antibody of the late immune response, which has
increased affinity and avidity.
 Upon a subsequent exposure of a previously immunized host to the same
immunogen, weeks, months, or even years later, there is a markedly enhanced
response that is characterized by the accelerated appearance of
immunocompetent T and B cells referred to as “memory” cells.
 Although IgM is produced initially in both the primary and secondary immune
responses, the duration and magnitude of IgM production in the secondary
immune response is transient and is associated with a greatly enhanced
production of antibody that is primarily of the IgG isotype.
 Subsequent antibody production is then converted from IgG to other
immunoglobulin isotypes by isotype switch.
 In the secondary immune response, the memory B cells that have already
switched their Ig isotype immediately begin to secrete that isotype.
 College: COLLEGE OF VETERINARY MEDICINE
Campus : Bayombong Campus

DEGREE PROGRAM BAS-DVM COURSE NO. VMIC 4

SPECIALIZATION COURSE TITLE Fundamentals of Immunology
YEAR LEVEL BAS-DVM 3 TIME FRAME WK NO. 5 IM
NO.

I. UNIT TITLE/CHAPTER TITLE

Chapter 5

II. LESSON TITLE

Subsets of T- lymphocytes

III. LESSON OVERVIEW

This chapter will discuss the different populations of T-lymphocytes and their functions, activation, and interactions with other cells.

XIX. IV. DESIRED LEARNING OUTCOMES

At the end of this chapter, the students will be able to distinguish the different types of Tlymphocytes and their associated function. The
student will also be able to explain how lymphocytes perform their functions and illustrate the mechanisms involved in activating them in the
presence of different pathogens/antigens.

V. LESSON CONTENT

XX. Introduction
• The T cell repertoire in a healthy adult is shaped by thymic selection (positive and negative), where naive CD4+ and CD8+ T cells can then
interact, and be primed, with “foreign” antigen in the secondary lymphoid tissues
• Antigen engagement via the T cell receptor (TCR) then shapes the repertoire of antigen-specific T cells and most likely the functional attributes
of the T cell
• Multiple phenotypes of both CD4+ and CD8+ T cells have been identified which have differing functions
• The key to understanding T cell immunity is knowing the types of T cells and how they expand and contract with antigen and how this process
is regulated
• In this section, we will deal with Treg cells and how immunity to microbes is regulated and suppressed

• Lymphocytes Perform Adaptive Immune Functions

• The cells of the adaptive immune system, in contrast to those of the innate immune system, interact with the environmental agent in a highly
discriminative way, i.e., they display specificity, heterogeneity, and memory.
• These functions are primarily carried out by two types of cells that are involved in the recognition of antigen:
o (1) the thymus-dependent or T lymphocytes, which participate in cellular responses against intracellular pathogens, organ
transplants, and malignant cells
o (2) the bone marrow or bursal-dependent B lymphocytes, which provide humoral immunity, i.e., antibody-mediated immunity
against extracellular pathogens, their toxins, and other environmental substances.
• As outlined in the previous section, a third group of cells involved in the presentation of antigen to T cells, i.e., APCs, include dendritic cells,
macrophages, and B cells (Table 1-8).
• APCs take up predominantly protein antigens, cut them into pepti-des, bind the peptides to major histocompatibility complex (MHC) molecules,
and display these presented antigens on their cell surface, where they can be recognized and bound by antigen receptors on T lymphocytes.
• T lymphocytes are identified by a surface cluster of differentiation (CD) molecule named CD3 and are comprised of two major groups: the CD4
and CD8 populations
• The CD4 cells display helper activities on other populations of cells, and in turn are subdivided into at least Th1, Th2, Th9, Th17 and T regulatory
(Treg) groups, each with a characteristic profile of production cytokines.
• The CD8 T cytotoxic population is the second major group of T lymphocytes that function in killing target cells; they are comprised of Tc1 and
Tc2 subpopulations with similar cytokine profiles as Th1 and Th2 cells.
• Collectively, the T lymphocytes play or facilitate a central role in the orchestration of all functions of the adaptive immune system and perform
four important tasks:
o (1) promotion of inflammation by cytokine production (Th1 and Th17 cells) o (2) helping B lymphocytes (Th2 cells) o

(3) regulating immunosuppressive responses (T regulatory cells) o (4) killing of unwanted target

cells (CTL)

XXI. How T cells “see” Antigen

• Because the role of T lymphocytes is to deal with intracellular infections and ‘‘altered self’’ cells (tumor cells), they must have a way to recognize
intracellular antigen.
• In addition to their role in innate immunity, dendritic cells and macrophages also play a major collaborative role in the presentation of antigen
to T lymphocytes of the adaptive immune system and are therefore referred to as APCs (Table 1).
• Following the uptake and digestion by APCs, foreign substances, usually proteins, are processed by proteolysis into peptide fragments that are
later presented to T cells in a highly discriminative manner.
• This process employs cell receptors consisting of molecules on both the surface of the APC membrane (i.e., MHC proteins) (see Chapter 10,
Bellanti JA (Ed). Immunology IV: Clinical
Applications in Health and Disease. I Care Press, Bethesda, MD, 2012 and the previous section) as well as a specific antigen-binding
receptor on the T cell membrane, the TCR
• Of these, the dendritic cells are the most potent APCs, and are particularly important in initiation and promotion of subsequent adaptive immune
responses.
• In addition to these cells of the innate immune system, B cells of the adaptive immune system, as described below, can also serve as APC Table
1. Various types of antigen-presenting cells
Type Location
Macrophages Widely dispersed in
tissues
Alveolar Lung
macrophages
Langerhans Skin
cells
 Kupffer Liver
cells
Microglial Central nervous
cells system
Dendritic cells Widely dispersed in
tissues
B lymphocytes Lymph
nodes and
other
lymphoid
tissues

XXII. Antigen Processing and Presentation Follows Different Pathways for Cytosolic (Endogenous) and Vesicular
(Exogenous) Antigen
• T lymphocytes play a pivotal role in both cell-mediated and humoral immune responses of the adaptive immune system.

• These functions are carried out by T lymphocytes that interact with antigen through the TCR.
• The processing of antigen can occur at two sites: (1) at the level of APCs or (2) at the target cell site.
• Phagocytes and other APCs play major roles in internalizing, processing, and presentation of ‘‘processed antigen’’ to T lymphocytes for induction
of immune responses carried out by both CD4 and CD8 lymphocyte populations.
• Antigen can also be processed and presented to T lymphocytes at the target cell site in a cell that has been infected with a virus, for example,
or modified by a chemical or by malignant transformation.
• Shown in Figure 1 is a schematic representation of the two modes of antigen processing at these two sites that determines which MHC the
processed antigen will react with.
Figure 1. Schematic representation of the two modes of antigen processing. Panel A: Shows the endogenous pathway, which presents processed
antigen (i.e., peptides) from a target cell to a CD8þ lymphocyte in the context of MHC-I. Panel B: Shows the exogenous pathway, which presents the
peptide products from an APC to a CD4+ lymphocyte in the context of MHC-II. [Reproduced with permission from Bellanti, JA (Ed). Immunology IV:
Clinical Applications in Health and Disease. I Care Press, Bethesda, MD, 2012].
• In the case of antigens processed by APCs by the exogenous pathway, CD4 T cells recognize antigen that has been processed into peptide
fragments (epitopes) that are then placed in a groove of the MHC-II molecule, and presented to the TCR on subsets of helper T cells (called CD4+
cells).
• Other antigens found within cells, e.g., target cells, are processed through an endogenous pathway and are delivered by MHC-I to TCR of
‘‘cytotoxic’’ T cells (CD8+ cells).

XXIII. The Interaction Between APC and T Cells Influences Which T Cells Are Activated
• CD4+ T cell activation results in the secretion of cytokines that help and regulate other cells (see Chapter 9, Bellanti, JA (Ed). Immunology
IV: Clinical Applications in Health and Disease. I Care Press, Bethesda, MD, 2012).
• The pattern of cytokine expression defines the subsets of CD4+ T cells: Th1, Th2, Treg1, Th3, and Th17 cells.
• Th1 cells secrete interferon gamma (IFN-y) and create a milieu in which key cytotoxic effectors— macrophages, natural killer cells, and cytotoxic
CD8+ T lymphocytes—are activated, generating cellmediated immunity.
• Th2 cells secrete IL-4 and IL-10 (and other cytokines) and help antigen-primed B lymphocytes differentiate into plasma cells and secrete
antibodies, the effector molecules of humoral responses.
• T cells, Treg cells, with the phenotype CD4+CD25+, express the signature transcription factor FOXP3 and usually secrete IL-10 and transforming
growth factor beta (TGF-B).
• Cells with this phenotype are thought to recognize self-antigens and function to prevent autoimmunity and are also involved in chronic viral
infections, allergy, transplantation, and malignancy.
• Th17 cells represent a wide variety of recently described cells involved in inflammation through the elaboration of proinflammatory cytokines
and interact with IL-23 (see Chapter 9, Bellanti, JA (Ed). Immunology IV: Clinical Applications in Health and Disease. I Care Press,
Bethesda, MD, 2012).
• As described in the previous section, T cells can recognize peptide fragments that have been processed and presented by APC, i.e., dendritic
cells (DC), macrophages, and B cells.
• Figure 1-21 depicts the shaping of T cell subsets after interacting with antigen and the polarization of T cells in response to different cytokines
• Production of Th1, Th2, Th17, and two populations of Treg cells Th3 and TR1 (Figure 2), which have a variety of interactions with other cells in
performing the following functions:
 o promotion of inflammation by cytokine production (Th1 lymphocytes); o helping B lymphocytes (Th2
lymphocytes); o regulating immunosuppressive responses (Treg lymphocytes).

Figure 2. Panel A: The two main T cell populations are CD4+ and CD8+ cells. The CD4 are helper T cells and are shown highlighted with the CD4+
subsets Th1, Th17, Th2, Th3, and Tr1 and shown below are the CD8 cytotoxic T cells (faded). Panel B: Shows the molecular events in the immunologic
synapse at the CD4+/dendritic cell interface together with the cytokines that induce the Th0 differentiation into each of the subsets.
[Reproduced with permission from Bellanti, JA (Ed). Immunology IV: Clinical Applications in Health and Disease. I Care Press, Bethesda, MD, 2012].

XXIV. Cytokines that Determine T-cell Subsets

• Specific cytokines are involved in shaping the two subsets of the T-cell system: CD4+ Thelper (Th) and CD8+ Cytotoxic T Lymphocytes (CTL)

• The Th population has several effector subsets (Figure 1), including Th1, Th2, Th17, and Treg, which have roles in delayed hypersensitivity,
antibody production, inflammation, and immunosuppression (or regulation), respectively
• Th are the key orchestrators of adaptive immunity in mammals, and each effector subset mobilises a distinct module of antimicrobial immunity:
o Th direct elimination of intracellular microbial pathogens and tumors o Th2 induce expulsion of helminths o Th17 promotes resistance to
extracellular bacteria and fungi, playing important roles in protection at mucosal surfaces and in promotion of autoimmune inflammation,
as well as participating in antitumor immune responses
 o Treg suppress inflammatory reactions and ensure host autoreactive lymphocytes do not mount a response against host tissues or
innocuous environmental antigens o CTL have Tc1 and Tc2 subsets: Tc1 destroy virally-infected or malignant cells (Figure 3)

Figure 3. Schematic representation of the two major pathways of T cell differentiation: the Th and Tc populations and their subsets. Following uptake
and processing of an antigen by an APC shown in the figure as a dendritic cell, peptide is presented either to the CD8 population in the context of
MHC-I or to the CD4 subpopulation in the context of MHC-II following which a cascading set of cellular lymphoproliferative and differentiative steps
are initiated under the inductive influence of cytokines that ultimately determine their effector functions [Reproduced with permission from Bellanti
JA (Ed). Immunology IV: Clinical Applications in Health and Disease. I Care Press, Bethesda, MD, 2012].
 XXV. T cell Classification
T-cell type T-cell Glycopro Antigenpresenting Foreign Function or
receptor tein molecule stimulus defining
type corecept characteristics
or
Naive Any Any Any Any Has not
encountered an
antigen
Th1 αβ CD4 MHC II Virus/intracell Activates
ular bacteria macrophages;
causes other
cells to go on
guard against
a virus,
quarantining
it
Th2 αβ CD4 MHC II Parasites Stimulates
eosinophils,
basophils, and
mast cells to
eliminate
parasite;
stimulates B cells
to produce IgE
and IgA
antibodies
Th9 αβ CD4 MHC II Parasites Supports CD4 +
T-cell expansion
and survival;
recruits mast
cells
Th17 αβ CD4 MHC II Extracellular Recruits
bacteria/fungi neutrophils,
which kill many
bacteria and
fungi
T-follicular αβ CD4 MHC II Any In follicles of
helper (Tfh) spleen and
tonsils,
stimulates
Bcell
production
of
highaffinity
antibodies
Regulatory αβ CD4 MHC II NA Regulates T-cell
T cell (Treg) activation and
proliferation
Cytotoxic T αβ CD8 MHC I Any Releases vesicles
lymphocyte containing
(CTL) perforin, which
punctures the
target cell, and
granzyme, which
induces
apoptosis,
into the vicinity
of infected cells,
destroying them

Central αβ CD4 or CD8 MHC II or MHC I, Any Responds to

memory respectively secondary
(Tcm) infections by
proliferating;
also circulates
in blood,
peripheral
organs, and
lymphoid
organs,
fighting
secondary
 infections, but
less so than
Tem; that is,
focuses on
proliferating

Effector αβ CD4 or CD8 MHC II or MHC I, Any Travels around

memory respectively in tissues
(Tem) fighting
secondary
infections; also
circulates
through blood
supply but
avoids
lymphoid
organs (spleen,
lymph nodes,
lymphatic
vessels); less
proliferative
than Tcm
Tissueresident αβ CD4 or CD8 MHC II or MHC I, Any Stays in the
memory respectively tissue where it
(Trm) previously
fought an
infection and
fights
secondary
infections
there; does
not recirculate
in blood or
revisit
lymphoid
organs
Virtual αβ CD8 Responds Any Antigen-
memory to inexperienced
cytokines, cell that leaves
not the thymus
antigens and becomes
an activated
memory cell
without first
encountering
an antigen;
cytokines can
activate this
cell type;
particularly
important
early in life,
when immune
system has not
seen many
antigens, and
late in life,
when it is
weakened
Innate αβ CD8 Responds Any Antigen-
memory to inexperienced
cytokines, memory cell
not that develops
antigens and becomes
activated in
the thymus
Memory αβ CD4 or CD8 MHC II or MHC I, MHC- Stem cell–
stem cell respectively restricted like
(Tscm) antigens progenitor
of all other
postthymic
T cells
 (both
memory
and
effector)
γδ T cells γδ Usually CD277 Bacteria In humans
doublenegative recognizes
(display pyrophosphate
neither CD8 intermediates
nor of bacterial
CD4) lipid synthesis;
in humans,
found in
peripheral
blood; may
recognize
other antigens,
too (little is
known about
this cell type)
Table 2. The function or defining characteristics of T cell types [Taylor, A.P. The Ever-Expanding T-Cell World: A Primer. The Scientist. August 7,
2017.

XXVI. B cell Interaction with CD4+ T cells

• The antigen primed B cells, expressing antigen-specific BCR’s, interacts with the Th2 CD4+ T cells (in the germinal centres)
via MHC-II

• This cognate interaction is critical for B cells to differentiate to plasma cells

XXVII. Th1 Cells Signal Macrophages to Kill Engulfed Intracellular Bacterial Pathogens
• Mycobacterium tuberculosis is an example of a bacterium that can be phagocytosed by macrophages and is able to protect itself from being
killed by virtue of its intracellular location within the phagolysosome.
• The organism can now replicate in the phagosome, protected from the harmful effects of the humoral antibody immune response.
• Th1 cells recognize peptides on the macrophage membrane in association with MHC-II, produce cytokines, and signal the macrophage with IFN-
g together with other cytokines to kill the bacteria.
• Other Th1 cytokines also attract more macrophages to the infection site and activate them to produce inflammatory cytokines that result in
delayed-type hypersensitivity, e.g., the TST.
• One outcome of the host-microbial interaction between the macrophage and the intracellular location of the tubercle bacillus is the killing of
the tubercle bacillus resulting from enhanced macrophage killing of the bacillus by activation by IL-12 and later Th1 production of IFN-g
• Or there is failure of killing when the replication of the tubercle bacillus overwhelms the macrophage capacity.
XXVIII. Activated CD8 Cytotoxic T Lymphocytes kill target cells
• Cytotoxic CD8+ T cells effect their function by recognizing peptide bound to MHC-I
• The peptide has been endogenously processed either directly (derived from viral genes, such as HIV) or indirectly, through cross-presentation
(derived from effete or dead bacterially infected cells, such as mTB).
• Figure 4 shows activated CD8+ cytotoxic T lymphocytes recognizing a bacterial peptide presented by HLA-B27 (derived from Immunopaedia
case study: 14 year old with severe hip pain)
• This causes liberation of cytotoxic granules (perforin and granzymes) from the CD8+ T cell which then cause lysis and apoptosis of infected target
cells
Figure 4. Recognition of a bacterial peptide by activated CD8+ cytotoxic T lymphocytes after crosspresentation and endogenous processing of the
bacterial proteins. Killing is effected by the release of granzymes and perforin from the activated CD8 cell upon contact. [from Immunopaedia case
study: 14 year old with severe hip pain].

Cell-mediated
immunity

VMIC 4 lecture
Topic
 XXIX. Duality of Immune System

Cell Mediated Immunity- Involves specialized set of

lymphocytes called T cells that recognize foreign antigens
on the surface of cells, organisms, or tissues:
• Helper T cells
• Cytotoxic T cells
T cells regulate proliferation and activity of other cells of
the immune system: B cells, macrophages, neutrophils,
etc.
Defense against:
• Bacteria and viruses that are inside host cells and
are inaccessible to antibodies.
• Fungi, protozoa, and helminthes
• Cancer cells
• Transplanted tissue
 Relationship Between Cell-Mediated and Humoral Immunity

Antibody production

T-Dependent antigens:
• Antibody production requires assistance from T helper (TH ) cells.
• A macrophage cells ingest antigen and presents it to TH cell. • TH cell
stimulates B cells specific for antigen to become plasma cells.
• Antigens are mainly proteins on viruses, bacteria, foreign red blood cells,
and hapten-carrier molecules.
T-Independent Antigens:
• Antibody production does not require assistance from T cells.
• Antigens are mainly polysaccharides or lipopolysaccharides with
repeating subunits (bacterial capsules).
• Weaker immune response than for T-dependent antigens.
 XXX. Cell Mediated Immune Responses
Primary function of cell mediated response
• Eliminate intracellular pathogens
• Eliminate tumor cells
Both Ag-specific and non-specific cells are involved
• Ag-specific: CD8+ cells (TC) and TH (DTH)
• Non-specific: Macrophages (MΦ), neutrophils, NK cells
Both Ag-specific and non-specific cells require cytokines

Humoral and cell mediated response collaborate with each other

•Example: MΦ use antibodies as receptors to recognize target
cells
 XXXI. Cell Mediated Immunity (CMI)
CMI may play a role in harmful conditions
• Hypersensitivity type IV (contact dermatitis)
• Graft rejection
•Autoimmune diseases
Cell mediated cytotoxicity is mediated by
• T-cytotoxic cells (Tc Cells)
• Natural killer cells (NK cells)
•Activated macrophages
XXXII. CMI works by complex mechanisms
 XXXIII. CMI helps in
Delayed hypersensitivity
Immunity in infections caused by obligate
and facultative intracellular parasites:
• tuberculosis, leprosy, listeriosis, brucellosis
• Fungi: Histoplasmosis, Coccidioidomycosis,
Blastomycosis
•Parasites: Trypanosomiasis
• Transplantation immunity: immunology in
transplantation, malignancy, pathogenesis of
autoimmune diseases
 XXXIV. Importance of CMI
DiGeorge Syndrome proves the importance
• No Thymus, No T-cell Mediated Immunity
• Extracellular Infections Are Effectively
Addressed
• Intracellular Infections Are NOT (viruses,
intracellular bacteria) addressed effectively Cell
Mediated Immunity Can Be Divided Into 2
Major Categories
• Effectors lyse target
 • 2 groups of cells: CTLs (specific) and NK, M (non-
specific)
• Effectors which are CD4+ and mediate DTH

• Induction of CMI
• Depends on Nature of Antigenic stimulus
• Best developed after following infection with
intracellular parasites
• Live vaccines highly stimulating • Killed vaccine not
very effective
• But effective if it contains Freund type adjuvant.
 Functions of T-cells

• Cytotoxic T-cells
recognize antigen on
surface of
virusinfected cells,
tumor cells, allograft
cells with MHC1 and
sectored lymphokines and destroy
target cells
 Functions of T-cells

• Only T cell dependent antigens lead to

development of CMI

• Certain chemicals which come in

contact with skin induces Delayed
hypersensitivity

• T Cell contain the specific receptor (

TCR )
 Functions of T-cells

• One epitope ( Antigen ) on contact with

receptor undergoes blast transformation

• Leads to Clonal proliferation

• The stimulated cells undergoes blast
transformation, Clonal proliferation

• Leads to Effectors cells and Memory cells

• T cell react on presentation with MHC

 Functions of T-cells

• Helper T cells when presented on surface of

macrophages or other cells complexes with
 Republic of the Philippines
NUEVA VIZCAYA STATE UNIVERSITY
Bayombong, Nueva Vizcaya
INSTRUCTIONAL MODULE
IM No.: IM-VMIC04-1S-2020-2021

Functions of T-
cells
MHC II molecule – leads to
release of Biological
Mediators Lymphokines – activate
Macrophages and kills
intracellular parasites

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 Republic of the Philippines
NUEVA VIZCAYA STATE UNIVERSITY
Bayombong, Nueva Vizcaya
INSTRUCTIONAL MODULE
IM No.: IM-VMIC04-1S-2020-2021

XXXV. T-cells and CMI

Cellular Components of Immunity:
• T cells are key cellular component of
immunity.

• T cells have an antigen receptor that

recognizes and reacts to a specific
antigen (T cell receptor).

• T cell receptor only recognize antigens

combined with major histocompatibility
(MHC) proteins on the surface of cells.

• MHC Class I: Found on all cells.

• MHC Class II: Found on phagocytes.

• Clonal selection increases number of T

cells.

NVSU-FR-ICD-095-00 (081220) Page 92 of _4_

 Republic of the Philippines
NUEVA VIZCAYA STATE UNIVERSITY
Bayombong, Nueva Vizcaya
INSTRUCTIONAL MODULE
IM No.: IM-VMIC04-1S-2020-2021

XXXVI. Broad view on cytokines

• Cytokines are a category of
signaling proteins and glycoproteins
that, like hormones and
neurotransmitters, are used
extensively in cellular communication

T cells only recognize

antigens associated with
MHC molecules on cell
surfaces

NVSU-FR-ICD-095-00 (081220) Page 93 of _4_

 Republic of the Philippines
NUEVA VIZCAYA STATE UNIVERSITY
Bayombong, Nueva Vizcaya
INSTRUCTIONAL MODULE
IM No.: IM-VMIC04-1S-2020-2021

NVSU-FR-ICD-095-00 (081220) Page 94 of _4_

 Republic of the Philippines
NUEVA VIZCAYA STATE UNIVERSITY
Bayombong, Nueva Vizcaya
INSTRUCTIONAL MODULE
IM No.: IM-VMIC04-1S-2020-2021

Central role of helper T

XXXVII.

cells

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