Course Code: MMV-105:

Course: Immunology (4 Credits=100 Marks)

Unit-I: Overview of immune system, primary and secondary organs of immune

system, cells of the immune system, innate immune response, complement
system, Humoral immunity and cell-mediated immunity.
 Questions

§ List the body s nonspecific defense mechanisms and explain the

function of each
§ Define specific resistance, and identify the properties of immunity
§ Distinguish between humoral (antibody-mediated) immunity and cell-
mediated immunity
§ Describe the mechanisms of B-lymphocyte activation and their
differentiation into plasma cells and memory cells
§ Explain the structure and function of antibodies
§ Describe the types of T- lymphoctyes and the role of each in the
immune response
§ Describe the primary and secondary responses to antigen attack
§ Identify the major components of the lymphatic system and explain
their functions
§ Describe the structure of lymphatic vessels
§ Explain the role of lymphocytes and where they are produced
§ Describe the functions of the lymphatic tissues and organs
§ Describe several examples of abnormal immune responses and their
role in immune disorders
Immune Cells
 Immunity I: Innate (nonspecific) Defenses
Lecture Outline

1. Overview of the Immune System: Innate vs. Adaptive Defenses

2. Innate-Nonspecific Defenses

A. First Line of defense: Physical barriers

B. Second Line of defense:

- Major cellular components

• Phagocytes
• Basophils

• Eosinophils

• NK cells

- Chemical signals

• Interferons

• Complement Proteins

• Inflammation

• Fever (pyrogens)
 Why do we need an Immune System?

Introduction:
Pathogens are microscopic organisms that cause disease
(Each attacks in a specific way)
Viruses, Bacteria, Fungi, Parasites, and Protozoans
Other environmental substances challenge the lymphatic system
Environmental pathogens (poison ivy, etc)
Toxins (not metals – joint transplants)
Abnormal body cells such as cancers

The Immune system is coupled with the Lymphatic system

 A typical immune response

INNATE IMMUNITY ACQUIRED IMMUNITY

Rapid responses to a Slower responses to
broad range of microbes specific microbes

External defenses Internal defenses

Skin Phagocytic cells

Humoral response
Mucous membranes Antimicrobial proteins (antibodies)

Secretions Inflammatory response

Invading
microbes Natural killer cells Cell-mediated response
(pathogens) Complement (cytotoxic
lymphocytes)
 Where and how do we defend against disease pathogens?

§ Immunity is
§ The ability to resist infection and disease
§ Many body cells and tissues are involved in the implementation of immunity
(Not just lymphocytes and other immune cells)
§ Innate (Nonspecific) Defenses (we are born with this capability)
§ Can involve the epithelium on the body surface (integument) or occur in
connective tissue, in the GI system and/or may involve a cellular response
§ Respond immediately to many different harmful agents
§ Do not require a previous exposure to a foreign substance
§ Adaptive (Specific) Defenses (these components develop with time)
§ Lymphocytes (B, T): Are major players in the immune response but other cells
and participants in the innate system work cooperatively
§ Identifies, attacks, and reinforces immunity to a specific pathogen

These 2 categories of immune mechanisms work together

 Overview of the Immune System

Immune System

Innate immunity Adaptive immunity

Immediate response to wide Delayed response to
array of substances specific antigen

Skin and mucosal Nonspecific T-lymphocytes B-lymphocytes

Membranes & barriers internal defenses (cell-mediated (humoral immunity)
(prevent entry) immunity)

Cells Chemicals Physiologic responses Plasma cells

(e.g., macrophages, (e.g., interferon, (e.g., inflammation, (synthesize and
NK cells) complement) fever) release antibodies)

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
 Innate - Nonspecific Defenses: 7 categories

§ 1st line of defense

§ Physical barriers: Skin and mucosal barriers - keep hazardous materials
outside the body
§ 2nd line of defense
§ Phagocytes: neutrophils and macrophages: engulf pathogens and cell debris
§ Immunological Surveillance: natural killer cells (NK cells) destroy abnormal
cells.
§ Interferons: Chemical messengers that coordinate the defenses against viral
infections. Antiviral proteins do not kill viruses but block replication in cell
§ Complement: Complement action of antibodies to destroy pathogens
§ Inflammation: Triggers a complex inflammatory response limiting the spread
of infection
§ Fever: A high body temperature which increases body metabolism,
accelerates defenses and accelerates body defenses
 Physical Barriers – 1st line of defense

• Outer layer of skin; Hair; Epithelial layers of internal passageways;

dermis

• Secretions that flush away materials: Sweat glands, lacrimal glands,

mucus, and urine

• Secretions that kill or inhibit microorganisms: Enzymes, antibodies (IgA

in tears), and stomach acid.

• Direction of secretion (one way direction - urination) can prevent or

retard the movement of pathogens into the body
 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Major cellular components of the Innate- Nonspecific System

Figure 21.4
All formed elements (except
T-lymphocytes) leave the bone
marrow and directly enter Erythrocyte
and circulate in the blood.
Platelets
WBCs
Neutrophil

Red bone marrow Eosinophil

= site of origin
Basophil

Monocyte Macrophage
Pre-T-lymphocyte

B-lymphocyte Plasma cell

T-lymphocytes
mature in the
Thymus
thymus prior to
circulating in T-lymphocyte T-lymphocyte
the blood. maturation
Phagocytes: engulf bacteria, release toxic chemicals, present
antigens
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Neutrophil, macrophage, eosinophil: Phagocytic cells

Infectious agent Macrophage Also an APC

engulfed Lysosome
Phagosome
Phagolysosome
destroys infectious
agent

Residue is exocytosed

Originally WBCs – they migrate into connective tissue

The clean-up crew : phagocytose debris and digest via lysosomes
Neutrophils enter first then macrophages (derived from monocytes)
Eosinophils involved with parasitic infections and antigen-antibody
complexes
 Basophils open up vessels & increase blood flow
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Basophil and mast cell: Proinflammatory chemical-secreting cells

Arteriole
Vasodilation
Basophil

Histamine
Increases capillary
permeability Capillary

Heparin
Anticoagulant
Eicosanoids
Increases inflamation Venule

(b)
 Eosinophils: Parasite-Destroying Cells

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Eosinophils: Parasite-destroying cells

Cytotoxic chemicals
Parasitic worm

Eosinophil
(d)

Eosinophils also phagocytose antigen-antibody complexes

How do phagocytes invade the area of infection or injury?

- Inflammatory factors –
released by mast cells, etc.
- Vasodilation – capillaries
become permeable
- Margination – WBCs slow
down & align on the vessel
wall
-Diapedesis – blood cells
leave vessels & enter the CT
-Chemotaxis – blood cells
follow a chemical gradient
(move toward the source ie.,
bacteria)
 Immunological surveillance: NK cells
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NK cell: Apoptosis-initiating cells

Perforin and
granzyme

Perforin forms a
transmembrane pore
Granzymes
enter
NK cell pore, causing
apoptosis of cell
Unhealthy or
unwanted cell

Apoptosis

Recognizes unhealthy cell (usually expressing abnormal proteins or viral

proteins – uses perforins (make a hole in the membrane) and granzymes
(initiate apoptosis – programmed cell death via gene expression
Interferons – signaling molecule (cytokine) released by viral-
infected cells

•Binds receptors of neighboring cells:

• promotes macrophage function and apoptosis of infected cell
• triggers synthesis of enzymes destroying viral RNA or DNA
• triggers synthesis of enzymes that inhibit synthesis of viral proteins
 Complement Proteins
~11 antimicrobial proteins in plasma – complements functions of antibodies
They have a number of functions (below) to defend against pathogens
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Opsonization Inflammation Cytolysis Elimination of

immune complexes
Complement Complement
Antigen

C Mast cell Basophil Neutrophil Macrophage Antibody

MAC
protein Complement
C
Pathogen Erythrocyte
Pathogen
Inflammation
Macrophage
Complement (C) cross-links
immune (antigen-antibody)
Complement (C) binds to Complement activates and attracts various cells of Complement proteins create complexes to erythrocyte and
pathogen; acts as opsonin innate immunity. MAC to lyse cell. transports to liver and spleen.

Opsonin – coats pathogen to make appear different and thus recognizable by

macrophages
Inflammation - Activates mast cells, basophils, neutrophils, and macrophages
to increase inflammatory response -
Cytolysis – causes cell lysis (Big MAC attack)
Eliminates Antigen-Antibody complexes on RBCs killed in spleen
 Innate Immunity: Inflammation

§ Redness - increased blood flow

§ Heat - increased blood flow and increased metabolic activity

§ Swelling - increase in fluid loss – capillaries to interstitial space,

capillaries become more permeable due to histamine and other chemicals

§ Pain - stimulation of pain receptors from compression from interstitial

fluid; chemical irritation by kinins, prostaglandins, microbe substances

§ Loss of function - (may occur in severe cases)

§ Acute inflammatory response

§ a local, nonspecific response -- typically lasts 8-10 days

§ sometimes persists in process of chronic inflammation

 Innate Immunity: Inflammation

• Immediate, local, nonspecific response

• Major effector of innate immunity that helps eliminate infectious

agents

• 1st step: chemicals like histamine, leukotirenes, prostaglandins and

chemotactic factors released

• 2nd step: response in blood vessels = vasodilation and increased

capillary permeability

• 3rd step: leukocytes (WBCs) recruited via margination and

diapedesis. Also cells undertake chemotaxis and migrate toward (up
the gradient) of chemical agents (bacterial secretions)

• Neutrophils, eosinophils, macrophages clean up the area

 Inflammation

Injured
tissue Formation of
exudate and washing
of infected area
Exudate
Bacteria
Lymphatic capillary
Chemotaxis Lymph

Chemical
gradient

1 Release of inflamatory 2 Vascular changes 3 Recruitment of 4 Delivery of Increase in fluid

and chemotactic factors include immune cells plasma uptake by lymphatic
• Vasodilation of • Margination proteins capillaries
arterioles • Diapedesis
Mast cells
• Increase in capillary • Chemotaxis
permeability Margination Diapedesis
• Display of CAMs
CAMs

Basophil

Neutrophil

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 Innate Immunity: Fever

• Fever
• Abnormal elevation of body temperature -- at least 1 C from normal (37 C)

• May accompany inflammatory response

• Due to excess fluid loss so requires increased fluid intake to prevent dehydration

• Events of fever
• Results from
• release of pyrogens such as interleukin 1, interferons

• toxins from infectious agents, drug reactions toxins, brain tumors

• Pyrogens released and circulate through the body

• target hypothalamus and cause release of prostaglandin E2

• raises temperature set point of hypothalamus

 Innate Immunity: Fever

• Benefits of fever
• Inhibits reproduction of bacteria and viruses
• Promotes interferon activity

• Increases activity of adaptive immunity

• Accelerates tissue repair

• Increases CAMs on endothelium of capillaries in lymph nodes

• additional immune cells migrating out of blood

• Recommended to leave a low fever untreated

• Risks of a high fever significant above 100 degrees F

• High fevers potentially dangerous above 1030 in children

• Changes in metabolic pathways and denaturation of proteins

• Possible seizures, irreversible brain damage at greater than 1060, death above 1090
 Summary of Innate - Nonspecific Processes

o Barriers – epithelium, secretions , fluid flow

o Cells: phagocytes (neutrophils, macrophages, eosinophils),

NK cells

o Chemical signals – inteferons, complement proteins,

inflammatory mediators, pyrogens for fever

Nonspecific (Innate) because each process works

no matter what the problem is. On an evolutionary basis
the innate mechanisms were present prior to the
development of lymphocytes and the Adaptive Processes
Adaptive immunity
 Adaptive immunity

Refers to antigen-specific defense mechanisms that take

several days to become protective and are designed to
remove a specific antigen. This is the immunity one
develops throughout life.

There are two major branches of the adaptive immune

responses: humoral immunity and cell-mediated
immunity.
 Humoral Immunity

§ humoral immunity involves the production of antibody molecules in

response to an antigen and is mediated by B-lymphocytes.

Cell Mediated Immunity

• CMI involves production of cytotoxic T-lymphocytes,
activated macrophages, activated NK cells and
cytokines in response to an antigen and is mediated by T-lymphocytes.
 Antigens

§ Ags are molecules that elicit an immune response in the body

§ Ags can be:

§ Proteins
§ Polysaccharides

§ Conjugates of lipids with

§ Proteins (lipoproteins)

§ Polysaccharides (glycolipids)
 Antigens II

§ Ags that enter body from environment include:

§ Inhaled macromolecules; e.g., cat hair proteins asthma
§ Ingested macromolecules; e.g. shellfish proteins allergy
§ Molecules introduced beneath the skin; e.g. splinter, vaccine
§ Exogenous antigens

• Ags generated within the cells of the host:

- Proteins encoded by viral genes that have infected a cell
- Aberrant proteins that are encoded by mutant genes; e.g. proteins from
mutated genes in cancer cells
- Endogenous antigens
Antigen Presentation

Initial immune response to any

Ag requires the Ag be recognized
by a T cell.
This is best exemplified by AIDS
w/loss of CD4+ T cells.
Two categories of Ags are
processed and presented to T cells
Dendritic by different mechanisms:
cell
B cell Exogenous Ags
Endogenous Ags

T cell activated; cytokines released;

Th1, activate MF; Th2, activate B cells
 Exogenous antigens

§ E. Ag’s (inhaled, ingested, injected), taken up by APCs:

§ Phagocytic cells; dendritic cells, macrophages

§ B lymphocytes (produce antibodies)

• APCs
- engulf Ags by endocytosis (endosome-lysosome)
- Ag degraded into short peptides
- peptides displayed at cell surface nestled w/i a class II histocompatibility
molecule
- recognized by CD4+ T cells
Endogenous Antigens

§ Ags that are generated w/i a cell; e.g.,

Mt bug, viral proteins in infected cells

§ Peptides displayed at cell surface

nestled w/I a class I histocompatibility
molecule

§ Recognized by CD8+ T cells

§ CD8+ T cells are cytotoxic

§ Have machinery to destroy infected cell

T cell activated; kills infected cell

B Lymphocytes: A Special Case
§ Process Ag by MHC II pathway but:
§ B cells engulf Ag by receptor mediated
endocytosis
§ BCRs are surface antibodies anchored in
plasma membrane

§ Affinity of BCR for an Ag epitope is so high that

the B cell can internalize the Ag at
concentrations thousands of times smaller than
needed for a macrophage

§ CD4+ T cell recognizes displayed Ag and is

stimulated to release cytokines

§ These stimulate B cells to grow into a clone of

cells; plasma cells

§ These plasma cells synthesize BCRs with

identical binding site for the Ag epitope but w/o
the transmembrane tail

§ The Abs are secreted

release Th2 cytokines and Interferons
 Cytokines

§ Small proteins – secreted by cells of

the immune system

§ Affect the behaviour of other cells

§ signalling molecules

§ Key players in innate and acquired

immunity
 Which cells release cytokines ?

Cells of the immune system:

§ Neutrophils – when they encounter a pathogen

§ Macrophages – when they encounter a pathogen

§ TLRs – bind to microbe / components of a microbe

§ NK cells – on encountering a microbe infected cell /tumour cell

§ Lymphocytes – when they are activated

 Examples of cytokines

§ Interferons

§ Interleukins

§ Tumour necrosis factor (TNF)

 Interferons (IFN)

§ Signalling proteins produced by virus infected monocytes and

lymphocytes

§ Secreted proteins – Key anti-viral proteins

§ “Interfere” with virus replication

§ Warn the neighbouring cells that a virus is around...

§ If we did not have IFNs – most of us may die of influenza virus infection
Clonal Expansion
Types of T cells