Introduction to Immunology 1

Chapter 16 & 17 of Tortora; pg 465 - 517.

Notes are mostly taken from Tortora, Funke and Chase. Microbiology: An Introduction. (12 Ed.) Pearson
 CONCEPT OF IMMUNITY

• Immunity – ability to ward off disease caused by microbes or their products, and to protect
against environmental agents such as pollen, chemicals and animal dander (very tiny particles of
skin that had been shed from animals with fur or feathers)
• Lack of immunity is referred to as susceptibility
• Generally, there are two types of immunity:
• Innate immunity – non-specific defence of host
• comprises the cells and mechanisms that defend the host from infection by other organisms
• does not provide long-lasting immunity to the host
• Acquired or Adaptive immunity – specific defence
• composed of highly specialized, systemic cells and processes
• eliminate pathogens or prevent their growth
• Provides long-lasting immunity
Innate immunity
 LEARNING OUTCOMES

• Describe the role of the skin and mucous membranes in innate immunity.
• Classify leukocytes, and describe the roles of granulocytes and monocytes.
• Describe the eight different types of white blood cells and their functions.
• Differentiate the lymphatic and blood circulatory system.
• Define phagocyte and phagocytosis and describe the process of phagocytosis.
• Identify six mechanisms of avoiding destruction by phagocytosis.
• List the stages of inflammation.
• Describe the cause and effect of fever.
• Explain the three pathways of activating complement system
 FIRST LINE OF DEFENCE

• Physical Factors
• Skin – i.e. the largest organ of human in terms of surface area and weight
• Very effective barrier against MOs invasions
• Consist of dermis and epidermis
• Dermis is the inner, thicker portion of the skin, composed of connective tissue
• Epidermis is the outer, thinner portion, in direct contact with the external environment
• Consist of many layer of continuous sheets of tightly packed epithelial cells
• The top layer of epidermal cells is dead and contain protective waterproof protein
called keratin
• Periodic shedding of the top layer effectively remove microbes
• Dryness of the top layer → not conducive for bacterial growth (most normal flora are
most abundant on moist areas of the skin)
Top layers
of epidermis
with keratin
Epidermis

Dermis

Taken from Tortora, Funke and Chase. Microbiology:

An Introduction. (12 Ed.) Pearson
 FIRST LINE OF DEFENCE

• Physical Factors
• Mucous membrane
• Consist of epithelial layer and an underlying connective tissue layer
• Lines the entire GI, respiratory and genitourinary tracts.
• Epithelial layer secretes mucus ( slightly viscous glycoprotein produced by goblet cells) –
• Mucus traps many MOs the enters respiratory and GI tract while ciliary escalator moves the
mucus up and out
• The flow of urine moves MOs out of the urinary tract, and vaginal secretions move MOs out of
vagina
• Peristalsis, defecation, vomiting, diarrhea also targets to expel MOs
 FIRST LINE OF DEFENCE

• Lacrimal apparatus – protects the eyes

• Manufactures and drains tears to dilute and wash away irritating substances and MOs before
infection occurs

Lacrimal glands

Upper
eyelid

Lacrimal
canal

Nasolacrimal
duct

Taken from Tortora, Funke and Chase.

Microbiology: An Introduction. (12 Ed.) Pearson
 FIRST LINE OF DEFENCE

• Chemical Factors
• Fatty acids in sebum and earwax inhibit the growth of pathogenic bacteria - low pH (3-5)
• Perspiration washes MOs off from skin
• Lysozyme found in tears, saliva, nasal secretion, and perspiration
• High acidity of gastric juice prevents microbial growth in the stomach
• Vaginal secretion- contains glycogen
• Glycogen is broken down to lactic acid by Lactobacillus (one of microflora of the vigina)
• Lactic acid lowers the pH (3-5) – inhibits microbes
• Urine (besides having lysozyme) also has low pH
 SECOND LINE OF DEFENCE

• Includes defensive cells, inflammation, fever and antimicrobial substances

• Before we go deeper, let’s look at components of blood

• Blood consist of fluid called plasma and formed elements (cells & cell fragments suspended
in plasma)
• Formed elements https://goo.gl/images/UVHGQa

• Erythrocytes or RBC
• Leukocytes or WBC
• platelets
 SECOND LINE OF DEFENCE

• Leukocytes are divided into two main categories based on their appearance
under a light microscope
I. Granulocytes – large granules in their cytoplasm; 3 types
1. Neutrophils (60-70% of leukocytes)
• Stained pale lilac
• Aka polymorphonuclear leukocytes (PMN) – nucleus have 2-5 lobes
https://goo.gl/images/99egwH
• Highly phagocytic and motile. Have the ability to leave the blood and
enter infected tissue

Taken from Tortora, Funke and Chase.

Microbiology: An Introduction. (12 Ed.) Pearson
 SECOND LINE OF DEFENCE

I. Granulocytes (cont.)
2. Basophils
• Blue purple with methylene blue
• Release substances like histamine that are
important in inflammation

https://goo.gl/images/miGogn

Taken from Tortora, Funke and Chase.

Microbiology: An Introduction. (12 Ed.) Pearson
 SECOND LINE OF DEFENCE

I. Granulocytes (cont.)
3. Eosinophils
• Stain red or orange with eosin
• Somewhat phagocytic and have the ability to leave the
blood
• Major function is to produce toxic proteins against
parasites such as helminths
• Their number increases during parasitic infections https://goo.gl/images/3cx9zB

Taken from Tortora, Funke and Chase.

Microbiology: An Introduction. (12 Ed.) Pearson
 SECOND LINE OF DEFENCE

II. Agranulocytes – also have granules in cytoplasm but not visible under light microscope; 3
types
1. Monocytes
• Not actively phagocytic until they leave circulating blood
• Mature into macrophages (active phagocytic)
• Macrophages also dispose warned out blood cells

Taken from Tortora, Funke and Chase.

Microbiology: An Introduction. (12 Ed.) Pearson
 SECOND LINE OF DEFENCE

II. Agranulocytes (cont.)

2. Dendritic cells
• Have long extensions that resembles dendrites of nerve cells
• Especially abundant in the epidermis of skin, mucous membrane, thymus and lymph
nodes
• Destroy microbes by phagocytosis and initiate adaptive immune response

Taken from Tortora, Funke and Chase.

Microbiology: An Introduction. (12 Ed.) Pearson
 SECOND LINE OF DEFENCE

II. Agranulocytes (cont.)

3. Lymphocytes – NK cell, T cells and B cells
• Natural killer cells (NK) found in blood and spleen, lymph nodes and red bone marrow
• Kill wide variety of infected cells and certain tumour cells
• Attack any body cells that are abnormal by releasing vesicles containing protein
perforins → creates channels in the membrane causing extracellular fluid to enter cell
→ cytolysis
• Also produce granzymes – protein digesting enzymes → apoptosis (self-destruction)
• T cells and B cells
• Non-phagocytic cells but play key roles in adaptive immunity (discussed later)
 Taken from Tortora, Funke and Chase.
Microbiology: An Introduction. (12 Ed.) Pearson
 SECOND LINE OF DEFENCE

• In cases of infection, often blood samples are taken to perform a differential white blood cell
count to find clues on the nature of infection
• Increased no. of eosinophils → indicates parasitic infection
• Increased no. of WBC (leucocytosis) → commonly seen in bacterial infection such as
meningitis, pneumococcal pneumonia, appendicitis and gonorrhoea
• Decreased no. of WBC (leukopenia) → commonly observed in cases of salmonellosis,
brucellosis, ricketssial infection and some viral infection
 Taken from Tortora, Funke and Chase.
Microbiology: An Introduction. (12 Ed.) Pearson
LYMPHATIC SYSTEM
Interstitial fluid
(between cells) Venule
Tissue cell
Arteriole
• The lymphatic system consists of fluid called Lymph in lymphatic
capillary
lymph, vessels called lymphatic vessel and a Lymphatic capillary
number of structures and organs containing Blood capillary
lymphoid tissue, and red bone marrow
Flow of fluid between arteriole, blood capillaries,
lymphatic capillaries, and venule
• Lymphoid tissue contains lots of lymphocytes
• Lymph nodes are the site of T cell and B cell Lymph in lymphatic
capillary
activation to initiate adaptive immunity
One-way
Lymphatic capillary opening
• Lymph carries microbes to lymph nodes where
lymphocytes and macrophages destroy the Interstitial fluid flow
pathogen
Tissue cells
• Another function of lymphatic system is to return
Lymphatic vessel
interstitial fluid to blood plasma via lymph vessel
Toward lymph node

Lymphatic capillaries and lymphatic vein

Figure 16.5 The lymphatic system.

Right Thoracic (left

lymphatic duct lymphatic) duct

Tonsil Right Left

subclavian subclavian
vein vein

Thymus
Lymph node
Thoracic duct
Spleen

Large intestine
Small intestine
Peyer’s patch
Lymphatic vessel
Red bone marrow

Taken from Tortora, Funke and Chase.

Microbiology: An Introduction. (12 Ed.) Pearson
 PHAGOCYTES

• Phagocytosis = ingestion of MOs or other substance by a cell

• Cells that performs phagocytosis → phagocytes
• When an infection occurs, both granulocytes and monocytes migrate to the infected area
• Monocyte enlarge and develop into actively phagocytic macrophages
• These cell leave the blood to enter infected tissue
• There are generally two types of macrophages
• Fixed macrophages are residents in tissues and organs
• Free (wandering) macrophages roam tissues and gather at sites of infection
 PHAGOCYTES

• Mechanism of phagocytosis
• Chemotaxis
• Chemical signals attract phagocytes to microorganisms
• Adherence
• Attachment of a phagocyte to the surface of the microorganism
• Adherence may be facilitated by opsonization: microorganism is coated with serum proteins
→ making ingestion easier
• Ingestion
• Pseudopods of phagocytes engulf the MOs and enclose it in a phagosome to complete
ingestion
• Digestion
• Microorganism is digested inside a phagolysosome
MICROBIAL EVASION OF PHAGOCYTOSIS

Inhibit adherence: Streptococcus pyogenes, S. pneumoniae

M protein, capsules
Kill phagocytes: Staphylococcus aureus
leukocidins
Lyse phagocytes: Listeria monocytogenes
membrane attack complex
Escape phagosome before Shigella, Rickettsia
lysosome fusion
Prevent phagosome– HIV, Mycobacterium tuberculosis
lysosome fusion
Survive in phagolysosome Coxiella burnetii
 INFLAMMATION

• Damage to body tissue triggers local defensive response called inflammation. Damages include
• Microbial infection
• Physical agent – heat radiant energy, electricity, sharp objects
• Chemical agents – acid, bases and gas
• Inflammation is usually characterized by four signs and symptoms → redness, swelling (edema),
pain, heat
• Function of inflammation:
• Destroys injurious agent or
• Limits its effects on the body
• Repairs and replaces tissue damaged by the injurious agent
 INFLAMMATION

• Inflammation response can either be acute or chronic depending on the course of infection
• What happens in inflammation?
• Microbial structures like flagellin and LPS will stimulate macrophages to produce cytokines such as
tumor necrosis factor alpha (TNF-) as well as histamine, kinins, prostaglandins and leukotrienes
• Histamine, kinins, and leukotrienes – promotes vasodilation and increase blood vessel permeability
where as prostaglandins intensify the action of histamine
• TNF- in the blood signals the liver to activate acute-phase proteins that cause vasodilation and
increased permeability of blood vessels → which causes swelling, heat and redness
• Increase permeability permits defensive substances to pass through the walls of blood vessels and enter
the injured area
• It also permits fluid to move to the tissues of the injury site → edema (accumulation of fluid) → swelling
• It also delivers blood clotting elements – prevent spread of microbes but results in collection of pus (mixture
of dead cells and body fluid) which is called abscess
Figure 16.9a-b The process of inflammation.

Tissue damage

Bacteria Epidermis

Blood
Dermis
vessel

Nerve Subcu-
taneous
tissue

Vascular reactions and phagocytosis

Chemicals such as histamine,

kinins, prostaglandins,
leukotrienes, and cytokines
(represented as blue dots) are
released by damaged cells.

Blood clot forms.

Abscess starts to form

(orange area).
• Next stage of inflammation - Phagocyte migration and phagocytosis
• As blood flow gradually decrease → margination is the sticking of phagocytes to blood vessels
in response to cytokines at the site of inflammation
• Phagocytes squeeze between endothelial cells of blood vessels via a process called
diapedesis (pronounced as “dai ap de sis”)
• Due to chemotaxis of chemicals produced such as kinins, leukotrienes and chemokines
• Chemokines also attract T cells thus also stimulate adaptive immune response
Figure 16.9a-b The process of inflammation.

Blood vessel
endothelium
Monocyte

Margination—phagocytes
stick to endothelium.

RBC
Bacterium

Diapedesis—phagocytes
squeeze between endothelial
cells.

Phagocytosis of
invading bacteria occurs.

Macrophage Neutrophil
• Tissue repair – the final stage of inflammation
• Cannot be completed until all harmful substances are removed or neutralized

• Tissues replace dead or damage cells by stroma or parenchyma producing new cells
• Stroma is the supporting connective tissue; parenchyma is the functioning part of the tissue
that is repaired
Figure 16.9a-b The process of inflammation.

(c) Tissue repair

Scab

Blood clot Regenerated epidermis

(parenchyma)

Regenerated dermis
(stroma)
 FEVER

• Besides local response (ie inflammation), systemic response is also activated via injury
• On of the most important systemic response = fever; abnormally high body temperature
• Fever is the third component of second line of defense (after phagocytosis and inflammation)
• Hypothalamus is normally set at 37°C
• Upon microbe invasion,
• phagocytic cells will trigger the release cytokines (interleukin-1) and TNF-
• Cytokines cause the hypothalamus to release prostaglandins that reset the hypothalamus to a higher
temperature → fever
• Body constricts the blood vessels, increase body metabolism and shivering occurs (which raises
temperature)
• Even though body temp is rising, the skin remains cold → chill (disappear when body temperature
reaches the set temperature by hypothalamus
• Temperature remains high until cytokines are removed
• As body temperature falls (known as crisis), vasodilation and sweating occurs → reduces body temp to
normal
 ANTIMICROBIAL SUBSTANCES

• The body also produces antimicrobial substances – final component of second line defence
• Among the most important – complement system, interferons, iron-binding proteins and
antimicrobial peptides
• The complement system
• Consist of over 30 proteins produced by liver that circulates in the blood serum that assist the
immune system in destroying microbes
• Act in a cascade in a process called complement activation
• Proteins are designated with uppercase C and numbered in order of discovery
• Activated fragments are indicated with lowercase a and b
ANTIMICROBIAL SUBSTANCES pathway of complement activation

classical

• The complement system

Microbe

• Classical pathway Antigen

• Antibodies bind to antigens, activating C1 C1

Antibody

• C1 splits and activates C2 and C4 C2 C4

• C2a and C4b combine and activate C3

C2b C2a C4b C4a
• C3a functions in inflammation
• C3b functions in cytolysis and
opsonization C3

C3a C3b

inflammation cytolysis opsonization

ANTIMICROBIAL SUBSTANCES
alternative

• The complement system

Microbe

• Alternative pathway Lipid–

carbohydrate
• C3 which are constantly present in the blood complex

combines with complement protein called

factors B, D, and P on microbe surface
• factors B, D, and P are attracted to microbial
surface material mostly lipid-carbohydrate
complex Microbe

B D P
• C3 splits into C3a and C3b, functioning the Factors

C3
same as in the classical pathway

C3a C3b

inflammation cytolysis opsonization

ANTIMICROBIAL SUBSTANCES
lectin

• The complement system

Microbe

• Lectin pathway Carbohydrate

containing
mannose
• Macrophages ingest pathogens, releasing
Mannose-binding
cytokines that stimulate lectin production in the lectin (MBL)

liver C2 C4

• Mannose-binding lectin (MBL) binds to

C2b C2a C4b C4a
carbohydrate containing mannose on the surface
of microbes, activating C2 and C4
• C2a and C4b activate C3, which functions the
C3
same as in the classical and alternative
pathways
C3a C3b

inflammation cytolysis opsonization

 ANTIMICROBIAL SUBSTANCES

• The complement system

• Outcomes of complement activation
1. Cytolysis
• Activated complement proteins create a membrane attack complex (MAC)

2. Opsonization
• Promotes attachment of a phagocyte to a microbe

3. Inflammation
• Activated complement proteins bind to mast cells, releasing histamine
Figure 16.12 Outcomes of Complement Activation

outcomes of complement activation

C3

Splits into activated C3a and C3b

cytolysis opsonization inflammation

C3a C3b C3a C3b C3a C3b

C5 C5

C5a C5b C5a C5b

C6 Histamine

C7 C8 C3a C5a
Microbe
C3a C5a
C9 receptor Mast cell receptor

Channel C3b protein Microbes Phagocytesa

C6
C7 C5b
C8
C9
Phagocyte

Microbes burst as extracellular Blood vessels become more

fluid flows in through transmembrane
Coating microbes with C3b
enhances phagocytosis. permeable, and chemotactic agents
channel formed by membrane attack attract phagocytes to area.
complex.
KEY CONCEPTS
The complement system is another way the body fights infection and destroys pathogens. This component of innate
immunity “complements” other immune reactions.
Complement is a group of over 30 proteins circulating in serum that are activated in a cascade: one complement
protein triggers the next.
The cascade can be activated by a pathogen directly or by an antibody–antigen reaction.
Together these proteins destroy microbes by (1) cytolysis, (2) enhanced phagocytosis, and (3) inflammation.
 ANTIMICROBIAL SUBSTANCES

• Interferons
• Cytokines produced by cells; have antiviral activity

• IFN-α and IFN-β: produced by cells in response to viral infections; cause neighboring cells to
produce antiviral proteins (AVPs) that inhibit viral replication
• IFN-: causes neutrophils and macrophages
to kill bacteria
 Figure 16.14 Antiviral action of alpha and beta interferons (IFNs).

New viruses replicated

in host cell infect
neighboring cells.

Transcription Translation Transcription Translation

Viral
Viral RNA
RNA Viral
RNA

Virus
replicates Alpha Viral
Infecting Antiviral
and beta replication
virus proteins
interferons inhibited
(AVPs)
Nucleus IFN-mRNA

Virus-infected host cell Neighboring cell

Viral RNA from The virus induces the host cell to Interferons make contact with uninfected AVPs degrade viral mRNA and
an infecting virus produce interferon mRNA neighboring host cells, where they bind either inhibit protein synthesis—and
enters the cell. (IFN-mRNA), which is translated to the plasma membrane or to nuclear thus interfere with viral
into alpha and beta interferons. receptors. Interferons induce the cells to replication.
synthesize antiviral proteins (AVPs).
 ANTIMICROBIAL SUBSTANCES

• Iron binding proteins

• Transferrin: found in blood and tissue fluids

• Lactoferrin: found in milk, saliva, and mucus

• Ferritin: found in the liver, spleen, and red bone marrow
• Hemoglobin: located in red blood cells
• Bacteria produce siderophores to compete with iron-binding proteins
 ANTIMICROBIAL SUBSTANCES

• Antimicrobial peptides
• Short peptides produced in response to protein and sugar molecules on microbes
• Inhibit cell wall synthesis
• Form pores in the plasma membrane

• Broad spectrum of activity