Cell Biology and Immunology

The immune system

Peter Heeringa
Pathology en Medical Biology
UMCG
1
p.heeringa@umcg.nl
 The immune system:
The complex network of cells, tissues, organs, and the substances they
make that helps the body fight infections and other diseases

• Lecture 1: A short history of immunity

• Lecture 2: Design of the immune system and
basic principles of immunity
• Lecture 3: Innate immunity: fast less-specific
responses
• Lecture 4: Acquired immunity: antigen specific
responses
• Lecture 5: Immune response pathways (bacteria)
• Lecture 6: Immune response pathways (viruses)
• Lecture 7: Disorders of the immune system: allergy and
autoimmunity
• Lecture 8: Disorders of the immune system: Transplantation and
cancer

6
 Lectures on immunology
Book:
Silverthorn, Human Physiology (latest edition): Chapter
24 (except the part on neuro-endocrine immune
interactions)
Presence during lectures is highly recommended!
Everything that will be presented during the lectures can
be asked at the examination. Lectures will provide more
in-depth information some of which is not mentioned in
the book chapter.

E-learning and in depth lecture:

- Acute and chronic inflammation
- Includes e-learning module that can be
followed at home. (see link to the module on
brightspace)

- Prof. Geert van den Bogaart: The dendritic cell

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 Immunology courses throughout the
curriculum
The immunology ‘track’

Immunology 0: Course Cell Biology and Immunology, first year bachelor, General concepts of
immunity

Immunology 1: Course Immunology, bachelor year 2, Basic molecular and cellular principles of
immunity

Immunology 2: Course Immunology and Disease, bachelor year 2, Immune-pathology and

disorders + Laboratory

Immunology 3: (Course Immunology and Infectious diseases, bachelor year 3, Research course)

Immunology 4: Master course, Immunology from bed to benchside and back, Immunology
research UMCG

Immunological research project?

8
 Immunity
• Immunitas (latin)
– Exempt from military service and
tax payment
– Protection by the state

• People who were given “immunitas”

were protected from threats

• Term was adopted by the medical

vocabulary to describe mechanisms
by which our body protects us from
pathogens

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 Immunity
Main goal:
Kill the pathogen without inflicting
injury to the host

10
 Questions to be answered

How is the immune system able to recognize pathogens that differ in

structure, life form and, size with a high level of sensitivity and
specificity?

Why do you get some infections like chicken pox (waterpokken) aka
varicella zoster only once?

Why do subsequent immune responses to a pathogen occur more

rapidly and more effectively than previous immune responses?

How does the immune system provide a high degree of sensitivity and
specificity to the broad array of pathogens without attacking self?

11
 Cell Biology and Immunology
The immune system

Lecture 1: A short history of immunity

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 Emergence of immunity: an overview
For ages, man has known the existence of immunity

430 B.C.: Thucydides (Greek historian

and general) describes that individuals are
rarely hit twice by “the plague” (“de pest”,
killed one quarter of the population of
Athens)

Yet it was with those who had recovered from the disease that the
sick and the dying found most compassion. These knew what it was
from experience, and had now no fear for themselves; for the same
man was never attacked twice – never at least fatally.

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 Emergence of immunity: an overview
Middle Ages: Rhazes (arabic scholar)
describes:
- Measles and smallpox are clinically
different diseases
- The phenomenon that survivors of small
pox do not get the disease twice
(“acquired immunity” as a result of
infection)

early 18th century: Chinese first practice

“variolation”. Made children to inhale
powder from crusted small pox lesions.

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 Emergence of immunity: an overview

1720: the French build

“le mur de la Peste” to control Yersinia pestis
the 1720 Plague epidemic in the Transmitted by fleas
Provence.

The plague killed half of the

inhabitants of Marseille

The plague also killed more than

half of the inhabitants of Avignon
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Emergence of immunity: an overview

Yersinia pestis
Transmitted by fleas

16
The first breakthrough and start of
modern immunology: 1798
Observation:
Milk-maids are protected against
smallpox

Cowpox
Hypothesis:
The pus in the blisters that milkmaids
received from cowpox (less virulent
(disease inducing) compared to
smallpox) protected them from
smallpox 17
 Cowpox is less virulent, yet provides immunity
against smallpox: variolation becomes vaccination
Vaccination comes from Vacca (Latin) = cow

Cow pox lesion from which Jenner

created his vaccine
it is presumed that Jenner was inspired by…
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 Geert Reinders; 1737 – 1815 (Bedum, Gn)
Dutch cattle farmer

Observed that the offspring of cattle

that had survived the ‘runderpest’ were
protected

Showed that calfs inoculated with virulent

material were protected from ‘the
runderpest”

mechanisms remain elusive for almost 100 years 19

Specific diseases are caused by specific germs
Robert Koch
Extracellular bacteria
(1843 - 1910)
Staphylococcus aureus
NBP 1905
Escherichia Coli

Intracellular bacteria
Mycobacteria
Lysteria

Viruses
Polio
Influenza
The first to link a pathogen to a
specific disease Fungi
Candida albicans
NBP 1905 for the discovery of
Mycobacterium tuberculosis as Parasites
the causative pathogen of Plasmodium
tuberculosis (believed to be an Leishmania
inherited disease at that time) 20
 “Koch’s postulates”
4 criteria to establish a causal
relationship between a
microbe and a disease:
1. The microorganism must be found in
abundance in the animals suffering from the
disease, but should not be found in healthy
animals

2. The microorganism must be isolated from a

diseased organism and grown in pure
culture

3. The cultured microorganism should cause

disease when introduced into a healthy
organism

4. The microorganism must be re-isolated from

the inoculated, diseased experimental host
and identified as being identical to the
original specific causative agent 21
 late 19th century:
Second immunological breakthrough

Louis Pasteur (1822 - 1895)

- real founder of modern immunology
- describes the basis of vaccination

Showed that artificially attenuated cholera

strains can be used to protect against
challenges with lethal cholera strains.

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Acquired immunological knowledge until 1900

• immunity can protect against diseases

• specific diseases are caused by specific germs (pathogens)
• immunity can be provided in a medical setting by
attenuating the virulence of pathogens (Louis Pasteur)
• distinct forms of immunity can be recognized: cellular vs
humoral

• But the physiologic mechanisms responsible for the

functions of immunity were still a mystery

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 Early 20th century:
emergence of immunological mechanisms
1884: cellular immunity is described and hardly appreciated

Ilya Metchnikoff (1845 -1915)

NBP 1908
Discovered that starfish (zeester) harbor
phagocytic cells (phagos= glutton=veelvraat)
and realized that some immune cells use the
same process to engulf and destroy certain
pathogens

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 Early 20th century:
emergence of immunological mechanisms
Emil von Behring (1854 - 1917)
NBP: 1901

recognizes the formation of “anti-toxins”

Showed that immunity can be transferred by

serum from an infected to a naive individual which
led to the introduction of serum therapy (diphteria
and tetanus)à passive immunity

Nobel prize laureate:

… he has opened a new road in medical science
and placed in the hands of the physician a
victorious weapon against illness and death.
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Serum therapy

New York Herald, Dec. 12, 1894

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 How does serum therapy work ?
Antibodies are introduced

Paul Ehrlich (1854 - 1915) introduces the term “anti-körper”

NBP 1908 (together with Metchnikoff)
“in recognition of their work on immunity” proposes the “side chain theory”

Antibodies: are normal cell products

which serve as cell membrane
receptors, and are not ‘‘made to order’’
to fit a given antigen

Antigen: Antibody Generator

Any substance that induces an immune
response

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 The side chain theory
From Ehrlich, P., ‘‘Croonian Lecture – on
Immunity.,’’ Proc. R. Soc. Lond. 66:424, 1900.
In an attempt to explain the observations by
von Behring, Erlich hypothesized that
antigens interact with receptors borne by cells,
resulting in the secretion of excess receptors
(antibodies)
leads to the publication of the
“horor autotoxicus” (the horror of self-reactivity
à autoimmunity
forsees the use of antibodies as
“magic bullets”
postulated that if a compound could be made that
selectively targeted a disease causing organism, then
a toxin for that organism could be delivered along
with the agent of selectivity. In this way, a "magic
bullet" would be created that killed only the organism
targeted. 28
 The complement system

Jules Bordet (1870 - 1961)

NBP 1919
In addition to antibodies, serum
contains heat labile proteins that
assist (complements) in the lytic
function of antibodies

Complement Dependent Cytotoxicity (CDC)

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 The early immunological toolbox

“Cellularists” “Humoralists”
phagocytes Antibodies and complement

Devour (verslinden) foreign matter neutralization and lysis

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Filling the gap between the humoralists and
the cellularists: “the truth lies in the middle”

(Sir) Almroth Wright (1861-1947) a.k.a. as

“Sir Almost Right”
Developed vaccine for Typhoid

“phagocytes do their work only when we

butter the germs appetizingly for them”

“opsonisation”
“ makes germs tastier”
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1920 – 1975: distinct leukocyte-subsets are
recognized and described
granulocytes
monocytes / macrophages
lymphocytes (B- and T- lymphocytes) (1956 - 1966)

the structure of antibodies is unravelled (1964 / 1974)

32
From: Yoffey & Drinker
Lymphatics, Lymph and
the Lymphoid System
1956
 How is the immune system able to recognize so
many pathogens? clonal selection and tolerance
Best known for clonal selection theory
Explains specificity, diversity, memory of
the adaptive immune system

Also introduced the term tolerance-

deletion of self-reactive clones
Burnet (1899 - 1985)
NBP 1960
1. The entire immunological repertoire develops spontaneously in the
host

2. Each [antibody] pattern is the specific product of a cell, and that

product is presented on the cell surface (as an Ehrlich-type receptor)

3. Antigen reacts with any cells that carry appropriate specific receptors,
to induce the activation of these cells to proliferation and differentiation

4. Some of these cells and their daughters differentiate (become

plasmacytoid) to form clones of antibody-forming cells, while others
survive as clones of [undifferentiated] memory cells.
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NBP 1984: Immunology meets technology

Köhler and Milstein

(1946 - 1995) (1927 - 2002)

monoclonal antibody
Development of a method of immunoglobulin
molecule production of a defined antibody with
defined specificity research / diagnosis /therapy
No patent!
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 Application of monoclonal antibodies
Imaging / diagnosis

highly specific

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Research Diagnostics Home Diagnostics
Point-of-care tests
UniCAP ®

IMMULITE â

ELISA

Varelisa
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 Application of monoclonal antibodies
Therapy

highly specific
B-cell malignancies Rheumatoid Arthritis

RituxiMab

CD20
RituxiMab B-cell
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 1985 - now: ~ 30 years of technical innovations:
a new era in immunology

• immune cell interactions with: - pathogens

- immune cells
• communication in the immune system- systems
immunology

• immune homeostasisà immune regulation

• immune related disorders / tumor immunology / immune

ageing
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Immune signatures to predict disease course

40
THE succes of Immunology

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COVID-19

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COVID-19

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Immunological science is very timely
• A lot is known, much more is still elusive

• Current technical possibilities allow

unraveling of immunological principles

• Immunological effector mechanisms are

exploited therapeutically
 Next lecture

Design of the immune system and basic

principles of immunity

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50
Cell Biology and Immunology
The immune system
Lecture 2:
Design of the immune system
and basic principles of immunity

51
 The immune system serves to
eradicate pathogens from the body
Kill the pathogen without inflicting injury to
the host
immunological definition of a pathogen:
pathogen = foreign

immunological definition of foreign:

foreign = not self
Thus: the immune system reacts to
non-self or altered- self
non-self may include - Bacteria
- Viruses
- Fungi
- Helminths
- Foreign material
- a transplanted organ

Altered-self may include - Damaged or ‘worn-out’ cells

- Tumor cells

N.B. non-self is not always harmful (pathogenic) !

The ideal immune response eradicates foreign
or altered matter in a way that does not inflict
harm to self-tissues

“waar gehakt wordt vallen spaanders”

“You cannot make an omelette without

breaking egss”

protective immunity is detrimental but life-saving

- ineffective immunity is life-threatening

- hyperactive immunity is life-threatening
- Incorrect immunity is life-threatening
Protective immunity is detrimental but life-saving

immune effector mechanisms are destructive

- the pathogen is killed

- collatoral damage to tissue is

inflicted

- tissue regenerates: repair or

scar-formation
 Ineffective immunity is life threatening:
Severe combined immunodeficiency syndrome
(SCID)
• Genetic disorder
• Absence of functional T
and B cells
• Patients very prone to
infections
• Can be treated by bone
marrow transplantation.

The "bubble boy" David Vetter lived in a

sterile plastic pod from birth until he
died at age 12.

56
 Ineffective immunity is life threatening:
Severe combined immunodeficiency syndrome
(SCID)
• Genetic disorder
• Absence of functional T
and B cells
• Patients very prone to
infections
• Can be treated by bone
marrow transplantation.
• Gene therapy is being
tested

57
Ineffective immunity is life-threatening
Immunodeficiency: AIDS

Acquired Immuno Deficiency Syndrome

(AIDS):

caused by HIV infection that targets immune

cells (T cells) and slowly undermines
immune function

Patients become susceptible to a variety of

viral, bacterial, and fungal infections.
Hyperactive immunity is life-threatening

Asthma/allergies:

uncontroled / allergic reaction to innocent

substances (allergens; e.g. house dust mite, food)
Incorrect immunity is life-threatening

Autoimmunity:

detrimental immune reaction to self tissues as a

result of unbalanced immune regulation e.g.
Rheumatoid Arthritis, type-1 Diabetes, etc.

60
 Know your enemy:
Characteristics of foreign matter

life-form of the infection

location of the infection

extracellular intracellular

gut skin blood

 Characteristics of foreign matter

the immune system encounters enormous size-

differences
virus parasite
 The challenge of immunity

• A universe of microorganisms
• Different structures, life-forms
and size

• Threat:
• Bacteria and viruses grow exponentiallyà the body must
respond in time once an infection occurs
• Rapid evolution of microorganismsà adaptable system
necessary
• The immune system must accomplish this without destroying
the body itself (discrimination between self and non/altered-
self)
63
 Effective immunity:
a complicated and delicate balance

Requirements for effective immunity :

• Barriers for prevention

• Recognition:
• Detection and identification of the foreign substance

• Communication and organization

• Coordination to mount the most optimal immune
response

• Effector mechanisms
• To destruct or suppress the invading pathogen
Organization of the immune system

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 Organization of the immune system

• Allows:

– Prevention (barriers)
– Fast response (innate immunity)
– Extracellular (humoral immunity) and
intracellular (cellular immunity) microbes Protection
– Adaptation (adaptive immunity)
– Specificity (innate and adaptive)
– Prevent recurrence (adaptive, memory)

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 The immune system can be seen as a
“diffuse, body-spanning organ”
Much of the immune system is integrated in other organs of the body wherever
pathogens are most likely to enter our body.

solid tissues fluid tissue fluid molecules

(cells) (plasma)

The mass of all immune cells in the body equals the mass of the brain!
 Lymphoid tissues are everywhere….

• Primary lymphoid tissues

– Bone marrow
– Thymus
– generative lymphoid organs

• Secondary lymphoid tissues

– Encapsulated:
• Spleen and lymph nodes
– Unencapsulated:
• Tonsils
• Gut associated lymphoid
tissue (GALT)
– Sites where immune
responses are initiated

68
 Lymphoid tissues are everywhere….
Primary lymphoid organs Secondary lymphoid organs
Bone marrow and thymus Spleen, lympnodes, GALT etc
Development and maturation Meeting place for immune cells
and antigen

69
 Primary lymphoid tissues
Generation and maturation of immune cells
Bone marrow: Thymus:
Generation of all immune cells Maturation T cells
(myeloid cells, Lymphoid cells (B and T cells)) Selection for non-self reactive T cells

70
 Secondary lymphoid tissues:
Lymphoid organs where mature immune cells interact with
pathogens and initiate immune responses: The spleen

• The spleen is highly

vascularized

• Monitors and filters

the blood for
“rubbish” including
pathogens but also
e.g aged red blood
cells

71
Secondary lymphoid tissues: Lymph nodes

• Lymph nodes are part of the

lymphatic circulation

• Lymphatic circulation ‘drains’

tissues, collects microbial
antigens and delivers these to
lymphnodes

• Immune cells in the

lymphnode sense and
intercept pathogens
preventing their spread
throughout the body by
initiating an immune response.

72
Secondary lymphoid tissues: Tonsils and GALT
• The tonsils:
are accumulations of lymphoid
tissue surrounding the openings
of the digestive and respiratory
tracts.

• Gut-Associated Lymphoid Tissue

- GALT
Small accumulations of
lymphocytes found scattered
beneath the epithelium
throughout the gastrointestinal
tract. The most prominent
accumulations occur in the ileum
and appendix in the form of
Peyer's patches.
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Lymphnodes at work

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 Fluid tissues:
An army of immune cells: not “one of a kind”
NK- T-
cell lymphocytes
lymphoid cells
Neutrophil Basophil
B-
lymphocytes
(LPC)
Bone Eosinophil

Monocyte /
(HSC) (MSC) Macrophage
(MPC)

platelets
erythrocytes

myeloid cells

cellular immunity
Plasma contains a plethora of soluble immune
components

humoral immunity

- immunoglobulins
- complement factors
- cytokines
- clotting factors
 Immune system

A network of tissues, cells and

soluble factors that:
• Protects the body against
invading pathogens
• Removes ‘worn-out’ cells
• Destroys abnormal/mutant cells
within the bodyà control of
cancer

77
Physical and chemical barriers that
prevent infection
• Three major interfaces between body
and external environment:
Skin, respiratory tract, gastrointestinal
tract

• Continuous epithelia protect against

entry of microbes

Your skin!!!

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 Primary barriers for pathogens
Physical and chemical
barriers

colonisation
multiple layers of resistance
protection (200 m2)
(2 m2)
 When the first barriers fail the internal
immune system takes over
Bacteria

Phagocytes
complement

antibodies
Viruses

Virus infected cell

T lymphocyte

NK cell
Helminths

Diversity of microorganisms requires

diversity of immune response and effector
mechanisms
the nature of the infection determines the
nature of the immune response: Tailor made Eosinophilic granulocytes
immunity
Different pathogens are dealt with by (combinations
of) different immune components

- Immune effector components have

their own specific effector-niche

- Immune components interact with

each other to maximize the effect

the immune response is orchestrated

in time:

- different immune components have

different kinetics
- allows combat of the infection in an
ordered way

Bergthaler A, Menche J. The immune system as a social network. Nat Immunol. 2017 Apr 18;18(5):481-482
Organization of the immune system
 Innate immune system

Fast, limited specificity, no memory

The innate immune system is ready to respond
immediately!

First internal line of defense

Innate Elimination of “danger”

immune
system

Observation of “danger”

85
 The innate immmune system:
killing and elimination of micro-organisms

Humoral

microörganismen
Lysis by complement system

recognition
Killing and elimination of uptake
micro-organisms Cellullar
enzymes
degradation
release of
degradation
products

Phagocytosis by specialized cells

 The innate immmune system:
inflammation and adaptive immune responses
inflammation

Pro-inflammatory
Micro-organisms cytokines

IL-1
TNFa
IL-6

Killing and elimination of

micro-organisms

Activation and direction of

adaptive immune system
Adaptive (acquired) immune
system

Slow, very specific, memory

The adaptive immune system is mediated by
antigen specific lymphocytes

B cells: humoral IR T cells: cellular IR

Membrane-bound T cell receptor

immunoglobulin (sIg)
Pathogen recognition by the adaptive immune
system is antigen specific
Antigen= “Antibody Generating molecule”
Any foreign (part of a) molecule that elicits an immune
response
Specific recognition of the pathogen is mediated by
lymphocytes that express antigen specific receptors

B cells: humoral IR T cells: cellular IR

Membrane-bound T cell receptor

immunoglobulin (sIg)
Number of potential antigens is almost
unlimited
Pathogen recognition by the adaptive immune
system
Specific recognition of the pathogen requires a vast repertoire of
specific receptors
- many different B- and T-cells are needed to obtain a large enough
repertoire
- each day, millions of new B- and T-cells are formed with new, randomly
generated receptors

B cells: humoral IR T cells: cellular IR

Antigen-
Antigen- Antigen- Binding site
binding binding site
site V Disulfide
Variable
V

bridge
Light Variable
V

regions
V

chain regions
C
C

Constant Constant
C C regions regions
Transmembrane
region Transmembrane
region
Plasma
membrane Plasma
Heavy chains b chain
membrane a chain
B cell Disulfide bridge
Cytoplasm of B cell Cytoplasm of T cell T cell
 Adaptive immune system:
unique antigen receptors

micro-organism (antigen)

Antigen receptor
lymphocyte

Etc.
Estimate 2.1012
lymphocytes

Number of specificities is almost unlimited, but every

lymphocyte is monospecific !! 1 clone =1 specificity
 B lymphocytes:
humoral immune responses
(extracellular micro-organisms)
Proliferation Differentiation Effector
Recognition
molecules

Memory cells (to be able to respond

faster and more efficient to a second
encounter with the same pathogen)
T lymphocyte development: cellular immune
responses (intracellular micro-organisms)

killer cells, CD8+

apoptosis

helper cells, CD4+

cytokines

CD= cluster of differentiation.

Cell surface molecules used to identify and distinguish
different immune cells
T lymphocyte development: cellular immune
responses (intracellular micro-organisms)
Innate vs adaptive immunity in time

Adaptive immune responses are slower but are more specific

and effective
98
 Adaptive immunity:
Specificity and memory

Antigen X and Y induce

a different immune response
(specificity)

The secondary response to

antigen X is more rapid and
larger than the primary
response to antigen X (memory)

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 The immune system: Summary

• A network of tissues, cells and soluble

factors that:
– Protects the body against invading pathogens
– Removes ‘worn-out’ cells
– Destroys abnormal/mutant cells within the bodyà
control of cancer

• Immune responses can also be harmful:

– Allergies, autoimmunity
– Transplant tissue rejection

100
 The immune system: Summary

• Is organized in such a way that it

– Prevents infection (barriers)

– Can act quickly upon infection (innate
immunity)
– Can combat extracellular (humoral
immunity) and intracellular (cellular
immunity) infection
– Can combat pathogens that change
their identity (adaptive immunity)
– Is specific for the pathogen without
harming the host (innate and adaptive
immunity)
– Can prevent recurrence of infection
(adaptive immunity)

101
 Next lecture

• Innate immunity: the fast but not so specific

immune response

epidermis
infection

dermis

102