Transcript The immune system

Introduction to Immunology
Milestones of Immunology
Immune system – an overview
Antigen
M. Buc
1
Definition of the subject
Immunology is a scientific
branch that studies
defence of an organism
against germs, cancer
cells, toxins etc.
Doan et al., 2008
M. Buc
2
Definition of the subject
Immunology is a scientific branch that
studies immunity, its cellular and
molecular processes that proceed after
a foreign substance, an antigen,
enters our body
M. Buc
3
Origin of the term
The term „immunity“ originates from Latin word
„immunitas“, what implies exemption from
various civic duties, juridical procedures, etc.
from which benefited senators of the Roman
empire
“Immunitas“ in immunology: an exemption
from contracting an infectious disease
M. Buc
4
Milestones of Immunology
Personalities who substantially
contributed to the development
of Immunology
Milestones of immunology
Ancient China (the 11th
century) – vaccination
against smallpox: children
were let to sniff a powder
prepared from crusts of
patients suffering from a
mild form of variola =
VARIOLATION
www.google.sk
It was a dangerous procedure,
however it was used as no
other possibility existed
M. Buc
6
Milestones of immunology
• In 1798 Edward
Jenner, a physician,
observed that that
milkmaids who had
contracted cowpox
were subsequently
immune to smallpox
• Jenner reasoned that
introducing fluid from a
cowpox pustule into
people might protect
them from smallpox
M. Buc
7
Milestones of immunology
Jenner inoculated an eight-year–
old boy with fluid from a
cowpox pustule and later
intentionally infected the child
with smallpox viruses. As he
predicted, the child did not
develop smallpox
www.google.sk
Jenner technique rapidly
replaced variolation as the
preferred method for
protecting humans against
smallpox
M. Buc
8
Milestones of immunology
In 1958 the WHO decided
to eradicate smallpox
by means of a mass
vaccination
It was so effective that it
had become the first
infectious disease
eradicated from the
earth
M. Buc
9
Louis PASTEUR (1822-1895)
L. Pasteur recognised that
aging of bacterial
(anthrax) colonies
weakened a virulence of
the pathogen and that
such an attenuated
(weakened) strain could
be administered to
protect (sheep) against
the disease
www.google.sk
M. Buc
10
Louis PASTEUR
He called this
attenuated strain a
vaccine (from the
Latin vacca,
meaning “cow”), in
honour of Jenner´s
work with cowpox
inoculation
M. Buc
11
Louis PASTEUR
In 1885 L. Pasteur prepared a vaccine for rabies
by drying the spinal cord of infected rabbits
The vaccine was administered to a young boy
who had been bitten repeatedly by a rabic
dog; his life was saved
The Pasteur work marked the beginning of the
discipline of immunology and L. Pasteur can
therefore be considered its founder,
the father of immunology
M. Buc
12
Emil von Behring (1854 - 1917)
He demonstrated that the
protection induced by
vaccination was
associated with the
appearance of
protective factors in the
blood
He called these factors
antibodies
www.google.sk
M. Buc
13
Ilja Metchnikov (1845 - 1916)
The discoverer
of phagocytosis
Laureate of the
Nobel prize
(1908)
www.google.sk
M. Buc
14
Robert KOCH (1843 - 1910)
The discoverer of the
etiological agent of
tuberculosis, cholera, and
anthrax
The discoverer of the
tuberculin reaction,
a cell mediated
inflammatory skin
inflammation
Laureate of the Nobel prize
in 1905
www.google.sk
M. Buc
15
Rodney Porter (1917 - 1985)
R. Porter discovered
the biochemical
structure of
antibodies
He was awarded the
Nobel prize in 1972
www.google.sk
M. Buc
16
Jacques MILLER
(1931- )
J. M. discovered a role
of the thymus in
immunity (1961)
The specific cellular
immunity is
mediated by cells
derived from the
thymus, i.e.
T-lymphocytes
www.google.sk
M. Buc
17
Jean DAUSSET (1916 - 2009)
The discoverer of
the major
histocompatibility
complex in man
Nobel prize award:
1980
www.google.sk
M. Buc
18
Georges J. F. Köhler
(1946 - 1998)
The co-discoverer (with
C. Milstein), of the
hybridoma technique
for the production of
monoclonal antibodies
www.google.sk
Both: Nobel prize
in 1984
M. Buc
19
Cesar Milstein
(1927 - 2002)
www.google.sk
20
Commentary
All mentioned scientists represent the top of all
others, more or less renown personalities
All of them contributed to the fact that
immunology belongs to the one of the most
developing scientific subjects
Knowledge of immunology is indispensable
in many scientific and medicine branches
M. Buc
21
THE IMMUNE SYSTEM
An overview of its structure and
function
The immune system (IS)
 From the morphological point of view, the immune
system is a diffuse organ; it weights app. 1 kg in adults
 Primary and secondary lymphoid organs
 Numerous leucocytes, macrophages, dendritic cells
etc., altogether are there app. 1012 cells
 Billions of molecules (antibodies, cytokines, regulatory,
anti-microbial, transport molecules, etc.) – 1020
M. Buc
23
Forms of immunity
Inherent – species, strain, individual
Acquired:
- active - natural (post-infectious)
- artificial (post-vaccine)
- passive - natural (mother - foetus)
- artificial (antisera, gamma globulin)
M. Buc
24
Biological functions of the immune system
The immune system
supervises integrity
and individuality
of an organism
 Discriminatory
 Surveillance
 Effector
It cooperates with other
systems of the body,
esp. nervous and
endocrine. They form
integrity system
 Memory
 Pathogenetic
M. Buc
25
Forms of immunity
Non specific (natural, innate)
Specific (adaptive)
M. Buc
26
Cells of the innate immunity
Phagocytes
Cytotoxic cells
Mediator cells
Neutrophils
Eosinophils
Monocytes
Macrophages
NK-cells
Basophils
Mast cells
M. Buc
27
Neutrophils
www.google.sk
M. Buc
28
Eosinophils
www.google.sk
M. Buc
29
Basophils
www.google.sk
M. Buc
30
M. Buc
Doan et al., 2008
31
Mast cells
www.google.sk
M. Buc
32
Monocytes
www.google.sk
M. Buc
33
M. Buc
34
Macrophages
www.google.sk
M. Buc
Tizard, 1995
35
Dendritic cells (DC)
Myeloid DC (antigen processing)
Plasmacytoid DC (production of IFN-I)
Folicular DC (capture of immune complexes, i.e.
complexes of antigens bound to its
antibodies)
M. Buc
36
Myeloid dendritic cell
www.google.sk
M. Buc
37
Foliclar dendritic cells
www.google.sk
M. Buc
38
LGL/NK cells

LGL – „large granular
lymphocytes“

NK – „natural killer
cells“
www.google.sk
M. Buc
39
Specific (adaptive) immunity
Antibody mediated
Cell mediated
M. Buc
41
Organs of the immune system
• Primary lymphoid organs
Bone marrow, thymus
• Secondary lymphoid organs
Lymph nodes, tonsils, spleen, Peyers
patches, appendix
M. Buc
42
M. Buc
43
Goldsby et al. 2000
Cells of the adaptive immunity
Antigen
presenting cells
Dendritic cells
Monocytes
Macrophages
Effector cells
T lymphocytes
B lymphocytes
Plasma cells
M. Buc
44
Lymphocytes
Lymphocytes are principal
cells of the specific
immune response
B lymphocytes
(bursa Fabricii
dependent
lymphocytes)
T lymphocytes (thymus
dependent
lymphocytes)
www.google.sk
M. Buc
45
M. Buc
46
M. Buc
47
M. Buc
48
M. Buc
49
The spleen
www.google.sk
M. Buc
50
M. Buc
51
Goldsby et al. 2000
Nature Rev Immunol
M. Buc
52
Recirculation
M. Buc
53
M. Buc
54
Tizard 1995
M. Buc
55
M. Buc
56
The number of cells in the peripheral blood
in adults
Erythrocytes
5 . 106/mm3
Leucocytes
5 – 10 . 103/mm3
Neutrophils
60%
Lymphocytes
35%
Monocytes
3%
Eosinophils
1%
Basophils
1%
Platelets
150–200.103/mm3
M. Buc
57
Doan et al. 2008
M. Buc
58
M. Buc
59
Mechanisms of non- and specific
immuinities
Characteristics of the mechanisms
of natural immunity
They are already present before the first encounter of an
antigen
They do not make any differences among antigens, the
reaction to each one is the same
The re-exposition of an organism with the same antigen
does not elicit any quantitative or qualitative response
compared to the first encounter
M. Buc
61
Characteristics of mechanisms
of the specific immunity
 Specificity
- The immune response is directed to one
particular antigen only, not to any other
 Diversity
- The immune system is able to distinguish the
enormous number of different antigens (109 –
1012)
M. Buc
62
Characteristics of mechanisms
of the specific immunity
•
Self limitation: The immune response
•
Memory: The immunity remembers an
•
Tolerance: The immune system
declines some time after fulfilment its role
antigen which elicited its induction. The reexposition to the antigen induces a prompt
and higher amplitude of the response to him
distinguishes self molecules from non self
M. Buc
63
oan et al. 2008
• The innate
immune system
reacts to a given
stimulus with a
constant
intensity,
regardless of
how many times
it has been
exposed to that
stimulus
M. Buc
• The specific
immune system
can adapt and
modify its
response after
each exposure to
a given stimulus64
A comparison of the non-specific and
specific immunity
Mechanisms of the specific immunity
are not superior over the non-specific,
on the contrary, they help them
to identify an intruder of the integrity
of the organism and to eliminate it
more efficiently
M. Buc
65
Mechanisms of innate immunity
1. Mechanisms of the first line of defence
(A constitutional make up of an organism)
2. Mechanisms of the second line
of defence
M. Buc
66
The first line of defence
• Skin
(pH, fatty acids, epithelial cell desquamation)
• Mucosa of the upper respiratory tract
(ciliated epithelium, cough, sneezing)
• Eye, oral cavity
(lysozyme)
M. Buc
67
The first line of defence
•
Stomach
(HCl)
•
Normal intestinal
flora
(Escherichia coli)
• Vagina
(Lactobacilus
Döderleini)
• Urine
(acidic pH)
M. Buc
68
Doan et al. 2008
M. Buc
69
The first line of defence
Kirkwood E and Lewis C 1983
M. Buc
70
The first line of defence
Kirkwood E and Lewis C 1983
M. Buc
71
Mechanisms of the second line
of defence
• Cellular components
- Phagocytes
- NK and NKT cells
• Humoral components
- Antibacterial proteins of the plasma
- Complement
- Carrier and inflammatory proteins
M. Buc
72
Goldsy et al. 2000
73
Mechanisms of specific immunity
Antibody mediated
Antibodies by themselves or by help of some
other components of IS destroy or neutralise
antigens

Cell mediated
T cells are responsible for. They destroy targets
foreing cells by themselves or they „call“
other cells to help them

M. Buc
74
ANTIGEN
Antigen

An antigen is a substance that is able
to induce an immune response

Antigens:
- microbes
- chemical substances (proteins, saccharides, ..)
- transplanted organs and tissues
- modified self molecules and cells
M. Buc
76
Basic properties of antigens
Foreignness and phylogeny distance
Biochemical structure
Relative molecular mass
Degradability
A dosage and the way of introduction
into the body
M. Buc
77
Foreignness of an antigen
Antigen must be foreign, i.e. an organism has
never met it before
The greater phylogeny distance between an
antigen and the body, the more immunogenic
the antigen is
M. Buc
78
Biochemical structure
The best antigens
Proteins, polypeptides
Polysaccharides
Glycoproteins, peptidoglycans
Glycolipids
Lipids and native nucleic acids are not antigenic
M. Buc
79
Mass relative
The higher Mr,
the better
induction
of the immune
response is
The cut-off value:
5 000
M. Buc
Goldsy et al. 2000
80
Degradability
Antigen has to be degradable by enzymes into
smaller parts, fragments; if not, the immune
response cannot be induced, e.g. steel nails
used in surgery at repositions of broken
bones, plastic material (shams) in
orthopaedics, etc.
On the contrary, if antigen is degraded too
quickly, too easily, is not antigenic too,
e.g. gelatine
M. Buc
81
Antigen dosage
 Low doses of an antigen do not induce an
immune response as they do not stimulate
sufficient numbers of cells of the immune
system – low zone tolerance
 High doses of antigen do not induce an
immune response as cells of the immune
system do not cope with its processing:
immunologic paralysis or high zone
tolerance
M. Buc
82
Ways of antigen introduction to the body
Blood borne antigens – they enter the spleen
I.m., s.c, mucosal ways – antigens enter
regional lymph nodes
Antigens elicit either antibody mediated or cell
mediated immune responses in dependence
of their structure
M. Buc
83
Biological factors in response to antigens
Early childhood (till two years of the life)
• Children do not respond to polysaccharide antigens
• Some bacteria (Streptococcus pneumoniae, Neisseria
meningitidis, Haemophilus influenzae) possess
in their capsules polysaccharide antigens
• Infections caused by these bacteria result to
pneumonias and meningitis – a life threatening
events
M. Buc
84
Biological factors in response to antigens
Old age (> 75)
Elderly persons do not produce antibodies
to polysaccharide antigens
Elderly persons are therefore also more susceptible
to infections by bacteria possessing polysaccharides
in their capsules (S. pneumoniae, N. meningitidis
and H. influenzae)
M. Buc
85
Biological factors
Women compared to men:

are generally more resistant to infections

their response to an antigen is more intensive

the levels of IgG a IgM as well as the numbers of T cells
are higher

leptin levels are higher in women than in men (leptin
stimulates T cells)
M. Buc
86
Properties of an antigen
Immunogeneicity – an ability to induce the
immune response
Specificity – an ability to react with effector
mechanisms of the immune system (i.e.
antibodies and lymphocytes)
M. Buc
87
Epitope
An epitope
(determinant)
is a part of the
antigen to which
an antibody or a
lymphocyte is
directedds
Doan et al. 2008
88
Virella 2001
M. Buc
89
Affinity
Doan et al. 2008
M. Buc
90
Epitope
versus
Hapten

The epitope is an integral part of the antigen

A hapten is an external part of the antigen, bound to it;
it can exist independently of the antigen, however is
unable to elicit the immune response

When hapten is bound to a carrier, it induces the
immune response and is able to react with induced
antibodies or lymphocytes

Hapten is able to react with induced antibodies or
lymphocytes also without carrier
M. Buc
91
Doan et al. 2008
M. Buc
92
Tizard 1995
M. Buc
93
Kindt, 2007
94
Heterophile antigens
Heterophile antigens are molecules present
in absolutely unrelated species that crossreact,
i.e. if one antigen induces antibodies
production, these will react with antigens
in other individual of different species
M. Buc
95
Weil  Felix reaction
in the laboratory diagnosis of epidemic typhus
Antibodies produced against Rickettsia prowasekii
react also with Proteus vulgaris, strain OX19
We detect antibodies against etiological agent of the
disease in a patients serum, i.e. non pathogenic
P. vulgaris and not R. prowasekii, is used as
antigen in this serological in vitro reaction
A laboratory worker is protected from being infected
M. Buc
96
Paul  Bunnel reaction
Antibodies characteristic for infectious
mononucleosis, of which Epstein-Barr virus
(EBV) is the etiological agent, react also with
sheep or cow erythrocytes
M. Buc
97
ABO blood groups

Discovered by K. Landsteiner and J. Jansky in 1900
and 1907, respectively

They discovered A, B, and O; the group AB was added
to them by A. von Decastello a A. Stürli in 1902
How should the blood group „O“ be called?
- should it be called „zero“ (0)?
- should it be called according to the letter „O“?
The correct nomenclature: „O“ = „ohne (without) A“
„ohne (without) B“

M. Buc
98
Biochemical structure of ABO antigens
The basis structure for all three ABO antigens:
H-substance = oligosaccharide + fucose
Blood group A: H-substance + N-acetylglucosamine
Blood group B: H-substance + galactose
M. Buc
99
M. Buc
100
M. Buc
101
ABO blood groups
Imunogenetic relationships
Phenotype
Genotype
Antigens
AB
A/B
A, B
A
A/A, A/H
A
B
B/B B/H
B
O
H/H
H/H
M. Buc
102
Antibodies against A- Bantigens are called
isohaemaglutinins
Phenotype Antibodies
AB
No
A
Anti-B
B
Anti-A
O
Anti-A,
anti-B
Newborns are born without
them; the first antibodies
appear between the moths
3 till 6 of their life
Antibodies are induced by
immunisation of the child
when colonised by bacteria
belonging to a normal
bacterial flora
M. Buc
103
Natural isohaemaglutinins
A blood group A child when colonised by
Escherichia coli, strain O86, develops anti-B
antibodies
A blood group B child when colonised by
Streptococcus pneumoniae, strain 14, develops
anti-A antibodies
Isohaemaglutinins are of IgM class and are present
in the plasma only, not in other body fluids
M. Buc
104
ABO antigens - distribution
ABO antigens are regarded blood groups because
of their paramount importance in blood
transfusions
In reality, they are tissue antigens as they are
present also in membranes of epithelial and
endothelial cells of many tissues and organs
App. 75% individuals contain ABO blood groups
in their tissue fluids = secretors
M. Buc
105
Rhesus system
Rh-system was discovered by K. Landsteiner
and A. S. Wiener, resp., in 1940
Rh-systemm is very complex, so far we recognise
app. 45 different antigens
The most significant Rh-antigens are: C or c,
E or e, and D or d
M. Buc
106
Rh-system

Rh-antigens are in reality epitopes of proteins
crossing the cell membrane 12-times and are
responsible for ammonium transfer

There are no natural anti-Rh antibodies in our
plasma

Rh-system is of a great importance in a
possible immunisation of RhD-negative mother
by RhD-positive erythrocytes of her child
M. Buc
107
Rh system
108
Rh-isoimmunisation
When a mother is RhDnegative (d/d)
and her partner is
either RhDhomozygous (D/D) or
heterozygous (D/d)
their child can be RhDpositive (DD or Dd)
M. Buc
109
Rh-isoimmunisation
Imumunisation of the mother usu. happens
during the delivery when the placenta is
being detached from the body of the uterus
what enables transfer of child's erythrocytes
to enter the blood stream of the mother
M. Buc
110
Rh-isoimmunisation
Rh-negative mother is sensitised by Rh-positive
erythrocytes of her child
Formation of antibodies follows
Antibodies are of IgG class and are able to cross
the placenta pregnancies that follow
M. Buc
111
Rh-isoimmunisation
Reactions of anti-RhD antibodies with foetal
erythrocytes results in their lysis
Haemolytic diesease of newborns subsequently
develops:
Easy forms: Haemolytic anaemia
Heavy f.: Erythroblastosis fetalis (hydrocephalus).
Bilirubin that results from haemoglobin, dissolves
in fat and in this from can cross haemo-encephalic
barrier and damage the developing brain
M. Buc
112
M. Buc
Kindt 2007
113
References
Doan, T., et al. Lippicotts Illustrates Reviews: Immunology. Philadelphia:
Wolters Kluwer 2008, 200 pp.
Goldsby, RA, Kindt TJ, Osborne BA. Kuby Immunology. 6. New York: WH
Freeman Comp 2000, 670 pp.
Kindt TJ, Goldsby, RA, Osborne BA. Kuby Immunology. 6. New York: WH
Freeman Comp, 2007, 574 s.
Kirkwood, E, Lewis C. Understanding Medical Immunol. New York: Jon
Wiley 1989, 179 pp.
Tizard IR. 1995. Immunology. 4. Philadelphia, New York, London, Sydney,
Tokyo: Saunders Coll Publ 1995, 544 s.
Virella G (Ed). Medical Immunology. 5. New York, Basel: Marcel Dekker,
2001, 656 s.
M. Buc
114