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Immune system – function
Innate and adaptive immunity
Dept. of Immunology
• Secretary: Room 440, Ms. K. Riegerová
• Board at 440 – any news!
• Assoc. Prof. Petr Kucera, Room 439
– Consultation hours Tue 14.00 – 15.30, or by
appointment (mail-to: [email protected] ,
[email protected])
• Teachers :
– Mgr. D. Plánská
([email protected])
– Dr. M. Cvačková FNKV (cvackova @fnkv.cz)
– Assoc.Prof. J. Novák
([email protected])
– Prof. I. Hromadníková Dept Cell pathology
(ilona.hromadnikova @lf3.cuni.cz)
Resources for immunology
• Cellular and Molecular Immunology, Abbas AK, 7 Ed,
2012, Elsevier
• I. M. Roitt, Delves PJ: Essential Immunology,
Blackwell Science, 11th Ed., 2006
• Basic Immunology, Abdul K. Abbas, Paperback· 336
Pages, 173 Illustrations Saunders, 2012
• Kindt TJ: Kuby Immunology, New York : W.H.
Freeman, 2006
• Parslow RG, Stites DP, Terr AI, Imboden JB: Medical
Immunology, Lange Medical McGraw Hill, 10th Ed.
2001
• Any other immunology textbook can be used
• Presentations, Study materials -VYUKA
• The term immunity is derived from the Latin
word immunitas, which referred to the
protection from legal prosecution offered to
Roman senators during their tenures in office.
• Historically, immunity meant protection from
disease and, more specifically, infectious
disease. The cells and molecules responsible
for immunity constitute the immune system,
and their collective and coordinated response
to the introduction of foreign substances is
called the immune response.
Early History of Immunology
• Recognition of innate IR:
– 1st century – description of inflammation
• Celsus described the 4 cardinal signs of inflammation:
– Redness (rubor)
– Swelling (tumor)
– Heat (calor)
– Pain (dolor)
– 200 AD – Galen described loss of function
Early History, Cont.
• Recognition of adaptive IR:
– 430 BC – Thucydides noted immunity to
reinfection by the same organism
– 15th century – early attempts to vaccinate against
smallpox occurred in China and Turkey
• Variolation – infectious material (scab) containing smallpox virus
inoculated through cuts in the skin
Cowpox and Smallpox
• In late 1700s, Edward Jenner noted that
milkmaids with cowpox did not contract
smallpox
– Jenner inoculated a boy with cowpox
– Later infected the child with smallpox
– Boy did not contract smallpox
Mechanism of Smallpox Immunity
• Vaccination with cowpox produced:
– Antibody to cowpox that cross-reacted with the
similar smallpox virus
– T cells – induced cell mediated immunity
– Memory B and T cells
• Exposure of immunized host to smallpox: Memory
cells reactivated  specific immunity to smallpox 
no clinical disease
Early History, Cont.
(a)
(b)
FIGURE 1-1 (a) Smallpox vaccine inoculation site after 3 days. (b) Same smallpox
vaccine inoculation site after 10 days.
Pasteur’s Experiments
• Pasteur performed a similar experiment with
Bacillus anthracis and sheep
 Sheep vaccinated with B. anthracis did not
become ill when exposed to a virulent strain,
while unvaccinated sheep sickened and died
• Human rabies trial
 Pasteur gave rabies vaccine to a child bitten by a
rabid dog  no rabies in child
Organ Transplantation
• Early attempts with xenografts (different species)
unsuccessful
• Controlled attempts resulting in organ rejection:
– 1908 – Carrel transplanted kidney cat to cat
– 1935 – first human kidney transplant by a
Russian surgeon
• 1954 – first successful human kidney transplant
– Donor and recipient were identical twins
Major Histocompatibility Complex
(MHC)
• 1980 – Snell, Dausset, and Benacerraf
described the MHC
– Contributed greatly to successful organ
transplants
• 1991 – Thomas and Murray awarded Nobel
Prize in medicine for their contributions to
transplant immunology
Additional Important Contributions to
Immunology
• 1900 – Bordet demonstrated that antibodies were
responsible for immunity to red blood cells (RBC) of
other species
• 1900 – Erlich proposed selective theory –
“lock and key”
• 1908 – Metchnikoff described phagocytosis
• 1930-40 – Breinl, Haurowitz, and Pauling proposed
the instructional theory – limited number of
antibody types
Additional Contributions, Cont.
• 1950s – Jerne, Talmadge, and Burnet proposed clonal
selection theory – lymphocyte specificity
predetermined
– Once the cell encountered antigen, activation and
proliferation would form a clone of cells capable of antigen
recognition
• 1964 – Glick demonstrated T and B lymphocytes in
chickens
• 1965 – Dreyer and Bennett proposed that 2 separate
genes encoded heavy or light chains
Additional Contributions, Cont.
• 1976 – Tonegawa and Hozumi confirmed the
separate gene theory
• 1984 – Jerne described immune regulation
• 1987 – Kohler and Milstein developed monoclonal
antibodies
• 1996 – Zinkernagel and Doherty defined the role of
the MHC in T cell antigen recognition
20th Century Immunology
• 1890 – Behring and Kitasato described “serum
antitoxins” (antibodies)
• 1905 – Koch described cellular immunity in
tuberculosis
• 1919 – Bordet discovered complement-mediated
lysis of bacteria
• 1930 – Kabat demonstrated that gamma globulin
proteins were responsible for agglutination and
precipitation
New Developments in Clinical
Diagnostic Immunology
• Molecular techniques to detect organisms and
diseases
• Cytogenetic techniques for genetic diseases and
cancers
• Histocompatibility testing to prevent organ rejection
• Flow cytometry and monoclonal antibodies for
disease testing
• Amplification methods to  test sensitivity
History of Allergy*
Charles Richet
(1850-1935)
Richet and Portier demonstrated that
repeated injections of jellyfish toxin
into a dog, instead of providing
protection, caused its death.
They used the term
anaphylaxis to
describe this, the opposite of
protection (prophylaxis).
*History of Allergy text adapted from “Essential Allergy.”
Photos courtesy of Oceanside Publications and William Coupon (Ishizaka photo).
Paul Portier
(1866-1962)
History of Immunology
• Von Pirquet noted that under some conditions,
humans, instead of developing immunity, had an
increase in reactivity: This he called allergy. He
put together the Greek words ‘allos,’ meaning
different or changed, and
‘ergos,’ meaning work or action.
• Arthus showed that non-toxic
Clemens von
substances, such as horse serum,
Pirquet
can, after repeated injections,
(1874-1924)
cause tissue injury and necrosis
(Arthus’ reaction).
NicholasMaurice Arthus
(1862-1945)
History of Immunology
• Coca and Cooke proposed the term
‘atopy’ for those clinical forms of allergy,
manifested by hay fever and asthma.
Thus, an inherited predisposition to
become
sensitized is a characteristic
feature of atopy.
Arthur
Fernandez Coca
(1875-1959)
Robert A. Cooke
(1880-1960)
History of Immunology
Prausnitz and Küstner showed that
atopic allergic sensitivity can be
passively transferred from one
individual to another by
a serum factor, which they
called reagin.
Carl Prausnitz
(1876-1963)
Heinz Küstner
(1897-1963)
History of Immunology
• It was not until 1967 that it was
shown by Ishizaka and Ishizaka and
by Johansson and Bennich that
reagin belongs to a new
immunoglobulin class, IgE.
Teruko and
Kimishige Ishizaka
S. Gunnar O.
Johansson
Hans Bennich
History of immunology – recent advances,
and Nobel prices
S. Brenner, H.R. Horvitz
J.E. Sulston
Principles of apoptosis
HIV infection
Tumor related virus infecton
- HPV and carcinoma
M. von Herrath
Nobel prize 2011
• Bruce A. Beutler a Jules A.
Hoffmann
– Activation of innate immunity
• Ralph M. Steinman
– Description of dendritic cells,
influence on adaptive
immunity
New Developments in Clinical
Diagnostic Immunology
• Molecular techniques to detect organisms and
diseases
• Cytogenetic techniques for genetic diseases and
cancers
• Histocompatibility testing to prevent organ rejection
• Flow cytometry and monoclonal antibodies for
disease testing
• Amplification methods to  test sensitivity
Definition of the immune system
• The immune system is an organization of cells
and molecules with specialized role in
defending against infection
• The immune system is able to recognize „self“
and „nonself“, and sometimes react
• To recognize correct and incorrect and act
• Ability to maintain the homeostasis of the
organism - do not harm to itself
„Motto of the immune system“
• „keep life going in harmony“
• to recognize and neutralize infection
(dangerous) – to protect
• to tolerate (when necessary) - autotolerance
• to maintain tissue integrity - homeostasis
• no isolated structures, but highly interactive network,
performing self decisions on the basis of multiple inputs
Immune Response
Immune response can be simple to very
complex
Recognition phase
 
Self
Non-self


Normally no IR
Response phase
General Types of Immunity
• Innate (natural)
– First line of defense
– Most primitive form of immunity
– General recognition
– No previous exposure to agent required
– Nonspecific
• Physical and chemical mechanical barriers
General Types of Immunity
• Adaptive (acquired)
– Specific response to infectious agent
– Specific recognition of small portion of organism
or triggering antigen
– Immunological memory for invader
– Can generate memory of initiator
– System should eliminate self-reacting cells
Innate Immunity, Cont.
Innate immune defenses located at different body sites.
Innate Immunity, Cont.
• Mucous membranes of respiratory, gastrointestinal,
and urogenital tracts
– Ciliated epithelial cells – trap and sweep away airborne
particles and organisms
– Goblet cells – produce mucus to make epithelial surface
sticky
– Enzymes in secretions inhibit invasion by organisms
The Immune System – Development in
different species
• Purpose of the immune response (IR):
– Mammals – most important aspect is to rid the
host of pathogens
– Invertebrates – can exhibit some amount of
immune response
• The most primitive aspect of the IR in any
species is its ability to distinguish self from
non-self
Immunity Across Species
Every species can manifest some immunity
• Invertebrates:
– Lack adaptive immunity (T and B cells)
– Have simple, nonspecific mechanisms to contain
microbes
Immunity Across Species, Cont.
• Vertebrates and some invertebrates:
– Have innate (natural) immunity
– Produce protective enzymes and peptides
– Have phagocytic cells
– Have receptors important in differentiating self
from non-self
– Can reject grafts from other species
taxa emerged in
evolution (mil.y)
Development
of vertebrates
adaptive immune
system
Structure of the immune system
1°
Thymus environment for T lymphocytes development –
epitelial cells, humoral attractant thymulin, thymosin alfa 1, 3,
thymopoietin, lymfoid cells (similar to blasts)
Bursa of Fabricius
mammals equivalent - lymphatic
tissue of the gastrointestinal tract foetal liver, postnatal
bone marrow
2°
Lymphatic nodes
Spleen
Mucosa associated lymphoid tissue - MALT (GALT) – Peyer plaques,
isolated lymphatic follicules, covered by lymphoepitelial cells – M cells
- BALT – following principal bronchi, M cells are near trachea
bifurcation, most cells are B cells
Blood cells lineage
Adaptive immunity
Recognition of foreign structures
• Cells of adaptive immunity
• B cells
– Immunoglobulins – membrane bound BCR – IgM, IgD
• T cells
– T cell receptor TCR
• BCR, TCR – individual, somatic muations, not
inherited – extreme high variability
Recognition of foreign structures
• Cells of innate imunity
– receptors directed against high number of structures on
microorganisms
– germline coded receptors, only few genes for those
receptors
– receptors for limited number of conserved molecular
patterns (common for microorganisms, distinguishable
from self patterns) – Pathogen Associated Molecular
Patterns - PAMPs
Toll - like receptors
• Example of PRRs
• TLRs originally described in insects
• Mammalian cells use to identify important
bacterial components - LPS, CpG
• After activation, TLR activate transcription
factors - activation of immune response genes
• Toll-like receptors, after PAMP recognition,
activate signaling pathways inducing
antimicrobial effector response
Structure, Location, and Specificities of TLRs
Fig. 4-2
Copyright
© 2011 by Saunders,
an imprint
Elsevier Inc.
Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2012
by Saunders,
an imprint
of ofElsevier
Inc.
DRUGS WHICH STIMULATE TOLL-LIKE
RECEPTORS
• In several situations, it is desirable to
stimulate the immune system. For example, it
would be helpful to boost the immune response
to cancers and some vaccines. Drugs have
been developed which bind Toll-like receptors
and give additional stimulus to the immune
system.
• For example, CpG is an unmethylated DNA
sequence normally only found in bacteria. CpG
binds to TLR9 and by activating the immune
system can be used to help to treat cancers
and improve responses to vaccines.
Basic words of immunology
• Antigen, Epitope (exo-,
auto, super-, allergens)
• Antibodies, Ig
• B cells, T cells
• MHC molecules
• Cytokines
• Immune memory
• Tolerance
•
•
•
•
Inflammation
Immunodeficiency
Hypersensitivity, Allergy
Autoimmunity
• Immunization
HLA
Human Leukocyte Antigen
human MHC
cell-surface glycoproteins
self vs. nonself distinction
present peptide Ag to T cells
transplantation
predictive – susceptibility to infection, autoimmunity
anthropology
CLASS I: A, B, C
CLASS II: DR, DQ, DP
CLASS III:
T cell Activation by an Activated APC
IL-1
IL-6
IL-12
IL-12 Receptor
CD28
“Signal 3”
B7
CD4+
T cell
LPS
T Cell
Receptor
“Signal 2”
TLR4
“Signal 1”
Peptide
MHC II
Signal 1: Specificity
Signal 2: Activation
Signal 3: Differentiation
Antigen Presenting Cell (APC)
T and B cell interaction
IL - 4
CD40L CD40
Th2
TCR
B cell
plasmatic
cell
costimulation
IL - 13
SPECIFIC
ANTIBODY
 Krejsek, 2004
Innate and adaptive immunity
Feature
Physical barriers
Soluble factors
Cells
Nonspecific
skin and mucosal membranes
enzymes (lysozym, Complement)
Acute phase reaction proteins
(CRP)
IF-, IF-
Macrophages, PMN, eosinophlis
Self, non self
Specificity
Memory
NK cells
yes
no
no
Specific
none
antibodies
lymphokins
T and B
lymphocytes
yes
yes
yes
Basic characteristics of innate and
adaptive immunity
fylogenetic age
type of the target infectious agens
recognition of foreign stuctures
characteristics of foreign structures
types of foreign structures
receptors
gene localization for receptors
heredity
receptors distribution
speed of the response
recognition of „self“ and „foreign“
regulatory activity
effector activity
immune memory
Innate and Adaptive Immunity
Phases of adaptive immune
responses
• recognition
of antigen
• the
activation of
lymphocytes
• elimination
of antigen
(the effector
phase)
• The duration
of each
phase may
vary
Types of adaptive immunity.
• In humoral immunity, B
lymphocytes secrete
antibodies that prevent
infections by and
eliminate extracellular
microbes.
• In cell-mediated
immunity, helper T
lymphocytes activate
macrophages to kill
phagocytosed microbes
or cytotoxic T
lymphocytes directly
destroy infected cells.
Active and passive immunity.
•
Active immunity is conferred by a host response to a microbe or
microbial antigen, whereas passive immunity is conferred by adoptive
transfer of antibodies or T lymphocytes specific for the microbe. Both
forms of immunity provide resistance to infection and are specific for
microbial antigens, but only active immune responses generate
immunologic memory. Cell transfers can be done only between
genetically identical donor and recipient (e.g., inbred mice) to avoid
rejection of the transferred cells.
Inflammation
• Complex of physiologic reactions to the
disruption of organism integrity
• Triggers- infection, chemical, physical,
ischemic
• Classical features
• Acute inflammation is a physiologic defense
reaction
• Chronic inflammation is usually pathologic
Basic features of immune response
against infection
Types of immune response against
bacterial infection
• Toxigennic bacterial infection
– Exotoxins – exclusive virulent factors. Immunity will
eliminate infection
– Endotoxins
• Encapsulated bacteria
– Microorganisms bypass phagocytosis by production of
surface polysacharides
• Intracellular bacteria
– Bypasse immunity, grow intracellulary, dominantly in
phagocytes (similarly to fungal or parasitic infection). T cell
response is essential
Key Concepts - Principles of Antiviral
Immunity
• Many human viral infections are successfully controlled by the
immune system
• Certain emerging viruses may overwhelm the immune system
and cause severe morbidity and mortality
• Other viruses have developed mechanisms to overwhelm or
evade the immune system and persist
• Individuals with defects in innate or adaptive immunity
demonstrate more severe viral infections
• T-cell immunity is more important for control than antibody
with many viral infections
• Antibody is important to minimize reinfection, particularly at
mucosal sites
• Immune memory is often sufficient to prevent secondary
disease, though not in all viral infections
Complex response of host against parasitic
infection
• Interaction of many different cell types
• Effect frequently local – different cell type
produce different mediators
• Strong impact of genetic factors to control the
response to specific parasites, differs between
individuals and populations
Helminth Infection – key characteristics
•
Divided into nematodes,
trematodes, and cestodes
•
Produce chronic infections that can
persist for decades
•
Characteristically cause morbidity
rather than mortality
•
Multicellular parasites that do not
multiply in the definitive host but
can reproduce sexually to produce
larval stages that ensure continued
transmission
•
The clinical manifestations of
lymphatic filariasis, including: (A)
mild lymphedema; (B) severe
lymphedema; (C) elephantiasis; and
(D) hydrocele.
Antitumor immunity
• NK cells kill many types of tumor cells - reduced class I
MHC expression and express ligands for NK cell
activating receptors
• Macrophages are capable of both inhibiting and
promoting the growth and spread of cancers,
depending on their activation state
Downloaded from: StudentConsult (on 8 May 2013 01:23 PM)
© 2005 Elsevier
Immunopathology
• Immunodeficiency
– SCID – Bubble baby
• Autoimmunity
– T1DM, SLE
• Allergy
– Atopy,
anaphylaxis
-
+
Autoimmunity
• When self-reacting cells persist and are not
destroyed, autoimmunity may result
– Abnormal IR to the host’s own cells or tissues
– Defect of central tolerance
– Defect of peripheral tolerance
– Autoreactive T cells or B cells target cells, tissue
antigens
– Pathogenic destruction of tissues or organs
Summary about immune system
•
•
•
•
•
Recognition of foreign, dangerous or wrong
Fight (sometimes)
Tolerate, when appropriate
Two arms – innate and adaptive
Both composed from cells and soluble
products
Types of Adaptive Immunity
Fig. 1-2
Copyright
© 2011 by Saunders,
an imprint
Elsevier Inc.Inc.
Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2012
by Saunders,
an imprint
ofofElsevier
Specificity Memory and Contraction
Fig. 1-4
Copyright
© 2011 by Saunders,
an imprint
Elsevier Inc.Inc.
Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2012
by Saunders,
an imprint
ofofElsevier
Classes of Lymphocytes
Fig. 1-5
Copyright
© 2011 by Saunders,
an imprint
Elsevier Inc.Inc.
Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2012
by Saunders,
an imprint
ofofElsevier
Phases of Adaptive Immune Responses
Fig. 1-6
Copyright
© 2011 by Saunders,
an imprint
Elsevier Inc.Inc.
Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2012
by Saunders,
an imprint
ofofElsevier
The Clonal Selection Hypothesis
Fig. 1-6
Copyright
© 2011 by Saunders,
an imprint
Elsevier Inc.Inc.
Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2012
by Saunders,
an imprint
ofofElsevier
Classes of lymphocytes.
•
B lymphocytes recognize soluble
antigens and develop into antibody
secreting cells. Helper T lymphocyt
recognize antigens on the surfaces
antigen-presenting cells and secret
cytokines, which stimulate differen
mechanisms of immunity and
inflammation. Cytotoxic T
lymphocytes recognize antigens on
infected cells and kill these cells.
Regulatory T cells suppress and
prevent immune response (e.g., to
self antigens). NK cells use recepto
with more limited diversity than T o
B cell antigen receptors to recogniz
and kill their targets, such as infect
cells