Transcript macrophage - immunology.unideb.hu

IMMUNOLOGY COURSE
26 LECTURES
11 SZEMINARS/PRACTICALS
2 lectures/week
Weeks 1-13
1 class/week
Weeks 1-11
BASIC IMMUNOLOGY and
PATHOLOGY
DEMO
1. BASIC + SEMINARS
2. PATHOLOGY + PRACTICALS
BOOKS
Peter Parham: The immune system (Garland Science)
2nd Edition 2005
Janeway C.A. Jr., Travers P., Walport M., Shlomchik M.:
Immunbiology (Garland Publishing) 5th Edition 2001
Rosen F., Geha R.: Case Studies in Immunology
(Garland Publishing) 5th Edition 2001
Abbas A.K., Lichtman A.H., Pober J.S.: Cellular and Molecular
Immunology (W.B. Saunders Company) 4th Edition 2000
www.immunology.unideb.hu
Username: student
PASSWORD: download
TESTS
IMMUNOLOGY
MICROBIOLOGY
EPIDEMIOLOGY
IMMUNOLOGY
BASIC
CLINICAL
ALLERGOLOGY
CELL BIOLOGY
GENETICS
BIOCHEMISTRY
BIOPHYSICS
IMMUNOGENETICS
IMMUNOGENOMICS
MOLECULAR
BIOLOGY
ENVIRONMENTAL
GENOMICS
IMMUNE DEFICIENCIES
HYPERSENSITIVITY REACTIONS
INFECTIOUS DISEASES
AUTOIMMUNITY
TUMOR IMMUNOLOGY
TRANSPLANTATION IMMUNOLOGY
HISTORY OF IMMUNOLOGY
Babylonian Epic of Gilgamesh (2000 B.C.)
diseases, pestilence
Egypt older dynasties
severe epidemics
Phobus Apolló
plague in the Greek army
Old testament
God’s punishment
1880 – First World War
study of disases, vaccines
1920 – 1960
scientific revolution, chemistry and biology
Immunological memory
Thucydides, historian, Athen
430 i.e. plague
„yet it was with those who recovered from the disease that the sick and the
dying found most compassion……. No fear for themselves; as no man was
never attacked twice – never at least fatally”
Immunity
Depletion theories
Immunitas (latin) – excemption from taxes
First infection depletes nutrients required for the
propagation of the pathogen
Variolation
Smallpox live, wild-type virus inoculated (from China)
but practiced in Europe too
FIRST VACCINATION
Edward Jenner 1796
Immunity (protection) can be induced (cowpox - smallpox)
Louis Pasteur
1880 rabies, 1888 Pastuer Institute
1884 Ilya Mechnikoff
Phagocytosis
Immunization with attenuated pathogens
CELLULAR IMMUNOLOGY
Koch Laboratory
Berlin 1890, Diphteria and Tetanus toxin
Antibodies in serum –
bound to relevant pathogens
Humoral factors
HUMORAL IMMUNE
RESPONSE
Emil Behring
Shimbasaru Kitasato
1. Many disease occurs only once (natural protection)
2. Some diseases can be prevented by vaccination
3. The blood contains anti-bacterial activity (anti-toxins, serum therapy)
MILESTONES OF IMMUNOLOGY RESEARCH I.
YEAR
NAME
DISCOVERY
NOBEL
PRIZE
1890
Emil von Behring
Anti-toxins
Serotherapy (diphteria)
1901
1890
Robert Koch
Tuberculosis, anthrax
Cellular immunity, tuberculin reaction
1905
1883
Elie Mecsnyikov
1908
1900
Paul Ehrlich
Phagocytosis, inflammation
Cellular protection
Side chain theory
1902
Charles Richet
(Paul Portier)
Anaphylaxis
1913
1894
Jules Bordet
Complement
Antibodies/bacteriolysis
1919
1900
Karl Landsteiner
A/B/0 blood groups - serology
1930
1940
Max Theiler
Vaccine against yellow fever
1951
Daniel Bovet
Anti-histamines, treatment of allergy
1957
MILE STONES OF IMMUNOLOGY RESEARCH II.
1944
Peter Medawar
Macfarlane Burnet
Acquired tolerance
Clonal selection theory
1960
1959
Rodney Porter
Gerald Edelman
Antibody structure
1972
Rosalyn Yalow
Roger Guillemin
Andrew Schally
Radioimmunoassay
Peptide hormon production in
brain
1977
1958
Baruj Benacerraf
Jean Dausset,
George Snell
Histocompatibility antigens
1980
1975
George Köhler
Cesar Milstein
Niels Jerne
Monoclonal antibody
1984
Susumi Tonegawa
Gene rearrangement
1987
E. Donnall Thomas
Joseph Murray
Transplantation immunology
1990
Rolf Zinkernagel, Peter
Doherty
MHC restriction
1996
1979
1974
Network theory
GENERAL CHARACTERIZATION OF THE IMMUNE
SYSTEM
GENERAL FEATURES OF THE IMMUNE SYSTEM
1. STRUCTURE – various cell types, diffuse
Cell communication
Th
Partners
Mode
macrophage
– direct
B
pathogen
– soluble factors
extracellular matrix
macrophage
Cell – to – cell
communication
2. ACTION – dynamic
Homeostasis – environmental factors
Replacement vs death
Adhesion
Homing
Migration
neutrophil
Activation vs differentiation
Endothelial cell
3. FUNCTION
Inflammed
tissue
4. SPECIAL FEATURES
Recognition – self - antigen - danger
Defense against pathogens
Recognize, prevent spread, clear from the body
Signal processing and transduction
Signal storage – learning, memory
Protection of self
SIMILARITIES TO THE NERVOUS SYSTEM
WHY IS THE IMMUNE SYSTEM SO IMPORTANT?
Species have been evolved in the presence of pathogens
PATHOGENS
Virus
Bacteria
3 hours
Viruses
3 hours
DIVERSITY
VARIABILITY
Multicellular parazites (helminths) Cells of human body: 90% microbes, 10% human
Monocellular parazites
1012 (1.5kg) bacteria in the gut
Human population: 7x109 (7 billion)
Biomass: 90% microbes
Animal mass
< 5 – 25x
microbes
TWO LINES OF IMMUNE DEFENSE
TWO TYPES OF IMMUNE RESPONSES
INNATE/NATURAL IMMUNITY
Innate immunity constitutes those
components that protect against
infection without any requirement for
prior activation or clonal expansion
First line of defense
Inherited
It is always present
Rapid response
Short term protection
ACQUIRED/ADAPTIVE
IMMUNITY
Requires the activation and
clonal expansion of cell to
protect against pathogens
PHYSICAL BARRIERS PROTECTING OUR BODY FROM
THE ENVIRONMENT
HAIR
BRONCHIAL TRACT
EYES
GASTROINTESTINAL
SYSTEM
Sinuses
Trachea
Lungs
Oral cavity
esophagus
Stomach
Intestines
NAILS
SKIN
Damage
Kidney
Bladder
Vagina
UROGENITAL SYSTEM
Infection
WALDEYER RING
Tonsils, adenoids
Palatinal, pharyngeal
lingual and tubar tonsils
Mucus
glycoproteins, proteoglycanes,
enzymes
EPITELIAL SURFACES ARE IMPORTANT
IN THE FIRST LINE OF DEFENSE
DEFENSE LINES OF NATURAL IMMUNITY
ANATOMIC BORDERS
Skin
Inhibits entry of pathogens, pH3 – 5 inhibits growth
Mucosa
Normal bacterial flora competes for binding sites and nutrients
Mucus keeps away pathogens from the surface
Cilia remove pathogens
PHYSIOLOGICAL BORDERS
Temperature
Physiological body temperature and fever inhibits growth of
certain pathogens
Low pH
Most pathogens are destroyed in the stomach
Chemical
Lysosym degrades bacterial cell wall
Type I interferons induce anti-viral resistance
The complement system is able to lyse bacteria and promotes
phagocytosis
PHAGOCYTOSIS/ENDOCYTOSIS
Many cells can take up microorganisms by receptor-mediated internalization
Special professional phagocytes (monocyte, neutrophil, macrophage) are able to
internalize, kill and degrade microorganisms
INFLAMMATION
Tissue damage and infection results in the leakage of anti-bacterial proteins and
peptides to the affected tissue
Phagocytic cells leave the blood stream and enter inflammed tissues
PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS
Toll receptor
CR3
(LPS)
Toll receptor
(fungi)
PHAGOCYTES (macrophages, dendritic cells, neutrophil granulocytes)
RECOGNIZE PATHOGENS BY PATTERN RECOGNITION RECEPTORS
RECOGNITION IS UNAVOIDABLE
Macrophage, dendritic cell – ACT AS TISSUE SENSORS
Neutrophil granulocytes – MIGRATE FROM THE BLOOD TO THE SITE OF
INFLAMMATION
WHAT IS RECOGNIZED BY INNATE AND ACQUIRED
IMMUNITY?
HOW DO THEY RECOGNIZE PATHOGENS?
RECEPTORS
Common pattern of groups of pathogens
Pathogen Associated Molecular Pattern
PAMP
Recognition by receptors
Pattern Recognition Receptor
PRR
9-13 various Toll-receptors
TLR family
Innate immunity
Ancient
Unique structural elements
Antigenic determinant
Recognition by highly specific
antigen receptors
B cell receptor BCR (sIg)
T cell receptor TCR
Several millions antigen receptors
Acquired immunity
450 million years
TOLL RECEPTORS RECOGNIZE VARIOUS MICROBIAL
STRUCTURES
Bacteria
Virus
CpG DNA
ssRNS
dsRNA
Peptidoglycane
Gram+
TLR3
IFN
TLR7
TLR8
TLR2
Interferon
producing cell
pDC
Flagellin
LPS
Gram-
TLR4
TLR6
TLR9
TLR5
Macrophage/Dendritic cell
ALL STRUCTURES ARE ESSENTIAL FOR THE SURVIVAL OR REPLICATION OF THE
PATHOGEN
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN
VARIOUS SPECIES
Prokariotic cells
Eukariotic cells
Mannose
Glucoseamin
Mannose
Galactose
Neuraminidase
PATTERN RECOGNITION BY MANNAN BINDING LECTIN
Bacterium
lysis
Complement
activation
LECTIN PATHWAY
CR3
Macrophage
Phagocytosis
Strong binding
No binding
THE ACUTE PHASE RESPONSE
IL- 6
Mannose binding
lectin/protein
C-reactive protein
Complement
MBL/MBP
Complement
Liver
Serum Amyloid Protein (SAP)
Phagocytosis, ECM stability
Fibrinogen
IL-6 induces the production of acute phase protiens
PHAGOCYTOSIS
Macrophages ingest and degrade particulate antigens through the use of long
pseudopodia that bind and engulf bacteria. The engulfed bacteria are degraded
when the phagosome fuses with a vesicle containing proteolytic enzymes
(lysosome), forming the phagolysosome. Specialized compartments also exist in
the macrophage to promote antigen processing for presentation to antigenspecific T cells.
MACROPHAGES ACTIVATE OTHER MECHANISMS OF INNATE IMMUNITY
CELLULAR AND HUMORAL MECHANISMS OF
INNATE IMMUNITY
PHAGOCYTOSIS
Phagocytosis
Intracellular killing
Phagocyte
Bacterium
COMPLEMENT
Complement proteins
Lysis of bacteria
Inflammation
Bacterium
INFLAMMATION
Complement-dependent phagocytosis
Cytokines
IL-12
Bacterium
LPS
NK-CELLS
Virus-infected
cell
TNF
IFN
NK-cell
Neutrophil
NK-cell
Macrophage
Lysis of infected cell
TWO LINES OF IMMUNE DEFENSE
TWO TYPES OF IMMUNE RESPONSES
INNATE/NATURAL IMMUNITY
ACQUIRED/ADAPTIVE
IMMUNITY
Phagocytes
(monocyte/macrophage,
neutrophil, dendritic cell)
B lymphocytes (B2)
Killer cells (NK cell, δ T cell)
B1 lymphocytes (CD5+)
CELLS
T lymphocytes
helper T cell
Enzymes
(lysozyme,transferrin,
lactoferrin, spermin, trypsin)
Antibacterial peptides
Complement system
Cytokines, chemokines
cytotoxic T cell
HUMORAL
FACTORS
Antibodies
CHARACTERISTICS OF INNATE IMMUNITY
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•
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•
NATURAL/INNATE
Rapid, prompt
response (hours)
No variable receptors
Limited number of
specificities
No improvement
during the response
No memory
Not transferable
Can be exhausted,
saturated
•
•
•
•
•
•
•
•
ADAPTIVE/ACQUIRED
Time consuming
Variable antigen receptors
Many very selective
specificities
Efficacy is improving
during the response
Memory
Can be transferred
Regulated, limited
Protects self tissues
COMMON EFFECTOR MECHANISMS FOR THE
ELIMINATION OF PATHOGENS
TWO LINES OF IMMUNE DEFENSE
INNATE/NATURAL IMMUNITY
Innate immunity constitutes
components that protect against
infection without any requirement for
prior activation or clonal expansion
First line of defense
Inherited
Always present
ACQUIRED/ADAPTIVE IMMUNITY
Requires the activation and clonal
expansion of cells to protect against
pathogens
Induced by antigen
Response is under genetic control
Depends on environmental stimuli
FUNCTIONAL ATTRIBUTES OF INNATE AND ADAPTIVE IMMUNITY
Chapter 1
Elements of the Immune System and their Roles in Defense
• The innate immune response causes
inflammation at sites of infection
• The adaptive immune response adds to an
ongoing innate immune response
• Potent immune responses require the
collaboration of innate and adaptive immune
responses
© Garland Science 2009
FIRST LINE OF DEFENSE BY INNATE IMMUNITY
EPITHELIAL CELLS
•Pattern recognition receptors (PRR)
•Cytokine, chemokine secretion
NEUTROPHIL GRANULOCYTES
•Phagocytosis
•Intracellular cytotoxicity
MONOCYTE – MACROPHAGE – DENDRITIC CELL NETWORK
•Pattern recognition receptors (PRR)
•Internalizing receptors
•Phagocytosis
NATURAL KILLER CELLS
•Cytoxicity
•Cytokine production
CELLS & MECHANISMS OF INNATE IMMUNITY
Soluble proteins – Defensins
Enzymes - Complement system - Chemotaxis
Recognition by Pattern Recognition Receptors (PRR)
Macrophage & dendritic cell subsets
Neutrophils
Pro-inflammatory and inflammatory cytokine secretion
Local effects
Systemic effects
Chemokine receptors & ligands – cell recruitment, other functions
Cytotoxicity – NK cells