IMMUNOLOGY COURSE

26 LECTURES

2 lectures/weekWeeks 1-13

BASIC IMMUNOLOGY and PATHOLOGY

11 SZEMINARS/PRACTICALS

1 class/weekWeeks 1-11

DEMO

1. BASIC + SEMINARS

2. PATHOLOGY + PRACTICALS

BOOKS

Peter Parham: The immune system (Garland Science)

3rd Edition

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

Some big and small questions:

How does the Immune system work?

How does the IS recognize pathogens?

How does the IS remember pathogens?

How do immune cells differentiate between pathogens?

Why the immune system almost never attacks food and self tissue?

Can knowledge of basic immunology help fighting:PathogensAutoimmune diseasescancer

IMMUNOLOGY

IMMUNOLOGY

MICROBIOLOGY

EPIDEMIOLOGY

CELL BIOLOGYGENETICSBIOCHEMISTRYBIOPHYSICSMOLECULAR BIOLOGY

BASIC

IMMUNE DEFICIENCIES

HYPERSENSITIVITY REACTIONS

INFECTIOUS DISEASES

AUTOIMMUNITY

TUMOR IMMUNOLOGY

TRANSPLANTATION IMMUNOLOGY

CLINICAL

ALLERGOLOGY

IMMUNOGENETICSIMMUNOGENOMICS

ENVIRONMENTAL GENOMICS

Babylonian Epic of Gilgamesh (2000 B.C.) diseases, pestilence

Egypt older dynasties severe epidemics

Variolation China,

1722 prine and princess of Wales permitted inoculation of their children

nofacial scarring

2% DEATH RATE

HISTORY OF IMMUNOLOGY

1880 – First World War study of disases, vaccines

1920 – 1960 scientific revolution, chemistry and biology

Edward Edward Jenner 1796Jenner 1796

Immunity (protection) can be Immunity (protection) can be iinduced (cowpoxnduced (cowpox - smallpox)- smallpox)

FIRST VACCINATIONFIRST VACCINATION

Louis PasteuLouis Pasteurr11880 rabies, 880 rabies, 1888 Pastuer Institute

Immunization with attenuated pathogens

1884 Ilya Mechnikoff

Phagocytosis

CELLULAR IMMUNOLOGY

KochKoch Laboratory Laboratory Berlin 1890Berlin 1890, , Diphteria and Tetanus toxinDiphteria and Tetanus toxin

Emil BehringEmil Behring ShimbasaruShimbasaru KitasatoKitasato

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)

HUMORAL IMMUNE RESPONSE

Humoral factors

Antibodies in serum –bound to relevant pathogens

YEAR NAME DISCOVERY NOBEL PRIZE

1890 Emil von Behring Anti-toxinsSerotherapy (diphteria)

1901

1890 Robert Koch Tuberculosis, anthraxCellular immunity, tuberculin reaction

1905

1883

1900

Elie Mecsnyikov

Paul Ehrlich

Phagocytosis, inflammationCellular protectionSide chain theory

1908

1902 Charles Richet(Paul Portier)

Anaphylaxis 1913

1894 Jules Bordet ComplementAntibodies/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

MILESTONES OF IMMUNOLOGY RESEARCH I.

1944 Peter MedawarMacfarlane Burnet

Acquired toleranceClonal selection theory

1960

1959 Rodney PorterGerald Edelman

Antibody structure 1972

Rosalyn YalowRoger GuilleminAndrew Schally

RadioimmunoassayPeptide hormon production in brain

1977

1958 Baruj Benacerraf Jean Dausset, George Snell

Histocompatibility antigens 1980

1975 George KöhlerCesar MilsteinNiels Jerne

Monoclonal antibody

Network theory

1984

1979 Susumi Tonegawa Gene rearrangement 1987

E. Donnall ThomasJoseph Murray

Transplantation immunology 1990

1974 Rolf Zinkernagel, Peter Doherty

MHC restriction 1996

MILE STONES OF IMMUNOLOGY RESEARCH II.

GENERAL CHARACTERIZATION OF THE IMMUNE SYSTEM

3. FUNCTION

Defense against pathogens

Recognize, prevent spread, clear from the body

Protection of self

2. ACTION – dynamic

Homeostasis – environmental factors

Replacement vs death

Activation vs differentiation

4. SPECIAL FEATURES

Recognition – self - antigen - danger

Signal processing and transduction

Signal storage – learning, memory

B

Th

GENERAL FEATURES OF THE IMMUNE SYSTEM

1. STRUCTURE – various cell types, diffuse Cell communication

Partners

Mode – direct

– soluble factors

macrophage

extracellular matrix

AdhesionHoming

Migration

neutrophil

Endothelial cell

macrophage

pathogen

Cell – to – cellcommunication

SIMILARITIES TO THE NERVOUS SYSTEM

Inflammed tissue

WHY IS THE IMMUNE SYSTEM SWHY IS THE IMMUNE SYSTEM SOO IMPORTANT? IMPORTANT?

VVirusesiruses

MMulticellular parazites ulticellular parazites (helminths)(helminths)

MMonocellular paonocellular parrazitesazites

VirusVirus

3 3 hourshours

3 3 hourshoursDIVERSITY

VARIABILITY

BacBacteriateria

PATHOGENS

SSppecies have been evolved in the presence of pathogensecies have been evolved in the presence of pathogens

Cells of human body: 90% microbes, 10% human

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 Innate immunity constitutes those components that protect against components that protect against

infection without any requirement for infection without any requirement for prior activation or clonal expansionprior activation or clonal expansion

ACQUIRED/ADAPTIVE IMMUNITY

Requires the activation and clonal expansion of cell to protect against pathogens

First line of defense

Inherited

It is always present

Rapid response

Short term protection

SinusesTracheaLungs

BRONCHIAL TRACT EYES

Oral cavityesophagus

StomachIntestines

GASTROINTESTINAL SYSTEM

HAIR

SKIN

NAILS

PHYSICAL BARRIERS PROTECTING OUR BODY FROM

THE ENVIRONMENT

Damage

Infection Mucus

glycoproteins, proteoglycans, enzymes

KidneyBladderVagina

UROGENITAL SYSTEM

WALDEYER RINGTonsils, adenoids

Palatinal, pharyngeal lingual and tubar tonsils

EPITELIAL SURFACES ARE IMPORTANT IN THE FIRST LINE OF DEFENSE

PHYSIOLOGICAL BORDERSTemperature Physiological body temperature and fever inhibits growth of

certain pathogens

Low pH Most pathogens are destroyed in the stomach

Chemical Lysosym degrades bacterial cell wallType I interferons induce anti-viral resistance The complement system is able to lyse bacteria and promotes phagocytosis

PHAGOCYTOSIS/ENDOCYTOSISMany cells can take up microorganisms by receptor-mediated internalization

Special professional phagocytes (monocyte, neutrophil, macrophage) are able to internalize, kill and degrade microorganisms

INFLAMMATIONTissue 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

ANATOMIC BORDERSSkin Inhibits entry of pathogens, pH3 – 5 inhibits growth

Mucosa Normal bacterial flora competes for binding sites and nutrients Mucus keeps away pathogens from the surfaceCilia remove pathogens

DEFENSE LINES OF NATURAL IMMUNITY

PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENSPHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS

Toll receptor

PHAGOCYTES (macrophages, dendritic cells, neutrophil granulocytes) PHAGOCYTES (macrophages, dendritic cells, neutrophil granulocytes) RECOGNIZE PATHOGENS BY PATTERN RECOGNITION RECEPTORS RECOGNIZE PATHOGENS BY PATTERN RECOGNITION RECEPTORS

RECOGNITION IS UNAVOIDABLERECOGNITION IS UNAVOIDABLEMacrophage, dendritic cell – ACT AS Macrophage, dendritic cell – ACT AS TISSUE SENSORS TISSUE SENSORS

Neutrophil granulocytes – MIGRATE FROM THE BLOOD TO THE SITE OF Neutrophil granulocytes – MIGRATE FROM THE BLOOD TO THE SITE OF INFLAMMATIONINFLAMMATION

CR3

Lectin

Lectin

Neg. Charged, Sulfated polysaccharidesDNA, Gram+ bacteria

LPS, Lipophosphoglycan ofLeishmania

WHAT IS RECOGNIZED BY INNWHAT IS RECOGNIZED BY INNAATE AND ACQUIRED TE AND ACQUIRED IMMUNITY?IMMUNITY?

HOHOW DO THEY RECOGNIZE PATHOGENS?W DO THEY RECOGNIZE PATHOGENS?

Common pattern of groups of pathogensCommon pattern of groups of pathogensPathogen Associated Molecular PatternPathogen Associated Molecular Pattern

PAMPPAMPRecognition by receptorsRecognition by receptors

Pattern Recognition ReceptorPattern Recognition ReceptorPRRPRR

9-19-133 various various Toll-Toll-rreecceptoreptorssTLR familyTLR family

SSeveral millions antigen receptorseveral millions antigen receptors

UUnique structural elenique structural elemmentsentsAntigenic determinantAntigenic determinant

Recognition by highly speciRecognition by highly speciffic ic aantigen receptorsntigen receptors

B cell receptorB cell receptor BCR (sIg) BCR (sIg)T cell receptorT cell receptor TCR TCR

RECEPTORS

InInnate immunitynate immunity

AncientAncient 450 450 million yearsmillion years

AAcquired immunitycquired immunity

MaMaccrorophage/Dendritic cellphage/Dendritic cell

TLR5TLR5

FlageFlagelllinlin

VViirusrus

TLR3TLR3

ddssRNARNA

TOLL RECEPTORS RECOGNIZE VARIOUS MICROBIAL STRUCTURES

TLR2TLR2

PeptidoglycanePeptidoglycane

Gram+

TLR4TLR4

LPSLPS

TLR6TLR6

Gram-

InterferonInterferonproducing cellproducing cellpDpDCC

IFN

BaBacctteeririaa

CpG DNACpG DNA

TLR9TLR9TLR7TLR7TLR8TLR8

ssRNSssRNS

ALL STRUCTURES ARE ESSENTIAL FOR THE SURVIVAL OR REPLICATION OF THE PATHOGEN

EEukariotic cellsukariotic cells

GluGluccooseseaminamin

MannMannoseose

GalaGalactosectose

Sialic acidSialic acid

GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES

MannoseMannose

ProkarProkariotic cellsiotic cells

PATTERN RECOGNITION BY MANNAN BINDING LECTINPATTERN RECOGNITION BY MANNAN BINDING LECTIN

Strong binding No binding

BaBacteriumcterium

lysis

Complementactivation

MacrophagePhagocytosis

CR3

LECTIN PATHWAY

Macrophages ingest and degrade particulate antigens through the use of long Macrophages ingest and degrade particulate antigens through the use of long pseudopodia that bind and engulf bacteria. The engulfed bacteria are degraded pseudopodia that bind and engulf bacteria. The engulfed bacteria are degraded when the phagosome fuses with a vesicle containing proteolytic enzymes when the phagosome fuses with a vesicle containing proteolytic enzymes (lysosome), forming the phagolysosome. Specialized compartments also exist in (lysosome), forming the phagolysosome. Specialized compartments also exist in the macrophage to promote antigen processing for presentation to antigen-the macrophage to promote antigen processing for presentation to antigen-specific T cells.specific T cells.

PHAGOCYTOSIS

MACROPHAGES ACTIVATE OTHER MECHANISMS OF INNATE IMMUNITY

ConsequenceConsequencess of of macrophage amacrophage activationctivationSynthesis of Synthesis of ccytokinesytokines

MIGRATION OF NEUTROPHILS

FROM BLOOD

TO INFLAMMED TISSUE

Neutrophil Transendothelial Migration (Diapedesis)

Liver

C-reactive proteinC-protein of S.pneumoniaeBinds phosphocolin of LPS

.

Complement

Serum Amyloid Protein (SAP)

Phagocytosis, ECM stabilityFibrinogen

Mannose binding lectin/protein

MBL/MBPComplement

IL- 6

THE ACUTE PHASE RESPONSE

IL-6 induces the production of acute phase protiens

Bacterium

Complement proteins Lysis of bacteria

Inflammation

Complement-dependent phagocytosis

COMPLEMENT

PhagocytosisIntracellular killing

PHAGOCYTOSIS Phagocyte

Bacterium

CELLULAR AND HUMORAL MECHANISMS OF INNATE IMMUNITY

INFLAMMATION

BacteriumLPS

Cytokines Neutrophil

NK-cell

Macrophage

TNF

IL-12

IFN

NK-CELLSVirus-infected

cell

NK-cell Lysis of infected cell

CELLS

HUMORAL

FACTORS

Phagocytes (monocyte/macrophage, neutrophil, dendritic cell)

Killer cells (NK cell, δ T cell)

B1 lymphocytes (CD5+)

B lymphocytes (B2)

T lymphocytes

helper T cell

cytotoxic T cellEnzymes (lysozyme,transferrin, lactoferrin, spermin, trypsin)

Antibacterial peptides

Complement system

Cytokines, chemokines

Antibodies

TWO LINES OF IMMUNE DEFENSE

TWO TYPES OF IMMUNE RESPONSES

INNATE/NATURAL IMMUNITY

ACQUIRED/ADAPTIVE IMMUNITY

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

CHARACTERISTICS OF INNATE IMMUNITY

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