BIOL 520 Advanced

Immunology W2009

BIOL 520 Advanced

Immunology W2009

Lecture 1Overview Immunology

Lecture 1Overview Immunology

Immunology

• Recognition of self and non-self– Antigens

• Elimination of non-self– Exogenous targets

Microbes Allergens Foreign material

– Endogenous targets Tumors

Two Arms of Host Defense

• Innate immunity– Natural immunity– Defense system

functional at birth– Preformed or

available within hours after infection

– Pattern recognition– Widely present in

nature

• Adaptive immunity– Acquired– Available within

days– Specificity– Memory– In higher

vertebrates

Innate Adaptive

Key Players in Immunology

Innate Adaptive

Cells PhagocytesEpithelial Cells

NK Cells

Lymphocytes(B-Ly, T-Ly)

Defense Proteins ComplementAntimicrobial (Poly)Peptides

Antibodies

Most Immune Cells are Found in Blood

Granulocytes

Monocytes

Lymphocytes

Natural Killer Cells

Some Immune Cells are Found in the Tissue

Mast cellsDendritic Cells

Hematopoiesis

Pluripotent Stem Cell

LymphoidProgenitor

GEMMProgenitor

Lymphocytes

NK-Cells

Erythrocytes

Megakaryocyte

Monocyte

Macrophage

Neutrophil BasophilEosinophil

Platelets

B-LyT-Ly

Plasmacell

ActivatedT-cell Dendritic cell

Defense Cells Have Specific Tasks

• Epithelial cells– Barrier (physical,

chemical)– Communcate

• Phagocytes– Ingest– Kill– Digest

• NK-cells– Lyse infected cells or

tumor cells

• B-lymphocytes– Produce antibodies

• T-helper lymphocytes– Strengthen defense

cells to improve their function

– Regulate immune responses

• T-killer lymphocytes– Lyse with specificty

infected cells or tumor cells

Epithelial Cell Defense

TLR

Microbial Products(LPS, PG, etc)

Antimicrobial Peptides

Cytokines

TLR: Toll-like receptor (pattern recognition)LPS: lipopolysaccharidePG: peptidoglycan

Opsonophagocytosis

1. Opsonization2. Attachment3. Engulfment4. Phagosome

formation5. Phagolysosome

formation6. Killing and digestion 1.

2./3.

4. 5.

6.

NK Cell Mediated Killing

• Triggered by two mechanisms– Antibody dependent cytotoxicity– Recognition of altered surface

molecules

• Mediated by:– Perforin

• Pore-forming toxin• Permeabilizes target cell membrane

– Granzyme• Enzyme• Induces apoptosis (cell suicide)

– TNF• Apoptosis

Packaged in

Granules

Recognition of Foreign Material

• Pattern Recognition• Toll Like receptors

– TLR1-10

• All involved in Immune defense– Intracellular region with

homology to IL1 receptor

• Activated directly by microbial products not normally found in host

• Specific antigen recognition

• Antigen Receptor• B cell receptor

– antibody molecule

• T cell receptor– TCR

TLRs and Their Ligands

Intracellular

Extracellular

Cytoplasmic membrane

PeptidoglycanTLR2

Effects of TLR Activation• Cytokine up-regulation and secretion

– Pro-inflammatory cytokines– Chemokines

• Reactive oxygen and nitrogen metabolites

• Antimicrobial peptide production– HBD2

• Up-regulation of surface molecules enhancing adaptive immune responses– Co-stimulatory signals– MHC-II

• Apoptosis

InnateImmunity

AdaptiveImmunity

Basic Structure of an Antibody Molecule

• 2 light and 2 heavy chains

• Disulfide bonds• Hinge region• N-terminus: variable,

antigen binding• C-terminus: constant

region, effector function– 5 isotypes

• IgD, IgM, IgG, IgA, IgE

Basic Functions and Distribution of Antibodies

Functional Activity IgM IgD IgG IgA IgE

Neutralization + - ++ ++ -

Opsonization + - +++

+ -

Sensitization for killling by NK cells

- - ++ - -

Sensitization of mast cells - - + - +++

Complement activation +++ - +++

+ -

Distribution IgM IgD IgG IgA IgE

Transport across epithelium + - - +++

-

Transport across placenta - -- +++

- -

Diffusion into extravascular sites

+/- - ++++

monome

r

T Cell Receptor• 2 chains

– Connected by disulfide bond

– Variable region– Constant region– Short cytoplasmic

tail

• Mostly and chain

• Some specialized T-cells have and chain ( T cells)

T-Cell Antigens

• Short contiguous amino acid (aa) sequence

• Processed antigens– Antigen must have

been unfolded and degraded

– Primary aa structure

• Only when bound to a specialized antigen presenting molecule (MHC)

APC

MHC

T-Ly

TCR Recognizes Antigen Presented by MHC Molecules • MHC: major

histocompatibility complex• First identified in

transplantation immunology • T cells recognize antigen

bound to an MHC molecule • Two types of MHC molecules

– MHC I: presents endogenous peptides

• Virus encoded• Produced by intracellularly

replicating microorganisms• Tumor antigens

– MHC II: presents exogenous peptides

• Uptake through phagocytosis and degradation in phagolysosome

MHC I CTL

MHC II TH

CTL and MHC I TH and MHC II

Apoptosis of Target Cell Immune modulation of target cellTH1, TH2: Activation

TH3: Inhibition

Immune Cells Interact via Cytokines and Surface

MoleculesInnate Adaptive

Cells PhagocytesEpithelial Cells

NK Cells

Lymphocytes(B-Ly, T-Ly)

Defense Proteins ComplementAntimicrobial (Poly)Peptides

Antibodies

Cytokines

• Soluble glycoproteins• ~ 25 kD• Cell to Cell communication

– Autocrine, paracrine,endocrine• Act by binding to specific receptors

– Receptor expression varies– Receptors can be shared by different

cells– Different cells can respond differently

Interleukins

Chem

okin

es

Growth Factors

Cytokines

Antimicrobial Peptides

• Natural peptide antibiotics• Amphiphilic

– Cationic– Hydrophobic

• Microbial killing through membrane permeabilization

+ + +

+ + +

+ + +

Complement

• System of plasma proteins• Activates a cascade of proteolytic

reactions and subsequent protein aggregation on the microbial surface but not on host cell surface

• Coat microbes with a substance that is bound by phagocytes (opsonization)

• Form pores on microbial surfaces triggering killing

• Release small peptides that contribute to inflammation

Lymphatic Tissue

• Central– Bone marrow – Thymus

• Secondary– Spleen– Lymph nodes– GALT (gut associated

lymphatic tissue)• Tonsils• Peyer’s patches• Appendix

Production

Interactionwith Ag

Maturation

Thymus

Immature T-Cells

Mature naive T-Cells

Hassall’s corpuscule

(Cell destruction?)

Bone marrow precursor

Blood stream

Lymph Node

The Spleen

Organization of the Spleen

• White pulpa– Leukocytes

arranged around the blood vessels and sinuses

• Red pulpa:– Blood vessels and

sinuses

• Marginal Zone– Border between

white and red pulpa

Peyer’s Patches

Time Course of the Immune Response

Infection Triggers an Innate Inflammatory Response

Dendritic Cells Initiate Adaptive Immune Responses

Adaptive Immune Responses Augment Innate Immune

Responses

References

• Janeway’s Immunobiology, 7th edition, 2008• Textbook of Hematology, McKenzie, 2nd

edition, 1996• Microbiology: An Introduction; Tortora et al, 8th

edition, 2004• http://www-medlib.med.utah.edu/WebPath/HE

MEHTML/HEMEIDX.html• http://www.siumed.edu/%7Edking2/erg/smallin

t.htm• Primary literature: available per request