BIOL 520 Advanced Immunology W2009
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BIOL 520 Advanced Immunology W2009. Lecture 1 Overview 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. Adaptive immunity Acquired

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BIOL 520 Advanced Immunology W2009

Lecture 1

Overview Immunology


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Immunology

  • Recognition of self and non-self

    • Antigens

  • Elimination of non-self

    • Exogenous targets

      • Microbes

      • Allergens

      • Foreign material

    • Endogenous targets

      • Tumors


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Two Arms of Host Defense

  • Adaptive immunity

    • Acquired

    • Available within days

    • Specificity

    • Memory

    • In higher vertebrates

  • Innate immunity

    • Natural immunity

    • Defense system functional at birth

    • Preformed or available within hours after infection

    • Pattern recognition

    • Widely present in nature

Innate

Adaptive



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Most Immune Cells are Found in Blood

Granulocytes

Lymphocytes

Monocytes

Natural Killer Cells


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Some Immune Cells are Found in the Tissue

Mast cells

Dendritic Cells


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Hematopoiesis

Pluripotent Stem Cell

Megakaryocyte

GEMM

Progenitor

Lymphoid

Progenitor

Platelets

Erythrocytes

Lymphocytes

Monocyte

Neutrophil

Basophil

Eosinophil

T-Ly

NK-Cells

B-Ly

Activated

T-cell

Dendritic cell

Macrophage

Plasma

cell


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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

Defense Cells Have Specific Tasks


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Epithelial Cell Defense

Microbial Products

(LPS, PG, etc)

TLR

Antimicrobial Peptides

  • TLR: Toll-like receptor (pattern recognition)

  • LPS: lipopolysaccharide

  • PG: peptidoglycan

Cytokines


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Opsonophagocytosis

  • Opsonization

  • Attachment

  • Engulfment

  • Phagosome formation

  • Phagolysosome formation

  • Killing and digestion

5.

6.

4.

2./3.

1.


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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)

    • TNFa

      • Apoptosis

Packaged in Granules


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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

Recognition of Foreign Material


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TLRs and Their Ligands

Extracellular

Peptidoglycan

TLR2

Cytoplasmic membrane

Intracellular


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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

Innate

Immunity

Adaptive

Immunity


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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



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2 chains

Connected by disulfide bond

Variable region

Constant region

Short cytoplasmic tail

Mostly a and b chain

Some specialized T-cells have g and d chain (gd T cells)

T Cell Receptor


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T-Ly

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)

MHC

APC


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TH

CTL

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 endogenouspeptides

      • Virus encoded

      • Produced by intracellularly replicating microorganisms

      • Tumor antigens

    • MHC II: presents exogenous peptides

      • Uptake through phagocytosis and degradation in phagolysosome

MHC I

MHC II


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CTL and MHC I

TH and MHC II

Apoptosis of Target Cell

Immune modulation of target cell

TH1, TH2: Activation

TH3: Inhibition



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Cytokines

Growth Factors

Interleukins

Chemokines

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


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+ + +

Antimicrobial Peptides

+ + +

  • Natural peptide antibiotics

  • Amphiphilic

    • Cationic

    • Hydrophobic

  • Microbial killing through membrane permeabilization

+ + +


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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


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Lymphatic Tissue

  • Central

    • Bone marrow

    • Thymus

  • Secondary

    • Spleen

    • Lymph nodes

    • GALT (gut associated lymphatic tissue)

      • Tonsils

      • Peyer’s patches

      • Appendix

Production

Interaction

with Ag

Maturation


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Thymus

Bone marrow precursor

Immature T-Cells

Mature naive T-Cells

Hassall’s corpuscule

(Cell destruction?)

Blood stream




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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







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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/HEMEHTML/HEMEIDX.html

  • http://www.siumed.edu/%7Edking2/erg/smallint.htm

  • Primary literature: available per request


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