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Basic Immunology

Preface
Immunology is a relatively recent discipline area in the life / biological sciences. It is an
integration of many sub-disciplines of biology, most notably: microbiology, parasitology,
histology, molecular and cell biology, physiology genetics and biochemistry. The course here is a
series of lectures providing comprehensive introduction to basic defense mechanisms that protect
individuals against infections and cancers.
In Immunology the student will become acquainted with theories and phenomena explaining
the interactions of animals and human beings with their environments, and with other living
organisms. Studies in immunology are leading to advances in clinical medicine, including
understanding allergies, transplant rejection, autoimmune diseases, such as rheumatoid arthritis
and insulin-dependent diabetes, and the development of new vaccines. The course should also
provide ample insights into areas of basic research as well as topics related to modern human
immunology. Students are expected to analyze disease processes in the light of current
immunological thinkinG

Course Objectives:
 To develop an awareness of experimental design and scientific methods
 To acquire a working vocabulary in immunology.
 To understand and discuss the development and evolution of the immune system.
 To gain an understanding of the key cells involved in the immune responsE
 To understand the relationship of antigen, antibody, and antigen receptor molecules.
 To gain a basic knowledge of the generation of diversity involved in antibodies and T-cell
antigen receptors.
 To distinguish and understand the humoral and cell-mediated immune responses.
 To gain a basic understanding of the current theories on the regulation of the immune
responsE
 To discuss the host's ability to mount an immune response to invading microorganisms
Tentative Lecture Syllabus of Immunology
Chapter 1 Introduction To Immunology
Chapter 2 Overview Of The Immune System
Chapter 3 Antigens
Chapter 4 Ig Structure and Function
Chapter 5 Organization and diversity of Ig Genes
Chapter 6 Antigen Antibody Interaction
Chapter 7 Complement System
Chapter 8 Cytokines
Chapter 9 CD And Adhesion Molecules
Chapter 10 MHC
Chapter 11 Innate Immunity And Innate Immune Cells
Chapter 12 APCs, Antigen Processing And Presentation
Chapter 13 Development Of Immune Cells
Chapter 14 T Cell Mediated Adaptive Immunity
Chapter 15 B Cell Mediated Humoral Immunity
Chapter 16 Immune Regulation
Chapter 17 Immune Tolerance
Chapter 18 Hypersensitivity

Teaching outline

Chapter 1 Introduction To Immunology


A Introduction To Immunity
1 Definition Of Immunity
2 Major Functions Of Immune System
B Historical Perspective
1 Early Phenomena And Theories Related To Immunity
2 Early Studies Of Humoral And Cellular Components Of The Immune System
3 Early Attempted To Explain The Specificity Of The Antibody–Antigen Interaction
4 Discovery Of Humoral And Cellular Immunity
5 The Nobel Prize Laureates In Immunology
6 Perspective And Importance Of Modern Immunology
C Lecture Schedule Of Immunology

Chapter 2 Overview Of The Immune System


A Innate And Adaptive Immune Systems
1 Innate(Non-Specific) Immune System
a Innate Immunity
b Non-Immune Mechanisms Of Defense
c Immune Cellular Components Of Innate Immunity
2 Adaptive(Acquired Or Specific) Immune System
a Adaptive Immunity
b Compositions Of Humoral And Cellular Immunity
3 Similarities And Differences Between Innate And Adaptive Immunity
B Tissues And Organs Of Immune System
1 Types And Structure Of Primary Immune Organs
a Bone Marrow
b Thymus
c Bursa Of Fabricius In Chickens
d Biological Functions Of Primary Immune Organs
2 Types And Structure Of Secondary Immune Organs
a Lymph Node
b Spleen
c Malt (Mucosal-Associated Lymphoid Tissue)
d Lymphoid Follicles
e HEV (High Endothelial Venules)
C Lymphocyte Homing And Re-Circulation
1 Lymphocyte Homing
a Homing
b Cell Surface Molecules
c Significance
d Where Do Memory Cells Home?
2 Lymphocyte Re-Circulation
a Homing
b Cell Surface Molecules
c Significance

Chapter 3 Antigens
A Antigen
1 Antigen
2 Haptens
3 Properties Of Antigen
4 Immunogen Vs. Antigen
B Factor That Influence Immunogenicity
1 Foreigness
a Determined During Embryonic Development
b Foreigness Increases With Phylogenetic Distance
2 Complexity
a Heterogeneity
b Size And Heterogeneity
3 Molecular Size
4 Charge
a Polar Sites Better Than Non-Polar
b What Types Of Bonds Are Necessary For Ag/Ab Binding?
5 Degradability
a Lysosomal Enzymes Must Recognise Ag
b LG Insoluble Molecules Better Than Sm., Soluble Ones
c Proteins With D-Amino Acids Not Immunogenic
C Immunogenicity Of Macromolecules
1 Proteins
2 Carbohydrates
3 Nucleic Acids
4 Lipids
D B-Cell Epitopes
1 Size And Shape Determined By Paratope
2 Epitopes H'philic And Accessible
3 Due To Sequential Or Non-Sequential AA On Protein Surface
4 Immunodominant Epitopes
E T-Cell Epitopes
1 Oligomeric Peptides
a MHC Binding Site Determines Size
b Best Sizes For MHC I And MHC II?
2 Trimolecular Interactions
a Agretope Binds MHC
b Epitope Binds TCR
3 Sequential Amino Acids
a Processed Inside Phagocytic Cell
b No Tertiary Structure Remains
4 Amphipathtic Peptides
a Used To Predict Immunodom.
b 18 Of 23 Immunodominant Peptides Were Amphipathic
5 MHC Determines Immunodominant Peptides:
a L-Cell (Fibroblast Experiment)
b MHC II Genes Transfected Into L-Cells
c Look For Activation Of T-Cells
6 SuperatIgEns
a Potent T-Cell Mitogens
b Cross-Link TCR And MHC Without Specificity
c How Can They Make Us Ill?

Chapter 4 Ig Structure And Function


I Immunoglobulin Structure
A Light And Heavy Chains
1 2 Light Chains
a LC Has 2 Globular Domains
b Both L And K LC In All Indiv.
2 Two Heavy Chains
a Has 4 Globular Domains
b CH Determines Ab Class
c Ab's Of The Same Class Have Essentially Identical C-Regions
d Biological Activities Assoc With CH
e ~110 Amino Acids Per Globular Domain
3 Variable (V) Region
a Differs Between B-Cell Lines
b V-Region On Each Chain
c Three Hypervariable Regions/Chain
4 Constant (C) Region
a Not Involved In Ag Binding
b Subclasses Determined Here
c Carbo. Chains Asssociate With CH2 Domains
5 Hinge Region
a Proline-Rich
b Provides Flexibility Between Fc And Fab
c Susceptibility To Proteases
B Proteolytic Cleavage Products
1 Papain
a Cleaves Above Disulfides
b Production Of Fab
c Production Of Fc
2 Pepsin
a Production Of Divalent F(ab')2
b Fc Fragments
C Ab Markers
1 Allotypes = Allelic Forms Of Same Ig Genes
a 1-4 AA Differences In C- Region
b Three Km Allotypes
c 25 Gm Allotypes
d How Would An Ab Be Raised To Distinguish Allotypes?
2 Idiotypes = Epitopes From Hypervariable Regions
a Anti-Idiotypic Abs Generated (Network Theory)
b How Would An Ab Be Raised To Distinguish Idiotypes?
3 Isotypes (Ab Classes)
a How Would An Ab Be Raised To Distinguish?
II Ig Isotypes
A IgG
1 Mol. Wt. 150,000
2 Divalent
3 1/2 Life = 23 Days
4 Biological Properties
a Opsonin
b Transfer Across Placenta
c Agglutination
d Precipitation
e Complement Activation
B Ig Isotypes: IgM
1 Mol. Wt. 900,000
2 J-Chain "Joining"
a For Polymerization
b Necessary For Secretion
3 Valence Of 10 Possible
4 Half Life = ~ 5 Days
5 Biological Properties
a B-Cell Receptor
-H'phobic Region Near C-Term.
b Earliest Ab Made
c Agglutinatiring On/Precipitation
d Complement Activation
6 Four HC Constant Domains
C Ig Isotypes: IgA
1 Secretory IgA (sIgA)
a Secretory Component
b J-Chain
c Tetravalent
d 415,000 Daltons
e Found In Body Secretions
2 Bio. Properties Of Secretory IgA
a Secretion
b Defense Of Mucosal Surfaces
c Agglutination/Precipitation
d Huge Amts. Produced/Day
D IgD
1 Primary Ig Receptor On B-Cells
2 180,000 Dalton Monomer
3 Membrane Spanning Region Near C-Term.
E IgE
1 Monomer Of Mol. Wt. 200,000
2 Attachment To Mast Cells Or Basophil Via Fc
3 Shortest 1/2 Life (~2days)
4 Increases During Parasitic Infections
5 4 HC Constant Domains
III Polyclonal Abs
1 What Are They?
2 How Different From Mabs?
IV Mouse Monoclonal Abs (Very Specific)
1 Fuse Myeloma Cell (Immortal) + B Lymphocyte (From Spleen)
2 Select For Hybridomas With HAT
a Lymphocytes Die In Culture
b Myelomas Die Due To HAT
c How Does This Work?
3 Test For Presence Of Mabs
4 Inject Hybridomas Into Mouse Peritoneal Cavity
a Amplify Ab Production (How?)
V Human Mabs
1 Why Are Human Mabs More Desirable Than Mouse?
2 What Have Been Some Problems Assocociated With Raising Human Mabs?
3 Problems Overcome By:
a Lympho. From 2 Individuals Cultured Together
b Transform Cells With Epstein-Barr Virus

Chapter 5 Organization And Diversity Of Ig Genes


I Overview Of Ig Gene Expression:
A Terms
1 Transcription/Translation
2 Exons
3 Introns
4 Processing Of Heterologous Nuclear RNA
5 Leader Sequence/Signal Sequence
B Ab Synthesis ----> Secretion
1 DNA Rearrangements In Developing B-Cell
2 Transcription Of Hnrna In Nucleus
a Processing Of Hnrna In Nucleus
3 mRNA Translated On RER
a Signal Sequence Synthesized 1st
b Glycosylation In Lumen Of RER
c Heavy And Light Chain Associate In RER
4 Movement To Golgi
a Transition Vesicles Fuse With Proximal Golgi
b Further Glycosylation
5 Formation Of Secretory Vesicles
6 Exocytosis
a Secretion Of Soluble Ig
b Expression Of Membrane-Bounded Ig
II Kappa Light Chain Rearrangement
A Organization Of Human Germ Line DNA
1 100 V-Genes
2 5 J Genes
3 One CK Gene
B Rearrange In Immature B-Cell
1 In Bone Marrow
2 V & J Join First
a Recombination Signal Sequences Complementary
b Loop Forms With DNA Between V And J
3 Recombinases Cut-Out Loop
a RAG 1 And RAG 2
b SCIDS
4 LIgAtion Of V Gene To J Gene By Recombinases
C Transcription Of HnRNA
1 Starts At Selected Vgene With Its Leader
2 Stops At End Of Ck gene
D Processing To mRNA
a Cut Out Intervening Sequences
E Translation Of mRNA On Ribosome
III Lamda LC Similar To Kappa
1 Similar Idea
2 Difference In region Of V And J
IV Heavy Chain
A DNA Rearrangements In Immature B-Cell
1 D + J 1st
2 V + DJ
3 V Encodes CDR1 And CDR2
4 D And J Encode CDR3
B Transcription
1 Starts With Selected V
2 Stops At End Of Last C Gene
C Differential Processing
1 Either Cm Or Cd Selected
2 M Chain processing
a Cut Out IVS
b If Membrane-Bound, M1 Amd M2 Selected
c If Secreted, S Selected
D Translation On Ribosome
E Class Switching
1 In Mature B-Cell
2 Switch Sites = DNA Seq. Upstream To Each C Gene
a Multiple Repeating Nucleotides
3 Assoc Of 5' Switch Of Cm With 5' Switch Of Appropriate C Gene
4 Intervening DNA Clipped Out By Recombinases
5 Induction By Cytokines
a Activation Of Class Specific Recombinases?
V Means Of Antibody Diversity
A HC Genes X LC Genes
1 Due To Rearrangements
B Junctional Flexibility
1 Coding Joint Deletions
a At DJ, VDJ And VJ
b Produce Different Amino Acids Encoded By Joint Regions
2 Non-Productive Alignments
a Absent Or Defective Polypeptide
3 Productive Alignments
a Functional Polypeptide
C N-Region Nucleotide Addition
1 Only In Hcs
2 Nucleotide Addition
a At V-D And D-J
b Not Encoded By The Gene
c Enzymatic Addition By Terminal Deoxynucleotidyl Transferase
3 Get Random AA Additions In HC Polypeptide
a Some Productive
b Some Nonproductive
D Somatic Mutation
1 Mutations In Matureb-Cell
a During DNA Replication
b Not Just At Joints
2 May Increase Or Decrease In Ig Affinity
3 Exp. With Phosphorylcholine
a Sequenced Germ Line T-15 Gene (HC Gene)
b Sequenced Mabs To Phosphorylcholine
c Some Reflected Somatic Mutation
4 Correlated With 2o & 3o Responses
5 Mutation Rate 106 X Greater Than In Other Genes
E Allelic Exclusion
1 Prevents Multispecificity Within A Single B-Cell
a Only One HC Allele And One LC Allele Expressed
b Yancopolos And Alt Model
2 Experiment With Transgenic Mice Carrying Rearranged M Gene
a How Did This Demonstrate Allelic Exclusion?
F Productive Vs. Non-Productive Rearragements
1 33 3% Of Rearrangements Successful
2 Only ~3 7% Of All Immature B-Cells Develop To Maturity
a How Was This Calculated?

Chapter 6 Antigen-Antibody Interactions


A General Characteristics Of Ag-Ab Interactions
1 Strength Of Antigen-Antibody Interactions
a Hydrogen Bonds
b Ionic Bonds
c Hydrophobic Interactions
d Van Der Waals Interactions
2 Affinity Vs. Avidity
a Affinity
b Avidity
3 Specificity
4 Cross-Reactivity
a Cross-Reactivity
b Examples: ABO Blood Ags Vs. Bacterial Components
5 Redundancy
A Epitope Redundancy = Ab Binds 2 Or More Distinct Epitopes
B Paratope Redundancy = Two Abs Bind Same Epitope
B Immunology Techniques Based On Antigen-Antibody Interaction
1 Precipitation Reactions
a Reactions In Fluids
b Reaction In Gels
— Mancini Radial Immunodiffusion
— Ouchterlony Double Immunodiffusion
— Immunoelectrophoresis
— Rocket Electrophoresis
2 Agglutination Reactions
a Direct Agglutination
— Ag Natural Constituent Of Cell
— ABO Blood Typing(Hemagglutination) And Bacterial Agglutination
b Passive Agglutination
— Attach Ag To Insoluble Matrix(Soluble Antigen)
— Latex Agglutination Test (IgG On Beads)
c Aagglutination Inhibition
— Small Quantities Of An Antigen
— Home Pregnancy Test Kit
e Sensitivity
f Comparison With Agglutination
3 Enzyme-Linked Immunosorbent Assay(ELISA Or EIA)
a ELISA And Applications
b Types Of ELISA
— Indirect ELISA
— Sandwich ELISA
— Competitive ELISA
— ELISPOT Assay
c Types Of Enzymes
— Horseradish Peroxidase (HRP)
— Alkaline Phosphatase(ALP)
— β-Galactosidase
d Types Of Substrate
— Chromogenic Substrate
— Luxiogenic Substrate
e Detection
— Chromogenic Reaction Based Assay
— Chemiluminescence
f Sensitivity
4 Radioimmunoassay(RIA)
a RIA And Usage
b Sensitivity
c Radioactive Isotope
— Gamma-Emitting Isotope: 125I
— Beta-Emitting Isotope: 3H
5 Western Blotting(WB) Or Immunoblotting(IB)
a WB And Applications
b Proteins Assayed
c SDS- Polyacrylamide Gel(SDS-PAGE)
— Molecular Mechanisms
— Concentration Selection
d Solid Phase Blotting
— 1st Antibody
— 2nd Antibody---Enzyme Conjugated
— Enzymes
— Substrates
e Detection
— Chromogenic Reaction Based Assays
— Chemiluminescence
f Sensitivity
6 Immunofluorescence
a Principles
b Fluorochromes
— Fluorescein
— Rhodamine
— Phycoerythrin
c Types Of Staining
— Direct Immunofluorescence Staining
— Indirect Immunofluorescence Staining
— Advantage Of Indirect Immunofluorescence Staining
d Applications
e Sensitivity
7 Immunoprecipitation(IP)
a Molecular Mechanisms
b Advantage And Applications
c Magnetic Beads Enhance Isolation Of Interested Protein By IP
8 Flow Cytometry And Fluorescence
a Flow Cytometry
b Mechanical Mechanisms
— How Many Cells Express The Target Antigen
— The Distribution Of Cells In A Sample Population
— The Cell Size
d Fluorochromes
— Fluorescein
— Rhodamine
— Phycoerythrin
c Multiple Applications
— Basic Researches: Cell Counting And Subset Identification
— Clinical Diagnosis: AIDS, Leukemia
9 Alternative Antigen-Antibody Interactions
a Protein A/G
— Bind To Ig Fc Region
— Applications
b Avidin Biotin System
c Streptavidin Biotin System
10 Immunoelectron Microscopy
a Direct Staining
b Indirect Staining
c Application And Advantage

Chapter 7 Complement
A Introduction
1 Complement System
2 Proteins Of Complement System
a Innate Component
b Regulatory Protein
c Complement Receptors
B Pathways Of Complement Activation
1 Classical Pathway
a Activators
b Cascade Activation
c Significance
2 Alternative Pathway
a Activators
b Cascade Activation
c Significance
3 Lectin Pathway
a Activators
b Cascade Activation
c Significance
4 Common Lytic Pathway
a Formation O F C5b67 Complex
b Formation Of Membrane Attack Complex(MAC)
C Biologically Active Products Of Complement Activation
1 Kinin Production
2 Anaphylotoxins
a C3a
b C4a
c C5a
3 Chemotactic Factors
a C5a
b C5b67
4 Opsinins
a C3b
b C4b
5 Other Biologically Active Products Of C Activation
a Degradation Product Of C3: C3d, C3e, C3b
D Biological Consequences Of Complement Activaton
1 Cell Ysis
a Broad Spectrum Of Target Lysis
b Major Of MAC
2 Mediate Inflammatory Response
— C3a, C4a, And C5a
3 Opsonization Of Antigen
— C3b And C4b
4 Viral Neutralization
5 Clearance Of Immune Complexes

Chapter 8 Cytokines
A Introduction
1 Cytokine
2 Major functions
B Properties Of Cytokines
1 General features Of Cytokines
2 Actions Of Cytokines: In Three Manners
a Autocrine
b Paracrine
c Endocrines
3 Cytokine Atributiions
a Pleiotropy
b Redundancy
c Synergy
d Antagonism
4 Classications Of Cytokines
a Lymphokines
b Monokines
c Interleukins(IL)
d Chemokines
5 Distinction Between Cytokines, Hormones And Growth Factors
C Cytokine Families: Cytokines Belong To Four Structural Families
1 The Hematopoietin Family
a Members
— IL-2 , 4
2 The Interferon Family
a Members
— IFNα, β, γ
3 The Chemokine Family
a Members
— IL-8, MIP-1
4 The Tumor Necrosis Factor Family
a Members
— TNFα, β
D Cytokine Receptors
1 Cytokine Receptor Families
a Immunoglobulin Superfamily Receptors
— IL-1, M-CSF, C-Kit
b Class I Cytokine Receptor Family (Also Hematopoietin Receptor Family)
— IL-2, 4, 7, 9, 12, 15, prolactin, et al.
c Class II Cytokine Receptor Family (Also Interferon Receptor Family)
— IFNα, β, γ, IL-10
d TNF Receptor Family
— TNFα, β, CD40, NGF
e Chemokine Receptor Family
— IL-8, MIP-1, MCAF, RANTES, et al.
2 Subfamilies Of Class I Cytokine Family: Signaling Units In Common
a GM-CSF Receptor Subfamily (Common β Subunit)
— GM-CSF, IL-3, 5
b IL-6 Receptor Subfamily (Common gp130 Subunit)
— IL-6, 11, CNTF, LIF/OSM
c IL-2 Receptor Subfamily (Common γ Subunit)
— IL-2, 4, 7, 9, 15
3 IL-2 receptor(IL-2R)
a Composition Of IL-2R
— α, β, γ Chains
b Forms Of IL-2R
— Low Affinity IL-2R
— Intermediate Affinity IL-2R
— High Affinity IL-2R
c Comparison Of Chains Of IL-2R Chains And Receptor
4 Cytokine Receptor Activated Signaling Pathways
a Overview of Signaling Pathway By IFNγ
b JAK-STAT Signaling
— STAT-JAK Interaction With Selected Cytokine Receptors
E Cytokine Atangonists
1 Cytokine Atangonists
2 Action of Cytokine Atangonists
a direct binding to cytokine receptors
— Receptor Atangonists: IL-1Ra
b direct binding to cytokines
— Soluble Cytokine Receptors: Soluble IFNγ Receptor
3 Biological Significance Of Cytokine Atangonists
F Cytokine Secretion by Th1 And Th2 Subsets
1 Development of Th1 And Th2 Cells
2 Cytokine secretion by Th1 Subset
a IFNγ, IL-2, TNFα
3 Cytokine secretion by Th2 Subset
a IL-4, 5, 6 10, 13
4 Cross-Regulation between Th1 And Th2 cells: Cytokine Enviroment Determines
a Shift Toward Th1
b Shift Toward Th2
5 Th1/Th2 Balance Determins Disease Outcomes
G Cytokine Related Diseases
1 Bacterial Septic Shock
a Endotoxin And IL-1, TNFα
2 Bacterial Toxic Shock by Superantigen
a Toxins And IL-1, TNFα
3 Lymphoid And Myeloid Cancer
a IL-6 And Cardiac Myxoma, Myeloma
4 Chaga`s Disease Caused By Parasite
H Therapeutic Application Of Cytokines And Cytokine Receptors
1 Application Of Cytokines
a IFNα, IL-2
2 Application Of Cytokine Receptors
a Anti-TAC: Anti high Affinity IL-2R
3 Example Of Clinical Use
I Cytokine In Haematopoiesis

Chapter 9 Cluster Of Differentiation And Adhesion Molecules


A Cluster Of Differentiation: CD
1 CD
2 Diagram of CDs
B Types Of Integral Membrane Protein
1 Type I
2 Type II
3 Type III
4 Type IV
5 Type V: GPI Anchored Protein
6 Type VI: GPI Anchored Protein
C Cell Adhesion Molecules
1 Integrin Family
a Structure Features
b Members
— VLA(Very Late Appearing Antigen)
— LFA
2 Immunoglobulin-Like Adhesion Molecules
a Structure Features
b Members
— ICAM (Intercellular Adhesion Molecule)
— VACM-1(Vascular ACM-1)
3 Selectin Family
a Structure Features
b Members
— L-selectin (CD62L)
— E-selectin (CD62E)
— P-selectin (CD62P)
4 Calcium Dependent Adhesion Molecules
a Structure Features
b Members
— E-Cadherin
— N-Cadherin
— P-Cadherin
D Leukocyte Migration And Inflammation
1 Lymphocyte Extravasation
a HEV: Site Of Lymphocyte Extravasation
b Lymphocyte Homing: Directed By Receptor
— Homing Receptors
— Addressin
c Naïve Lymphocyte Recruit To Secondary Immune Organs
d Effector And Memory Cell Adopt Different Trafficking Manner
e Adhesion Molecules In Extravasation
2 Chemokines In Inflammation
a Types Of Chemokines
— C-C Subgroups
— C-X-C Subgroups
b Chemokine Receptor Profiles Mediated Leukocyte Activity
3 Other Mediators Of Inflammation
4 Inflammation Process
a Neutrophils Play An Early And Important Role In Inflammation
b Inflammatory Responses May Be Localized Or Systemic
— Localized Inflammatory Response
— Systemic Acute-Phase Response
5 Chronic Inflammation Develops When Antigen Persists
6 Role Of IFNγ And TNFα In Chronic Inflammation
E Anti-Inflammation Agents
1 Antibody Therapies Reduce Leukocyte Extravasation
2 Corticosteroids Are Powerful Anti-Inflammatory Drugs
3 NSAIDS Combat Pain And Inflammation

Chapter 10 Major Histocompatability Complex


A Discovery Of MHC
1 History
2 Human And Mouse MHC
3 Terms
a Histocompatibility
b MHC
c MHS
d HLA
e H-2
B General Organization Of MHC
1 Location & Function Of MHC Regions
a Class I Genes And Organization
— Classical Class I Genes: A, B, C
— Nonclassical Class I Genes: G, E
— Encoded Proteins
b Class II Genes
— Classical Class II Genes: DR, DP, DQ
— Nonclassical Class II Genes: TAP1 And 2, LMP 2 And 7
— Encoded Proteins
c Class III Genes
— TNFα
— Heat Shock Protein
— Complement
C Structure And Functions Of MHC Molecules
1 Class I MHC Molecules
a Cellular Distribution
b Chains, Structure And Domains
a Peptide Bound
— Peptide Bind Cleft
— Exogenous Pathway Processed Peptide
— Peptide Features
— Peptide Length
d CD Molecules Interacted With MHC-Peptide Complex
— Regions Of TCR Contact
— CDR Interact
e Cell Expression Pattern
2 Class II MHC Molecules
a Cellular Distribution
b Chains, Structure And Domains
c Peptide Bound
— Peptide Bind Cleft
— Exogenous Pathway Processed Peptide
— Peptide Features
— Peptide Length
d CD Molecules Interacted With MHC-Peptide Complex
— Regions Of TCR Contact
— CDR Interact
e Cell Expression Pattern
3 Similarity And Difference Of Class I And Class II MHC Molecules
D Polymorphism Of MHC
1 Multiple Alleles Among Members Of Population
2 Duplicated Genes: Polygenic
a For Example: HLA-A, -B, And -C)
3 MHC Haplotype
4 Linkage Disequilibrium
5 Co-Dominant Expression
6 Clinic Significance
E Regulation Of MHC Expression
1 Transcriptional Regulation
2 Regulation By Cytokines
3 Regulation By Viruses
F MHC And Immune Responsiveness
G MHC And Susceptibility To Disease
1 MHC As Binding Site For Pathogen
2 Major Epitopes On Pathogen Mimic MHC
a Ignore Pathogen
3 Reduction In MHC Polymorphism In Population
a Cheetah = Much Inbreeding
b Dutch Immigrants To So. America
4 Clinical Relevance

Chapter 11 Innate Immunity And Innate Immune Cells


I Cells Of The Immune System
A Monocytes/Macrophages (Agranulocytes)
1 Pluripotent Stem Cells ---> Myeloid Cells ---> Monocytes
2 Monocytes Enter Tissues After ~ 8 Hrs And Become Macrophage
3 Difference Between Two?
4 Types Of Macrophages: Free And Fixed Macrophages
B Granulocytic Cells
1 Pluripotent Stem Cells ---> Myeloid Cells ---> Granulocytes
2 Neutrophils
3 Eosinophils
4 Basophils
C Mast Cells
D Dendritic Cells
1 Ag Presenting Cells (APC)
2 Bind Ag In Tissues Then Migrate To Lymphoid Tissues
3 Retain Ag For Months Or Years
4 Follicular Dendritic
5 Interdigitating Dendritic
6 Langerhans Cells In Skin
II Innate Immunity (Non-Specific)
A Anatomic Barriers
1 Skin
2 Mucus Membranes
B Physiologic Barriers
1 Lysozyme
2 Gastric Juices
3 Interferons Alpha & Beta
4 Complement
5 Fever
C Phagocytic And Endocytic Barriers
1 Endocytosis
a Pinocytosis
b Receptor-Mediated Endocytosis
2 Phagocytosis
a Phagocytosis
b Process Of Phagocytosis
D Inflammatory Barriers
1 Characteristic:
2 Three Major Events:
a Vasodilation
b Increased Capill. Permeability
c Influx Of Phagocytosic Cells:
E Cellular Components
1 Phagocytic Cells
a Neutrophils --- Lobed Nucleus And Cytoplasmic Granules
b Macrophages :
c Monocytes: In Circulation
2 Phagocyte To Infection
a Chemotaxis
b Attachment: Scavenger Receptor;
c Respiratory Burst And Phagocytosis
d Three Modes Of Intracellular Killing
— By Lysosomal Antibacterial Substances
— By Products Of The Respiratory Burst
— Oxygen-Dependent, Myeloperoxidase-Dependent Killing
3 Other Cells
4 Major Roles Of Innate Immune Cells
a Antigen Eradication
b Antigen Presenting To Adaptive Immune Cells
c Cytokine Productioin
Chapter 12 APCs And Antigen Processing And Presentation
I Antigen presenting cell
A APC: Antigen Presenting Cell
B Types Of APC
1 Professional APC: Express MHCⅡ Molecules
a Dendritic Cell
b Macrophage
c B Lymphocyte
2 Nonprofessional APC:
a Endothelial Cells,
b Epithelial Cells,
c Fibroblast, Etc
C Ag Capturing ----Endocytosis
1 Phagocytosis
2 Pinocytosis
3 Receptor-Mediated Endocytosis
D Characteristics Of APCs
1 Macrophages
a Stem From Monocytes In Blood
b Distributed Throughout Body, Versatile
c Capture Antigens
— Phagocytosis
— Pinocytosis
— Receptor-Mediated Endocytosis
2 Identification Of DC:
a Identification Of DC
b Source Of DC: Pluripotent Hematopoietic Stem Cells
c Classification Of DC
d Development And Maturation Of DC
e Antigens Capturing
3 B Cells
a Recognize Soluble Ags:
b Soluble Ag By Pinocytosis
c Specific Receptor Endocytosis
II A Rereview Of B And T Cell Receptors For Antigen
1 B Cell
a Use Cell Surface-Bound Immunoglobulin As A Receptor
b Recognize The Soluble Form Antigen
2 T Cell
a Antigens Are Proteins,
b Processed And Presented
B MHC Restriction
1 Self T-Cells Only Bind Self MHC
2 CD4+Cells Bind MHC II
3 CD8+ Cells Bind MHC I
C Cytosolic Processing pathway
1 MHC I + Endogenous Polypeptide
2 Ubiquitin Binds And Targets Protein
a Proteasome Digestion
b LMP Subunits May Target Production Of Specific Peptides
3 In ER, MHC I Binds Molecular Chaperone
a Clnexin, For Example
b Involved In Folding Of MHC I
c Also Associate With β2 Microglobulin
4 TAP Transport Of Peptides Into ER
a ATP-Dependent Process
b Association Of MHC I/Calnexin
c MHC I Binds Peptide
5 Dissociation Of Calnexin
6 Transport To Golgi: Secretory Vesicle
D Endocytic Processing Pathway
1 MHC II
2 Internalization Of Protein (Exogenous)
a Receptor-Mediated Endocytosis Of Foreign Protein.
b Phagocytosis By Macrophage
3 MHC II Binds "Invariant Chain" In ER
a Involved In Folding Of Alpha And Beta
b Involved In Routing Of MHC II Through Endocytic Pathway
4 Fusion Of Golgi Vesicle With Lysosome
a Invariant Protein Degraded
b CLIP Remains Bound To Cleft
5 Fusion Of Endosome/Phagosome With Lysosome
6 Low Ph Makes MHC II Floppy
-Exchange Of CLIP For Foreign Peptide
7 Exocytosis And Stabilization Of MHC/Peptide

Chapter 13 Development of immune cells


A Hematopoiesis
1 Stem Cells: Pluripotent
2 Two Major Pathways: Lymphoid And Myeloid
3 Multipotent Stem Cell
a Myeloid Stem Cell---> Progenitor Cells
b Lymphoid Stem Cell
— Progenitor B
— Progenitor T
4 Hematopoietic Growth Factors
a Colony Stimulating Factors
— Multilineage Colony-Stimulating Factor (Multi-CSF Or IL-3)
— Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)
— Macrophage Colony Stimulating Factor (M-CSF)
— Granulocyte Colony-Stimulating Factor (G-CSF)
— Erythropoietin
b Cytokine
B T-Cell Maturation
1 Progenitor T In Bone Marrow
a Migrates To Thymus
— 1st Occurs During Embryonic Life
b Chemotactic Factor Attracts Thymocytes
— From Thymic Epithelial Cells
2 Double Negative
-No CD4 Or CD8
3 Double Positives
a Rearrangement Of Beta Gene
b CD4 And CD8 Expressed
c Rearrangement Of Alpha Gene
d CD3 Expressed
4 Thymic Selection
a Positive Selection
b Negative Selection
5 Single Positives Appear
6 99% Of T-Cells Die Before Maturity
C B Cell Development
1 The Maturation Of B Cells: Site
a The Bone Marrow Of Higher Vertebrates
b The Bursa Of Fabricius In Birds
2 Process Of Maturation Of B Cells
3 The Immature B Cell
a Cell surface BCR
b Negative Selection.
4 Mature B Cells
a Co-Expression Of IgD And IgM
5 Mature B Cells
a Activation, Proliferation, And Differentiation

Chapter 14 T Cell Mediated Adaptive Immunity


A CD Molecules Associated With T Cells
1 TCR/CD3 Complex:
a TCR
— Types Of TCR And Cell Distribution
— Structure And Domains Of TCR
— TCR Interaction With Peptide And MHC Molecules
— Biological Functions Of TCR
b CD3
— Structure Of CD3
— Cell Distribution Of CD3
— Biological Functions Of CD3
2 T Cell Co-Receptor: CD4 And CD8
a Co-Receptor: CD4 And CD8
b CD4
— Structure Of CD4
— Cell Distribution Of CD4
— CD4 Contacts With MHC
— Biological Functions Of CD4
c CD8
— Structure Of CD8
— Cell Distribution Of CD8
— CD8 Contacts With MHC
— Biological Functions Of CD8
3 Co-Stimulatory Molecules On T Cells
a CD28/B7(CD80/86)
— Cell Distribution
— Biological Functions: Signal 2
b CD152/B7
— Cell Distribution
— Biological Functions: Activation Induced Inhibitory Signal 2
c ICOS/ICOSL
— Cell Distribution
— Biological Functions: Activation Signal
4 Other CD Molecules On T Cells
a CD2/CD58
b CD11/CD18
B T Cell Subsets
1 Naïve, Activated And Memory T Cell Subsets
a Naïve T Cells
b Activated T Cells: CD45RA+
c Memory T Cells: CD45RO+
2 CD4+ And CD8+ T Cell Subset
a CD4+ T Cells: T Helper(Th)
— Th1: Cytokine Profile
— Th2: Cytokine Profile
b CD8+ T Cells: T Cytotoxic(Tc) Or Cytotoxic T Lymphocyte(CTL)
— Tc1: Cytokine Profile And Killing
— Tc2: Cytokine Profile And Killing
3 αβTCR T Cells And γδTCR T Cells
a αβTCR T Cells
— Type And Structure Of TCR
— Distribution
b γδTCR T Cells
— Type And Structure Of TCR
— Distribution
— Biological Functions
C T Cell Activation
1 Two Signal Model Of T Cell Activation
a Antigen Recognition
— MHC Restriction Of Antigen Recognition
— Process Of T Cell Binding To Antigen
Process Of Binding
Immunological Synapse
b Two Signal Activation Of T Cells
— Signal 1: Ag/MHC + TCR
— Signal 2: Co-Stimulation
— Cytokines
2 Intracellular Signal Transduction For T Cell Activation
a General View Of Signal Transductions
— JAK-STAT
— MAPK
— PI-3K
— NF-κB
— Small G Protein Coupled Pathway
3 Overview Of TCR Mediated Signal Transduction
a Extracellular Engagement Of Antigen
b Intracellular Pathways
4 T Cell Mediated Response To Antigen
a CD4+ T Cell Response
— Th1 Response
— Th2 Response
— Balance Between Th1 And Th2 Response
Clinic Significance
b CD8+ T Cell Response
— Generation Of CTL
Signal 1: Ag/MHC + TCR
Signal 2: Co-Stimulation
Cytokines Signaling For IL-2/IL-2R
— Function Of CTL
Direct Cytotoxicity To Target Cells: Tumor, Viral Infected Cells
Clinic Significance: Graft Rejection
— Mechanisms Of CTL Mediated Target Killing
Process Of CTL Mediated Target Lysis
Fas-Fasl Pathway Of Target Lysis: Apoptosis
Perforin/Granzymes Pathway

Chapter 15 B Cell Mediated Humoral Immunity


A CD Molecules Associated With B Cells
1 BCR/CD79a/CD79b Complex:
a BCR
— Types, Structure And Domains Of BCR: mIgM And mIgD
— Cell Distribution
— BCR Interaction With Peptide
— Biological Functions Of BCR
— Comparison Of TCR And BCR
b CD79a/CD79b
— Structure Of CD79a/CD79b
— Cell Distribution Of CD79a/CD79b
— Biological Functions Of CD79a/CD79b
2 B Cell Co-Receptor: CD19, CD21, CD81, CD225
a Co-Receptor: CD19, CD21, CD81, CD225
b CD19
c CD21
— CD21 Contacts With C3d
— Biological Functions Of CD21
3 Co-Stimulatory Molecules On B Cells
a CD40/CD40L(CD154)
— Cell Distribution
— Biological Functions: Signal 2 To B Cells
b CD80/CD86
— Cell Distribution
— Biological Functions: Activation Signal 2 To T Cells
4 Other CD Molecules On B Cells
a Class II MHC
b CD22
B B Cell Subsets And Function
1 Naïve, Activated And Memory T Cell Subsets
a Naïve B Cells
b Activated B Cells:
c Plasma Cells
d Memory B Cells:
2 B Cell Subset Based On CD5
a CD5+ B Cells: B-1 Cells
— Origin And Distribution
— Surface Markers
— Response And Functions
b CD5–B Cells: B-2 Cells
— Origin And Distribution
— Surface Markers
— Response And Functions
C B Cell Activation: Thymus Dependent(TD) Antigen Induced B Cell Activation
1 Two Signal Model Of B Cell Activation
a Antigen Recognition
— Antigen Recognition
— Features Of B Cell Binding To Antigen
Cross Linking
Lipid Raft
Immunological Synapse
b Two Signal Activation Of B Cells
— Signal 1: Ag + BCR
— Signal 2:
Conjugate Formation Between T And B
Contact Dependent Help: CD40/CD154 Interaction
Signal Provided From Th Cytokines
2 Overview Of BCR Mediated Signal Transduction
a Extracellular Engagement Of Antigen
b Intracellular Pathways
3 Site Of Humoral Response And T/B Cell Cooperation
a Site Of Antigen Trapping
b Site Of B Cell Activation
c Process Of B Cell Activation
4 Germinal Centers And Antigen Induced B Cell Differentiation
a Somatic Hypermutation
— Somatic Hypermutation: Definition And Key Points
— Significance
b Affinity Maturation
— Affinity Maturation: Definition And Key Points
— Significance
c Class Switching
— Class Switching
— Cytokines Influence Switching: Help Of T Cells
d B Cell Receptor Revision
— Receptor Revision
— Key Points And Significance
5 B Memory Cells And Plasma Cells Formed In Germinal Center
a B Memory Cells: Comparison With Naïve B Cells
b Mechanisms Of Memory
— FDCs
— Iccosomes
6 Thymus Independent(TI) Antigen Induced B Cell Activation
a TI-1 Antigen
b TI-2 Antigen
D B Cell Functions In Antigen Response
a Antibody Production
— Neutrolization
— Opsonization
— ADCC
— Placenta Transfer
b Antigen Presentation
— Features Of Antigens Presented
— Presentation Pathway
c Immune Regulation
— Features Of Antigens Presented
E The Humoral Immune Response
1 Primary Immune Response
a Key Points
b Clinic Significance
2 Secondary Immune Response
a Key Points
b Clinic Significance

Chapter 16 Immune Regulation


A Introduction Of Immune Regulation
B Regulation By Antigen
1 Nature Of Antigen
a TI-Ag
b TD-Ag
c Soluble Protein Ag
d Intracellular Organisms
2 Size Of Antigen
3 Dose Of Antigen
a Th1/Th2 Balance
4 Route Of Injection
5 Structure Similarity
6 Antigen Binding Affinity
C Regulation By Antibody
1 Negative Feedback Of IgG
a Antibody Blocking
b Receptor Cross-Linking
2 Positive Feedback Of IgM
a Enhance Oposinization
b Stimulate Anti Idotypic Response
3 Clinic Consequence And Application
a Vaccination
b Rh Incompatibility
D Regulation By Immune Complex
1 Augment Immune Response:
a Activate Complement System
b Oposonization
2 Inhibit Immune Response
a Receptor Cross-Linking
E Regulation By Lymphocytes
1 Regulation By T Cells
a Treg
b Th Subsets
c Tc Subsets
2 Regulation By B Cells
3 Regulation By NKT And NK Cells
4 Regulation By Antigen Presenting Cells
a Antigen Presentation
b Co-Stimulation
c Cytokine And Chemokine Production
5 Structure Similarity
F Idotypic Modulation Of Immune Response
1 Idotype
2 Anti-Idotype Antibody
a Ab1: Idotype
b Ab2b: Internal Image
c Ab2a: Anti-Idotype
d Ab3: Anti-Anti-Idotype
3 Idotype-Anti-Idotype Network: Significance
G Regulation Through Activation Induced Cell Death
H Neuroendocrine Modulation Of Immune Response
1 The Neuro-Endocrine-Immune System
2 Example: IDDM
I Genetic Modulation Of Immune Response
1 MHC Association With Disease

Chapter 17 Immune Tolerance


A Introduction Of Immune Tolerance
1 History Background
2 Loss Of Self Tolerance: Autoimmunity
B Factors Affecting Immune Tolerance
1 Genetic Factors
2 Aging Of Cells
3 Aging Of Host
4 Immunologically Suppressive Agents
C Characteristics Of Immune Tolerance
1 Host Age On Tolerance
2 T And B Cell Tolerance
3 High Dose And Low Dose Tolerance
4 Specificity
D Molecular Mechanisms
1 Central Tolerance(Negative Selection)
a Clonal Deletion
— Thymuic Education
— Bone Marrow Education
b Receptor Editing
2 Peripheral Tolerance
a T Cell Peripheral Tolerance
— Immune Privileged Antigens
— Clonal Anergy Of Self-Reactive T Cells
Fas-Fasl Mediated AICD
Lack Of Co-Stimulation
CD152/B7 Induced T Cell Anergy
Lack Of Cytokine Sustaining And Suppressive Cytokines
Regulation By Treg
b B Cell Peripheral Tolerance
— Lack Of Antigen Stimulation
— Follicular Exclusion
— Clonal Anergy Of Self-Reactive B Cells
— Anti-Idotype Antibody In Tolerance
E Clinical Significance
1 Setup Of Immune Tolerance
a Organ And Tissue Transplantation
b Oral Tolerance
d Allergy
d Autoimmune Disease
2 Methods In Setup Of Immune Tolerance
3 Breakdown Of Immune Tolerance
a Tumor Or Caner
b Sustained Viral Infection
c Vaccine Invalidation
4 Methods In Breaking Down Of Immune Tolerance

Chapter 18 Hypersensitivity
I Introduction
A Hypersensitivity
Undesirable (Damaging, Discomfort-Producing And Sometimes Fatal) Reactions
B Major Types
a Type I - IgE-Mediated Hypersensitivity
b Type II - Antibody-Mediated Cytotoxic Hypersensitivity
c Type III - IC Mediated Hypersensitivity
d Type IV - Delayed-Type Hypersensitivity
II Type I (Immediate Hypersensitivity)
a IgE Mediated
b Symptoms 2 - 30 Minutes
A Sensitization Phase
1 Allergen Activates T helper
a Release Of Il-4
2 Allergen And Il-4 Bind B-Cell
a Plasma Cells Make IgE
3 IgE Binds Mast Cell Or Basophil
4 Passive Transfer Of Sensitization Possible
5 FcεRI (Member Of Ig Superfamily)
a IgE Receptor
b Alpha Chain Interacts With CH3 - CH3 And CH4 - CH4 Of IgE
c Beta Chain
d Two Gamma
B Activation Phase
1 Cross-Linking Of FcεRI By Allergen
a Aggregation Of Receptors
b Activation Of TPKs Due To Transauto Phosphorylation
c Methylation Of Phospholipids In Plasma Membrane
d Calcium Increases Lead To
e Activation Of Adenylate Cyclase
f Subsequent Decrease In Camp Required For Degranulation
2 Affinity Of IgE For Allergen Important
a If Low Affinity, Aggregate Will Not Persist Long Enough
b High Affinity Means Aggregate Forms Long Enough To Complete Cascade
C Effector Phase
1 Histamine Release (Primary Mediator)
a Increased Vascular Permeability
b Contraction Of Smooth Muscles
c Nasal And Lacrimal Secretions
d Release Of Mucus From Goblet Cells
2 Anti-Histamines
a Compete With Histamine For Histamine Receptors
b Ethylamine Group
3 Leukotrienes And Prostaglandins
a Secondary Mediators
b Cause:
c Effects Longer Lasting
D Allergic Reactions
1 Allergic Rhinitis
a Hay Fever
b Upper Respiratory Problems
c Genetic
2 Asthma
a Contraction Of Smooth Muscle In Airways
b Mast Cells In Lower Respiratory Tract Degranulate
c Leukotrienes May Bear Greatest Responsibility
d Why Seeing An Increase?
3 Systemic Anaphylaxis (Anaphylactic Shock)
a Explosive Release Of Many Mast Cells
b Symptoms:
c Intervention With Epinephrine
4 Food Allergies
a Gi Distress
b Atopic Urticaria
E Diagnosis/Treatment Of Allergies
1 Skin Sensitivity Testing
a Scratching Or Intradermal Injection Of Allergen
b Look For Wheal (Swelling Due To Serum) And Flare
2 Hyposensitization
a Gradually Increase Dose Of Allergen
b Possibly Effective Due To:
F Reasons For Allergic Susceptibility
1 MHC Presents Allergen
2 TCR Recognize MHC/Allergen
3 Differential Response Of T Cells To Allergen
4 Defect In IgE Suppression
5 Increased Permeability Of Respiratory And G I Tracts To Allergen
6 Increased Sensitivity To Histamine
7 Increased IgE Receptors On Mast Cells
III Type II (Ab-Mediated Cytotoxic)
1 Mechanism:
a IgG And IgM Binding To Fixed Target Ags
b Lysis Of Cell
2 .Typical Disease
a Erythroblastosis Fetalis
b Transfusion Rxns
IV Type III (Immune Complex)
1 Mechanism
a Involve Reactions Against Soluble Antigens Circulating In Serum.
b Ab-Ag Immune complex Are Deposited In Organs,
2 Typical Disease
a Serum Sickness (Generalized)
b Localized = Arthus Rxn.
c Autoimmune
V Type IV= Delayed Hypersensitivity
1 Mechanism
a Cell Mediated Immunity
b Sensitization Of Subpopulation Of Th
c Influx And Activation Of Macrophages
— Release Of Lytic Enzymes
— Erythema And Induration
d Variety Of Cytokines Released
2 Examples:
a Tuberculosis
b Graft Rejection
c Contact Dermatitis
— Poison Oak
— Pentadecacatechol (Hydrophob )
— Phagocytosis By Langerhans Cells
— Presentation By MHC II To TDTH
— Phago. By Langerhans Cells
— Presentation By MHC II To Tdth

References:
1 Fundamental Immunology 5th edition (2003): by William E., Md Pau.
2 Immunology 5th edition(2002): by Goldspy AA, Kindt TJ, Osborne BA, Kuby J.
3 Essentials of Clinical Immunology(1999): by Chapel, Helen.; Haeney, Mansel.; Misbah, Siraj.; Snowden,
Neil.
4 Innate immunity: R. Alan B. Ezekowitz MB ChB, DPhil, FAAP.
5 Immunolgy 6th edtion(2001), by Ivan Roiit, Jonathan Brostoff, David Male.
6 Cellular and Molecular Immunolgy 4th (2000): by Abul K Abbas, Andrew H, Lichman Jordan S. Pober.
7 Medical Immunology 10th (2002): by Tristram GP, Daniel PS, Abba IT, John BI.