Clinical Immunology

Preface
The immune system is the body`s major defense against infection. However, it also presents a
major obstacle to the transplantation of foreign tissues and accounts for a number of diseases
involving reactions against self tissues. Thus the subject here involves a study of how the body
brings about self- versus non-self discrimination or, as some would suggest, harmful versus non-
harmful discrimination. Following on from an understanding of the basic immunology, a major
goal of clinical immunology is to pointed to both medical students and practicing clinicians that
this subject is useful for diagnosis and management of variety of human diseases.
These include: the molecules and cells to achieve improvements in the control of infectious
diseases and in the therapy of autoimmune disorders and certain cancers, the classical and modern
immune diagnosis techniques in clinic and basic research diagnosis, the division of new discipline
of therapeutic immunology their major applications in treatment of human diseases.

Tentative Lecture Syllabus of Clinic Immunology

Chapter 1 Introduction And Infection Immunity
Chapter 2 Type I And II Hypersensitivity
Chapter 3 Type III And IV Hypersensitivity
Chapter 4 Autoimmune Disease
Chapter 5 Transplantation Immunology
Chapter 6 Tumor Immunology
Chapter 7 Reproductive Immunology
Chapter 8 Immunohematology
Chapter 90 Gastrointestinal And Live Disease
Chapter 10 Primary Immunodeficiency
Chapter 11 Secondary Immunodeficiency
Chapter 12 Vaccination
Chapter 13 Immunotherapy
Chapter 14 Immunological Techniques And Diagnosis

Teaching outline

Chapter 1 Infection Immunity

I Immunity To Viruses
A Viruses
1 A Small Segment Of Nucleic Acid
a Wrapped In A Protein Or Lipoprotein Shell
2 An Obligate Intracellular Parasite Dependent On Cells On
a Provision Of Energy
b The Provision Of Raw Materials
c Protein Synthesis
3 Virus Entry
a Mucosal Surfaces
b Puncturing Skin (Insect Bites, Needles)
B Innate Immune Response To Viruses
 1 Type I Interferon
a IFN-α, IFN-β, IFN-ω, IFN-κ
b Antiviral State
c Enhancement Of CD8+ Tc
2 Natural Killer Cells
a Cytotoxic For Virally Infected Cells
－ Majority Of Viruses Downregulate MHC I To Evade T Cell Recognition
b ADCC
3 Inflammatory Mediators (Cytokines)
C Immunity To Viruses: Specific Response
1 T Cells
a CD8+ Cytoxic T Cell
2 B Cells
a Antibodies Block:
－ Binding To Cell
－ Entry Into Cell
－ Uncoating Of Virus
b ADCC
II Immunity To Bacteria
A Mechanism Of Protection
Bacterial Surface Structure: Gram+, Gram-
1 Phagocytes
a Most Bacteria
2 Complement
a A Few, Mostly Gram-Negative Bacteria
3 Antiboday
a Fimbriae Or Flagella, Or May Be Covered By A Protective Capsule
4 Cell-Mediated Adaptive Immunity
a Against Intracellular Bacteria
B Innate System
1 Barriers Of Entry - First Line Defence
2 Recognition Of Pamps - The Second Line Of Defence
C Most Bacteria Are Killed By Phagocytes
1 Chemotaxis
2 Attachment Of The Phagocyte To Bacteria
3 Triggering The Uptake
4 Triggering Of Microbicidal Activity
D Antiboday Provides An Ag-Specific Protective Mechanism
1 Toxin Neutralization
2 Preventing Bacterial Adherence
3 Facilitates Phagocytosis
4 ADCC
E T Lymphocyte
1 T Helper Lymphocytes CD4+
a Th1 Type
－ Activation Of Macrophages Leads To Microorganisms Killing
 b Th2 Type
－ Stimulation Of B Cells To Produce Antibodies
2 Cytotoxic T Lymphocytes CD8+
III Immunity To Protozoa And Worms
A Features Of Parasitic Infections
1 Parasites Infect Very Large Numbers Of People
a Epidemiology
b Mode Of Infection
c Sites Of Infection
2 Common Feacture Of Parasitic Infection
B Effector Mechanism
1 First – Parasite Must Overcome Innate Immunity
2 Humoral Mechanisms
－ Eliminate Extracellular Parasites
a Complement
－ The Alternative Pathway
－ A Lectin-Mediated Pathway
b Alternative Madiators
－ Trypanosome Lysis Factor 1 (TLF1)
－ TLF2
c Cytokines
－ Tnfa
3 Cellular Mechanisms
a Macrophages
b Neutrophils
c Eosinophils
d Mast Cells
e Platelets
f NK Cell
g NK T Cells
h γδT Cells
i B1 Cellsc

Chapter 2 Hypersensitivity: I and II

I Introduction
1 Hypersensitivity
Undesirable (Damaging, Discomfort-Producing And Sometimes Fatal) Reactions
2 Four 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 Reasons For Allergic Susceptibility
1 MHC Presents Allergen
2 TCR Recognises 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
B Allergens / Antigens
1 Inhalant Allergens
2 Injected Allergens
3 Ingested Allergens
C Mechanism
1 Sensitization Phase
2 Activation Phase
3 Effector Phase
-Bronchoconstriction, Mucus Secretion, Vasodilatation, Vascular Permeability ,Etal
D Typical Disease
1 Allergic Rhinitis
a Symptoms
－ Ocular Symptoms
－ Nasal Congestion
－ Sneezing
－ Rhinorrhea (Anterior/Posterior)
－ Ear Complaints
－ Cough
b Treatments
－ Avoidance - Environmental Control
－ Pharmacologic Therapy
Topical Anticholinergics
Decongestants
Mast Cell Stabilizers
Oral Steroids
Nasal Steroids
Antihistamines (Oral, Topical, Nasal, Eye Drops, Inhaled)
－ Immunotherapy – Allergy Shots
2 Asthma
a Symptoms
－ A Persistent Irritable Cough
－ Difficulty In Breathing
－ Shortness Of Breath
－ Tightness And Heaviness Of The Chest
－ Wheezing
b Acute Responses Of Asthma
－ Bronchoconstriction, Vasodilation And Some Buildup Of Mucus.
c Chronic Responses Of Asthma
－ Caused By Cytokine And Eosinophil Products
3 Systemic Anaphylaxis (Anaphylactic Shock)
a Explosive Release Of Many Mast Cells
 b Symptoms:
－ Fluid In Respiratory Tract
－ Smooth Muscle Contraction Of Bronchioles
－ Shock Due To Fluid Loss Into Tissues
c Intervention With Epinephrine
－ Increases Camp Levels In Mast Cells
－ Relaxes Smooth Muscles In Bronchioles
－ Decreased Vascular Permeability
4 Food Allergies
a Gi Distress
－ Vomiting And Diarrhea
－ Histamine Release Of Mast Cells In GI Tract Lining
b Atopic Urticaria
－ Hives = Wheal And Flare
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
－ What Does Size Correlate With?
2 Hyposensitization
a Gradually Increase Dose Of Allergen
b Possibly Effective Due To:
－ Release Of Blocking Ab
－ Increase In T-Cell Suppression Of IgE Production
III Type II (Ab-Mediated Cytotoxic)
A Mechanism:
1 IgG And IgM Binding To Fixed Target Ags
2 Lysis Of Cell
A Activation Of Complement
B ADCC
B Typical Disease
1 Hemolytic Disease Of The Newborn
a Rh- Mom And Rh+ Baby
2 Transfusion Reaction
a Antiboday To Abo Ags Lyse Rbcs
－ Hb Release Due To Ab + C' Lysis
－ Bilirubin Toxic
－ Fever, Chills, Nausea
B Protein Collects In Kidney
－ Glomerulonephritis, Hemoglobinuria
－ How Treated?
3 Drug Induced Hemolytic Anemia
4 Graves’ Disease

Chapter 3 Hypersensitivity: III and IV

I Type III (Immune Complex)
A Mechanism
1 Involve Reactions Against Soluble Antigens Circulating In Serum.
2 Ab-Ag Ic Are Deposited In Organs,
A Activate Complement, And Cause Inflammatory Damage.
B Typical Disease
1 Serum Sickness (Generalized)
A Horse Ab To Snake Venom
B Activation Of C' Components
C Arthritis, Glomerulonephritis, Rashes With Edema
D Severity Depends On?
2 Localized = Arthus Rxn.
A Subcutaneous Injection
B Mild Swelling & Redness Tissue Necrosis
3 Autoimmune
A Lupus = Anti-DNA Ab
－ Kidney, Heart Damage
B R.A. = Damage To Synovial Membrane
II Type Iv = Delayed Hypersensitivity
A Mechanism
1 Cell Mediated Immunity
2 Sensitization Of Subpopulation Of Th.
A TDTH
3 Influx And Active Of Macrophages
A Release Of Lytic Enzymes
B Erythema And Induration
4 Variety Of Cytokines Released
A Macrophage Chemotactic Factor
B γ-Interferon
C Il-2
D Migration Inhibition Factor
E Tumor Necrosis Factor
B Examples:
1 Tb
A Mycobacterium Tuberculosis
－ Ingested By Alveolar Mφ
－ How Does It Survive?
B Tubercle Forms In Lung
C Calcification
D Intracellular Microbes May Be Reason For Delayed Hypersensitivity
2 Graft Rejection
3 Contact Dermatitis
A Poison Oak
B Pentadecacatechol
－ Attaches To Skin Protein
C Phagocyte By Langerhans Cells
D Presentation By MHC II To TDTH
 － Cytokine Release
－ Redness And Pustules
C Patch Test
1 Diagnose Delayed Allergic Reactions

Chapter 4 Autoimmunity
A Introduction To Autoimmunity
1 History Background
2 Autoimmunity Vs. Tolerance
B Antibody-Mediated Autoimmunity
1 Myasthenia Gravis
a Ab Vs. Acetylcholine Receptor
— Blocking Antibody
b Lose Muscle Activity Since No Response To Nerve Signals
c Lose Muscle Activity Since No Response To Nerve Signals
2 Graves Disease
a Ab Vs. TSH Receptor Mimics TSH
— Activating Ab
b By Pass Negative Feedback Control
— Normally:
-Elevated T4 Inhibits TSH And TRF Release
-Decreased T4 Allows Release Of TSH And TRF
— Ab Causes T4 Release Regardless Of T4 Levels
c Hyperthyroidism
— Symptoms?
C Immune Complex-Mediated
1 Systemic Lupus Erythematosus
a Immune Attacks Vs Many Different Tissues
b Skin
— Butterfly Rash:
— Extreme Sun Sensitivity
-Release Of DNA Due To Skin Cells Damage
-May Be Why Sun Exacerbates Symptoms
c Ab Often Present To DNA, Nucleoproteins, Histones, Nucleolar RNA
— Fluor. Anti-Nuclear Ab Test
d Often Complexes Cause Glomerulonephritis
— Hematuria
— Proteinuria
— Complement And Phagocyte Activation
e Is There An Environmental Trigger?
— Immunize Animals With Klebsiella
— Get Ab To Capsular Polysacch. Of Kleb.
— Ab Cross-Reacts With Human DNA
2 Rheumatoid Arthritis
a Immune Problems
b Immunological Diagnosis
 c Treatment
D Ab And T-Cell Mediated Immunity
1 Multiple Sclerosis
a Immune Problems:
— Immune Response To Myelin Sheath
— Immune Cells Cross Blood-Brain Barrier
-Complement Activation
-Lytic Enzymes Released From Phagocytic Cells
-Phagocytosis Of Ag/Ab Complexes
— Progressive Disability
-Impaired Motor Function
-Impaired Sensory Function
-Impaired Memory Is Most Common Cognitive Problem
2 Causes
a Environmental?
b Genetics
3 Treatments
a Immunosuppressive Agents
— Steroids = Stabilize Phagocytic Membranes
b Copaxone Injections
— Synthetic Peptide Of MBP
— Induce Tolerance
c Beta-Interferon
— Tested Because Anti-Viral
— Appears To Change Course Of Disease
-Decrease Exacerbations
-Decrease Lesion Size
-Decrease Disability
d Gamma-Interferon Trials Had To Be Stopped
E Causes Of Autoimmunity
1 Polyclonal Activator
a T- Independent Response
b Polyclonal Trigger For B-Cells
2 Molecular Mimicry
a Rheumatic Fever
b Heat Shock Proteins
3 Abnormal Expression Of MHC II
a On Cells Formerly W/O MHC II
b Due To Gamma-Interferon
c Insulin-Dependent Diabetes =High Levels Of MHC I & II On Pancreatic Beta-Cell
d Active Lupus = High Levels Of Gamma Interferon

Chapter 5 Transplantation Immunology

A The Origins Of Transplantation Immunology
1 Early History
a History, Principles, And Discoveries Of Immunogenetics
B Terminology
1 Autograft
2 Allograft
3 Isograft
4 Xenograft
C Immunological Basis Of Graft Rejection
1 Early History Donor Antigens Responsible For Graft Rejection
a Major Histocompatibility Antigens
— MHC I And MHC II
b Minor Histocompatibility Antigens
c Other Antigens Of Potential Importance
2 Components Of The Immune System Involved In Graft Rejection
a Antigen-Presenting Cells
b B Cells And Antibodies
c T Cells: Major Roles
d Other Cells
3 Allograft Rejection Displays Specificity And Memory
4 Stages Of Cell Mediated Graft Rejection
a Sensitization Stage
b Effector Stage
D Clinical Manifestation Of Graft Rejection And Mechanisms
1 Hyperacute Rejection
a Rejection Caused By Preformed Antibodies: Immune Complex
b Immediate
2 Acute Rejection
a Mediated By T Cell Response
b About 10 Days After Transplantation
3 Chronic Rejection
a Both Humoral And Cellular Response Of The Recipient
b Months To Years After Transplantation
E General Immunosuppressive Therapy
1 Mitotic Inhibitors:
a Azathioprine
b Cyclophosphamide
c Methotrexate
2 Corticosteroids: Suppress Inflammation
a Prednisone
b Dexamethasone
3 Certain Fungal Metabolites
a Cyclosporin A (CSA)
b Fk506 (Tacrolimus)
c Rapamycin(Sirolimus)
4 Total Lymphoid Irradiation
F Specific Immunosuppressive Therapy
1 Monoclonal Antibody To Suppress Graft Rejection Response
a Anti-CD3
 b Anti High-Affinity IL-2 Receptor
c Anti CD4
d Anti Cell Surface Adhesion Molecules: ICAM-1
2 Blocking Co-Stimulation Signals: Induce Anergy
a Break Down CD28/B7: For T Cells
b Enhance CD152/B7: For T Cells
c Break Down CD40/CD154: For B Cells
G Immune Tolerance To Allograft
1 Privileged Site Accept Antigenic Mismatches
2 Early Exposure To Alloantigens
H Clinical Transplantation
1 Factor Influence Frequency Of Organ Or Tissues Transplanted
a Clinical Situation
b Availability Of Organs And Tissues
c Difficulty In Performing Transplantation
d Specific Factors That Aid Or Hinder Acceptance Of The Particular Transplant
2 Organs Or Tissues Transplanted Overview
a Most Commonly Transplanted: Kidney
— Problems
-Shortage Of Donor Organ
-GVHD
b Bone Marrow Transplantation
— Treatment Of Leukemia, Anemia, And Immunodeficiency
c Heart Transplantation
— Challenging Operation
d Lung Transplantation
e Liver Transplantation For
— Treat Congenital Defects And Damage From Viral Or Chemical Agents
f Pancreas Transplantation
— Offers A Cure For Diabetes Mellitus
g Skin Grafts
— Treat Burn Victims
I Clinic Immunological For Transplantation
1 HLA Typing
a Microcytotoxicity Test: Based On CDC
b Mixed-Lymphocyte Reaction (MLR)
— Further Quantify The Degree Of Class II MHC Compatibility
2 RBC Typing
J Current Problem And Answer
1 Shortage Of Available Organs And Tissues
2 Xenograft: Answer To The Problem

Chapter 6 Tumor Immunology

A Introduction To Tumor And Immune Phenomena
1 Origin Of Tumor
a Terminology:
 — Tumor
— Benign
— Malignant Tumors
b Types Of Malignant Tumors
— Cancer
— Sarcoma
— Leukemia And Lymphoma
2 Malignant Transformation Of Cells
a Chemical Agents:
b Physical Agents:
c Viral Factors
d Oncogenes And Cancer Induction
B Evidences For Immune System In Tumor Response
C Tumor Antigens
1 Tumor Specific Transplantation Antigens(TSTA) Or TSA
a TSA
b Features Of TSA
c Why?
2 Tumor Associated Transplantation Antigens(TATA) Or TAA
a TAA
b Features Of TAA
c Examples
— AFP And Clinical Significance
— CEA And Clinical Significance
3 Clinic Application Of Tumor Antigens
D Tumor Immunity
1 Specific Immunity
a Humoral Immunity
— Antibodies Against Tumors
b Cellular Immunity: Key Roles
— CTL Cytotoxicity
2 Non-Specific Immunity
a NK
— Activity Of NK Cells
b Activated Macrophages
E Tumor Invasion Of The Immune System
1 Lack Of Neo-Antigen
2 Lack Of Co-Stimulation
3 Lack Of MHC I
4 Tumor Secret Immunosuppressive Molecules
5 Tumors Shed Their Neo-Antigen
6 Imbalance Of Th Subsets
7 Loss Of Fas And Express Of FasL
8 Resistance To CTL Killing
F Tumor Immunotherapy
1 Passive Immunotherapy
 a Adoptive Cellular Immunotherapy
b Cytokine
c Anti-Tumor Antibody
2 Active Host Immune Response
a Active Non-Specific Immunity
— Bacterial Product
— Cytokine
— Synthetic Molecules
b Active Specific Immunity
— Cytokine Therapy
— Monoclonal Antibody Therapy
— Tumor Vaccine: Tumor Cells And Tumor Antigen
— Enhance Co-Stimulation
— Enhance APC Activity
— Gene Therapy

Chapter 7 Reproductive Immunology

Objective
The Purpose Of The This Lecture Is To Acquaint The Student With Basic Principles Of The Immune Response
Relevant To Reproductive Processes With Focus On Female Reproductive Immunology.
A Introduction
1 Anatomy
a Male
b Female
2 Mucosal Immunity Of Female Genital Tract
c Immune Barriers
c Immune Cells
— Intraepithelial And Subepithelial Lymphocytes
— Differential Location Of CD4 And CD8 T Cells
— Decidual NK
— Other Innate Immune Cells
3 Defense Against Pathogens Vs. Tolerance To Sperm “Invasion”
a Immunity Against Pathogens
— Innate And Adaptive Immunity
b Immunity To Sperms:
— Tolerance
— Immunological Pathology By Sperm
4 The Ovary And Testis
a The Testis
— Immune Privilege
b The Ovary
— Non-Privileged Organs
B Immunologcial Mechanisms In Implantation And Pregnancy
1 The Role Of The Uterus
a Not Immunological Privileged
b Cell Types And Percentage In Decidua
 — Macropahages : 25%
— NK Cells: 45%
— T Cells: 20%, αβT And γδT
— Stromal Cells: 20%
2 The Role Of The Placenta
a Immunological Barrier
b Expression Of Classical And Non-Classical MHC I Molecules
— Classical MHC I: No
— Non-Classical MHC I: Yes
c Bias Between Th1 And Th2
— Bias Away From Th1
3 Maternal Mechnisms
a Local Non-Specific Factors
b Existence Of Non-Classical HLA-G
c Existence Of Non-Specific Lgl
C Pregnancy And Maternal Infection
1 Background: Altered Susceptibility To Infection In Pregnancy
a Reduced Th1 Activity
b Decreased NK Cytotoxicity
D Protection Of The Fetus And Neonate Against Infections
1 Cellular Development Of The Fetus
2 Placental Transfer Of IgG
a Ways Of IgGTransfer
— Specific Receptors On The Trophoblast For Fc Region
— Time Period Of Transfer
— Serum Ig Level And Age: Before And After Birth
-Physiological Trough: 3-6 Months
-Maturation Of Antibody Production
3 Immunological Value Of Breast Feeding
a Protective Molecules In Human Milk
b Protective Cells In Human Milk
E Disorders Of Pregancy
1 Recurrent Spontaneous Abortion
a Factors Cause Abortion
b Immunological Cause Of Abortion: 10%
— Anticardiolipin Antibody
— Anti-Phospholipid Antibody
c Immunotherapy
2 Outcome Of Pregnancy In SLE
a Immunolgical Problems
— Antiphospholipid Antibody
— Lupus Anticoagulant Antibody
b Therapy
3 Pre-Eclampsia
a Immunological: Excess Production Of Maternal And/Or Placental IL-2 And TNF
b Bias Toward Th1
 4 Alloimmunization
a Immunoloical Events
— Sensitization Of Mother With Fetus Antigen
— Passive Transfer Of IgG Through Placenta
— Active Immune Response
b Disorders
— Rh Incompatibility
— ABO Incompatibility
— Alloimmune Neonatal Thrombocytopenic Purpura
— Idiopathic Thrombocytopenic Purpura
5 Organ Specific Autoimmunity In Prenancy
— Transient Grave`S Disease
— Diabetes Millitus

Chapter 8 Immunohematology
A Introduction: Blood Groups
1 ABO Blood System
2 Rh Blood System
3 Laboratory Determination Of Blood System
a Direct Hemagglutination
b Indirect Antiglobulin Test
— Butterfly Rash:
— Extreme Sun Sensitivity
-Release Of DNA Due To Skin Cells Damage
-May Be Why Sun Exacerbates Symptoms
B Blood Transfusion Immunology
1 Compatibility Testing
2 The Cross-Match
3 Major Cross-Match
4 Minor Cross-Match
5 Implications Of Positive Antibody Screening For Transfusion
C Blood Transfusion Reactions:
1 Hemolytic Reactions
a Pathogenesis
— Intravascular Hemolytic Reactions
— Extravascular Hemolytic Reactions
b Clinical Presentation
c Laboratory Investigation
2 Nonhemolytic Immune Transfusion Reactions
a Antileukocyte Antibodies
b Anti-IgA Antibodies.
D Hemolytic Disease Of The Newborn (Erythroblastosis Fetalis)
1 Pathogensis
a Immunological Destruction Of Fetal And/Or Newborn Erythrocytes: IgG
b Two Types Of Incompatibility: Anti-D And Anti-A Or B
c Mechanisms Of Sensitization
 — Rh-Negative Mother
— Rh+ Fetus
— Second Rh+ Baby Affected
2 Epidemiology
3 Clinical Presentation
4 Immunological Diagnosis
a Direct Coombs (Antiglobulin) Test
5 Prevention And Treatment
a Administration Of Anti-D IgG Antibodies
E Immune Hemolytic Anemias: RBC Disorders
1 Autoimmune Hemolytic Anemia (Warm Antibody Type)
a Pathogenisis
b Diagnosis
— Direct Antiglobulin (Coombs) Test: Ab Coated On RBCs
— Indirect Antiglobulin Test: Ab In Serum
2 Cold Agglutinin Disease And Cold Agglutinin Syndrome
a Pathogenisis
— IgM(Mostly) React With RBC Antigen At Low Tempreture
b Clinical Presentation
— Hemolysis
c Laboratory Diagnosis
— Cold Agglutination Testing
3 Warm Agglutinin Syndrome
a Pathogenisis
— IgG React With RBC Antigen
b Clinical Features
－ Hemolysis
－ Anemia
c Laboratory Diagnosis
— Direct Warm Agglutination Testing
4 Drug Induced Immune Hemolytic Anemia: Mechanisms
a Immune Complex Formation
b Drug(Hapten) Adsorption
c Non-Specific Adsorption
d Unknown Mechanisms
F Platelet Disorders
1 Immunological Mechanisms For Platelet Destruction
a Antibody To Platelet: ADCC
b Antibody To Platelet: CDC
c Antibody To Drugs Or Other Antigen That Absorbed To Platelet: CDC
d Lymphocyte Mediated Lysis
2 Idopathic Thrombocytopenic Purpura
a General Considerations
— Immunological Mechanisms
b Clinical Features
c Immunologic Diagnosis
 — IgG Detection
d Treatment
3 Drug Induced Immune Thrombocytopenias
4 Quinine Inducedb Thrombocytopenia With Hemolytic Uremic Syndrome

Chapter 9 Gastrointestinal And Liver Disease

A Introduction
1 Normal Immune Mechanisms
a Non-Specific Immunity:
— Barriers
— Cells
b Specific Immunity
— Mucosal Immune System: Galt
— Antibodies: IgA
— Peyer`S Patch
— Intraepithelial Lymphocytes(IEL)
2 Spectrum Of Intestinal Immune Response
a Local Immune Response
b Systemic Immune Response
c Oral Tolerance
B HIV And Gut
a HIV Infects Lymphocytes And Macrophages
C Gastritis
1 Atrophic Gastritis And Pernicious Anemia
a Atrophic Gastritis:
— Autoimmune Gastritis
b Pernicious Anemia
— Clinical Features
— Immunoligical Pathologic Mechanisms
-Gastric Parietal Cell Antibody: 90%
-Intrinsic Factor Antibody: 75%
D Food Induced Gastrointestinal Disease
1 Food Allergy
2 Coeliac Disease: Gluten Sensitive Enteropathy
a Epidemic: Small Bowl Enteropathy
b Immunologic Mechanism
— Hypersensitivity To Gluten
— Runs In Family: Genetic Susceptibility
d Immunologic Tests
— Antibody Against Gluten
— Gluten Induced Autoantibodies To Connective Tissues
3 Autoimmune Enterophathy
a Antibodies To Epithelial Cells
b Antibodies To Goblet Cells
4 Inflammatory Bowl Diesease
a Crohn`S Disease And Ulcerative Colitis
 — Difference Between Crohn`S Disease And Ulcerative Colitis
— Immune Mediated Pathogenesis: Inflammation
— Genetic Factors And Environmental Factors In The Disease
E Liver And Liver Diseases
1 Current Overview Of The Liver Immune System
a Innate Immune System
b Adaptive Immunity
— Which One Is More Important?
2 Liver Diseases
a Viral Hepatitis
— HAV
— HBV
— HCV
— Immunity Against Hepatitis Viruses
— Virus Invasion Of Immune System
— Treatment Of Hepatitis: Vaccine, IFN
b Liver Cancer
— Problems Of Immune Unresponsiveness
— Immunologic Treatment:
— Problems In Liver Transplantation
3 Alcohol Induced Liver Disease
a Dysfunction Of Mononuclear System
b L Proinflammatory Cytokines
4 Drug Induce Liver Disease
a Hypersensitivity Reaction
b Direct Toxic

Chapter 10 Primary Immunodeficiency Diseases

Primary Immunodeficiencies Are Inherited Defects Of The Immune System.
I Specific Immune Mechanisms
II Nonspecific Immune Mechanisms.
I Specific Immune System
A Disorders Of Lymphoid Stem Cells
1 Severe Combined Immunodeficiency (SCID):
a 50% Is X-Linked
b The Other Half Is Autosomal.
c Characterized
－ Absence Of T Cell And B Cell Immunity
－ Absence (Or Very Low Numbers) Of Circulating T And B Lymphocytes.
－ Thymic Shadows Are Absent On X-Rays.
－ Susceptible To A Variety Of Bacterial, Viral, Mycotic And Protozoan
Infections.
2 X-Linked Severe SCID
a Defect In Gamma-Chain Of IL-2
b Shared By IL-4, -7, -11 And 15
3 The Autosomal Scids
 a Defects In ADA, PNP
4 Other Genetic Defects Leading To SCID
a RAG1
b RAG2
c IL7-Alpha.
5 Diagnosis
a Enumeration Of T And B Cells
b Immunoglobulin Measurement.
6 Treated With Bone Marrow Transplant
B Disorders Of T Cells
1 Digeorge's Syndrome:
a Hypoparathyroidism, Congenital Heart Disease, Low Set Notched Ears And Fish Shaped
Mouth.
b Abnormal Development Of Fetus
c No Genetic Predisposition
d Not All Digeorge Syndrome Babies Have Thymic Aplasia.
e Treatment: A Thymic Graft
f Caused By A Deletion In Chromosome 22
C T Cell Deficiencies With Variable Degrees Of B Cell Deficiency
1 Ataxia-Telangiectasia:
a Lack Of Coordination Of Movement (Ataxis) And Dilation Of Small Blood Vessels Of
The Facial Area (Telangiectasis).
b B Cell Numbers And IgM Concentrations Are Normal To Low.
c IgG Reduced
d IgA Reduced
e Arise From A Breakage In Chromosome 14
2 Wiskott-Aldrich Syndrome:
a Normal T Cell Numbers With Reduced Functions,.
b IgM Reduced But IgG Normal.
c Both IgA And IgE Elevated.
d Poorly Respond To Polysaccharide Antigens
－ Prone To Pyogenic Infection.
e Defective WASP Protein
3 MHC Deficiency (Bare Leukocyte Syndrome):
a Defect In The MHC CIITA Protein Gene
b Fewer CD4 Cells And Infection Prone.
c Defect In TAP Gene And Not Express The Class-I MHC Molecules
－ Deficient In CD8+ T Cells.
D Disorders Of B Lymphocytes
1 X-Linked Infantile Hypogammaglobulinemia:
a B Cell Numbers And All Immunoglobulin Levels Are Very Low.
b Failure Of B-Cell Maturation Associated
－ Defective B Cell Tyrosine Kinase (Btk) Gene.
c Diagnosis
－ Enumeration Of B Cells
－ Immunoglobulin Measurement.
 2 Transient Hypogammaglobulinemia:
a IgG Synthesis May Not Begin Until 2-3 Years Old.
b Delay Attributed To Poor T Cell Help.
c A Transient Deficiency Of IgG
d Treated With Gamma-Globulin
3 Common Variable Hypogammaglobulinemia:
a Acquired Deficiencies Of IgG And IgA In The 2nd Or 3rd Decade Of Their Life
b Susceptible To Pyogenic Bacteria And Intestinal Protozoa.
c Treated With Specially Prepared Γ-Globulin.
4 IgA Deficiency:
a 20% Also Have Low IgG
b Susceptible To Infections.
c High Incidence Of Autoimmune Diseases And Lymphoid Malignancies.
d Laboratory Diagnosis Is Based On IgA Measurement.
5 Selective IgG Deficiency:
a Different IgG Subclasses.
b Susceptible To Pyogenic Infections.
6 Hyper-IgM Immunodeficiency:
a Low IgA And IgG; Abnormally High Levels Of IgM.
b Cannot Make A Switch From IgM To Other Classes
－Defect In CD40L On Their CD4 Cells.
c Susceptible To Pyogenic Infection
D Treated With Intravenous Γ-Globulins.
II Nonspecific Immune Systems
Phagocytic And NK Cells And The Complement System
A Defects Of The Phagocytic System
Lead To Increased Susceptibility To A Variety Of Infections.
1 Cyclic Neutropenia:
a Marked By Low Numbers Of Circulating Neutrophil
－ Approximately Every Three Weeks.
b Lasts About A Week
c Due To Poor Regulation Of Neutrophil Production.
2 Chronic Granulomatous Disease (CGD):
a Marked Lymphadenopathy, Hepato- Splenomegaly And Chronic Draining Lymph Nodes.
b Poor Intracellular Killing And Low Respiratory Burst.
c Due To A Defect In NADPH Oxidase
－ Phagocytic Respiratory Burst.
d Diagnosed On The Basis Or Poor NBT Reduction
e Treatment:Interferon-Γ.
3 Leukocyte Adhesion Deficiency:
a Lack The Complement Receptor CR3
－ Cannot Respond To C3b Opsonin.
b May A Defect In Integrin Molecules,
c Diapedesis
－ Cannot Respond Effectively To Chemotactic Signals.
4 Chediak-Higashi Syndrome:
 a Reduced (Slower Rate) Intracellular Killing And Chemotactic Movement
－ Inability Of Phagosome And Lysosome Fusion
－ Proteinase Deficiency.
b Respiratory Burst Is Normal.
B Disorders Of Complement System:
a Susceptibility To Infections.
b Genetic Deficiencies
－ Increased Infections.
c The Most Serious Is The C3 Deficiency

Chapter 11 Secondary Immunodeficiency － HIV

I Types
A HIV-1
1 Nucleocapsid (P24, P17) Surrounds
a 2 Strands RNA
b 2 Molecules Of Reverse Transcriptase
c Integrase, Protease, Ribonuclease H
2 Viral Envelope
a Lipid Bilayer
b gp120 & gp41
c Also Human MHC
B HIV-2
1 Spreads More Slowly Than HIV-1
2 Mostly Found In West Africa
3 75% Homology W/ SIV
4 Evidence Of Cross-Species Transmission In Lab Technicians
5 Salk Vaccine Theory
II Binding And Entry
A Viral Entry
1 gp120 Binds CD4 On T-Cell
-T-Cell Also Binds Chemokine Receptor
2 Fusion Of Membranes
a gp41 (Fusogenic Domain)
b Fusin = Co-Factor On T-Cell
B Modification Of Nucleocapsid By Proteases
C Replication
1 DNA Made Via Reverse Transcriptase
a RNA Used As Template-"Retrovirus"
b AZT Inhibits
c High Mistake Rate
－ 1 In 2,000 Nucleotides Mutated
2 Ribonuclease H Chops Out RNA
3 2nd DNA Strand Made
4 DNA Enters Nucleus
a Integration Into Host Genome -Via Viral Integrase
b Becomes Provirus
III Viral Genome
A Long Terminal Repeats
1 5' LTR
a Enhancer And Promoter Sequences
b Binding Site For NF-κb
2 3' LTR
a Polyadenylation Site
B Regulatory Genes
1 Overlapping
2 Different Proteins Expressed Via:
a Differential Processing
b Reading Frame Differences
3 Proteins Increase Rate Of Transcription Or Translation Of Gag, Pol And Env
4 Rev, Tat, Nef = Regulatory Proteins
C Structural Genes
1 Each Encodes Large Polypeptide Which Is Further Cleaved
2 Gag = Encodes Capsid Proteins
3 Pol = Encodes:
a Reverse Transcriptase
b Protease
c Integrase
4 Env = Encodes gp120 And gp41
IV Transcription And Assembly
A RNA Polymerase II
1 Recognition Of Long Terminal Repeats
2 NF-κΒ Proteins Bound Here
a T-Cell Activation By Other Foreigners Leads To Synthesis Of HIV Proteins
b Via NF κB Activation
B Three Transcripts Made
1 9kb = Nucleic Acid Core
2 4 Kb = One IVS Cut Out
－ Encodes Structural Proteins
3 2kb = Two Or More IVS Cut Out
a Split Genes Spliced During Processing
b Encodes Regulatory Proteins
c Translated First.Why?
d Rev Enters Nucleus And Binds 4kb And 9kb
－ Translocation To Cytoplasm
C Translation Of Structural Proteins
D Assembly Of Virions
1 Aggregation Of 9kb RNA And Viral Proteins In Cytoplasm
2 Budding From Cell
3 Protease Modifies Viral Proteins
Protease Inhibitors Are A Recent Treatment
V Clinical Aspects
A Category A
 1 >500 CD4/Ml
2 Asymptomatic Or
3 Flu-Like Illness
4 Persistent Generalized Lymphadenopathy
a Lymph Nodes Being Destroyed Since Huge Viral Burden
b Dendritic Cells Especially Harbor Virus
5 Burst Of HIV Replication
6 Immune Response Fights But Slowly Loses
B Category B
1 CD4 Count = 499 - 200
2 Candidiasis
3 Pelvic Inflammatory Disease
4 Herpes Zoster
5 Fever, Diarrhea
6 Idiopathic Thrombocytopenia
C Category C
1 <200 CD4/Ml
2 Toxoplasmosis
3 Kaposi's Sarcoma
4 Pneumocystis Carinii
VI Why So Much T-Cell Destruction?
1 Complexes Of gp120/gp41 May Bind T-Cell
2 Apoptosis When Stimulated With Foreign Ag
VII Vaccines
A None In Phase III Trials
1 Lg.-Scale Tests Designed To Evaluate Effectiveness In Humans
B gp120 Vaccine
1 Abs Raised Which Neutralized Lab HIV Infection
2 Abs Did Not Neutralize Patient HIV Isolates
3 Why Not Effective?
C Current Vaccine Strategies
1 Whole Killed Viruses
a Require Rigorous Inactivation
2 Pseudoviruses
a Empty Lipid Shells
b Carry HIV Genes
c Difficult To Manufacture In Stable Form
3 Recruiting T Lymphocyte
a Insert HIV Genes Into Virus Which Is Not Harmful
b Cells Will Make HIV Proteins And Express Via MHC I
c Attract T Lymphocyte
4 Combination Strategies
A Canarypox Virus 1st

Chapter 12 Vaccination
A Active And Passive Immunization
 1 Passive Immunization
Involves Transfer Of Preformed Antibodies
a Natural Maternal Antibody
b Immune Globulin
c Humanized Monoclonal Antibody
d Antitoxin
2 Active Immunization
Elicits Long-Term Protection
a Natural Infection
b Vaccines
－ Attenuated Organisms
－ Inactivated Organisms
－ Purified Microbial Macromolecules
－ Cloned Microbial Antigens
Expressed As Recombinant Protein
As Cloned DNA Alone Or In Virus Vectors
－ Multivalent Complexes
B Designing Vaccines
1 Establishing Protective Immunity.
a Identify Good Immunogens
b Neutralizing Antibodies, Th And CTL Responses
c One Dose Can Elicit Long-Term Protection
2 Preventing Pathogenesis Of Immune Response
3 Route For Immunization
4 Adjuvants.
a Types Of Adjuvants.
b Mechanism Of Adjuvants.
C Whole-Organism Vaccines
1 Attenuated Viruses And Bacteria
a Cause Immunity Without Disease
2 Pathogenic Organisms Are Inactivated
a By Heat Or Chemical Treatment
D Purified Macromolecules As Vaccines
1 Bacterial Polysaccharide Capsules
2 Toxoids
a Manufactured From Bacterial Toxins
3 Proteins From Pathogens
4 Synthetic Peptides
a By Recombinant Techniques
E Recombinant-Vector Vaccines
1 Vector Vaccines
a Vaccinia Virus
b The Canarypox Virus
c Attenuated Poliovirus
d Adenoviruses
e Attenuated Strains Of Salmonella
 f The BCG Strain Of Mycobacterium Bovis
g Certain Strains Of Streptococcus
2 The Procedure
Vaccinia Vector Carries A Foreign Gene From A Pathogen
F DNA Vaccines
1 Plasmid DNA Encoding A Protein Antigen
2 Effective Vaccine
a Humoral Immunity
b Cell-Mediated Immunity.
G General Issues
1 Efficacy
2 Cost
3 Safety
4 Stability

Chapter 13 Immunotherapy
A Introduction
1 Why Immunotherapy
a Immunotherapy Of Cancer
b Why The Emphasis On Antibodies?
c Advantage Of Immunotherapy
B Immunomodulators
1 Intact Microbes: Bacillus Calmette-Guérin And Corynebacterium Parvum
2 Streptococcus Pyogenes And Propionibacterium Avidum
3 Bacteriolytic Therapy Of Tumors
4 Other Immunostimulatory Bacterial Agents
5 Thymic Hormones And Analogs
6 Cytokines
7 Soluble Co-Stimulatory Molecules
C Antibody Therapeutics
1 Potential For “Tailor-Made” Therapeutics
2 Potential For Therapeutic Application
3 Engineered Antibodies For Therapy
a Structure Overview Of Antibody
b Modifying Variable Regions
c Engineering Constant Regions
d Novel Antibodies And Antibody Derivatives For Human Therapy
e Bispecific Antibodies
f Antibody Expression For The Manufacturing Process
4 The Problem Of Immunogenicity
a Antibody Engineering To Reduce Immunogenicity
b Are humanized antibodies nonimmunogenic?
c Prophylactic Induction Of Tolerance To Therapeutic Antibodies
5 Engineering Antibodies For Cancer Therapy
a Overview
b Diversity Of Experimental Strategies
 6 The Clinical Application Of Antibodies
a Why Are There So Few Antibodies In Clinical Practice?
b Some Clinical Highlights
D Immunoconjugates
1 Introduction
2 Immunotoxins
3 Monoclonal Antibody–Drug Conjugates (Chemoconjugates)
4 Antibody-Directed Enzyme Prodrug Therapy (Adept)
5 Radioimmunoconjugates
6 Immunoliposomes
7 Other Emerging Immunoconjugate Strategies
E Cellular Therapeutics
1 Nonspecific Cellular Therapy
a Lymphokine-Activated Killer Cells
— IL-2
— IL-15
b Natural Killer Cells
c Dendritic Cells
— Primed DCs
— Dendritoma
d Macrophage-Activated Killer Cells
2 Specific Cellular Transfer
a Genetically Engineered Cells
— Cytokine
— Co-Stimulation
— Adhesion Molecules
b Graft-Versus-Leukemia T Cells And Graft-Versus-Tumor Effects
c Regulatory T Cells
3 Marrow Transplantation
a Allogeneic Bone Marrow Transplantation
b Autologous Bone Marrow Transplantationn
c New Developments In Bone Marrow Transplantation
F Conclusions

Chapter 14 Immunological techniques and diagnosis

A Introduction
B Antigen-Antibody Interactions
1 Agglutination
a Direct
b Passive
2 Precipitation
a Single Immunodiffusion test
b Double Immunodiffusion test
c Counter Immunoelectrophoresis test
d Rocket Immunoelectrophoresis
3 Immune Labeling Technique
 a Direct And Indirect Immumofluorescence Method
b Enzyme immunoassay(EIA) or ELISA
c Radioimmunoassay(RIA)
d Western Blotting
e Immunoprecipitation
f Flow cytometry
g ELISPOT
C Isolation Of Pure Antibodies
1 Precipitation Of Gamma Globulins In 30-50% Ammonium Sulphate
2 Gel Filtration
3 Ion Exchange Chromatography
4 Affinity Chromatography
D Monoclonal Antibody Production
E Assays For Immune Complex
1 C1q Binding Assay
3 Precipitation Of Immune Complex
4 Immune Complex In Autoimmune Diseases
F Isolation Of Lymphocyte Populations
1 Pbn Isolation By Ficoll Supported Gradient Centrifuging
2 Fluorescence-Activated Cell Sorter(FACS) Of The Isolation Of Cell Population
3 Biomagnetic Separation(MACS)
a direct
b Indirect
4 Panning Remove Of Unwanted Cells: Relies On Complement
G Effector Cell Assay
1 Antibody Production
a Plaque Forming Cell Assay: For IgG or IgM
b ELISPOT
2 Effector Cytotoxicity
a Chromium Release Assay
b MTT Assay
c 3H –thymidine Incorporating Assay
d Antigen Specific T Cell: MHC-Peptide Tetramer
3 Effector cell proliferation
b indirect
b MTT assay
c 3H –thymidine incorporating assay
b indirect
4 Lymphocyte migration
a Lymphocyte migration
b Samper-Woodroofe assay for adhesion molecules
c 3H –thymidine incorporating assay
5 Lymphocyte surface molecules
a Immunohistochemistry
b Immunofluorescence assay
c Flow cytometry
H Clinical applications: examples
J Conclusion