Introduction to The Immune System Pin Ling ( 凌 斌 ), Ph.D. ext 5632; lingpin@mail.ncku.edu.tw...

Introduction to The Immune System

• Pin Ling ( 凌 斌 ), Ph.D.

ext 5632; lingpin@mail.ncku.edu.tw

• References:

1. Abbas, A, K. et.al, Cellular and Molecular Immunology (6th ed., 2007), Chapters 1 & 2

2. Male D., J. Brostoff, D. B Roth, and I. Roitt Immunology, 7th ed., 2006.

Keys toward Learning Immunology

• Lectures => Deliver the “Key Concepts” of Immunology.

• Workbook => Apply the “Knowledge” from Immunology to the “Solutions” of clinical problems.

• Textbook reading => Help learn the details and build up the comprehensive knowledge of immunology

1. What we teach is the current knowledge about Immunology.

2. Most would stand forever and Some may change in the

future.

3. So Keep your mind Open! You could be the next “One” to

make a breakthrough in the Immunology.

Evaluation

For the Immunology Section:

• Examination => 70 %

• Attendance & Class performance => 30%

OutlineOutline

• The Origin of the Immune The Origin of the Immune

Concept Concept

• Overview of Immunity to Microbes

• Features & Components of Innate &

Adaptive Immunity

• Summary & Question

The Origin of Immune Concept-I

1. The term “Immunity” => Latin word “Immunitas” => Protection from legal prosecution (Roman senators)Biological definition => Protection from infectious diseases

2. The concept of immunity => existed in ancient Greek & Chinese => the experienced view

3. The medical view of immunity => Edward Jenner (1796)Observation => Milkmaids generally get No SmallpoxHypothesis => Pus from vaccinia (cowpox)

=> Protect milkmaids from smallpox Test => Inoculate materials from cowpox pus

=> Protect a young boy from smallpox (Protective immunity)

Vaccinia => Vaccination (also called Immunization)

The first vaccination against smallpox

Adopted from www.ebinrushed.com/history/images/history_7.jpg

Exudate from a cowpox pustule on the hand of milkmaid Sarah Nelmes was inserted into scratches on the arms of James Phipps, May 14, 1796.

The Origin of Immune Concept-II

4. The concept of “Immunity” developed gradually over time through many scientific findings: => Robert Koch (1905 Nobel Laureate) => Infectious

diseases caused by microorganisms=> Louis Pasteur => Vaccines against cholera & rabies=> These clinical successes => The search of underlying mechanism of “Protection of Infectious Diseases”=> The development of “Immunology”

5. Advances in technology (e.g., Cell culture, Monoclonal Ab, Flow cytometry, Genetic engineering…etc) have facilitated our understanding of the immune system and its functions. “Descriptive Science” => “Experimental Science”

Edward Jenner

Eradication of smallpox

Vaccines for common infectious diseases

Still no effective vaccines for many infectious microbes, e.g., HCV, HIV, Dengue virus…..etc

OutlineOutline

• The Origin of Immune Concept

• Overview of Immunity to Overview of Immunity to

MicrobesMicrobes

• Features & Components of Innate &

Adaptive Immunity

• Summary & Question

Key concepts about immunity-I

1. The immune system has evolved to (1) Protect against the invading pathogens (or foreign substances) and to (2) Maintain tissue homeostasis (damaged cells or cancer). Meanwhile, microbes (outside) and tumors (inside) have

evolved to survive in the host.

2. The immune system (in vertebrates) consists of (1) Innate immunity and (2) Adaptive immunity => An integrated system of host defense => Cells & molecules function cooperatively Antigen-presenting cells => Lymphocytes => Effector cells

3. Innate immunity is evolutionally the more conserved host defense system:

- Existed in both Invertebrates & Vertebrates - Provides the first line of defenses against infections - “Activates” and “Programs” adaptive immune responses

Key concepts about immunity-II

5. Adaptive immunity evolved later: - Existed only in Vertebrates - Provides the more potent and diverse defenses

against infections - Develops as a response to infection and adapts to the

infection

6. The immune system may fail => Immunodeficiency, Hypersensitivity, & Autoimmune diseases.

7. Normal immune responses can be obstacles in medical cases, e.g., organ transplantation

Better Understanding of Immunology Help manipulate immune responses Solve the medical problems

Overview of immune responses

Innate vs Adaptive immunity

The immune system has the ability to recognize some self components:- The Normal condition => prevent self-recognition- The “Pathological Conditions” => occur self-recognition

Phagocytosis by innate immunity-I

1. Cells w/ phagocytic ability: Macrophage, Neutrophil, & Dendritic cells.

2. Phagocytosis serves two key functions:(1) Killing microbes(2) Antigen (Ag) Presentation

Phagocytosis during innate immunity-II

Inflammation: 1. A “Hallmark” of innate immune response (Call for

help)2. Local accumulation of immune cells & molecules

against microbes3. Function to eliminate infections but often cause

tissue damage & diseases 4. Link to the development of many diseases, e.g.,

Cancer, Cardiovascular disease, ….etc.

Elie Mechnikoff:The Pioneer of Innate Immunity1. The Discovery of Phagocytes & Phagocytosis

2. The Nobel Laureate in Medicine 1908

Adopted from Nature Immunology, July 2008

Paul Ehrlich: One of the fathers of humoral adaptive immunity

1. The Discovery of Antibody

functions

2. The Nobel Laureate in Medicine 1908

The development of modern Immunology in 20th century mainly centers on understanding the Adaptive Immune System.

Adopted from Nature Immunology, July 2008

Interaction between innate and

& adaptive immunity1. Innate immunity => Ag presentation (by Dendritic cells)

2. Adaptive immunity => Ag recognition (by T & B lymphocytes)

Overview of adaptive immune responses

OutlineOutline

• The Origin of Immune Concept

• Overview of Immunity to Microbes

• Features & Components of Features & Components of Innate & Adaptive Immunity Innate & Adaptive Immunity

• Summary & Question

Features of Adaptive immunity

(107 ~ 109)

(vaccination)

Specificity, Memory, and Homeostasis of Adaptive

Immunity

Clonal expansion of lymphocytes

Types of adaptive immunity1. Humoral immunity => Molecules in body fluid, e.g. Antibody (Ab) => Key player => B cells => Target extracellular microbes & toxins

2. Cell-mediated immunity => Key player => T cells => regulate other immune cells => Target intracellular microbes, e.g. viruses, bacteria

For innate immunity, it also includes Humoral & Cellular components for immune defense

Active vs. Passive immunity

Active immunity => A host response to a microbe (Ag) => specific and long-term immune defense (memory)Passive immunity => Adoptive transfer of Ab or lymphocytes specific for a microbe (or Ag) => specific, instant but transient immune defense

Serum therapy => Humoral immunity & Passive immunity Serum (Ab) from animals recovered from diphtheria infection => Naïve animals => Resistant to diphtheria infection

Adaptive immune recognition: 1. Antigen (Ag) receptors on T & B lymphocytes.2. These Ag receptors generated by “somatic gene recombination”3. They recognize diverse Antigens (peptides) from microbes or non-self.Innate immune recognition: Q: How do host cells recognize invading pathogens at the first place? Scientists have no answer to this until the end of the 20th century.

Innate vs. Adaptive Immune Innate vs. Adaptive Immune RecognitionRecognition

Charles A. Janeway, M.D.Yale Univ.

The “Renaissance” of innate The “Renaissance” of innate immunityimmunity

In 1989, Janeway => Immune recognition of microbes => Detection of conserved molecular patterns, referred to PAMPs (Pathogen-Associated Molecular Patterns) with features:

1. Invariant among a given class of microbes.2. Have essential roles in microbial physiology. 3. Recognized by receptors of the innate immune system, called PRRs (Pattern-Recognition Receptors). 4. Innate immunity regulates adaptive immunity

Julie A. Hoffmann, Ph.D.Strasbourg, France

The “Renaissance” of innate The “Renaissance” of innate immunity-IIimmunity-II

In 1996, Hoffmann’s group Toll functions as a PRR in Drosophila

The Discovery of Toll and Toll-like The Discovery of Toll and Toll-like receptor (TLR)receptor (TLR)

Cell. 1996 Sept 20; 86(6):973-83

The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults.

Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA.

Institut de Biologie Moleculaire at Cellulaire, UPR 9022 du Centre National de la Recherche Scientifique, Strasbourg, France

Nature 388, 394 - 397 (24 July 1997)

A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.

Medzhitov R, Preston-Hurlburt P, Janeway CA Jr.

Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8011, USA.

Key concepts in innate immunity

1. The innate immune system mainly recognizes common structures shared by classes of microbes, => Pathogen Associated Molecular Patterns (PAMPs), e.g., LPS, Peptidoglycan, Microbial DNA & RNA. 2. Host receptors that recognize PAMPs are called Pattern- Recognition Receptors (PRRs), which are encoded in “Germline” DNA=> limited Diversity.

3. Innate immunity not only provide the first line of defenses but link to the program of adaptive

immunity.

4. PRRs may also recognize components from injured or dead

host cells => Autoimmune diseases

Examples of Pattern-Recognition Receptors (PRRs)

Toll-like Receptors

Locations of Different PRRs

Body fluids-Soluble PRRs

Cellular PRRs- Cell surface

- Endosomes

- Cytosol

Soluble Pattern Recognition Receptors-Complement

activation pathways

Epithelial barriers prevent the

entry of microbes

Cellular components of the immune system will be discussed extensively in Lecture #2.

Failure of the immune system

1. Ineffective response

- Immunodeficiency

2. Overactive response

- Hypersensitivity

3. Auto-reactive response

- Autoimmunity

OutlineOutline

• The Origin of Immune Concept

• Overview of Immunity to Microbes

• Features & Components of Innate & Adaptive Immunity

• Summary & QuestionSummary & Question

SUMMARY

1. Protective immunity against microbes is mediated by the

early response of innate immunity and the later response of

adaptive immunity.

2. Innate immune responses are initiated by recognition of

common microbial structures (PAMPs) by Pattern- Recognition Receptors (PRRs) on innate immune cells. - Provide the first line of host defense - Activate and regulate the adaptive immunity

3. Adaptive immune responses are initiated by recognition of

foreign antigens by specific lymphocytes. - Provide more potent, specific (Ag), & broad protection - Develop immune memory for the next exposure - Feedback regulate innate immunity

Questions

1. Why is it necessary to vaccinate against tetanus only every 10

years, though antibodies against the toxoid disappear from the

circulation within a year?

2. Why is the vaccine against tetanus always effective, whereas

the vaccine against influenza protects on some epidemics but not

others?

The End & Thank you

Interaction between innate and

& adaptive immunity

1. Innate immunity => Ag presentation (by infected cells)

2. Adaptive immunity => Ag recognition (by T & B lymphocytes)

The Interface between innate and adaptive immunity

Beutler, B. et al., Nat Immunology 2004