Immunology (원어강의)

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Textbook: Janeway’s Immunobiology, 8th Ed. (E. Public)

Handouts: e-class

Attendance: 20 %

Exams: Midterm 40% + Final 40%

Missing classes equal or more than 4 days = F

Being late to the class twice: considered as ONE absence

Evaluation

1. Introduction & Basic Concepts in Immunology (Chapter 1)2. Innate Immunity: The first line of defense (Chapter 2)3. The induced responses of innate immunity (Chapter 3)4. The induced responses of innate immunity (Chapter 3)5. Antigen Recognition by B-cell and T-cell Receptors (Chapter 4)6. The Generation of Lymphocyte Antigen Receptors (Chapter 5)7. Antigen Presentation to T-lymphocytes (Chapter 6) 8. Midterm Exam9. Signaling through Immune System Receptors 1 (Chapter 7)10. Signaling through Immune System Receptors 2 (Chapter 7)11. The Development and Survival of Lymphocytes (Chapter 8)12. T-Cell mediated Immunity (Chapter 9)13. The Humoral Immune Response (Chapter 10)14. Dynamics of Adaptive Immunity (Chapter 11)15. The Mucosal Immune Sustem (Chapter 12)16. Final Exam

Class Schedule

Immunology ???

• The immune system detects a wide variety of agents and distinguishes between “self” and “non-self” to protect the human body.

• Non-self: pathogen, allergen, cancer cell, etc

• Application of immunology: Vaccination

Vaccination

• Latin word, Vacca = Cow

• Latin word, Vaccinia = Cowpox

• Administration of a weakened or attenuated strain of disease causing agent (to immunize against that agent)

• Robert Koch: Infectious diseases are caused by microorganisms (viruses, bacteria, fungi, parasites).

Ch. 1. Basic Concepts in Immunology

♦ Innate Immune Response

♦ Adaptive Immune Response

Humoral Immune Response: Antibody-항체에 의한 면역반응

Cell-mediated Immune Response:

Immune System:

Ex) Macrophage

Innate vs. adaptive immunity• Innate immunity

– First line of defense (present in all individuals at all times)– Immediate (0 – 4 hours)– Non-specific– Does not generate lasting protective immunity

• Adaptive immune response– Is initiated if innate immune response is not adequate: more

efficiently eliminate infections (late, > 4 days)– Antigen-specific immunity– Generates lasting protective immunity (immunological

memory)– Recognize antigens by antigen receptors

A functional Immune System requires,

1. Immunological Recognition2. Immune Effector Function3. Immune Regulation4. Immunological Memory

1. Cells of the immune system

???

The immune system depends on White Blood Cells (WBCs) or Leukocytes

Bone Marrow makes WBCs.

WBCs develop and mature in BM

WBCs 1. Reside in tissue2. Circulation in the bloodstream3. Circulating in the lymphatic system as

lymph

WBCs divided into the lymphoid and myeloid lineages

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

1. Innate Immune System: Myeloid cells and NK cells

Lymphocytes: B and T cells

WBCs divided into the lymphoid and myeloid lineages.

Cells of the immune system

2. Adaptive Immune System: B and T cells

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

1) Innate Immune System:

1.Myeloid cells: monocytes/macrophages, neutrophils, eosinophils, basophils, mast cells and dentritic cells

2.Lymphoid cells: NK cells

Monocytes/Macrophages

• Resident in almost all tissues• Phagocytosis (engulf) and killing

of microorganisms (bactericidal)• Activate T cells: Antigen

Presenting Cells (APCs)• Monocyte is a young macrophage

in blood.• Differentiated into macrophages

in tissues.• Induce inflammation

Monocyte

MQ

Neutrophil

• Granulocytes• Phagocytosis• Short life span (few days)• Very important cells in innate

immune responses at “clearing” bacterial infections.

Eosinophils and Basophils

• Granulocytes• Short life span• Engulf and Kill parasites which are

too big for MQ and Neutrophils• Involved in allergic inflammation

Eosinophils

Basophils

Mast cells

• Unknown functions• Regulate allergic responses• Protect the internal surfaces

of the body against pathogens including parasitic worms

Dendritic Cells

• Phagocytose and degrades microorganisms • Macropinocytosis• The main function is to activate T cells: Antigen

Presenting Cells (APCs)• mature in tissue and migrate into the lymph

nodes

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Natural Killer Cells

• Large granular lymphocytes (not B or T)

• Part of the innate immune system (non-specific for antigen)

• Kill tumor cells• Kill cells infected with certain

viruses (intracellular pathogens)

2) Adaptive Immune System:

B and T lymphocytes

B and T Lymphocytes

• Antigen specific cells

• Recognize and bind antigens using antigen receptors

• Each lymphocyte has a unique variant of a prototype antigen receptor: diverse populations

• Inactive in the absence of an infection

• Lymphocytes that have not been activated by antigen: “naïve lymphocytes”

• Lymphocytes that have met their antigen become activated and have differentiated further into fully functional lymphocytes: “effector lymphocytes”

JPEG file adapted fromJaneway’s Immunobiology,

8th Ed.

B Lymphocytes

B Cell Receptor (BCR)

B

B

BBBBB

Antibody = immunoglobulin (Ig)

T Lymphocytes

T

T Cell Receptor (TCR)

T

APC

Tc Th Treg

Cytotoxic T Helper T Regulatory T

Cytotoxic T: kills infected cells

Helper T: activate Ag stimulated B cells to differentiate and produce Ab,also activate MQ to be more efficient at killing engulfed pathogens

Regulatory T: suppress activity of other lymphocytes

Effector T cells

Activated B and T cells differentiate into memory cells: long-lasting immunity

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

◆ Lymphocytes are originated from BM, but mature in the bone marrow (B) or the thymus (T).

◆ Lymphocyte resides in lymphoidtissues or organs where mature naïve lymphocytes are maintained and adaptive Immune response are initiated.

◆ Lymphoid organs: central (primary) or peripheral (secondary)

Central: bone marrow and ThymusPeripheral: lymph nodes, spleen mucosal lymphoid tissues of the gut, the nasal and respiratory tract and the urogenital tract and other mucosa

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

How does the immune system works?

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Inflammation (MΦ, Neutrophils)

Cytokine: i) any protein that is secreted by cells and affects the behavior of nearby cells with appropriate receptors, ii) changes vascular permeability and adhesive properties of the endothelial cells

Chemokine: secreted proteins that attract cells bearing chemokine receptors such as neutrophils and monocytes out of the blood stream and into the infected tissue

MΦ and neutroiphils (latter recruited) are the main cell types (Inflammatory cells). Monocytes are also recruited and further differentiated into MQ.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

- Dendritic cells (DC) have receptors for bacterial components called lipopolysaccharide (LPS). LPS stimulates the DC to engulf and degrade the pathogen.

- Also, DC continually take up extracellular materials such as virus particles and bacteria by the receptor-independent mechanism called macropinocytosis.

- The main function of DC is to carry pathogen antigens on their surface to peripheral lymphoid organs to present to T lymphocytes (function as APC).

- After taking up Ag, DC migrates to peripheral lymphoid organs and matures into a highly effective APCs to stimulate the T cells to proliferate and differentiate.

Dendritic Cells

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Innate immune cells must discriminate the self from the non-self.

Innate immune cells recognize Pathogen-Associateed Molecular Patterns (PAMPs) using Pattern Recognition Receptors (PRRs): Less specific than lymphocyte receptors (BCR or TCR).

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

- Lymphocytes are only in the blood, lymph and lymphoid organs.

- Therefore, pathogens and lymphocytes meet in the peripheral lymphoid organs such as lymph nodes, spleen and the mucosal lymphoid tissues.

- Pathogen antigens are carried from sites of infection to the peripheral lymphoid organs by primarily DC (or other APCs such as MΦ).

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

1. Have receptors (BCR or TCR) specific for the antigen.

2. Requires “Antigen Presenting Cells (APCs)” in order to be activated.

Lymphocytes (B or T cells) for the adaptive immune system

Antigen Presenting Cells (APC)

• Highly specialized• Process antigen and display peptide fragments on

cell surface• Present Ag to adaptive immune cells, especially T-

cells to activate.• B cells require signals from T cells and Ag to

produce Abs.• Macrophages, Dendritic cells and B-cells

- Lymphocytes require Ag binding to the receptor and co-stimulatory signals.

- Ag binding without co-signal induce clonal deletion or an inactive state known as anergy

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Explained by Clonal Seletion theory

• Clonal Deletion: Self-reactive lymphocytes will be eliminated by apoptosis (cell programmed cell death).

• Clonal Expansion: Only those lymphocytes that encounter an antigen will proliferate to produce many identical progeny and differentiate into effector cells.

Lymphocytes (B or T cells) development

JPEG file adapted fromJaneway’s Immunobiology,

8th Ed.

The four basic principles of clonal selection:

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

- Lymphocyte Receptors (BCR or TCR) have i) constant region (1 out of 5) and ii) variable region (infinite variety).

- Variable region recognizes antigen and constant region has effector function to dispose of the antigen bound.

BCR vs TCR1. Structure2. No secreted form for

TCR3. TCR does not bind Ag

directly: only recognize Ag bound on the surface of other cells

Lymphocyte Receptors

BCR (Ab): 2 heavy chains and 2 light chains

TCR

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

How are lymphocytes able to contain the infinite variety of the receptors?

Somatic gene rearrangement (recombination)

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Epitope: Antigenic determinant

Ab recognizes the surface antigens on pathogens living outside cells

BCR (antibody)

JPEG file adapted fromJaneway’s Immunobiology, 8th

Ed.

TCR recognizes antigens that have been generated inside cells and are being displayed on their surface: only recognize antigenic peptides when they are bound to a particular cell-surface protein called Major Histocompatibility Complex (MHC).

TCR

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

1. A lymphocyte recognizes a specific Ag on an activated APC.

2. Stops migrating, less dense chromatin, enlarge, increased transcription and translation (becomes lymphoblast).

3. Proliferate and divide (a large clone of identical lymphocytes).

4. Differentiate into effector B cells (also called “plasma B cells”, secrete Abs) or T cells (cytotoxic T cells, helper T cells or regulatory T cells).

5. Most of lymphocytes will die, but some persist (memory cells)

Lymphocyte activation

JPEG file adapted fromJaneway’s Immunobiology, 8th

Ed.

Immunological memory:

The secondary Ab response occurs after a shorter lag phase, higher level and produces Ab of higher affinity (= affinity maturation)Affinity maturation occurs because of selection of BCR with higher affinity.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

B cells: Effector B cells (plasma B cells, secrete Abs)

T cells: Effector T cells (Tc to kill, Th to activate B cells, Treg)

Effector Lymphocytes

- deals with extracellular forms of pathogens and their toxic products.

- Constant region (5 different forms) determines the Ab classes or isotypes. Also determines an antibody’s functional properties, the way to dispose Ags.

Ab’s way to protect against pathogens or their toxic products:1. Neutralization2. Opsonization (for bacteria that has an outer coat

that is not recognized by the PRR of phagocytes3. Complement activation (complement

compounds: constant region of Ab is the receptor for compelement system, complement components bound to the bacterial surface can directly kill bacteria and also coat the pathogen surface to be engulfed by phagocytes.

Humoral Immune response (=Ab mediated):

JPEG file adapted fromJaneway’s Immunobiology, 8th

Ed.

- deals with intracellular forms of pathogens and activates B cells.- Effector T cells contain either CD8 (Tc) or CD4 (Th).- CD4 Th cells can differentiate further into Th1 or Th2.

Cell-mediated immune response (T cell)

Tc (CD8)

Th (CD4)Th1

Th2

Tc (CD8)

Th (CD4)Th1

Th2

Effector T cells

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Tc (CD8)

Th (CD4)Th1

Th2

Effector T cells

Th1: controls intracellular bacterial infection (Mycobacterium tuberculosis), stimulates the fusion of MQ lysosomes with the vesicles containing the bacteria and stimulate MQ antibacterial mechanisms and activates B cells.

Th2: only to activate B cells

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

TCR only recognizes Ag presented with MHC on the surface of the cells.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

MHC class I: - presents peptides derived from proteins synthesized in the cytosol such as fragments of viral proteins

- binds CD8- All nucleated cells express MHC I

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

MHC class II: - present peptides derived from proteins in intracellular vesicles such as peptides from pathogens living in MΦvesicles or internalized by phagocytic cells and B cells

- APCs express MHCII- binds CD4.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Proper immune responses are critical.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.