Overview of Immunology Organs and tissues Cells Molecules － Antibodies － Complement － Cytokines － MHC Components of IS Functions of IS Pathology of IR * IS: Immune system IR: Immune response Applications Prevention Diagnosis Therapy Antigen (Ag) Immune Responses Control mechanisms Hypersensitivity Autoimmune disease Immunodeficiency Tumor Transplantation rejection

Consequences of IR Physiology Immunologic defense Immunologic homeostasis Immunologic surveillance Pathology Hypersensitivity Immunodificiency Autoimmune diseases Tumor immunology Transplantation rejection

Overview of Immunology Organs and tissues Cells Molecules － Antibodies － Complement － Cytokines － MHC molecules Antigen (Ag) Immune Responses Control mechanisms Hypersensitivity Autoimmune disease Immunodeficiency Tumor immunology Transplantation Components of IS Functions of ISPathology of IR * IS: Immune system IR: Immune response

Components of IS -- Organs and tissues Questions: 1.Which organs belong to the immune system? 2. Describe the functions of bone marrow and thymus. 3. What are the functions of secondary lymphoid organs? 4. Terms: MALT—IS / Location / function

Components of IS -- Organs and tissues Questions: Describe the mature T cell properties in peripheral lymphoid organs from the functions of thymus. Functions of thymus: -- 4 分 Positive selection Negative selection Mature T cell properties: -- 4 分 Recognition: TCR / MHC + Ag(no-self) Classification: CD4 / CD8

— — Bone Marrow Primary source of pluripotent stem cells All haemopoietic cells Place for B cell maturation — — Thymus Place for T cell maturation Primary Lymphoid Organs (Central Lymphoid Organs)

Cells of IS are produced from haemopoietic stem cells (HSC) in BM. Stromal cells (epithelial cells, fibroblast, macrophage) is required for the differentiation of a particular lineage. Cytokines( CSF) produced from stromal cells provide the local environment for the hematopoiesis. Primary Lymphoid Organs-- Bone Marrow

Large numbers of functionally antigen specific T cells are matured in thymus. Each of T cells has only one specificity. T cells are selected using their receptors ( positive and negative selection) Primary Lymphoid Organs -- Thymus

Lymph nodes Place of immune response to pathogen entering the tissues Spleen Place of immune response to blood borne infections MALT Place of immune response to mucosal surfaces Secondary Lymphoid Organs

Lymph nodes - Situated alone lymphatic vessels (p30) - Filter of the lymph - Contain T/B lymphocytes and phagocytes (p29) - Place of immune response to pathogen entering the tissues

Spleen -- Situated on the left side of the body below the diaphragm -- Filter of the blood -- Contain T/B lymphocytes and phagocytes -- Place of immune response to pathogen entering the blood

Overview of Immunology Organs and tissues Cells Molecules － Antibodies － Complement － Cytokines － MHC molecules Antigen (Ag) Immune Responses Control mechanisms Hypersensitivity Autoimmune disease Immunodeficiency Tumor immunology Transplantation Components of IS Functions of ISPathology of IR * IS: Immune system IR: Immune response

Components of IS -- Cells Questions: 1. Which cells belong to the immune system? 2. The functions of mononuclear phagocytes are….? 3. Try to explain the classification and function of lymphocytes.

The cells of immune system recognize antigens by their receptors, please explain how the cells of followings recognize target antigens: Macrophage: PRR -- 2 分 NK cell: KIR/ KAR-- 2 分 T cells:TCR-- 2 分 B cells:BCR-- 2 分

4. Terms: CD : Marker / identification by mAb / function TCR : Location / structure / function BCR : Location / structure / function PRR : Location / functions KIR : Location / functions KAR : Location / functions

— — Mononuclear phagocyte system Monocyte Macrophage Dendritic Cells — — Granulocytes Neutrophils Basophils Eosinophils — — Lymphocytes T lymphocyte B lymphocyte NK (Natural killer cells) Cells of Immune System-Classification

Ag DCs Th1 Tc B Ab PMN NK Th2 Complement Functions in Immune Response (IR) Targetcells MHCCK MHCCK CKs CKs

— — Phagocytosis — — Antigen presentation — — Cytokine secretion Mononuclear Phagocyte System

— — T lymphocyte — — B lymphocyte — — Natural killer cells (NK) Lymphocytes T H1 T H2

Infected cells Virus Bacterium IL-1 Perforin Granzymes TNFa/TNFb Killing Cellular immunity BCR Antibody Neutralizing Complement activating NK ADCC Mq Phagocytosis MAC PMN Lysis C3b C3a/C5a Humoral immunity

TH (CD4 + CD3 + ) ¹ ¹TH1: Help Tc and macrophages by secretion of IFN/γ/IL-2 ¹ ¹TH2 ： Help B cells by secration of IL-4, IL-5,IL-6 TC (CD8 + CD3 + ) ¹ ¹Killing of target cells by releasing perforin and granzymes Functions of T cells

  Antibody production Functions of B cells

Antibody Production by B cell Th2

NK

— — Neutrophils — — Basophils — — Eosinophils Granulocytes

Overview of Immunology Organs and tissues Cells Molecules － Antibodies － Complement － Cytokines － MHC molecules Antigen (Ag) Immune Responses Control mechanisms Hypersensitivity Autoimmune disease Immunodeficiency Tumor immunology Transplantation Components of IS Functions of ISPathology of IR * IS: Immune system IR: Immune response

Components of IS -- Ab 1.Try to describe the biological function of antibodies. 2. Terms: mAb / Ab / ADCC

4. Terms: mAb / Ab / ADCC : Artificial / hybridoma / property / application mAb : Artificial / hybridoma / property / application Ab: Generation cell / structure/ classes/ functions ADCC: Ab / Fab-target / Fc-NK / cytotoxocity

How to understand the antibodies and complement are the molecules that are involved in both physiological and pathological consequences of immune response by using examples. Antibodies -- 4 分 : Physiological / Pathological Complement -- 4 分 : Physiological / Pathological

Complementarity determining region (CDR)

Functions of Antibody  Role of Ab alone  Role of Ab in complement activation  Role of Ab with effector cells

1 、 Role of Ab alone  To Neutralize virus and toxins and blocks their biological activity (IgG).  To inhibit microbes attachment to mucosal epithelial cells (IgA).

2 、 Role of Ab in complement activation To Activate the classical pathway of complement to lysis of the Ag by binding to Ag (IgG/ IgM).

3 、 Role of Ab with effectors cells Macrophage and neutrophil: Opsonization and phagocytosis of microbes (IgG) NK cell and eosinophil: Antibody-dependent cellular cytotoxicity(ADCC) (IgG) Basophil and mast cell: Type I hypersensitivity – allergy (IgE)

FcrR (CD16) IgG NK cells

Sensitization against allergens pollen

Result – – Vasodilatation, – – Vascular Leakiness, – – Smooth Muscle Contraction, – – Mucus Secretion.

Overview of Immunology Organs and tissues Cells Molecules － Antibodies － Complement － Cytokines － MHC molecules Antigen (Ag) Immune Responses Control mechanisms Hypersensitivity Autoimmune disease Immunodeficiency Tumor immunology Transplantation Components of IS Functions of ISPathology of IR * IS: Immune system IR: Immune response

Components of IS -- Complement 1. Try to describe the pathways that are involved in activation of complement. 2. The functions of complement include …. 3. Term: MAC– activation of C / components / function

— — Anaphylatoxins: C3a, C5a — — Chemotaxis: C5a — — Opsonization: C3b — — Lysis of the microbes:MAC Functions of complement

Overview of Immunology Organs and tissues Cells Molecules － Antibodies － Complement － Cytokines － MHC molecules Antigen (Ag) Immune Responses Control mechanisms Hypersensitivity Autoimmune disease Immunodeficiency Tumor immunology Transplantation Components of IS Functions of ISPathology of IR * IS: Immune system IR: Immune response

Components of IS -- Cytokines 1. Try to explain how cytokines play their functions in immune response? 2. The are…… 2. The General characteristics of CKs are…… 3. Terms: CKs – generation / functions 3. Terms: CKs – generation / functions

Infected cells Virus Bacterium IL-1 Perforin Granzymes TNFa/TNFb Killing Cellular immunity BCR Antibody Neutralizing Complement activating NK ADCC Mq Phagocytosis MAC PMN Lysis C3b C3a/C5a Humoral immunity

General characteristics of CKs y Small molecules y Secreted by ： ⑴ Immune Cells; ⑵ Related cells - Autocrine - Paracrine - Endocrine y Bind with specific receptor y Effector : - Pleiotropy - Synergy - Redundancy - Antagonism

Overview of Immunology Organs and tissues Cells Molecules － Antibodies － Complement － Cytokines － MHC molecules Antigen (Ag) Immune Responses Control mechanisms Hypersensitivity Autoimmune disease Immunodeficiency Tumor immunology Transplantation Components of IS Functions of ISPathology of IR * IS: Immune system IR: Immune response

Components of IS – MHC molecules 1. Describe the biological functions of MHC molecules. 2. Terms: MHC -- genes / classes / functions HLA – Human MHC

Components of IS – MHC molecules MHC molecules are the important molecules in transplantation rejection, why ? Transplantation rejection = Immune response Ag : graft -- MHC-- 3 分 IR: APC -- MHC Direct pathway – 2.5 分 Indirect pathway – 2.5 分

Biological functions of MHC — — Immune Response — — Transplantation — — Related with diseases

Deletion T differentiation

Ag APCs Th1 Tc B Ab PMN NK Th2 Complement MHC in immune response Targetcells MHCCK MHCCK CKs CKs Target MHC

Ag presentation

Ag APCs Th1 Tc B Ab PMN NK Th2 Complement MHC in immune response Targetcells MHCCK MHCCK CKs CKs Target MHC

Virus infection

Recognition Activation Effects Rejection Immune response to graft

Overview of Immunology Organs and tissues Cells Molecules － Antibodies － Complement － Cytokines － MHC molecules Antigen (Ag) Immune Responses Control mechanisms Hypersensitivity Autoimmune disease Immunodeficiency Tumor immunology Transplantation Components of IS Functions of ISPathology of IR * IS: Immune system IR: Immune response

Functions of IS -- Ag 1. Try to explain the biological meanings of antigens that are related with medicine with 2 or 3 examples. 2. Terms: (1)Antigenic determinant (2) Hapten; (3) Adjuvant

(1)Antigenic determinant: Ag / specificity (2) Hapten: property / carrier (3) Adjuvant

Functions of IS – IR : innate immunity? 1. What kind of factors might be involved in innate immunity? 2. Terms: OOpsonization – Ab -Fc / C-CR / phagocytes/ target cells PRR– location / functions KIR – location / function KAR – location / function

Natural immune response Natural immune response ( Innate Immunity) — External defenses — Cell effects — Molecular effects

Mq/DCs Phagocytosis

NK KAR KIR

Functions of IS – IR : Adaptive immunity? 1. What kinds of factors determine the specificity of immune response? 2. How could lymphocytes be activated? 3. Describe the biological effects of humoral and cellular immune response. 4. Try to explain the relationship between the innate immunity and adaptive immunity.

Ag APC Th1 Tc B Ab PMN NK Th2 Complement Immune Response(IR) Targetcells MHCCK MHCCK CKs CKs

Adaptive Immune Response Adaptive Immune Response (Acquired Immunity) — Antigen presentation — Antigen recognition — Activation of cells — Effects

Antigen presentation — — Types of APCs ● Monocytes/Macrophage ● Dendritic cells ● B lymphocytes — — Pathways of antigen processing ● Class I processing pathway ● Class II processing pathway

Antigen Recognition   T cell recognition of Ag   B cell recognition of Ag

Adaptive Immune Response Adaptive Immune Response (Acquired Immunity) — Antigen presentation — Antigen recognition — Activation of cells — Effects

Activation of Cells — — Signals ● Antigen ● Co-stimulators ● Cytokines — — Signal transduction

Th-2

Adaptive Immune Response Adaptive Immune Response (Acquired Immunity) — Antigen presentation — Antigen recognition — Activation of cells — Effects

Effects of adaptive immune response Antibody response （ Humoral immunity ） T cell response （ Cellular immunity ）

Infected cells Virus Bacterium IL-1 Perforin Granzymes TNFa/TNFb Killing Cellular immunity BCR Antibody Neutralizing Complement activating NK ADCC Mq Phagocytosis MAC PMN Lysis C3b C3a/C5a Humoral immunity

Functions of IS – Control mechanisms How to understand the immune response to a particular Ag could be maintained in a proper level ?

Regulation of Immune Response Regulation of Immune Responses neuro- endocrine system + -

Overview of Immunology Organs and tissues Cells Molecules － Antibodies － Complement － Cytokines － MHC molecules Antigen (Ag) Immune Responses Control mechanisms Hypersensitivity Autoimmune disease Immunodeficiency Tumor immunology Transplantation Components of IS Functions of ISPathology of IR * IS: Immune system IR: Immune response

Pathology of IR – Hypersensitivity 1. Describe the mechanisms of hypersensitivity. 2. What kind of cells will be involved in type I hypersensitivity and how ? 3. Try to give some examples of diseases that are belong to type II and type III hypersensitivity.

Type-I Hypersensitivity (Allergy) Pollen Insect venoms Animal dander Fungi Worms Food Drugs Allergen

Result – – Vasodilatation, – – Vascular Leakiness, – – Smooth Muscle Contraction, – – Mucus Secretion.

Type-II Hypersensitivity (Ab-dependent Cytotoxic) Complement activation NK PMN Ag + Ab lysis Killing phagocytosis

Type-III Hypersensitivity (Immune Complex)

Type IV hypersensitivity (Delayed reaction)

Pathology of IR -- Autoimmune disease (AD) 1. Why does the immune system not attack self-tissue in normal conditions? 2. How could the self–tissue become the targets of immune system ? 3. How are the tissue destroyed by immune system ? 4. Terms: Self-tolerance : self-Ag / no response / specificity Self-tolerance : self-Ag / no response / specificity

Innate Immunity Adaptive Immunity -- Central tolerance -- Peripheral tolerance Self-tolerance

Self-tolerance – Innate Immunity -- Cells ： 1. Mononuclear phagocyte system 2. Granulocytes 3. Natural killer cells (NK) -- Molecule: Complement

  Central tolerance   Peripheral tolerance Self-tolerance -- Adaptive Immunity

Selection of T cells in thymus

DCs Th1 Tc B Ab PMN NK Th2 Complement Immune response to self – Self-Tolerance Targetcells MHCCK MHCCK CKs CKs Self

3. How are the tissue destroyed by immune system ? Antibody mediated (type Ⅱ ) Immune complex mediated (type III) T-cell mediated (type IV)

Mechanisms Complement activation NK PMN Ag + Ab lysis Killing phagocytosis

Mechanism

Type IV hypersensitivity mediated AD Pancreatic Beta cells IDDM Loss of insulin production Brain cells Multiple sclerosis (MS) Demyelination of CNS, Paralysis

Pathology of IR -- Tumor 1. How could the tumor cells escape the surveillance of immune system? 2. What kinds of mechanisms could the tumor cells be destroyed by immune system? 3. Do you have any ideas about the strategies of immunotherapy? 4. Term: TAA—tumor/ quantity TSA – tumor/ quality

IL-1 Perforin Granzymes TNFa/TNFb Killing Cellular immunity !! BCR Antibody Complement activating NK ADCC Mq PhagocytosisLysis C3b Humoral immunity ! Tumor cells shed tumor-Ag shed tumor-Ag

Mechanisms of tumor escape Variation of tumor antigens Co-stimulator decrease Co-stimulator decrease Down-regulation of MHC expression Down-regulation of MHC expression Immune suppression of tumor Immune suppression of tumor Masking of tumor cell antigen Masking of tumor cell antigen

1. Variation of tumor antigens

2. Co-stimulator decrease

3. Down-regulation of MHC expression

4. Immune-suppression of tumor Tumor cells

5. Masking of tumor cell antigen

Immunotheropy of tumors Preventive specific, T cells

Pathology of IR -- Transplantation rejection 1. What is the reason of transplantation rejection? 2.Do you have any ideas about how to overcome the transplantation rejection? 3. Terms: GVHR/ HVGR/ MLR(MLC) 4. Terms: GVHR: Ag-recipient / IS -graft HVGR: Ag – graft / IS - recipient MLR(MLC): method / application

Recognition Activation Effects Rejection Immune response to graft

Indirect and direct pathways

Prevention of rejection   Family grafting   Tissue typing   Cross-matching   Immunosuppression

Family grafting ac ac Twins Homozygotes

Tissue typing

Cross-matching -1 (Tritium)

graft APC Th1 Tc B Ab PMN NK Th2 Complement Suppress T cell activationgraft MHCCK MHCCK CKs CKs

Pathology of IR -- Immunodificiency Terms: AIDS – HIV-gp120/ CD4-T / IS / clinical

Overview of Immunology Organs and tissues Cells Molecules － Antibodies － Complement － Cytokines － MHC molecules Antigen (Ag) Immune Responses Control mechanisms Hypersensitivity Autoimmune disease Immunodeficiency Tumor immunology Transplantation Components of IS Functions of ISPathology of IR * IS: Immune system IR: Immune response