Medical Immunology Department of Immunology Yiwei Chu 储以微 ywchu@shmu.edu.cn 2010-7-7.

Medical ImmunologyDepartment of Immunology

Yiwei Chu储以微

ywchu@shmu.edu.cn

2010-7-7

Exam: 9th July (Friday)

8:30-10:30am

Inspector: Dr. Lu Qing Dr. Gao Bao

2010-7-7

Department of Immunology

Rui He

Xiaowu HongQing Lu

Bo Gao

Wei Xu

Yiwei Chu

Haifeng Gao

Yunlu Lin

IMMUNITY ---protection from disease (infectious disease)

IMMUNE SYSTEM --- organ, cell, molecule and gene

IMMUNE RESPNSE --- response to the foreign substances

Define of Immunology

IMMUNE FUNCTIONS

---immune defence (infectious disease)

--- immune surveillance

--- immune homeostasis

Define of Immunology

IMMUNITY ---protection from disease (infectious disease)

IMMUNE SYSTEM --- organ, cell, molecule and gene

IMMUNE RESPNSE --- response to the foreign substances

Define of Immunology

Innate and Adaptive Immunity

Adaptive Immune Responses

Cellular Components

Adaptive Immune Responses

• Lymphocytes - B, Th, CTL, NKT

• Antigen-presenting cells(APCs)- DC, Mj, B

• Effector cells - Activated T cells, mononuclear phagocytes

Basic Immunology

Recognition Activation Effection

Ag (antigen) double recognition humural immunity

APC double signaling cellular immunity

(antigen presenting cell)

Antigen (Ag)

Chapter 1 Definition of antigen

Substances that combine specifically

with a B or T cell’s antigen-binding

receptors can then induce an immune

response are called antigens.

Chapter 2 Characteristics of antigen

（ 1 ） immunogenicity

（ 2 ） antigenicity

The antigen molecule generally pose two natures, that is

Antigenic determinants or epitopes are the

immunologically active regions of an

immunogen that bind to antigen-specific

membrane receptors on lymphocytes

(TCR/BCR) or to secreted antibodies.

(1) Antigenic determinants or epitopes

1 Conformational epitope

Nonsequential polypeptides or polysaccharide on the

surface of the molecules,

Native conformation,

2 liner epitope

A sequential amino acid fragment,

Linear determinant,

Inside of the antigen molecule

Structure of epitopes

(complimentarity

determining region,

CDR) :

formation of the Ag binding site

Framework region （ FR ) :

maintaining the 3- dimensional configuration

(3) hypervarible region (HVR)

(complimentarity determining region,) CDR

4. Ab-dependent Cell-mediated cytotoxicity, ADCC

enhance NK killing

Immune Responses to Tumors

APCs are immunocytes that can uptake,

process and present antigens to other

lymphocytes.

CONCEPT

Dendritic Cells (DCs)

Macrophages (M)

B Lymphocytes

Professional APCs

Ralph.M.Steinman, 1973

I. Dendritic Cells (DCs)

The invariant chain is cleaved to leave a peptide fragment, CLIP, bound to the

MHC class II molecule

CLIP (class II-associated invariant-chain peptide)

MHC class II molecule combined with peptide

Cytokines are polypeptides produced by the cells of innate and adaptive immunity in response to microbes and other antigens as a result of cellular activation.

Cytokines initiate their actions by binding to specific membrane receptors on target cells.

The cellular responses to most cytokines consist of gene activation, resulting in the expression of new functions and sometimes the proliferation of the target cells

What are cytokines?

Cytokine actions may be local and systemic

Autocrineaction

Endocrine action

circulation

act at a distance from the site of infection

Paracrine action act on a nearby cell

act on cytokine-producing cell itself

inflammation

BloodSecondary lymphoid organs

Primary lymphoid organs

Tissue

directing migration of leukocytesChemokines

Physiologic traffic of lymphocytes through the organs

(1) inflammatory stimuli

(2) Constitutively produced in lymphoid organs

to inflammatory sites

Cellular sources

IL-2

• a growth factor for antigen-stimulated T lymphocytes

• responsible for T cell clonal expansion after antigen recognition

Natural Killer cells (NK cells)

A type of cytotoxic lymphocytes

The principal physiologic role1. Defense against infections by viruses and some other intracelluar

microbes

2. Rejection of tumors

The mechanism of effector function

Perforin

Granzyme

Pathogen-associated molecular patterns (PAMPs)

Small molecular motifs conserved within a class of

microbes

Usually essential for survival of the microbes

Recognized by cells of innate immune system

Activate innate immune response

PAMPs Source Principle innate immune response

LPS Gram-negative bacteria Macrophage activationcell wall

dsRNA Replicating viruses Type I IFN production by infected cells

Unmethylated CpG DNA

Bacterial DNA Macrophage activation

N-formylmethionine Bacteria protein neutrophil and macrophage activation

Mannose-richglycans

Microbial glycoproteins phgocytosisor glycolipid opsonization complement activation

Examples of PAMPs

Patterns recognition receptors (PRRs)

Proteins expressed by cells of innate immune system

Present on the cell surface, in endosomal vesicles, and

in the cytoplasm

The subsets of CD4+Th cells

How they are induced, What cytokines they produce What effector mechanisms they activate

Development of Th1 and Th2 subsets

Membrane Ig (mIg)

Mature B cell ： mIgM ＋ mIgD

BCR-Igα/Igβ complex

BCR/mIgM

Surface receptor

1) B cell antigen receotor (BCR)

BCR-Iga/Igb complex

2. BCR coreceptor

CD19 B-specific surface marker

signal transduction

CD21 CR2 ， receptor for C3d-bound Ag

CD81 BCR － coreceptor ligation

induce reversible palmitoylation of CD81

to stabilize the CD19/CD21/CD81 complex

Help and strengthen the BCR-Ag-signaling

JBC 2004;279:31973

B cell activation

B cell epitope

BCR-Iga/Igb coreceptor complex

TCR-CD3BCR-Iga/b

Two-signal activation model for T cells

naive

activation

co-stimulatory molecules

anergynone

Two-signal activation model for B cells

Signal 1 and signal 2 are not simultaneous

But in two steps, signal 2 from Th cells

Signal 3

B-1 cells （ peritoneal cavity ） marginal zone (MZ) B cells （ spleen ）

frequent Ag encounter. Secreting essentially germline-encoded, polyreactive natural Abs, respond rapidly and vigorously to pathogens

express Toll-like receptors (TLR),provide costimulation to GC B cellsimportant link between the innate and adaptive immunity

MZ B cells

innate immune functions

location mucosal sites spleen, LN

Ig-producing way naturally Ag-inductive

specificity poly-reactive highly specific

Ag TI Ag TD Ag

（ polysaccharide ）

Ig class Ig M IgG

affinity low high

B1 B2/FO B

Significance of humoral immunity

eliminate extracellular bacterium and toxin

eliminate extracellular virus

Antigen crosslinks mIg(BCR), generating signal 1, which leads to increased expression of class II MHC and costimulatory B7.

Antigen–BCR complexes are internalized by receptor-mediated endocytosis and degraded to peptides, which are bound by class II MHC and presented as peptide–MHC complexes.

Th cell recognizes Ag–class II MHC and B7-CD28 co-stimulation on B-cell membrane which activates TH cell.

Th cell begins to express CD40L.Interaction of CD40 and CD40L provides signal 2.

Th cell release large quantities of cytokines(IL-4) signal 3 to support the progression of the B cell replication and differentiation.

Early events ：follicle （ B ） -paracortex （ T ） border,

B activation and T-B activation

Small amounts of Ab production

Late events ：At the germinal center

Presence of Ag and Th

Affinity maturation

Ig class switch (IgM IgG)

Memory B

Early and late event in Ab response to TD antigen

General Features and Mechanisms

Immunologically specificCentral tolerance:

induced in generative lymphoid organs immature self-reactive lymphocyte

The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens

T Lymphocyte Tolerance

Central T Cell Tolerance Peripheral T cell Tolerance

Burnet: Clonal selection hypothesis

Peripheral T cell Tolerance

Antigen recognition without adequate costimulationUse CTLA-4 to recognize costimulators on APCsActivation induced cell death (AICD)Regulatory T LymphocytesFactors that determine the tolerogenicity of self antigens

Tumor Antigen

• Tumor-specific antigen

Antigen that are expressed on tumor cells but not on normal cells

were called tumor- specific antigens; some of these antigens are

unique to individual tumors, whereas others are shared among

tumors of the same type.

Tumor Antigen

• Tumor-associated antigen

Tumor antigens that are also expressed on normal cells were called

tumor-associated antigens; in most cases, these antigens are

normal cellular constituents whose expression is aberrant or

dysregulated in tumors

Evasion of Immune Responses

Class I MHC expression may be down-regulated on tumor cells so that they cannot be recognized by CTLs.

Tumor lose expression of antigen that elicit immune responses.

Tumors may fail to induce CTLs because most tumor cells do not express costimulators or class II MHC molecules.

The products of tumor cells may suppress antitumor immune responses.

Tumor antigens may induces may induce specific immunologic tolerance.

57

Difference between Direct Recognition and Indirect Recognition

Direct Recognition

Indirect Recognition

Allogeneic MHC molecule

Intact allogeneic MHC molecule

Peptide of allogeneic MHC molecule

APCs Recipient APCs are not necessary

Recipient APCs

Roles in rejection Acute rejection Chronic rejection

Degree of rejection Vigorous Weak

58

Host versus graft reaction (HVGR) Conventional organ

transplantation

Graft versus host reaction (GVHR) Bone marrow transplantation Immune cells transplantation

Classification of Allograft Rejection

59

Conditions

Enough immune competent cells in grafts

Immunocompromised host

Histocompatability differences between host and graft

II.Graft versus host reaction (GVHR)

Hypersensitivity

Tissue injury caused by an immune response that is inadequately controlled or inappropriately targeted to host tissues

Type I: ImmediateType II: CytotoxicType III: Immune complex

Type IV: cell mediated or delayed

GELL AND COOMB’S CLASSIFICATION

Types of hypersensitivity reactions

THANK YOU

THANK YOU