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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.
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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
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Host versus graft reaction (HVGR) Conventional organ
transplantation
Graft versus host reaction (GVHR) Bone marrow transplantation Immune cells transplantation
Classification of Allograft Rejection
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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
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