Medical Immunology Department of Immunology
Yiwei Chu 储以微
[email protected]
2010-7-7
Exam: 9th July (Friday) 8:30-10:30am
Inspector: Dr. Lu Qing Dr. Gao Bao
2010-7-7
Department of Immunology Yiwei Chu
Wei Xu
Rui He
Yunlu Lin Qing Lu
Xiaowu Hong
Bo Gao
Haifeng Gao
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
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
Innate and Adaptive Immunity
Adaptive Immune Responses
Adaptive Immune Responses Cellular Components
• 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
(antigen presenting cell)
cellular immunity
Chapter 1 Definition of antigen Antigen (Ag) 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 The antigen molecule generally pose two natures, that is （1）immunogenicity （2）antigenicity
(1) Antigenic determinants or epitopes 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.
Structure of 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
(3) hypervarible region (HVR) (complimentarity determining region,
CDR) :
formation of the Ag binding site Framework region（ FR ) : maintaining the 3- dimensional configuration
CDR
(complimentarity determining region,)
4. Ab-dependent Cell-mediated cytotoxicity, ADCC enhance NK killing
Immune Responses to Tumors
CONCEPT
APCs are immunocytes that can uptake, process and present antigens to other lymphocytes.
Professional APCs Dendritic Cells (DCs) Macrophages (M) B Lymphocytes
I. Dendritic Cells (DCs)
Ralph.M.Steinman, 1973
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
What are cytokines? 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
Cytokine actions may be local and systemic
Autocrine action
Paracrine action
act on cytokine-producing cell itself
act on a nearby cell
circulation
Endocrine action
act at a distance from the site of infection
Chemokines Primary lymphoid organs
Secondary lymphoid organs
directing migration of leukocytes Blood
Tissue
inflammation
Cellular sources (1) inflammatory stimuli
to inflammatory sites
(2) Constitutively produced in lymphoid organs Physiologic traffic of lymphocytes through the organs
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 role 1.
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
Examples of PAMPs PAMPs
Source
Principle innate immune response
LPS
Gram-negative bacteria cell wall
Macrophage activation
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-rich glycans
Microbial glycoproteins or glycolipid
phgocytosis opsonization complement activation
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
Surface receptor 1) B cell antigen receotor (BCR) BCR/mIgM Membrane Ig (mIg) Mature B cell： mIgM ＋ mIgD
BCR-Igα/Igβ complex
BCR-Iga/Igb complex
2. BCR coreceptor Help and strengthen the BCR-Ag-signaling 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
JBC 2004;279:31973
BCR-Iga/Igb coreceptor complex B cell epitope
B cell activation
TCR-CD3
BCR-Iga/b
Two-signal activation model for T cells
activation
co-stimulatory molecules none
naive
anergy
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
MZ B cells
innate immune functions
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 cells important link between the innate and adaptive immunity
B1
B2/FO B
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
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 Bcell 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 and late event in Ab response to TD antigen
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 Memory B
IgG)
General Features and Mechanisms Immunologically specific Central tolerance: induced in generative lymphoid organs immature self-reactive lymphocyte The repertoire of mature lymphocytes cannotcannot recognize ubiquitousubiquitous or widely repertoire of mature lymphocytes recognize disseminated self antigens self antigens or widely disseminated
T Lymphocyte Tolerance Central T Cell Tolerance Peripheral T cell Tolerance
Burnet: Clonal selection hypothesis
Peripheral T cell Tolerance
Antigen recognition without adequate costimulation Use CTLA-4 to recognize costimulators on APCs Activation induced cell death (AICD) Regulatory T Lymphocytes Factors 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.
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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Classification of Allograft Rejection
Host versus graft reaction (HVGR) Conventional organ transplantation
Graft versus host reaction (GVHR) Bone marrow transplantation Immune cells transplantation
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II.Graft versus host reaction (GVHR) Conditions
Enough immune competent cells in grafts Immunocompromised host Histocompatability between host and graft
differences
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Hypersensitivity Tissue injury caused by an immune response that is inadequately controlled or inappropriately targeted to host tissues
Types of hypersensitivity reactions
GELL AND COOMB’S CLASSIFICATION
Type I: Type II: Type III: Type IV:
Immediate Cytotoxic Immune complex cell mediated or delayed
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