Transcript Medical Immunology

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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