Transcript 投影片 1

Immune system:
how life fight against invaders!
4-18-2016
Multicellular organism:
the heaven of bacteria/virus and parasites
The three layers of vertebrate immune defenses.
血清療法的發明人！
Using horse serum against
diphtheria toxin to treat patients.
http://nobelprize.org/nobel_prizes/medicine/laureates/1901/
血清療法帶來的新思維
抗白喉毒素血清中的有效成分是什麼？
怎麼產生的？為什麼可以解毒？
抗毒素(抗体)與毒素(抗原)結合，
帶引出二個重要的概念：
1, 結構的辨識 (specificity)；
2, 分子問的親和力(affinity)。
“antitoxines represent nothing more than side-chains reproduced in
excess during regeneration, and therefore pushed off from the
protoplasm, and so coming to exist in a free state…….”
http://nobelprize.org/nobel_prizes/medicine/laureates/1908/
Challenge of acquired immunity
1, how to specifically recognize infinite
different foreign molecules;
2, how to distinguish self from non-self!
Conceptual framework of acquired immunity
• Clonal selection hypothesis
– Variation: randomly generated.
– Inheritance.
– Selection by foreign antigens.
Normal median survival time of A strain skin on CBA mice is 11 days.
Injected CBA mice in utero with tissues from A strain mice, then grafted with A
strain skin at adult. Three of them accepted for more than 2 months (tolerance)
Transfer of lymphoid tissue from CBA donors immunized with A strain
tissue caused rapid rejection of the previously tolerated grafts.
Cooper MD, Raymond DA, Peterson RD, South MA, Good RA.
The functions of the thymus system and the bursa system in the
chicken.
J Exp Med. 1966;123:75–102.
Cells of the adapted immune system
• Lymphocytes
– B cells
• Plasma cells (Ab producing)
– T cells
• Cytotoxic (CTL)
• Helper (Th)
–
–
–
–
Th1
Th2
Th17
T-reg
The basic structure of an immunoglobulin molecule.
Hybridization of labeled RNA probes, specific for the entire k gene (V ＋Ｃ) and for
the 3’ end that encodes the C region, to fraction of digested DNA separated by
agarose gel electrophoresis.
N. Hozumi and S. Tonegawa, 1976, Proc. Nat’l. Acad. Sci. USA 73:3629.
For light chain variable region : 30 V X 5 J = 150.
For heavy chain variable region: 45 V X 23 D X 6 J = 6,000.
150 X 6,000 = One million
plus 1,000 X from imprecision junction and 1,000 X from hypermutation
Total variation is around 100 billion!
Organization of the major histocompatibility complex in mice and
humans.
Snell GD & Higgins GF 1951, "Alleles at the histocompatibility-2 locus in the mouse
as determined by tumor transplantation", Genetics 36:306–310
How T cell recognizes specific
antigen?
Through cell surface receptor namely
T cell receptor (TCR)
Organization and recombination of TCR loci.
Zinkernagel-Doherty experiment demonstrating that MHC restriction is
required for activation of a cytotoxic T-cell response.
If T cell receptor can recognize antigen directly,
what role of MHC played in TCR recognition?
T cell
TCR
Ag
Figure 23.22 Peptide binding and MHC restriction.
Signals involved in T-cell activation and termination.
Perforin- and granzyme-mediated cell killing by cytotoxic T cells.
Why T cell need MHC for its
antigen recognition?
Collaboration between T and B cells is required to initiate the production of antibodies.
Collaboration between
T and B cells is
required to initiate the
production of
antibodies
How memory T
cells are generated?
Science 315: 1673-4; 2007
How tumor cells suppress cytotoxic T cells?
Can w e block such inhibitory pathway to reactivate T
cells to kill tumor cell?
MHC pathway of antigen processing and presentation.
Class II MHC pathway of antigen processing and presentation.
Positive and negative selection of the T cell repertoire:
To expand T cell population and to eliminate clones
recognize self antigen
Innate immune system
• Pattern recognition receptor
– LPS for Toll-like receptor
– dsRNA/ DNA for interferons induction
• Complement proteins
• Phagocytes (cells) (e.g., macrophages)
• Natural killer (NK) cells
The three pathways of complement activation converge
Figure 2-18
Combination of adaptive and
innate immune responses
Innate immunity
Innate immunity
Macrophages can engulf and digest bacteria
Macrophage
about to eat a
bacterium
http://www.biochemweb.org/neutrophil.shtml
Arm race between immunity and pathogens
Pathogens have also developed ways to remove some of the cell’s critical
proteins, often so that they can escape detection by the immune system.
For example, in the adaptive immune system, T lymphocytes
(T cells) recognize viral fragments (peptides) bound to MHC proteins.
It’s hard for a virus to hide out in a cell if the cell surface MHC proteins
contain viral fragments that can be recognized by T cells.
What’s a virus to do?
Get rid of the host MHC proteins!
For every strategy a virus comes up with, the
immune system (usually) has an answer…
Natural killer cells recognize cells that do not express
adequate levels of MHC proteins on their surface.
They respond to “missing self”.
Natural killer (NK) cells
• Identify targets based on “missing self”
– Two types of NK receptors: inhibitory and activating
– If inhibitory receptor recognizes a self protein (a class I MHC molecule) on a target
cell, the NK cell is turned OFF even if activating receptor binds a ligand on the same
target cell
– If activating receptor binds a ligand, but inhibitory receptor does not (target cell has
down-regulated class I MHC proteins), NK cells kill
– Many virally-infected cells and tumor cells down-regulate expression of class I MHC
molecules (NK cells important for preventing cancers)
Molecular mechanisms of natural killer cell activation in response to cellular stress
Cell Death and Differentiation (2014) 21, 5–14
How does bacteria fight for viral infection?
Does bacteria have immunity against viral infection? ，
Innate immunity of bacteria: modification and
restriction system
Acquired immunity of bacteria: CRISPR (clustered
regularly interspaced short palindromic repeats) system
Science 341: 833-836; 2013
J Bacteriol. 169: 5429–5433; 1987.
Identification of genes that are associated with DNA repeats in
prokaryotes
Molecular Microbiology 43, 1565–1575; 2002
CRISPR elements in Yersinia pestis acquire new
repeats by preferential uptake of bacteriophage DNA,
and provide additional tools for evolutionary studies.
Microbiology. 2005; 151:653–663.
CRISPR provides acquired resistance against viruses in prokaryotes.
Science. 2007; 315:1709–1712
Bacteria get vaccinated! Nature 513: 175-6; 2014
New Tool for Genome Surgery Science 339: 768-9; 2013
•
•
•
•
•
1. Constructionist “ side chain theory “ (Ehrlich)
2. Instructionist “antigen template theory “ (Pauling)
3. Selectionist “natural selection theory “ (Jerne)
4. “Clonal selection theory “ (Burnet, Talmage, Jerne)
5. Seminal confirmatory experiments (Tonegawa, Nossal,
Lederberg, many others)
Conceptual framework of acquired immunity
• Clonal selection hypothesis
• Two kinds of recognition
• Generation of Diversity (God’s problem)
– Allelic exclusion (only one allele of H/L chain is
expressed)
• Self and non-self discrimination
Conceptual framework of acquired immunity
• Clonal selection hypothesis
• Two kinds of recognition
• Generation of Diversity (God’s problem)
– Allelic exclusion (only one allele of H/L chain is
expressed)
• Self and non-self discrimination
Conceptual framework of acquired immunity
• Clonal selection hypothesis
• Two kinds of recognition
• Generation of Diversity (God’s problem)
– Allelic exclusion (only one allele of H/L chain is
expressed)
• Self and non-self discrimination
Specificity of adaptive immune
response
• Resides with Ag R on T
and B cells
• TCR and BCR – both
specific for only ONE
antigenic determinant
• TCR is monovalent
• BCR is divalent
T cell
B cell
TCR
BCR
Major distinguishing markers
Marker
B cell
CTL
T-helper
Antigen R
BCR (surface Ig)
TCR
TCR
CD3
--
+
+
CD4
--
--
+
CD8
--
+
--
CD19/ CD20
+
--
--
CD40
+
--
--
Sequence of Events in B-Cell Activation
by a Thymus-Dependent Ag
Important B-cell Differentiation Events
Take Place in Germinal Centers
1. Affinity maturation
2. Class switch
3. Formation of plasma cells and memory cells
Immune cells and other blood cells made in bone marrow -- all are
descendents of self-renewing stem cells
Make variable antibodies
Membrane-bound variable T cell receptors
Kill cells that are missing self proteins
Phagocyte
Phagocyte
Note these are adult
stem cells, NOT
embryonic stem cells.
Binding of mannose-binding
lectin, a plasma protein, initiates
lectin pathway of complement
activation.
MBL discriminates self
carbohydrates from
non-self carbohydrates by
recognition of a particular
pattern of sugar residues
Figure 2-11
Figure 2-35 part 3 of 3
One of the end results of complement activation -- the
membrane attack complex kills a cell
Electron micrographs of ~100 Å diameter membrane attack complex channels
How the acquired immunity
evolved ?
Rag1/2 mediated diversity generation for
immunoglobulin and TCR only appear after
jawed vertebrate (500 millions years)
The sea lamprey ｉｓ often called “living fossils” because they are thought to have
changed little since they arose 450 million to 500 million years ago, as part of a branch of
jawless creatures that split off early from the rest of the vertebrate tree