Download Recent discoveries on evolution of immune systems

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
EVOLUTION
in immunity
Technical University of Denmark - DTU
Department of systems biology
Sunday, 14 June 2009
EVOLUTION OF THE IMMUNE
SYSTEM
716
Genomes and evolution
since
the
Echinoderms
Sea
Tubulins
urchin
verte
Hagfish
Cartilaginous
Zebrafish,
A
PufferfIsh
Mammals
Mouse
Reptiles
Birds
Chick
600
400
I
(
200
0
MIllIon years ago
C 1996 Current Oplnton I” Genetics & Development
relationships
phyla. (The exact branching
among
extant deuterostome
order of lampreys
classes
and hagfish
the last round
of homogenization
impossible
fish
Shark
I
of the second
before
Amphioxus
I
and actins-representatives
Lamprey,
Cephalochordates
L
gene.
lawless fish
Tunicate
I------
target
of terminal target gene-are
encoded
by multiple
because
they need to be expressed
at high leve
undergo
periodic
homogenization
by gene conversi
cycles of duplication
and loss. Homogenization
paralogs, by whichever
mechanism,
erases their mo
evolutionary
record which renders inference
of any
Urochordates
Sunday, 14 June 2009
of all jawed
Innate immunity
Toll like Receptor
(TLR)
of terminal
Phylogenetic
ancestor
(reviewed
in [18]). The historical
record of genomeevents that is retained
in fundamental
regulators
b
of stringent
selective constraints
is thus erased in th
Protostomes
800
last common
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
Fiaure 1
and
is a matter
third
class
of
terminal
target
gene
comprises
ubiquitously
expressed,
single-copy
housekeeping
such as manganese
superoxide
dismutase
and the
subunits
of RNA polymerases.
As these genes a
required
in several copies
to maintain
a high
expression
level, they have survived genome duplic
merely as single copy genes. In this class of terminal
gene, records of past duplications
are thus also lost
Finally,
the fourth
class of terminal
target
g
exemplified
by the olfactory receptor and immunoglob
gene families.
These
proteins
interact
with liga
environmental
origin and potentially
unlimited
di
Structural
alterations
in the absence of regulatory c
allow new duplicates
to interact with novel ligands.
duplicated Technical
paralogsUniversity
that ofinteract
Denmark with
- DTU new ligand
positively
selected,
which
has caused
o
Department
of systems
biology expansion
gene families since the origin of vertebrates
and
their records of early genome-wide
events.
Technical University of Denmark - DTU
Department of systems biology
Sunday, 14 June 2009
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
TOLL LIKE RECEPTORS
TLRs share a prototypical
organization of N-terminal (N)
extracellular leucine-rich repeat
(LRR) motifs.
TLRs are dimerized and the
ectodomain forms a horseshoeshaped solenoid.
François Leulier & Bruno Lemaitre
Nature Reviews Genetics 9, 165-178 (March 2008)
Technical University of Denmark - DTU
Department of systems biology
Sunday, 14 June 2009
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
TOLL LIKE RECEPTORS
CAN RECOGNIZE PATTERNS
EVOLUTION OF THE IMMUNE
SYSTEM
716
Genomes and evolution
since
the
last common
ancestor
of all jawed
(reviewed
in [18]). The historical
record of genomeevents that is retained
in fundamental
regulators
b
of stringent
selective constraints
is thus erased in th
Protostomes
of terminal
target
gene.
Echinoderms
Sea
Tubulins
urchin
Lamprey,
before
Cephalochordates
Amphioxus
Hagfish
Cartilaginous
fish
Zebrafish,
PufferfIsh
Mammals
Mouse
Reptiles
Birds
Chick
I
I
600
400
I
(
200
0
MIllIon years ago
C 1996 Current Oplnton I” Genetics & Development
Phylogenetic
Sunday, 14 June 2009
relationships
phyla. (The exact branching
among
extant deuterostome
order of lampreys
the last round
of homogenization
third class immune
of terminal system
target
gene
Adaptive
A
Shark
L
of the second
lawless fish
Tunicate
I------
and actins-representatives
of terminal target gene-are
encoded
by multiple
because
they need to be expressed
at high leve
undergo
periodic
homogenization
by gene conversi
cycles of duplication
and loss. Homogenization
paralogs, by whichever
mechanism,
erases their mo
evolutionary
record which renders inference
of any
Urochordates
800
verte
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
Fiaure 1
classes
and hagfish
and
is a matter
impossible
comprises
ubiquitously
expressed,
single-copy
housekeeping
such as manganese
superoxide
dismutase
and the
subunits
of RNA polymerases.
As these genes a
required
in several copies
to maintain
a high
expression
level, they have survived genome duplic
merely as single copy genes. In this class of terminal
gene, records of past duplications
are thus also lost
Immunoglobulins
(Abs and TCRs)
Finally,
the fourth
class of terminal
target
g
exemplified
by the olfactory receptor and immunoglob
gene families.
These
proteins
interact
with liga
environmental
origin and potentially
unlimited
di
Structural
alterations
in the absence of regulatory c
allow new duplicates
to interact with novel ligands.
duplicated Technical
paralogsUniversity
that ofinteract
Denmark with
- DTU new ligand
positively
selected,
which
has caused
o
Department
of systems
biology expansion
gene families since the origin of vertebrates
and
their records of early genome-wide
events.
EVOLUTION OF THE IMMUNE
SYSTEM
716
Genomes and evolution
since
the
last common
ancestor
of all jawed
(reviewed
in [18]). The historical
record of genomeevents that is retained
in fundamental
regulators
b
of stringent
selective constraints
is thus erased in th
Protostomes
of terminal
target
gene.
Echinoderms
Sea
Tubulins
urchin
Lamprey,
before
Cephalochordates
Amphioxus
No Immunoglobulins
the last round of homogenization
Hagfish
Cartilaginous
Zebrafish,
A
PufferfIsh
Mammals
Mouse
Reptiles
Birds
Chick
I
I
600
400
I
(
200
0
MIllIon years ago
C 1996 Current Oplnton I” Genetics & Development
Phylogenetic
Sunday, 14 June 2009
relationships
phyla. (The exact branching
among
extant deuterostome
order of lampreys
classes
and hagfish
impossible
fish
Shark
L
of the second
lawless fish
Tunicate
I------
and actins-representatives
of terminal target gene-are
encoded
by multiple
because
they need to be expressed
at high leve
undergo
periodic
homogenization
by gene conversi
cycles of duplication
and loss. Homogenization
paralogs, by whichever
mechanism,
erases their mo
evolutionary
record which renders inference
of any
Urochordates
800
verte
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
Fiaure 1
and
is a matter
third
class
of
terminal
target
gene
comprises
ubiquitously
expressed,
single-copy
housekeeping
such as manganese
superoxide
dismutase
and the
subunits
of RNA polymerases.
As these genes a
required
in several copies
to maintain
a high
expression
level, they have survived genome duplic
merely as single copy genes. In this class of terminal
gene, records of past duplications
are thus also lost
Finally,
the fourth
class of terminal
target
g
exemplified
by the olfactory receptor and immunoglob
gene families.
These
proteins
interact
with liga
environmental
origin and potentially
unlimited
di
Structural
alterations
in the absence of regulatory c
allow new duplicates
to interact with novel ligands.
duplicated Technical
paralogsUniversity
that ofinteract
Denmark with
- DTU new ligand
positively
selected,
which
has caused
o
Department
of systems
biology expansion
gene families since the origin of vertebrates
and
their records of early genome-wide
events.
Hagfish
Lamprey
Technical University of Denmark - DTU
Department of systems biology
Sunday, 14 June 2009
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
ADAPTIVE IMMUNITY?
•Capacity
•The
of transplantation rejection
responses to skin allografts is specific
•Accelerated
second-set rejections indicates immunological
memory.
Technical University of Denmark - DTU
Department of systems biology
Sunday, 14 June 2009
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
ADAPTIVE IMMUNITY
•Able
to produce serum antibodies.
•Responses
have been connected with cells that are
morphologically similar to the lymphocytes from jawed
vertebrates
Technical University of Denmark - DTU
Department of systems biology
Sunday, 14 June 2009
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
CHALLENGE WITH BACTERIA
Somatic diversification of variable
lymphocyte receptors in the agnathan
sea lamprey
Zeev Pancer1,2, Chris T. Amemiya6, Götz R. A. Ehrhardt1,5, Jill Ceitlin7, G. Larry Gartland1,4 & Max D. Cooper1,2,3,4,5
1
Division of Developmental and Clinical Immunology, Departments of 2Medicine, 3Pediatrics and 4Microbiology, and the 5Howard Hughes Medical Institute,
University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
6
Molecular Genetics Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, 98101, USA
7
University of Michigan, Ann Arbor, Michigan 48109, USA
...........................................................................................................................................................................................................................
Although jawless vertebrates are apparently capable of adaptive immune responses, they have not been found to possess the
recombinatorial antigen receptors shared by all jawed vertebrates. Our search for the phylogenetic roots of adaptive immunity in
the lamprey has instead identified a new type of variable lymphocyte receptors (VLRs) composed of highly diverse leucine-rich
repeats (LRR) sandwiched between amino- and carboxy-terminal LRRs. An invariant stalk region
tethers
theof VLRs
the cell
Technical
University
Denmarkto
- DTU
of systems
biology for an
surface by means of a glycosyl-phosphatidyl-inositol anchor. To generate rearranged VLR genes of Department
the diversity
necessary
anticipatory immune system, the single lamprey VLR locus contains a large bank of diverse LRR cassettes, available for insertion
Sunday, 14 June
2009 an incomplete germline VLR gene. Individual lymphocytes express a uniquely rearranged VLR gene in monoallelic fashion.
into
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
articles
Nature 430, 174-180 (8 July 2004)
© 20
8. Alder, M.N. et al. Nat. Immunol. 9, 319–327
(2008).
10. Gai, S.A. & Wittrup, K.D. Curr. Opin. Struct. Biol. 17,
467–473 (2007).
amenable to molecular engineering, and the
presence of usually two or three hypervariNEWS AND VIEWS
able solvent-exposed sites per module should
facilitate targeting of these residues by random mutagenesis in vitro to increase affinity
Lamprey VLR
genefor
Mammalian antibody genes
or alter specificity, as previously
shown
Heavy chain
Light chain
engineered synthetic LRR proteins1. Finally,
Preassembly
VLRs
LRR in lamprey lymphocytes are assembled
LRR LRR LRRIan MacLachlan
LRR
SP
Stalk
V V V
J J J
C
V V V
D D J J J
C
germline
NT
NT
CT
CT
CT
by a process of gene conversion through
genes
homologous regions that can span just a few Leukocyte-directed, small interfering (si)RNA against cyclin D1 shows
nucleotides. To increase the combinatorial Assembly
promise for treatment of inflammatory bowel disease.
RAG-mediated
diversity of a VLR library, it might there- from flanking
rearrangement
LRR cassettes
foreCbeC possible to recapitulate this process
C C
C C
C C
by shuffling domains through homologous
Colitis and
Crohn’s
diseaseMature
are debilitating of treatment—can bring about long-term
C
C C C CCCC
LRR inflammatory
recombination
in vivo using yeast surface
they are encumbered
bowel diseases
in which the remission,
SP LRR
Stalk
GPI Hydrophobic
CP
V J C
V D J by
C dose-limlymphocyte
CT
NT
genes causing iting side effects. A recent paper by Shimaoka
display10. The most ancient antigen receptors digestive tract becomes inflamed,
may soon take a central place in the biotech- severe diarrhea and abdominal pain that and colleagues1 in Science describes a more
can lead to life-threatening complications. targeted approach in which siRNA against
nology arena.
Although anti-inflammatory and immu- cyclin D1 (CyD1) is directed to leukocytes
1. Binz, H.K., Amstutz, P. & Plückthun, A. Nat.
Cell-bound
nosuppressive
drugs—the
two main classes expressing β7 integrin.
Biotechnol. 23, 1257–1268 (2005).
antigen receptors
N
EWS
A Nature
N D430,V 174–180
I E W(2004).
S
2. Pancer,
Z. et al.
CyD1, a cell cycle regulator, is upregulated
3. Herrin, B.R. et al. Proc. Natl. Acad. Sci. USA 105,
locally, in association with inflammatory
2040–2045 (2008).
bowel disease, in both epithelial and immune
Ian MacLachlan is at Protiva Biotherapeutics
4. Kim, H.M. et al. J. Biol. Chem. 282, 6726–6732
1 show that
(2007).
cells.
Shimaoka
and
colleagues
Inc., 100-3480 Gilmore Way, Burnaby,
BC,
Humoral
5. Pancer, Z. & Cooper, M.D. Annu. Rev. Immunol. 24,
Canada, V5G 4Y1.
leukocyte-directed CyD1 siRNA inhibits the
antibodies
497–518 (2006).
e-mail: [email protected]
intestinal inflammatory response in a mouse
6. Alder, M.N. et al. Science 310, 1970–1973 (2005).
LRR V
LRR V
LRR V
LRR V
LRR V
LRR V
LRR V
LRR V
LRR V
LRR V
LRR 1
LRR V
LRR 1
The oldest antibodies newly discovered
Zeev
Pancer
&
Roy
A
Mariuzza
Figure 1 Assembly of lamprey variable lymphocyte receptors (VLRs), compared with the V(D)J-rearrangement that gives rise to mammalian antibodies.
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
LRR 1
siRNAs with guts
otechnology
VOLUME
26 by
NUMBER
4 APRIL
2008
VLRNATURE
genes ofBIOTECHNOLOGY
jawless vertebrates are
assembled
sequential
insertion
of LRR cassettes from flanking arrays into the incomplete germline gene via gene 4 0 3
Lamprey
antibodies
provide
stable andactivating
high-avidity
alternatives
immunoglobulins.
conversion.
Jawedmonoclonal
vertebrate antibody
genes are assembled
via recombination
gene (RAG)-mediated
joining to
of immunoglo
bulin gene fragments
consisting of variable (V), diversity (D) and joining (J) elements, as well as constant (C) exons. The mature antigen receptorsin both cases are expressed on
the surfaces of lymphocytes and can be secreted to the plasma. A VLR comprises a set of highly diverse LRR modules capped by disulfide-bonded
N-terminal LRR (LRRNT, 24-32 amino acids) and C-terminal LRR (LRRCT,
45-62 amino acids) modules. The 25-residue LRR1 is followed by one to eight
6,7 (Fig.
agglutinated
anthrax
spores
1,000The
search
for
alternatives
to
immunoglobVLR
1).
The
selected
cassettes
are
24-residue LRRVs and then a 16-residue LRR, the connecting peptide (CP). There are two or three hypervariable sites in solvent-exposed positions in each of
efficiently
than
an equivalent am
ulin
antibodies
has led
to binding
scaffolds
sequentially
the germthese
modules.
The invariant
portions
of VLRs include
an N-terminal
secretion incorporated
peptide (SP) and into
an 81-residue
C terminus
that contains
a threonine/prolineof Denmark - DTU
richsuch
stalk (33
acids) and
a glycosyl phosphatidylinositol
(GPI)gene
membrane
anchorage
tethers the VLRTechnical
to the lyUniversity
mphocyte
surface.
Seven
mouse
monoclonal
antibody,
demo
as amino
lipocalins,
fibronectins,
ankyrin line
framework
to motif,
formwhich
the functional
Department of systems biology
cysteines
in the
22-residue
hydrophobicdomains
C-terminal1.domain
participate
in This
VLR oligomerization.
repeats
and
src homology
mature
VLR.
process can generate a vast its high avidity for the antigen. By c
But can
none of these are natural antigen receptors.
Sunday, 14 June 2009
repertoire of VLRs, estimated at over 1014
monomeric form of this VLR that
TLRs share a prototypical
organization of N-terminal (N)
extracellular leucine-rich repeat
(LRR) motifs.
TLRs are dimerized and the
ectodomain forms a horseshoeshaped solenoid.
François Leulier & Bruno Lemaitre
Nature Reviews Genetics 9, 165-178 (March 2008)
Technical University of Denmark - DTU
Department of systems biology
Sunday, 14 June 2009
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
TOLL LIKE RECEPTORS
CAN RECOGNIZE PATTERNS
GENOME DUPLICATIONS
716
Genomes and evolution
since
the
last common
ancestor
of all jawed
(reviewed
in [18]). The historical
record of genomeevents that is retained
in fundamental
regulators
b
of stringent
selective constraints
is thus erased in th
Protostomes
of terminal
target
gene.
Echinoderms
Sea
Tubulins
urchin
Lamprey,
before
Cephalochordates
Amphioxus
Hagfish
Cartilaginous
Zebrafish,
A
PufferfIsh
Mammals
Mouse
Reptiles
Birds
Chick
I
I
600
400
I
(
200
0
MIllIon years ago
C 1996 Current Oplnton I” Genetics & Development
Phylogenetic
Sunday, 14 June 2009
relationships
phyla. (The exact branching
among
extant deuterostome
order of lampreys
classes
and hagfish
the last round
of homogenization
impossible
fish
Shark
L
of the second
lawless fish
Tunicate
I------
and actins-representatives
of terminal target gene-are
encoded
by multiple
because
they need to be expressed
at high leve
undergo
periodic
homogenization
by gene conversi
cycles of duplication
and loss. Homogenization
paralogs, by whichever
mechanism,
erases their mo
evolutionary
record which renders inference
of any
Urochordates
800
verte
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
Fiaure 1
and
is a matter
third
class
of
terminal
target
gene
comprises
ubiquitously
expressed,
single-copy
housekeeping
such as manganese
superoxide
dismutase
and the
subunits
of RNA polymerases.
As these genes a
required
in several copies
to maintain
a high
expression
level, they have survived genome duplic
merely as single copy genes. In this class of terminal
gene, records of past duplications
are thus also lost
Finally,
the fourth
class of terminal
target
g
exemplified
by the olfactory receptor and immunoglob
gene families.
These
proteins
interact
with liga
environmental
origin and potentially
unlimited
di
Structural
alterations
in the absence of regulatory c
allow new duplicates
to interact with novel ligands.
duplicated Technical
paralogsUniversity
that ofinteract
Denmark with
- DTU new ligand
positively
selected,
which
has caused
o
Department
of systems
biology expansion
gene families since the origin of vertebrates
and
their records of early genome-wide
events.
GENOME DUPLICATIONS
716
Genomes and evolution
since
the
last common
ancestor
of all jawed
(reviewed
in [18]). The historical
record of genomeevents that is retained
in fundamental
regulators
b
of stringent
selective constraints
is thus erased in th
Protostomes
of terminal
target
gene.
Echinoderms
Sea
Tubulins
urchin
Lamprey,
before
Cephalochordates
Amphioxus
Hagfish
Cartilaginous
Zebrafish,
A
PufferfIsh
Mammals
Mouse
Reptiles
Birds
Chick
I
I
600
400
I
(
200
0
MIllIon years ago
C 1996 Current Oplnton I” Genetics & Development
Phylogenetic
Sunday, 14 June 2009
relationships
phyla. (The exact branching
among
extant deuterostome
order of lampreys
classes
and hagfish
the last round
of homogenization
impossible
fish
Shark
L
of the second
lawless fish
Tunicate
I------
and actins-representatives
of terminal target gene-are
encoded
by multiple
because
they need to be expressed
at high leve
undergo
periodic
homogenization
by gene conversi
cycles of duplication
and loss. Homogenization
paralogs, by whichever
mechanism,
erases their mo
evolutionary
record which renders inference
of any
Urochordates
800
verte
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
Fiaure 1
and
is a matter
third
class
of
terminal
target
gene
comprises
ubiquitously
expressed,
single-copy
housekeeping
such as manganese
superoxide
dismutase
and the
subunits
of RNA polymerases.
As these genes a
required
in several copies
to maintain
a high
expression
level, they have survived genome duplic
merely as single copy genes. In this class of terminal
gene, records of past duplications
are thus also lost
Finally,
the fourth
class of terminal
target
g
exemplified
by the olfactory receptor and immunoglob
gene families.
These
proteins
interact
with liga
environmental
origin and potentially
unlimited
di
Structural
alterations
in the absence of regulatory c
allow new duplicates
to interact with novel ligands.
duplicated Technical
paralogsUniversity
that ofinteract
Denmark with
- DTU new ligand
positively
selected,
which
has caused
o
Department
of systems
biology expansion
gene families since the origin of vertebrates
and
their records of early genome-wide
events.
Fish & Shellfish Immunology, Volume 26, Issue 6, June 2009, Pages 843-849
Zhenhui Liu, Lei Li, Hongyan Li, Shicui Zhang, Guangdong Ji and Yanling Sun
Technical University of Denmark - DTU
Department of systems biology
Sunday, 14 June 2009
CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS
It has recently been demonstrated that this organism
contains histocompatibility-relevant genes and lymphocyte
immune signaling-relevant genes, i.e., components that
may be recruited by adaptive immune processes.