TBA =

Analogies and homolgies

in the evolution of immune systemsin the evolution of immune systems

Louis Du Pasquier

University of Basel

Homologies A state of similarity in structure and anatomical position but not necessarily in function

between different organisms indicating a common ancestry or evolutionary origin

Take the immune system of man and look

in other species what has been conserved (sequence comparison):

It helps determining what is essential and what is accessory

Analogies Structural or behavioural similarity in terms of functions between unrelated species or organisms but

that do not share a common ancestral or developmental origin

Follow the solutions selected from unicellular organisms to Vertebrates after

an exposure to a pathogen

LRR TLR/IgSF IL1R

TIR

RNAi?

Scav R. Mannose R. Lectin R.

Intracellular systems

RIG1, PKR, NLR, TRIM

NK

AID

RAG T-B IgSF

APC MHC pres.

Thymus, BM,

rep.selections

Clonal selection

Effectors:Abs, CTLs,Thelp

specificity,memory

Co receptors

Co stimulators

Fc receptors ITIM

Cytokines

Chemokines

INNATE ADAPTIVE

PDC

Type I IFNAcute phase

Pentraxins

Epithelia Macrophages Granulocytes

C’

Lymphocytes Lymphoid organsLiver

Phagocytosis

RNAi?

Effectors: AMP, Cytokines,…

specificity,memory

regulation

Affinity maturation

A constellation:

many modules

not necessarily linked to one another

Immunity in man

A system:

Centered on lymphocytes

locked in a coevolutionary unit

Fat Column

Typhlosolis

Thymus Epigonal organ

Leydig’’’’s organSpleen

Rectal gland

GALTSpleen

Thymus

Kidney

Bone Marrow

Spleen

Bone Marrow

GALT

Thymus

Lymph

nodes

Thymus

Nodes?

Bursa

GALT

Spleen

Bone Marrow

Spleen

Peyer’’’’sPatches

GALT

Thymus

GALT

GALT

THYMUSSPLEEN

BONE MARROW

GALT

THYMUS

SPLEEN

BONE MARROW

LYMPH NODES?

GERMINAL CENTERS

RAG

TCR

MHC sg

Ig gen conv

GALT

THYMUS

SPLEEN

BONE MARROW

LYMPH NODES

GERMINAL CENTERS

RAG

TCR

MHC

Ig comb gen con NAR!

Good Ab matrur.

Germ line rearranged V

Early ontogeny

Mutated later

Multiple C3 Microbicidal peptides

““““Innate”””” γδγδγδγδ T and B cells

GALT

CDsLy

TF Ly?

GALT

EPIGONAL (LEYDIG)

THYMUS

SPLEEN

RAG

TCR γδαβγδαβγδαβγδαβ

MHC

Ig NAR no comb

Poor Ab matur.

GALT

HEAD KIDNEY

THYMUS

SPLEEN

RAG

TCRgdab

MHCI/II

Ig comb/no com

Poor Ab matur.

RAG

TCRgdab

MHC sg

Ig sw comb

PoorAb matur.

Ig gen conv

Good Ab matur.?

VERTEBRATA

AGNATHA

GNATHOSTOMATA

OSTEICTHYES

AMPHIBIA

REPTILIA

AVES

MAMMALIA

ANURA

TELEOSTEI

CHONDRICHTHYES

Flajnik MF, Miller K, Du Pasquier FI 2003

UROCHORDATES

DEUTEROSTOMEHEMICHORDATES

ECHINODERMS

MOLLUSKS

ANNELIDS

CEPHALOCHORDATES

VERTEBRATES

Ciona

Branchiostoma

Strongylocentrotus

Biomphalaria

AGNATHANS

GNATHOSTOMES

Petromyzon

PLATHYHELMINTHS

anus

2R

PROTOSTOME

MOLLUSKS

SIPUNCULIDS

NEMERTEANS

ARTHROPODS

NEMATODES

CNIDARIA

PORIFERA

PLACOZOA

INVERTEBRATES

Anopheles, Drosophila, Penaeus

Biomphalaria

Protozoa

mouth

Selective pressures and constraints on the immune systems

• Should be rapid and efficient at eliminating specifically the danger

• Innate components, constitutive elements

• Should confer to each individual within a species the best chances of survival under changing environment conditions.

• Somatic adaptation

• Should have diversity and flexibility, should be regulated (up and down regulation)

• Many solutions: gene families, many molecular categories, Treg

• Should be economical i.e. should not use too much genetic material, too many cells.• Should be economical i.e. should not use too much genetic material, too many cells.

• Somatic adaptations, combinatorial usage of elements

• Memory, transfer of protection to the progeny could be useful.

• Clonal selection. Inheritable specificities. Maternal transfer of Antibodies

• Should not react with self.

• Selection

• peripheral tolerance

• (Modulations of the above are likely under the influence of life histories of the organisms)

TRIM B30.2

Nematostella Branchiostoma

HOMOLOGY

Conservation

CLASSICAL LECTIN

Ab-Ag(IgM or IgG/Y)

C3, C4, (a2m, TEP)

C3:

C4:

a2m:

TEP:

From Diploblastic

Jawed vertebrate

All metazoa

Protostomes

MBL (Ficolin) C3

C1qrs(C1r cleaves C1s)

MBL-MASP [C3-H2O]B(D cleaves B)

C4(Cleaved by C1s or MASP2)

[C3-H2O]Bb(Bb cleaves C3 in plasma)

C2a

Microbial surface;

properdin (factor P)

stabilizes

C3aInflammation

ALTERNATIVE

Th

ioest

er

C4b C2(C1s or MASP2

cleaves C2)

C3(Cleaved by

C2b or Bb)

Fundamental Immunology 2008

HOMOLOGY

Conservation

C4b C2b(C3 convertase)

C2a

(Factors H, I and

CR4 inhibit)(CR1 inhibit)

C3b Bb(C3 convertase)

C4b C2b C3b(C5 convertase)

C3b Bb C3b(C5 convertase)

C3b

C5(Cleaved by

C2b or Bb)

MAC: C5b C6 C7 C8 (C9)n (CD59 inhibits)

C3a

C5b

C5aC2, BC2:

B:

Amphibian, mammal

Diploblastic

C1r, C1s, MASP

C3, C4, C5, a2m, TEP, CD109

C5a > C3a > C4a

Jawed vertebrates

Opsonization

C3b:

TEP:

From Diploblastic

Protostomes

Cell Lysis

MAC (C5b-9):

MACPF:

Jawed vertebrates

All animals

C1r, C1s:

MASP:

Jawed vertebrates

Deuterostomes

C1q, MBL

C1q:

MBL:

Jawed vertebrates

Deuterostomes

Ho

mo

log

ies

Fu

ncti

on

Nature Reviews Microbiology, (2008) 6(3):181-6.)

Clustered Regularly Interspaced Short Palindromic Repeats

The diversification of immuno-receptors

• Simultaneous threats: Viruses, bacteria, fungi, individuals of the same species, variants of self.

• Simultaneous responses: original diversity of immune mechanisms, receptors and effectors. Multiple evolutionary lines some shared between plants and animals. Ability to recognize self from non-self, danger signals.

• Constitutive „receptors “at the origin of proteolytic cascades (PPO, C‘) Phagocytosis, encapsulation, and subsequent destruction of pathogens (macrophage) intra and extracellular receptors, RNA interference

• Inducible responses often articulated around conserved domains and signalling

Early in evolutionJ

• Inducible responses often articulated around conserved domains and signalling cascades with up and down regulation (AMP, antibodies, CTL proliferation etc)

• Receptor -Signal -Effector

J.L Theodor

Flajnik Du Pasquier Fundamental Immunology 2008

A great but an endless diversity due to constraints: IgSF, LRR, Lectins, PGRP, GNBP,

C‘, thioester forming proteins, Fibronectin, EGFJ

So one expects sharing, scoop of committment, combinatorial usage of elements etc.

Although rodent and human NK cells use different classes of inhibitory

class I–specific receptors, downstream signaling events are similar. Both

inhibitory rodent Ly49 receptors and human KIRs have cytoplasmic tails

that contain ITIMs that transduce inhibitory signals by recruiting and

activating cytoplasmic protein tyrosine kinases

KIR Ly49

LRR Ig

Roux, Kenneth H. et al. (1998)

Proc. Natl. Acad. Sci. USA 95, 11804-11809

IgM IgD IgG IgAIgE

CAMELID

IgG

IgM IgY IgA

IgM IgY

IgM IgY IgX

Mammals

Birds

Reptiles

Amphibians

IgXCAMELID

IgG

IgM

IgNAR/IgW

IgD

IgY

IgE

IgG

IgMgj

IgA

IgD-likeIgF

Switch

IgM IgD-like

IgM IgNARIgW

Teleost Fish

Cartilaginous

Fish

IgGIgG

IgMgj

Hansen J et al, PNAS 2005 102:6919-24Ohta y and Flajnik MF PNAS 2006 103:10723-8 Zhao Y et al PNAS 2006 103:12087-12092

Danilova et al Nat. Imm.2005 Mar;6(3):295-302.

Ig Z,T

Immunoglobulin isotypes in Vertebrates

Conservation

Homology

analogy no analogy

Convergence

Diversification of receptors

Polymorphism

Modularity

Creation of multigene familiesCreation of multigene families

via tandem duplications and polyploidization

(whole genome duplication 2R

4 paralogs)

Science 3 December 2010: Vol. 330 no. 6009 pp. 1381-1385

Innate immunity of Drosophila

Somatic adaptations

More diversity

andand

J.towards individualization of immune responses

Zhang et al. Science. 2004 Jul 9;305(5681):251-4.

Zhang et al. Science. 2004 Jul 9;305(5681):251-4. Moné et al PLOS Neg Trop Dis 2010 4:e813

> 30000 isoforms of DSCAM molecules

Homolog of the human Down Syndrom Cell Adhesion Molecule

Schmucker et al. 2000 Cell. 2000 Jun 9;101(6):671-84, Science. 2005 Aug

18Brites D.et al, Biol Evol. 2008 Jul;25(7):1429-39.

VLRC?Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14304-8. Epub 2010 Jul 26.

Schatz D Nature Imm. 2007 8:551-553

CSR

Two enzymes involved with the preceding somatic events:

AID and RAG

AID: Activation -Induced ( Cytidine) deaminase

• Removes the amino group from the cytidine

• Involved in three separate somatic diversification processes: somatic mutation, gene conversion and class switch recombination of IgSF members of Gnathostomes

• Could it be involved in LRR somatic modifications in agnathans?• Could it be involved in LRR somatic modifications in agnathans?

• i.e. could a AID homolog be involved in an analogous process? Yes

• Pancer Z et al Nature Imm. 2007 8:647-656

• RAG 1 and 2 (Recombination activating gene)

• Present in Echinoderms , not hemocytes expressed early during gastrulation

• Rast J et al PNAS 2006 103: 3728-3733

Diversification of immune receptors

Many different processes selected during evolution can make the number

of receptors much larger than the number of genes that encode them

Population level• Polymorphism (receptors and effectors: lectins, C’ related, AMPs, srcr, Ig, TCR,

MHC etc)

Individual level• Peptides Combinatorial association of polypeptide chains: Ig H.L, TCR αβ γδ,

TLRs, PGRPs,… •

• Nucleic acids• RNA• RNA• Alternate splicing: e.g. SRCRs,PGRPs, FREPs, DSCAM, Fester…• (Arthropods,Mollusks,Echinoderms, Urochordates, Vertebrates)• Post transcriptional level: 333/185 (Echinoderms)

• DNASomatic rearrangement: Ig, TCR (combinatorial joining) (Gnathostomes)Somatic gene conversion: Ig Vertebrates.LRR AgnathansSomatic mutations: Ig from sharks on. Mollusks?

Individualization of responses

Problems of expression

Autoimmunity?

Lymphocytes

=units of selection

Selective environments

Vertebrates

Selective environments

Thymus, stroma of lymphoid organs

MHC ClassI and II molecules

Invertebrates?

Not known

Class I and Class II pathways of presentation:

Class I LMP TAP self, viruses

ClassII external antigens:

MHC

There have not always been “lymphocytes”

Epithelial immunity: Sponges, Hydra…

They came with mesoderm

Hydractinia ( Cnidaria)

Nicotra, L Buss et al

Permanent chimaera Rejection reaction

Hyperplasy, killing with nematocysts

Two closely linked loci Alr1 and Alr2 IgSF (3D) apparently with ITIM ITAM related signalling

Curr Biol. 2010 Jun 22;20(12):1122-7

Mammals Insects

Hartenstein V. Annu. Rev. Cell Dev .Biol. 2006 22:677-712

Division of the work

Antigen Presenting Cell

CD200R CD80/86 CD58 CD48 SLAM6 SLAM7 SLAM CD84 CD40 CD47 MHC ClassIICD166TIM4

CD22

Antigen specific receptor :

we have seen different choices in Vertebrates: LRR, Ig SF, (recent IgSF V-C1 domains)

Analogies

What about the “context”?

CD200 CD28

CTLA4

BTLA

CD2 CD244 SLAM6 SLAM7 SLAM CD84 CD40L

CD6, 5

SIRPγ CD4 TCR CD3γδε

TIM1

T Cell

CD45 CD52

Homologies between invertebrates IgSF members and Vertebrates IgSF coreceptors

C2

S-S

V

S-STM Cyto

C2

S-STM

S-SCyto

C2

S-S

V

S-S

C2

S-STM Cyto

S-S

V

S-S

S-S

C2 C2C.i CD 166-L

(CD6 ligand)

C.i CTX/JAM-L

C.i Nectin-L

S-S

C1-l

S-STM Cyto

V

S-SEGF EGF

(Du Pasquier L CTMI (2000) 248:159-185

Du Pasquier L.et al (2004) Imm. Rev.198: 233-248)

S-S

VB.l VCTX-L

CD 47-L (SIRP ligand)

C2

S-S

V

S-STM Cyto ITIM

B.l. VCnp. (CTX/JAM-L)

S-SS-S

B.s. FuHC (IgSF4-L) (De Tomaso et al. 2005 Nature 438 :454-9)

(Yu et al 2005 JI 174: 3493-3500)

(Sato A et al 2003 Immunogenetics 55:423-7)

Position on human chromosomes of homologs of Invertebrates IgSF members

**

*

****

*

*

*

*

Du Pasquier L.et al (2004) Imm. Rev.198: 233-248 Du Pasquier L. (2005) Science 309:1826-7 + unpublished

*

*

*

**

*

*

*

*

*

*

Antigen Presenting Cell

CD200R

CD200

CD80/86

CD28

CTLA4

BTLA

CD58

CD2 CD244

CD48 SLAM6

SLAM6

SLAM7

SLAM7

SLAM

SLAM

CD84

CD84

CD40

CD40L

CD6, 5

CD47

SIRPγ CD4 TCR CD3γδε

MHC ClassIICD166TIM4

TIM1

T Cell

CD45

CD22

CD52

CD40

CD40L SIRPγ CD4 TCR

MHC ClassIITIM4

TIM1ICAM

CD11

CD52

Fat Column

In adult

ThymusEpigonal organ

Leydig’’’’s organ Spleen

Rectal gland

GALTSpleen

Thymus

Kidney

Bone Marrow

Spleen

Bone Marrow

GALT

Thymus

Lymph

nodes

Thymus

Nodes?

Bursa

GALT

Spleen

Bone Marrow

Spleen

Peyer’’’’sPatches

GALT

Thymus

THYMUS

SPLEEN

GALT

HEAD KIDNEY

DCs

THYMUS

SPLEEN

GALT

BONE MARROW

DCs

NK

RAG AID

Ig comb Switch

TCR γδαβγδαβγδαβγδαβ

CD3γ/δγ/δγ/δγ/δ

THYMUS

SPLEEN

GALT

BONE MARROW

LYMPH NODES?

GERMINAL CENTERS

FDCs

NK

RAG AID

Ig no comb, gen convSwitch

TCR γδαβγδαβγδαβγδαβ

CD3γ/δγ/δγ/δγ/δ

THYMUS

SPLEEN

GALT

BONE MARROW

LYMPH NODES

GERMINAL CENTERS

FDCs

NK

RAG AID

Ig comb, gen convSwitch

TCR γδαβγδαβγδαβγδαβ

CD3 with γγγγ and δδδδMHCI/II

Rectal gland

Typhlosolis

In larva

Thymoid

GALT

NK?

AID-L (2CDA)gen conv

LRR

VLR A , B

allograft memory?

Il17,8

TNFa

CxCR8

THYMUS

SPLEEN

GALT

EPIGONAL

DCs

NK?

RAG AID

Ig no combinat.

TCR γδαβγδαβγδαβγδαβ

MHCI/IITB-cell memory

Poor Ab matur.

Il2/15

DCs

NK

RAG AID

Ig combinat.

TCR γδαβγδαβγδαβγδαβ

MHCI/IITB-cell memory

Poor Ab matur.

TH1 TH2

TypeII IFN

Il20 TGF b

CD3γ/δγ/δγ/δγ/δMHC I/IITB-cell memory

Poor Ab matur.

Il4

TGFb

Treg

CD3γ/δγ/δγ/δγ/δMHC I/IITB-cell memory

Good Ab matur.?

Il2/15

MHCI/IITB-cell memory

Good Ab matur.

Treg

TH1,2,17

VERTEBRATA

AGNATHAGNATHOSTOMATA

OSTEICTHYES

AMPHIBIA

REPTILIA

AVES MAMMALIA

ANURA

TELEOSTEI

CHONDRICHTHYES

Thymoid