Genetic diversity of HLA-A2: evolutionary and functional significance

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Genetic diversity of HLA-A2: evolutionary and functional significance

**0202 A*0203 AW205

A*0207 A.*0210 A'0211 A'0213 A'0214

Table 2. Polymorphic amino acid pc&ions in the a, and q domains of HlA.AW

gene producff

T

A*0203

E

W

I

AW204 *w2,7

.

A=0207 AWZL5N A%7211

.

A*0212 A*0213

.;::

.

.

:

:

E

192,216 A*0206 A*0210

Y Y

A*0205 A*0214

I

A*0208

~

A*0202

k L.. L.. 2

N

~

1:

‘Red textindicata reidus thattvpi an akk W, “95and ,.I%)

&

:

:

..w.

L.....W. L.....W. tgoup (e.g.the~‘o~1-,vlated goup is typi,ia bym,

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example. A”OZ”I-.

A”nxw

and

AwllkcstrKtcd

CTL

hd”C

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brsn

show” to recognize different epitopes of influcnra virus”, although

Ovrrali. !he data discussed above demonstrate that polymtrrphbm

the fine spcclflcitles of the AVJ2U2 and A’IJ?flS rrsp”“bes h”xrr not

or mutabon wthm

been defined. Simd.wly, AV201- and AWOZ-w.stricted

re-

pmcesstng and prcscnbtion to T cells. although the extent to xvhirh

spunses to the malaria parasite M~ssrodr~~rn fdcpvwn recognized

this uccun for A.02 remana to be e,!ablishcd. Population studies

epitopm derived from sepdratu parasite anhgens”. Barouch

have shown differential

and calleayes”

peptlde-p&cd

AVZ-expressing

spectfic CTLs. Of pnt~ular

rntrrrst

CTI.

Recently,

recognition of

cell iinps by peptidr-AVZOIi” these studies was the failure

oi a” influenza mdnix protern IFhIP)-specific, A’OZOi.re~tncted CTL

suggest that the selection of A’02 variants may be based on theu ability to bind ddfuent peptides, moot probably derived fron local pathogens or pathogenic strains. The nature of the polymorphism among the known A’02 allclcs suggtrts groups, r&ted

to AWOl

that they fall xnto tw”

and A’0205 respectiv++ I” addition. se-

of 3zg-

que”
binding oi the peptide to the A’U2UI gene product at the

allrlcs to br disrurercd. The recent deeelomnent of DNA-bawd

line to recognize peptidempulscdA”0202 torgct rclls. in spk “ilkant

HLA-AZ can haw a dramatic eifect on antigen

peptide concentrations As I” skdles

used in the CTL assay,

of allorccogmhon, the US

methods for typing HLR

of HLA-IV

mutan&

class

I gcnes’“‘l means that serologically

silent polymuryhisms. such as AV? alletic variants. can be readily

hits demonstrated the s.~gnlficance of polymorphism m HLA-A’V? for

detected. The polymorphism within HLA-A’02

antigen presentation”“4’. For instance,

cations for organ iransplantation, immunity to infection and suxcp

mutant I-IL&AZ

study of the presentation

by

molecules cf three differcnt A’O?Ol-restricted viral

peptide epitopes to antxgen-specific C-rf_z hdi show”

thd

all

of the mtitants te.ted affected recogmtmn ot two or mo,e of the peptides by the CTLs

(Ref. 411. One of thne

mutants. a single

tymsine to cysteme wb?titutio”

at position V?, which abrogated

presentation of all three wwl

epltopes, corresponded to the

sequenre of A*0207 that was found at high frequency m Singapore Chinese’. Furthermore,

certain HLA-A2

mutants

that showed

dimmlshed binding of a peptide epitope were able to present this cpitopr to antigen-spxific CTLs vnth equal rfficicnq

to ‘wild-type

A’0201 while, in the maprity of casu5. diminished binding was

may have impli-

tibility to auhrimmune diseases. In wew of the genetic vnrmtion m HLA-A’02 1” drffrrrnt

populations, and its potential ngnificance for

.mtige” prcscntatio” tu T ~4,.

systematic studies using these “ah,-

rally occurring variants are required in order t” elucidate fully the structnrr-fur&o”

relationships of polymorphism in HLA-A?.

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Bypassing the antigen to control rheumatoid arthritis Pierre Miossec, Pascale Chomarat

and Julie Dechanet