Identification by genomic typing of non-DR3 HLA class II genes Associated with Myasthenia Gravis

49

II-26

Abstracts

IDRISS DJILAU-SAIAH, SOPHIE CAILLAT-ZUCMAN, *JACQUES SCHMITZ ANDJ EAN-[aRAN~OtS BACH thserm U25 and *Department of Pediatrics, Hopital Necker. 161 Rue de

11-25

Sevres, Paris. France

SOPHIE CAILLAT-ZUCMAN. ERIC BERTIN. JOSE TIMSIT, CHRISTIAN BOITARD, *ROGER ASSAN and JEAN-FRANCOISBACH lnserm U25, Hopital Necker, 161 Rue de S%vres, Pans and *Service de Diabetotogie, Hopltal BichaL Pans, Prance

TRANSPORTER GENES IN P R E D I S P O S I T I O N I N S U L I N DEPENDENT DIABETES M E L L I T U S ROLE OF TAP

TO

C,eneuc control of insulin dependent diabetes mellitus (IDDMI is mainly dependent oe HLA genes in the major hismcompatibility complex (MHC). The recent identification of TAPI and TAP2 (transporters associated with antigen processing) genes, located in the HLA class 11 regJon, has provided new insights in the immunogenetic approach of IDDM pathogenesis. The TAP genes participation was investigated in 167 Caucasian IDDM patieets and 98 normal controls using oligotyping after DNA amplification. The TAP2*0201 allele had a dominant protective effect (relative risk RR=0.3, Pc<0.001), additive to that of the DRBI*15 DQBI"0602 haplotype (RR=0.06, Pc<0.05) but antagonist to the susceptibility associated with the DRBI*03 DQBI*0201 and/or DRB1 *04 DQB1 *(1302 haplotypes (RR=l.l,ns). Conversely, the TAP2*OIOI allele had a Wedispoeang effect in the homozygous state (RR--3.4.Pc
T O C E L I A C DISEASE TRANSPORTER GENES POLYMORPHISM SUSCEPTIBILITY

AND

PEPTIDE

Compelling evidence focuses on the responsability of a particalar cis or tmns encoded ~ ~ hetemdimer (u 1"0501/61 "0201 ) in susceptibility to celiac thsease (CD). However, the participation of additional iedepaedent genetic factms within the major h i ~ p a f i b i l i t y

complex (MHC) may not be

excluded. The polymorphism of TAP (Transporter associated with antigen procesmng) genes, coding for proteins required for delivery of antigenic popttdes to HLA class I molecules, was thus investigated. HLA class 11 DRBI, DQA1, DQB1, DPBI, TAPI and TAP2 allelic polymorphism was studied in 77 Caucasian CD patients fullfillieg ESPGAM criteria and 213 Caneasian no~nul controls, using oligotyping after geeomic amplification by the polymemse chain reaction. Suscep~bility to CD was clearly associated with the DRBI*03 and DRBI*07 alleles (relative risks RR=IS. and 6.0 respecuvely, Pc
11-28

II-27 LAISE VIEIRA. ~gDPHIECAILLAT ZUCMAN. PHILIPPE GAJDOS*. SYLVIA C O H E N - K A ~ N S K V #, A L B A N CASTEL~§ A N D JEAN-FRANCOIS B A C H

thserm U25, Hopitul Necker. 161 Rue de S%vres, Paris, France *Service de RKaeimation medicale, Hopital Raymond Pomcard. Garches+ Prance. #Laburatoire d'lmmunolo~e. Hopital Mane Lannelougue. Le PlessisRobinson, france I D E N T I F I C A T I O N BY G E N O M I C T Y P I N G O F N O N - D R 3 ElLA

CLASS 11 G E N E S

destmmion.

ASSOCIATED

WITH

MYASTHENIA

GRAVIS Myasthenia gravis (MG) is an autoimmune disease due to the blockade of neuromuscular conduction by autoantibodias directed against the acetyl choline receptor (AChRL However, histological and immunogenetic findings support the general befief of a wide heterogeneity of the disease. HI.A ~ a t t o n

with MG was

studied th a series of 114 Caucasian MG patients and 215 Caucasian normal controls umng class I and class 11 genotyping after PCR amplification. Positive association was found with DRB 1*03, particularly in women (RR=2.6) and in early MG onset (RR=3.4). DRB3*, D Q B I * , D Q A I * D P B I * and B (B8 and BI8) genotypmg revenled that the assoaation was lm'edonnnantly with the HLA B8 DRBI*03 DRB3*0101 DQBI*0201 haplotype frequency was also

DQAI*0501 ancestral hapiotype. The

increased in patients with thymic hyperplasia

(RR-~.S) and was greatly reduced in patients with thymoma (RR=035). However,

ANNA

ALDENER£w

BJORN ROSENLUND2, 9 E T E R BISTOLETTI 1 AND OLLE OLERU]Pl

tCenter for BioTechnology, Karolinska Institute, NOVUM, Huddinge, S-141 57 H u d d i n g e , S w e d e n and D e p a r t m e n t s of c l i n i c a l I m m u n o l o g y and 2Obstetrics and G y n e c o l o g y , K a r o l i n s k a I n s t i t u t e at H u d d l n g e H o s p i t a l , H u d d i n g e , S w e d e n

N o a s s o c i a t i o n w i t h D Q 3 o r DQBI*03 alleles in S w e d i s h p a t i e n ~ w i t h s q u a m o u s cell c a r c i n o m a o f t h e c e r v i x u t e r i I n t r o d u c t i o n . Few m a l i g n a n t d i s o r d e r s h a v e r e p r o d u c i b l y b e e n f o u n d to be a s s o c i a t e d w i t h a l l e l e s of the H L A c l a s s II region. In 1991, it w a s r e p o r t e d that a l a r g e p r o p o r t i o n of p a t i e n t s w i t h i n v a s i v e s q u a m o u s cell c a r c i n o m a of the c e r v i x c a r r i e d the DQ3 s p e c i f i c i t y (i). In the two s u b s e q u e n t l y p u b l i s h e d r e p o r t s d i v e r g o n t r e s u l t s w e r e o b t a i n e d : in B r i t i s h p a t i e n t s no a s s o c i a t i o n w a s o b s e r v e d (2) and in N o r w e g i a n p a t i e n t s a w e a k DQ3 a s s o c i a t i o n was found (3). We w e r e i n t e r e s t e d in i n v e s t i g a t l n g t h i s issue in S w e d i s h p a t i e n t s by h i g h r e s o l u t i o n g e n o m i c t y p i n g t e c h n i q u e s . M a t e r i a l a m d m e t h o d s . 50 p a t i e n t s w i t h i n v a s i v e s g u a m o u s c e l l c a r c i n o m a of the c e r v i x uteri and 250 h e a l t h y c o n t r o l p e r s o n s w e r e s t u d i e d . D R - D Q t y p i n g was p e r f o r m e d by T a q I D R B D Q A - D Q B R F L P a n a l y s i s . D Q B I and D Q A I t y p i n g was p e r f o r m e d b y P C R a m p l i f i c a t i o n w i t h s e q u e n c e - s p e c i f i c p r i m e r s (PCR-SSP). R e s u l t s . No i n c r e a s e of the DQ3 s p e c i f i c i t y was f o u n d in the p a t i e n t s . F u r t h e r m o r e , the f r e q u e n c i e s of the D Q 3 - a s s o ciated DQBI alleles, DQBI*O30I-DQBI*0303, were very similar in p a t i e n t s and c o n t r o l s , see Table. Sufamary Of findlngs in 3 published studles (i-3} and the present study of HLAoDQ specificxtxes xn squamous cell cervical carcxnoma. Ethnic group

DQ3 pat

16 out of 48 paUents carrying this 8.1 ancestral haplotype were recombinams showing absence of B8 In--4) or of DR3 In=10). Analysis of other alleles further revealed the existence of two significant assoctauous. MG was positively asseaated

G e ~ a n (i)

with the DQBI*0604 allele (RR=3.4), particularly in patients with thymoma

Norwegian (3)

(RR=5.7). Furthermore. the thsease was negatively associated with DRBI*01 in

Swedish

females (RR=032). Preliminary. data indicate Lhat the allelic distribution of TAPI and TAP2 genes, coding for peptide transporters, was similar among MG patients and comxols. These data suggest that MG is placed under the control of at least three distinct genes 11 a class II predisposing gene in the 8.1 ancestral haplotypc. 2/ a thymomaassoaated class II allele: DQB I ~

and 3t a pmtecove allele: DRB1 *01.

British (2)

pau ctr pat ctr pat ctr pat ctr

n=66 n=109/2019 n=64 n=166/857 n=168 n=ll8 n=50 n=250

ctr

DQBI* 0301

0302

0303

88% 41-50% 63% 43-66% 67% 51% 56%

30% 28% 4% 32% 26% 9% Conaluaion. The intriguing observation that squamous cell c a r c i n o m a of the cervix, p r o b a b l y v i t a l l y induced, w a s a s s o c i a t e d w i t h the s e r o l o g i c a l s p e c i f i c i t y DQ3 was not c o n f i r m e d in the p r e s e n t s t u d y u t i l i z i n g g e n o m i c t y p i n g t e c h n i q u e s . 60%

Reflrencml l. Wank R, Thomssen C. Nature 1991: 352: 723. 2. Glew SS et el. Nature 1992: 356: 22. 3. Helland ~ ~t el. Nature 1992: 356: 23.