- Email: [email protected]
The major histocompatibility complex and disease
The major
histocompatibility
complex and disease
J.l. Bel1 Institute
of Molecular Current
Medicine, John Radcliffe Hospital, Opinion
in Immunology
Introduction There has been further progress in dissecting the genetic basis of autoimmune disorders in the last year, in particular with the identifïcation of the sequences within the major histocompatibility complex (MIX) responsible for disease susceptibility. For three diseases, this progress has been particularly pronounced: type 1 diabetes, coeliac disease and multiple sclerosis (MS). In addition, the last year has provided substantial ìnsight into the other nonhuman leukocyte antigen (HLA) genes found within the human MHC. These studies provide a wealth of new candidate genes that may encode susceptibility to given HL& associated diseases.
Type I diabetes Progress in this area of HIAassociated disease has centred around efforts to confìrm initial suggestions that HIA-DQ represents the major susceptibility lotus in this disease. Original speculation that DQ was important was based on restriction fragment length polymorphism (RFLP) analysis and sequence correlation among DQ molecules that distinguished susceptibility haplotypes from protective ones (Todd et aC, Nuture 1987, 329599-604). Strong confirmation of a role for DQ has come from ethnic studies. Fletcher et al. [ 1] have identified two haplotypes associated with disease susceptibility in Afro-Caribbean populations which are neutral in Caucasian populations: DR7 and DR9. In bla&, both of these haplotypes have new restríction fragment patterns around HL&DQ. Todd et ul. [ 21 have subsequently characterized both of these haplotypes by sequencing. They established that the DR7 haplotype associated with diabetes susceptibility in bla& differs from that in Caucasians at the DQu lotus only. The DQa lotus on this haplotype in blacks is identical to that on the DQ haplotype in Caucasians, a strong susceptibility haplotype. The DR7 haplotype in Caucasians is neutral for diabetes susceptibility, an unexpected finding as it shares its DQfi locus with the DR3 haplotype. The DQcr on the Caucasian DR7 haplotype must be responsible for the neutral effect of this haplotype and when it is replaced with a susceptibility-associated DQct in the black population, the
Oxford,
UK
1989, 2:114-116
DR7 haplotype becomes a susceptibility haplotype. These ethnic studies are very important as they make use of recombination events that alter haplotypes and permit the identification of susceptibility determinants outside their normal context. Another ethnic study has explained diabetes associations in Indian populations [3]. In these populations, the major disease susceptibility loei also concur with HLA-DQ RFLP. In addition, the HLA-DQ pattern associated with HLA-DR2 and protection from diabetes in Caucasians is found on another haplotype, DRw6, in the Indian population. In Indians, it is this haplotype which is associated with protection from diabetes, consistent with DQ having a role in disease protection. Although most of the evidente points to HIA-DQ being the MHC-encoded susceptibility molecule in diabetes, several papers suggest that there is a more complicated pattern of susceptibility [4]. Tait et al. [5] have shown that the strong association with DQw8pcDQ3.2) on DR4 haplotypes is only evident in DR3/4 patients and not in DR1/4 patients. Another study [6] suggests that DR4 susceptibility arises from only two DR4 subtypes, Dw4 and DwlO, while the Dw14 subtype is not associated tith susceptibility. Extended haplotype associations cannot be accounted for by DQ alone, implying that there is an additional DR effect or that another gene bas an effect. On balance, the evidente that DQ has a primary role remains compelling, but to complete the story it may be necessary to incorporate other loei on particular haplotypes.
Coeliac disease The strong association between coeliac disease and HL% DR3, particularly the Al/B8/DR3 haplotype, bas been clearly defmed serologically. It had previously been suggested that HLADP was the lotus on this haplotype that encodes susceptibility (Howell et al, Proc Nat1 Acad Sci USA 1988, 85:222-226). Several papers addressing this problem have appeared (Sollid et al., 1988) [7]. Identification of the lotus on the DR3 haplotype responsible for susceptibility has, in the past, proved diflìcult.
Abbreviations HLAhuman leukocyte antigen; MHC-major histocompatibility complex; MS-multiple sclerosis; PCR-polymerase chain reaction; RFLP-restriction fragment length polymorphism.
114
@ Current
Science
Ltd ISSN 0952-7915
The major histocompatibilitycomplex and diseaseBel1
‘I’he sequence of the DQa and p alleles is identical in all DR3 haplotypes and the DBB is shared by the sec ond susceptibility haplotype, DR7. Sollid et al, [81 have shown that in DR7 patients, the second haplotype is in variably DR5 or DR3. Both these haplotypes share the same DQa chain, implying that the same a/j3 heterodimer is present in all DR3 and DR7 patients. This is stiong evidence that DRw2 is a susceptibility determinant. $n additional lotus may also be present on the DR3 hadotype as there is markedly increased Al/B8/DR3 association with the disease and this haplotype has the same DQw2 as other DR3 haplotypes. It has been suggested that this locus is HLA-DP. The study of HLA-DP has been greatly facilitated by the identiiîcation of a large number of dif ferent DPP alleles defìned by sequence polymorphism [9]. These molecular studies revealed that only a small proportion of DP varlability was previously detectable using primed lymphocyte typing. Molecuku DP typlng using the polymerase chain reaction (PCR) has been applied to coellac disease and has suggested that, in Italian patients, there is an association with the DP4.2 and DP3 alleles in addition to the DQw2 association. More work will be required to establish that this association is not due to linkage disequilibrium with the DR3 extended haplotype, as has been found in northern Europeans.
Non-HIA MHC genes Two papers have been published recently which describe careful searches of the region between complement and HIA-B for new transcribed sequences 114,151. These papers have revealed a remarkably high density of expressed genes, in the region of up to one expressed product every 23 kilobases. ‘I’his does not include new tissue-specifìc transcripts which may have been missed by the strategies used. The genes have been identlhed by screenlng messenger RNA with cosmids or by looking for Hpa tiny fragment islands in this region. In total, 17 new genes are described in these papers, all of which are expressed in a large number of different cell types. ~ny of these genes may be potential disease susceptibility loei and need to be characterized for polymorphism and function. The prospects are good, should this progress continue, that the non-HLA genes throughotit the MHC will all be cloned soon, adding a new dimension to studies of HLA and disease.
Annotated references and recommended reading 0
00
Multiple sclerosis ‘I’he MHC association with MS is with HLADR2 in white Caucasian individuals, although ethnic studies have indicated that there are increased frequenties of DR4 and DRw6. Comparison of these three sequences has revealed a sequence in DQfl that may be associated with MS [lol. ‘I’his could be best substantiated by establishing there there is a bias among DR6 subtypes in MS pa tients to the DR6associated DQB chains possessing this sequence. Other data provide suggestive evidente that haplotypes other than DR2 may contribute to MS susceptibillty [ 1lf This group found that a MspI polymorphism, detected with DQu , was found at an increased frequency among MS patients. This MspI polymorphism is associated with several haplotypes but may be linked to susceptibility factors that have not been del%&. ‘I’he most important development in the understanding of genetic susceptibility to MS has been the observation that both T cell receptor a- and B-chain haplotypes may be associated with disease. Oksenberg et al. [12] have provided evidente that RPLP deiïned by both Va and Ca fragments are increased in frequency in MS patients. In an extensive study of 40 multiplex families with MS, Seboum et al. [ 131 have shown that T cell receptor p-chain haplotypes segregate with the disease. This is further strong evidente of a role for T cell receptor gennline polymorphism in disease susceptibility, although, as with MIX determinants, this effect is likely to be small.
Of interest Of outstanding interest
1. 0
FIETCHER J, Mt~ovxz C, ODUGBESAN 0, JF.NKM D, BRADWEIL AR, BARNEP AH: Trans-racial studies implicate HLA-DQ as a component of genetic susceptibility to type-1 (insulin1988, 31864-870. dependent) diabetes. Diabew RFLP analysis is used in this study to chamcterize haplotypes associated with diabetes in an AfroCaribbean population. A DQg RFLP pattem unique to black.5 and absent in Caucasians was found associated with the DRw9 and some DR7 haplotypes. This particukir RFLP pattem is signihcantly increased h diabetes patients, indicating that DQ is Ekely to be the lotus responsible for susceptibility in this population.
2.
TODD JA, MJO~IC C, FWKHER J, JENKIIS D, BMLWELL AR, Bm AH: Identifïcation of susceptibilty loei for insulindependent diabetes meRitus by trans-racial gene mapping. Nature 1989, 33B587-588 This paper extends the observation which kientified a novel DR7 subtype based on DQg RFLP pattems. DR7 is an exceptiod haplotype as it does not possess an aspartic acid at position 57 and yet does not confer susceptibity to disease in Caucasians. This study shows that the DQa chain on the suscepdble DR7 haplotype in black popukttions is identical to that found on the DR4 haplotype in Caucasians, suggesting that the presence of a susceptible DQa chain on DR7 can resuk in DR7 becoming a haplotype associated with diabetes. ??m
FUTCHER J, ODUGBESAN 0, MJOWZ C, M&CKAY E, BI?ADWEIL AR, BARNETIAH: Class B HLA DNA polymorphisms in type-1 (insuBn-dependent) diabetic patients of North Indian origin. D&beroIo* 1988, 31343350. Using RFW for D@ and DXu, this s~dy reveakì that in an ethnic population from notthem India the DQB polymorphisms associated with diabetes are the sarne as those seen in white Caucasians. In addition, the RFJ_Pnomrally associated with protection from diabetes on the DR2 haplotype in white Caucasians are present on a different haplotype, DRw6, in northem Indians. Interestin&, it is tbis haplotype which is associated with protection against diabetes in this ethnic population, again strengthening the case for DQ in susceptibility and protection to this disease.
3. 0
115
116
Antigen recognition 4. oo
THOMSQN G, ROBINSONWP, K~HNERMK, JOE S, MACD~NAID MJ, G~TIXHAU JL, BAIWXA J, RICH SS, BEJ, BAUER MP, PLANEN J, TAIT BD, ~CHOBERE, MAARWR, L~JDVIGSSON J, IJNDBLOM B, FARIDNR, THOMPSONC, DESCHAMPS 1: Genetic
heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians wlth InsuKndependent diabetes mellitus. Am J Genet 1988, 43799-816. The most comprehensive review of the serological data associating par ticular HL4 alleles wlth insulindependent diabetes mellitus. This study has compiled the data from a large number of independent studies and has estabiished a hierarchy of risk factors for developing type 1 diabetes across a tide range of ciass Il haplotypes. 5. 0
TAE BD, MIW G, HARREQNLC: Association of HLA-DQw3 (TAlO-) with type 1 diabetes occurs wlth DR3/4 but not DR1/4 patients. Diubetes 1988, 37~92-29. The DQw3 ass&ation with diabetes is discus& ln this paper, par ticularly the DQ3.2 association which has been previously descrlbed. These authors demonstmte that the prevalente of 3.2 is most protinent in DR3/4 individuals,whlle in individualswho are DR1/4 one sees no preferent for the DQ3.2- assocaited DR4 haplotype. The decrease in B44-DR4 haplotypes is shown not to be the result of the DQw3 effect, but implies that this haplotype bas an additional effect. 6.
SHEEHYMJ, SCHARFSJ, ROWEJR, DEGIMENEZ MHN, MESKELM, A diabetes-susceptlble HLA haplotype is best defined by a comblnation-of HLA-DR &d HLA-DQ alleles. I Clin Invest 1989, 83830-835. Although I-IL&ljR is str&gly associated with’susceptibility to type 1 diabetes and the DR4 haplotypes tith DQ3.2, are these the most associated with the disea~? This paper demonstrates that certain haplotypes do not conform to these ruIes. In particular, susceptibility to diabetes seems to be conJ&d to the Dw4 and DwlO, DR4 haplotypes aud not the Dw14 haplotype, independent of DQ3.1 and 3.2 status. ??
ERUCH HA, NEPOM BS:
7.
BUGAWAN TL, ANGELINI G, IARRICK J, AURICCHIO S, FERRARA GB, ERLICH HA (Letter to the Editor) A comblnation of a particular HU-DPB allele and an HL&DQ heterodlmer confers susceptibility to coellac disease. Nature 1989, 339:47&472. Using the PCR-based typing system for HL&DP alleles, this paper suggests that there is an association between DPw.2 and DPp3 and coeliac disease. ??
8.
Som LM, MARKIJ~~EN G, GJERDEJEH, VARTDALF, THORSBY E: Evidente for a primary association of celiac response to a partlcular HL&DQ a/p heterodimer. J E@ Med 1989, 169:345-350. HIADR3 is the haplotype most strongly associated tith coeliac disease but individu& are also commonly found with HIADR7 haplotypes. This paper uses prevlously published sequence information to suggest that the DQ molecule on these haplotypes is responsibie for this susceptibility. The strongest evidente for this point of viw is that DR7 individualswho have the same JX@ as DR3 individualsinvariably have DR3 or DR5 as their second haplotype if they are coeliac patients. The DR3 and DR5 haplotypes share identical DQa alleles, implying that the a heterodimer from DQ is likely to be responsible for susceptibility. ??e
BUGAWANTL, HORN GT, LONG C, MICKEISON E, HANSENJA, FERRARA GB, ANGELINIG, ERUCH HA: Analysis of HLA-DP allelic sequence polymorphism using in vfhu enzymatic NDA amplification of DP-a and DP-fl loei. J Immunoll988, 141:4030. Nuclelc acid sequencing of PCR-amplilïed DPB alleles in this paper demonstrates that the nurnber of polymorphic variants is much larger 9.
?? o
than that predicted ptiousiy. A total of 14 diEerent alleles bas been defmed and a method for PCR typing these different alleles is described. 10.
G, RIORSBY E: VAPJDALF, SOLLIDLM, VANDWKB, MARK~SSEN Patients with multiple sclerosis carry DQBl genes which encode shared polymorphic amino acid sequences. Hum Immund 1989, 25:103-110. In merent etbnic subpopulations, HL&DR2, DR4 and DRw6 are asso ciated tith MS susceptibility. This paper describes the identication of a DQB sequence v,hich is shared between these haplotypes and which is present in a large number of MS patients. 0
11. ??
HF,ARDRNS, CULLENC, MIDDLETOND, HAWKINSSq FRANCIS DA, HERNJEC, MCDONALLI WI, BATCHELOR JR, IXCHLER RI: An allelic cluster of DQa restriction fragments is associated
with multiple sclerosis: evidente that a second haplotype may influence disease susceptihility. Hum Immund 1989, 25:111-124. When a population of MS patients and controls are independently pooled and screened with a large nurnber of restriction endonucleases and several HIA-D region probes, a unique M@ fragment is found to be more prominent with the DQu probe and the enzyme Ms#. This fragment, a 3.2 kilobase DQa band was observed in 31% of patients and only 4% of controls. The fragment is not associated tith the DR2 haplotype and can be present on the second haplotype in individuals tith disea~, irnplying that more than the Dl72 haplotype may be responsible for disea.~ susceptibility. 12. 0
OKSENBERG JR, SHE~ M, BEGOVICH AB, ERUCHHA, BERNARD CC, CAVAUSFORZALL, STEIIWANL T-cell receptor V, and
C, alleles associated wlth multiple sclerosis and myasthenla gravìs. Proc Nat1 Acad Sci LISA 1989, 86~9-2. T cell receptor a-chti V-and-C-region polymorphisms are described in this paper. Both a Va and Ca RPLP are found to be associated tith MS. This is the fìrst clear association of T cell receptor polymorphisms at a germline leve1 tith disea~ susceptibility. 13. 0
SEBOURNE, ROBINXINMA, Doom TH, CLLILIA TA, KINDT TJ, HAUSERSL: A susceptibilty lotus for multiple sclerosis
is Iinked to the T cell receptor $ chain complex. Ceu 1989, 5710951100. AlEcted sib-pair analysis is used to study the role of T ceII receptor pchain genes in susceptibility to MS. The authors have studied 40 such families and described descent between MS sibling pairs. This is strong support for a role for the T celI receptor in this disease. 14.
SPIEST, BIANCKG, BREWAHANM, SANDSJ, STROMINGER JL: A
nw cluster of genes withln the human major histocompatiblllty complex. Science 1989, 243:214-216. Cosmid mapping of 435 kilobases of DNA tirhin rhe HL4 benveen the turnour necrosis factor lotus and HLLB bas permitted the search for a nw transcribed loei. NW HL&B-associated transcripts (BATs) were identified and mapped in this region. Akhough constitutively expres&, these genes may have a role in human disease. 0
SARGENTA, Dm D, CAM~BELL RD: Identifïcation of multiple HTP lsland associated genes in the human major histocompatibility complex class III region. EMBO J 1989, 8:2305-2312. Tbis paper describes a careful study of 541 kilobases of genomic DNA and the characterization of 12 nw genes lying between complement and HL4-B. This paper demonstrates the very high density of expres& loei within the MHC and protides numerous candidate loei for diseasz associations. 15. *@
histocompatibility
complex and disease
J.l. Bel1 Institute
of Molecular Current
Medicine, John Radcliffe Hospital, Opinion
in Immunology
Introduction There has been further progress in dissecting the genetic basis of autoimmune disorders in the last year, in particular with the identifïcation of the sequences within the major histocompatibility complex (MIX) responsible for disease susceptibility. For three diseases, this progress has been particularly pronounced: type 1 diabetes, coeliac disease and multiple sclerosis (MS). In addition, the last year has provided substantial ìnsight into the other nonhuman leukocyte antigen (HLA) genes found within the human MHC. These studies provide a wealth of new candidate genes that may encode susceptibility to given HL& associated diseases.
Type I diabetes Progress in this area of HIAassociated disease has centred around efforts to confìrm initial suggestions that HIA-DQ represents the major susceptibility lotus in this disease. Original speculation that DQ was important was based on restriction fragment length polymorphism (RFLP) analysis and sequence correlation among DQ molecules that distinguished susceptibility haplotypes from protective ones (Todd et aC, Nuture 1987, 329599-604). Strong confirmation of a role for DQ has come from ethnic studies. Fletcher et al. [ 1] have identified two haplotypes associated with disease susceptibility in Afro-Caribbean populations which are neutral in Caucasian populations: DR7 and DR9. In bla&, both of these haplotypes have new restríction fragment patterns around HL&DQ. Todd et ul. [ 21 have subsequently characterized both of these haplotypes by sequencing. They established that the DR7 haplotype associated with diabetes susceptibility in bla& differs from that in Caucasians at the DQu lotus only. The DQa lotus on this haplotype in blacks is identical to that on the DQ haplotype in Caucasians, a strong susceptibility haplotype. The DR7 haplotype in Caucasians is neutral for diabetes susceptibility, an unexpected finding as it shares its DQfi locus with the DR3 haplotype. The DQcr on the Caucasian DR7 haplotype must be responsible for the neutral effect of this haplotype and when it is replaced with a susceptibility-associated DQct in the black population, the
Oxford,
UK
1989, 2:114-116
DR7 haplotype becomes a susceptibility haplotype. These ethnic studies are very important as they make use of recombination events that alter haplotypes and permit the identification of susceptibility determinants outside their normal context. Another ethnic study has explained diabetes associations in Indian populations [3]. In these populations, the major disease susceptibility loei also concur with HLA-DQ RFLP. In addition, the HLA-DQ pattern associated with HLA-DR2 and protection from diabetes in Caucasians is found on another haplotype, DRw6, in the Indian population. In Indians, it is this haplotype which is associated with protection from diabetes, consistent with DQ having a role in disease protection. Although most of the evidente points to HIA-DQ being the MHC-encoded susceptibility molecule in diabetes, several papers suggest that there is a more complicated pattern of susceptibility [4]. Tait et al. [5] have shown that the strong association with DQw8pcDQ3.2) on DR4 haplotypes is only evident in DR3/4 patients and not in DR1/4 patients. Another study [6] suggests that DR4 susceptibility arises from only two DR4 subtypes, Dw4 and DwlO, while the Dw14 subtype is not associated tith susceptibility. Extended haplotype associations cannot be accounted for by DQ alone, implying that there is an additional DR effect or that another gene bas an effect. On balance, the evidente that DQ has a primary role remains compelling, but to complete the story it may be necessary to incorporate other loei on particular haplotypes.
Coeliac disease The strong association between coeliac disease and HL% DR3, particularly the Al/B8/DR3 haplotype, bas been clearly defmed serologically. It had previously been suggested that HLADP was the lotus on this haplotype that encodes susceptibility (Howell et al, Proc Nat1 Acad Sci USA 1988, 85:222-226). Several papers addressing this problem have appeared (Sollid et al., 1988) [7]. Identification of the lotus on the DR3 haplotype responsible for susceptibility has, in the past, proved diflìcult.
Abbreviations HLAhuman leukocyte antigen; MHC-major histocompatibility complex; MS-multiple sclerosis; PCR-polymerase chain reaction; RFLP-restriction fragment length polymorphism.
114
@ Current
Science
Ltd ISSN 0952-7915
The major histocompatibilitycomplex and diseaseBel1
‘I’he sequence of the DQa and p alleles is identical in all DR3 haplotypes and the DBB is shared by the sec ond susceptibility haplotype, DR7. Sollid et al, [81 have shown that in DR7 patients, the second haplotype is in variably DR5 or DR3. Both these haplotypes share the same DQa chain, implying that the same a/j3 heterodimer is present in all DR3 and DR7 patients. This is stiong evidence that DRw2 is a susceptibility determinant. $n additional lotus may also be present on the DR3 hadotype as there is markedly increased Al/B8/DR3 association with the disease and this haplotype has the same DQw2 as other DR3 haplotypes. It has been suggested that this locus is HLA-DP. The study of HLA-DP has been greatly facilitated by the identiiîcation of a large number of dif ferent DPP alleles defìned by sequence polymorphism [9]. These molecular studies revealed that only a small proportion of DP varlability was previously detectable using primed lymphocyte typing. Molecuku DP typlng using the polymerase chain reaction (PCR) has been applied to coellac disease and has suggested that, in Italian patients, there is an association with the DP4.2 and DP3 alleles in addition to the DQw2 association. More work will be required to establish that this association is not due to linkage disequilibrium with the DR3 extended haplotype, as has been found in northern Europeans.
Non-HIA MHC genes Two papers have been published recently which describe careful searches of the region between complement and HIA-B for new transcribed sequences 114,151. These papers have revealed a remarkably high density of expressed genes, in the region of up to one expressed product every 23 kilobases. ‘I’his does not include new tissue-specifìc transcripts which may have been missed by the strategies used. The genes have been identlhed by screenlng messenger RNA with cosmids or by looking for Hpa tiny fragment islands in this region. In total, 17 new genes are described in these papers, all of which are expressed in a large number of different cell types. ~ny of these genes may be potential disease susceptibility loei and need to be characterized for polymorphism and function. The prospects are good, should this progress continue, that the non-HLA genes throughotit the MHC will all be cloned soon, adding a new dimension to studies of HLA and disease.
Annotated references and recommended reading 0
00
Multiple sclerosis ‘I’he MHC association with MS is with HLADR2 in white Caucasian individuals, although ethnic studies have indicated that there are increased frequenties of DR4 and DRw6. Comparison of these three sequences has revealed a sequence in DQfl that may be associated with MS [lol. ‘I’his could be best substantiated by establishing there there is a bias among DR6 subtypes in MS pa tients to the DR6associated DQB chains possessing this sequence. Other data provide suggestive evidente that haplotypes other than DR2 may contribute to MS susceptibillty [ 1lf This group found that a MspI polymorphism, detected with DQu , was found at an increased frequency among MS patients. This MspI polymorphism is associated with several haplotypes but may be linked to susceptibility factors that have not been del%&. ‘I’he most important development in the understanding of genetic susceptibility to MS has been the observation that both T cell receptor a- and B-chain haplotypes may be associated with disease. Oksenberg et al. [12] have provided evidente that RPLP deiïned by both Va and Ca fragments are increased in frequency in MS patients. In an extensive study of 40 multiplex families with MS, Seboum et al. [ 131 have shown that T cell receptor p-chain haplotypes segregate with the disease. This is further strong evidente of a role for T cell receptor gennline polymorphism in disease susceptibility, although, as with MIX determinants, this effect is likely to be small.
Of interest Of outstanding interest
1. 0
FIETCHER J, Mt~ovxz C, ODUGBESAN 0, JF.NKM D, BRADWEIL AR, BARNEP AH: Trans-racial studies implicate HLA-DQ as a component of genetic susceptibility to type-1 (insulin1988, 31864-870. dependent) diabetes. Diabew RFLP analysis is used in this study to chamcterize haplotypes associated with diabetes in an AfroCaribbean population. A DQg RFLP pattem unique to black.5 and absent in Caucasians was found associated with the DRw9 and some DR7 haplotypes. This particukir RFLP pattem is signihcantly increased h diabetes patients, indicating that DQ is Ekely to be the lotus responsible for susceptibility in this population.
2.
TODD JA, MJO~IC C, FWKHER J, JENKIIS D, BMLWELL AR, Bm AH: Identifïcation of susceptibilty loei for insulindependent diabetes meRitus by trans-racial gene mapping. Nature 1989, 33B587-588 This paper extends the observation which kientified a novel DR7 subtype based on DQg RFLP pattems. DR7 is an exceptiod haplotype as it does not possess an aspartic acid at position 57 and yet does not confer susceptibity to disease in Caucasians. This study shows that the DQa chain on the suscepdble DR7 haplotype in black popukttions is identical to that found on the DR4 haplotype in Caucasians, suggesting that the presence of a susceptible DQa chain on DR7 can resuk in DR7 becoming a haplotype associated with diabetes. ??m
FUTCHER J, ODUGBESAN 0, MJOWZ C, M&CKAY E, BI?ADWEIL AR, BARNETIAH: Class B HLA DNA polymorphisms in type-1 (insuBn-dependent) diabetic patients of North Indian origin. D&beroIo* 1988, 31343350. Using RFW for D@ and DXu, this s~dy reveakì that in an ethnic population from notthem India the DQB polymorphisms associated with diabetes are the sarne as those seen in white Caucasians. In addition, the RFJ_Pnomrally associated with protection from diabetes on the DR2 haplotype in white Caucasians are present on a different haplotype, DRw6, in northem Indians. Interestin&, it is tbis haplotype which is associated with protection against diabetes in this ethnic population, again strengthening the case for DQ in susceptibility and protection to this disease.
3. 0
115
116
Antigen recognition 4. oo
THOMSQN G, ROBINSONWP, K~HNERMK, JOE S, MACD~NAID MJ, G~TIXHAU JL, BAIWXA J, RICH SS, BEJ, BAUER MP, PLANEN J, TAIT BD, ~CHOBERE, MAARWR, L~JDVIGSSON J, IJNDBLOM B, FARIDNR, THOMPSONC, DESCHAMPS 1: Genetic
heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians wlth InsuKndependent diabetes mellitus. Am J Genet 1988, 43799-816. The most comprehensive review of the serological data associating par ticular HL4 alleles wlth insulindependent diabetes mellitus. This study has compiled the data from a large number of independent studies and has estabiished a hierarchy of risk factors for developing type 1 diabetes across a tide range of ciass Il haplotypes. 5. 0
TAE BD, MIW G, HARREQNLC: Association of HLA-DQw3 (TAlO-) with type 1 diabetes occurs wlth DR3/4 but not DR1/4 patients. Diubetes 1988, 37~92-29. The DQw3 ass&ation with diabetes is discus& ln this paper, par ticularly the DQ3.2 association which has been previously descrlbed. These authors demonstmte that the prevalente of 3.2 is most protinent in DR3/4 individuals,whlle in individualswho are DR1/4 one sees no preferent for the DQ3.2- assocaited DR4 haplotype. The decrease in B44-DR4 haplotypes is shown not to be the result of the DQw3 effect, but implies that this haplotype bas an additional effect. 6.
SHEEHYMJ, SCHARFSJ, ROWEJR, DEGIMENEZ MHN, MESKELM, A diabetes-susceptlble HLA haplotype is best defined by a comblnation-of HLA-DR &d HLA-DQ alleles. I Clin Invest 1989, 83830-835. Although I-IL&ljR is str&gly associated with’susceptibility to type 1 diabetes and the DR4 haplotypes tith DQ3.2, are these the most associated with the disea~? This paper demonstrates that certain haplotypes do not conform to these ruIes. In particular, susceptibility to diabetes seems to be conJ&d to the Dw4 and DwlO, DR4 haplotypes aud not the Dw14 haplotype, independent of DQ3.1 and 3.2 status. ??
ERUCH HA, NEPOM BS:
7.
BUGAWAN TL, ANGELINI G, IARRICK J, AURICCHIO S, FERRARA GB, ERLICH HA (Letter to the Editor) A comblnation of a particular HU-DPB allele and an HL&DQ heterodlmer confers susceptibility to coellac disease. Nature 1989, 339:47&472. Using the PCR-based typing system for HL&DP alleles, this paper suggests that there is an association between DPw.2 and DPp3 and coeliac disease. ??
8.
Som LM, MARKIJ~~EN G, GJERDEJEH, VARTDALF, THORSBY E: Evidente for a primary association of celiac response to a partlcular HL&DQ a/p heterodimer. J E@ Med 1989, 169:345-350. HIADR3 is the haplotype most strongly associated tith coeliac disease but individu& are also commonly found with HIADR7 haplotypes. This paper uses prevlously published sequence information to suggest that the DQ molecule on these haplotypes is responsibie for this susceptibility. The strongest evidente for this point of viw is that DR7 individualswho have the same JX@ as DR3 individualsinvariably have DR3 or DR5 as their second haplotype if they are coeliac patients. The DR3 and DR5 haplotypes share identical DQa alleles, implying that the a heterodimer from DQ is likely to be responsible for susceptibility. ??e
BUGAWANTL, HORN GT, LONG C, MICKEISON E, HANSENJA, FERRARA GB, ANGELINIG, ERUCH HA: Analysis of HLA-DP allelic sequence polymorphism using in vfhu enzymatic NDA amplification of DP-a and DP-fl loei. J Immunoll988, 141:4030. Nuclelc acid sequencing of PCR-amplilïed DPB alleles in this paper demonstrates that the nurnber of polymorphic variants is much larger 9.
?? o
than that predicted ptiousiy. A total of 14 diEerent alleles bas been defmed and a method for PCR typing these different alleles is described. 10.
G, RIORSBY E: VAPJDALF, SOLLIDLM, VANDWKB, MARK~SSEN Patients with multiple sclerosis carry DQBl genes which encode shared polymorphic amino acid sequences. Hum Immund 1989, 25:103-110. In merent etbnic subpopulations, HL&DR2, DR4 and DRw6 are asso ciated tith MS susceptibility. This paper describes the identication of a DQB sequence v,hich is shared between these haplotypes and which is present in a large number of MS patients. 0
11. ??
HF,ARDRNS, CULLENC, MIDDLETOND, HAWKINSSq FRANCIS DA, HERNJEC, MCDONALLI WI, BATCHELOR JR, IXCHLER RI: An allelic cluster of DQa restriction fragments is associated
with multiple sclerosis: evidente that a second haplotype may influence disease susceptihility. Hum Immund 1989, 25:111-124. When a population of MS patients and controls are independently pooled and screened with a large nurnber of restriction endonucleases and several HIA-D region probes, a unique M@ fragment is found to be more prominent with the DQu probe and the enzyme Ms#. This fragment, a 3.2 kilobase DQa band was observed in 31% of patients and only 4% of controls. The fragment is not associated tith the DR2 haplotype and can be present on the second haplotype in individuals tith disea~, irnplying that more than the Dl72 haplotype may be responsible for disea.~ susceptibility. 12. 0
OKSENBERG JR, SHE~ M, BEGOVICH AB, ERUCHHA, BERNARD CC, CAVAUSFORZALL, STEIIWANL T-cell receptor V, and
C, alleles associated wlth multiple sclerosis and myasthenla gravìs. Proc Nat1 Acad Sci LISA 1989, 86~9-2. T cell receptor a-chti V-and-C-region polymorphisms are described in this paper. Both a Va and Ca RPLP are found to be associated tith MS. This is the fìrst clear association of T cell receptor polymorphisms at a germline leve1 tith disea~ susceptibility. 13. 0
SEBOURNE, ROBINXINMA, Doom TH, CLLILIA TA, KINDT TJ, HAUSERSL: A susceptibilty lotus for multiple sclerosis
is Iinked to the T cell receptor $ chain complex. Ceu 1989, 5710951100. AlEcted sib-pair analysis is used to study the role of T ceII receptor pchain genes in susceptibility to MS. The authors have studied 40 such families and described descent between MS sibling pairs. This is strong support for a role for the T celI receptor in this disease. 14.
SPIEST, BIANCKG, BREWAHANM, SANDSJ, STROMINGER JL: A
nw cluster of genes withln the human major histocompatiblllty complex. Science 1989, 243:214-216. Cosmid mapping of 435 kilobases of DNA tirhin rhe HL4 benveen the turnour necrosis factor lotus and HLLB bas permitted the search for a nw transcribed loei. NW HL&B-associated transcripts (BATs) were identified and mapped in this region. Akhough constitutively expres&, these genes may have a role in human disease. 0
SARGENTA, Dm D, CAM~BELL RD: Identifïcation of multiple HTP lsland associated genes in the human major histocompatibility complex class III region. EMBO J 1989, 8:2305-2312. Tbis paper describes a careful study of 541 kilobases of genomic DNA and the characterization of 12 nw genes lying between complement and HL4-B. This paper demonstrates the very high density of expres& loei within the MHC and protides numerous candidate loei for diseasz associations. 15. *@