What is new in HLA in 1988?

E. D. Albert

___ 10

_

What is New in HLA in 1988?

INTRODUCTION

In the 3 years between the 9th! and the 10th International Histocompatibility Workshop, IS the field of histocompatibility testing has experienced the application of a wide variety of new techniques in the characterization of histocompatibility molecules (HLA antigens) and the identification of some of their functions. A large number of HLA genes has been cloned and transfected into mammalian cells. The gene product has been expressed on the cell surface, precipitated by monoclonal antibodies and the proteins have been characterized in one-dimensional (lD) and two dimensional (2D) gel electrophoresis. Class I antigens have been analysed using ID gel electrophoresis and it could be shown, that with very few exceptions the established HLA-A, -B and -C specificities can be subdivided on the basis of their electrophoretic mobility." Some of the splits detected in biochemistry have been found to be very highly correlated or even identical with the splits identified in serology." Class II alpha- and beta-chains have been characterized in 2D gel electrophoresis and it could be shown, for example for the DQ-beta-chains, that the variability detected in 2D gel electrophoresis corresponds very closely to the serological definition or to the RFLP patterns of the corresponding genes." T-cells of proliferative or cytotoxic function have been cloned which detect, either by allospecificity or by restriction specificity, epitopes on HLA antigens. Monoclonal antibodies have been defined, which are directed against monomorphic determinants of the various types of class II antigens, so that inhibition studies with these monoclonal antibodies can be used to determine against which type of molecule (for example DR(3 or DQ(3) the T cells are directed. Many specificities detected by serology, biochemistry and/or RFLP-patterns can also be detected by T cells.'? HLA-genes and alleles are now being studied on the level of the DNA, utilizing restriction-fragment-length-polymorphism (RFLP), allowing analyses of structural genes and flanking regions with a much improved power of resolution. Specificities of the HLA-DR, DQ and DP-series can now be typed on the level of the DNA. 2,3,28 Moreover, many DR- and DQ-specificities can be subdivided using RFLPs, thus

207

208

Albert

providing considerably more genetic information than mere serology.l-' As the number of HLA-alleles, which are sequenced on the level of the DNA is increasing monthly, so is the possibility of applying synthetic oligonucleotides corresponding to critical regions of the gene for direct DNA-typing. The technique of pulsed field gel electrophoresis allows now the separation of larger fragments of DNA (up to 200 kb) which can then by hybridized with the various gene probes facilitating the analysis of the orientation of closely linked genes and the detection of deletions or duplications in certain regions of the HLA chromosorne.i':" This methodology has become most important because it is now clear that there is not only an extensive polymorphism of the alleles of the various loci, but that there is also polymorphism in the sense that for example one chromosome may carry up to four different DR-beta-chain genes, while other chromosomes carry only one. Finally, the analysis of crystallographic data of the first HLA antigen to be crystallized has yielded exact information as to the tertiary structure of the HLA-A2 molecule.t-" which now allows the identification of amino acids, which, although in different parts of the amino acid sequence, are neighbours within the folded molecule and thus form a joint epitope. Furthermore, it has been seen, that the HLA-A2 molecule possesses a groove, which is most likely the structural feature responsible for the receptor-like function of HLA molecules. The size of this groove however suggests that antigen must be processed (i.e. digested) in order to fit there. 5•6 From these results it can now also be deduced which amino acid substitutions are expected to alter the receptor-like interaction with antigen and which amino acids substitutions would be involved in sites recognized by the T cell receptor restriction speclficity.S" It can be expected now, that on the basis of these new results, there will be numerous attempts to explain in more functional terms the involvement of histocompatibility antigens in transplantation, immune response and disease association.

DEFINITIONS For the proper use of HLA nomenclature, it may be helpful to briefly review some of the technical terms used in HLA nomenclature: The HLA phenotype represents the sum of all antigens or markers found for a given individual. The HLA genotype, which can be deduced unequivocally only by means of a family analysis, describes the combination of antigens and markers inherited from the father and from the mother. A genotype consists of two hap!otypes, which describe the combination of HLA antigens and markers inherited together on one parental chromosome. Haplotypes, which show a high linkage disequilibrium ( = association between antigens belonging to different but closely linked loci) are sometimes referred to as 'extended haplotypes' or as 'supratypes', terms which express in a certain way some mystical meaning given to these haplotypes. However, these terms are not helpful as they are not exactly defined and thereby only add to confusion. For example, the so called 'extended haplotype' AI, B8, DR3 is not really extended, but in reality probably shorter than most other haplotypes and does not really become any longer at all, even if one extends the testing of these individuals or families to include the C2 and C4 complement allotypes. If one is using the extent of the linkage disequilibrium between the different markers on the chromosome to distinguish

209

HLA in 1988 Table 10-1 New Names for Genes in the HLA Region" Name

Previous Equivalents

Molecular Charateristics

HLA-E

E, '6.2'

HLA-DRA HLA-DRBI

DRalpha DR/3I, DRIB

HLA-DRB2 HLA-DRB3

DR/3I1, DR2B DR/3I11, DR3B

HLA-DRB4 HLA-DQAI HLA-DQBI HLA-DQA2

DR/3IV, DR4B DQalphal, DQIA DQ/3I, DQIB DXalpha, DQ2A

HLA-DQB2

DX/3, DQ2B

HLA-DOB HLA-DNA HLA-DPAI HLA-DPBI HLA-DPA2 HLA-DPB2

DO/3 DZalpha, DOalpha DPalpha I, DPIA DP/3I, DPIB DPalpha 2, DP2A DP/32, DP2B

Associated with class I 6.2 kB Hind III fragment (24) DR alpha-chain DR/31 chain determining specificities DRI, DR3, DR4, DR5 etc. Pseudogene with DRI3-like sequences DR133 chain determining DRw52 and Dw24, Dw25, Dw26 specificities (33) DR/34 chain determining DRw53 (18) DQ alpha-chain as expressed DQ/3 chain as expressed DQ alpha-chain related sequence, not known to be expressed DQ/3 chain related sequence, not known to be expressed DO/3 chain DN alpha-chain DP alpha-chain as expressed DP/3 chain as expressed DP alpha-chain related pseudogene DP/3 chain related pseudogene

between so called 'supratypes' and normal haplotypes, one would have to define first a cut-off point for strong linkage disequilibrium. Linkage disequilibrium is however strongly dependent on the population in which it is tested and therefore does not represent an absolute value. An antigen represents the sum of all structural features of a single molecule which can be recognized by antibodies or T cells. Analysis of antisera, of monoclonal antibodies and of antigens shows, that each HLA molecule (= antigen) possesses various structural features, to which antibodies can bind or which may be recognized by T cells. These structural features are called epitopes. The term specificity is used to describe the property of an antiserum or a monoclonal antibody to distinguish between cells (or molecules) which are positive or negative for this specificity. The term specificity is also sometimes used, somewhat loosely, to describe the property of a cell or a molecule reacting positively with a number of antisera or with a monoclonal antibody. The term allele describes a variant gene at a given locus and it is reserved for the entire DNA sequence of a polymorphic gene coding for a polypeptide chain as for example Dk-bet> or DQ-alpha.

THE NEW NOMENCLATURE FOR GENES AND ALLELES The Xth International Histocompatibility Workshop 198715 has produced a wealth of new data and knowledge about the genetics of the HLA system. As is

Albert

210 Table 10-2 New Designations of HLA-A and B Alleles" New HLA Alleles

HLA Specificity

A*OZOI

AZ AZ AZ AZ

A*OZOZ A*OZ03 A*OZ04

B*0701 8*070Z

Previous Equivalents (ref.) AZ.Z(l6)

AZ.1/ AZ.4(l6) AZ.3?(16) AZ.3?(l6)

8*Z701

BZ7 8Z7 8Z7

8*2704 8*2705 8*2706

827 827 827

(Z7) (16, Z7)

(27) (27) (36) (4)

B7 87

8*Z70Z 8*Z703

References for Sequence Data

Z7f(ZI) Z7e(21), 27K(22), 827.2(Z3) 27d(21), 27J(22) 27b(21), 27c(22), 827.3(23) 27a(ZI), Z7W(22), 827.1(23) 270(22)

(31) (34) (13, 32) (39) (34, 40) (38).

customary, the WHO Nomenclature Committee for Factors of the HLA System has .met after the workshop and has in view of the most recent developments decided on an extension of the Common Nomenclature for HLA genes, alleles and antigens.I? In its decisions, the committee has followed closely the recommendations on Nomenclature by the Human Gene Mapping Conference.P The gene loci within the HLA system are named with the prefix HLA and capital letters, separated by a dash. In the case of loci coding for class I products, a single letter is added (A, B, Cor E; reserving F, G, H and so on for further so far undetected class I gene loci). For the class II products, the gene loci are named with two letters, signifying the region (such as DR, DQ, DP, DO, DN) and the letter A for alpha-chain loci and B for beta-chain loci. If there are more than one alpha- or beta-chain loci in the respective class II region, as is the case for DR, where there may be one, two, three or four different beta-chain genes in the region, then these loci are numbered with arabic numbers I, 2, 3 and 4 respectively. A list of new designations for HLA loci is given in Table 10-1. It is now for the first time possible to give definite names to alleles, for which the entire sequence has been determined and confirmed. As an example may serve the different gene sequences for HLA-B27 molecules: In order to maintain the relationship with the original serologically determined specificity B27, the first allele for which the amino acid sequence was known is then named HLA-B*2701 and the following B27 subtypes are named HLA-B*2702, HLA-B*2703 and so on. The introduction of the * has been necessary to separate the designations for the gene locus from the designation for the allele number. Thus, if one is referring to the allele, the full designation HLA-B*2701 must be used or a shorthand version of this B2701 in italic writing. Tables 10-2 and 10-3 give a listing of the final Nomenclature for sequenced alleles, recognized today.

211

HLA in 1988 Table 10-3 New Designations of HLA-D Region Alleles" New HLA Alleles

HLA·DR Specificities

HLA-D Associated (T cell defined) Specificities

References

DRBI*0401 DRB I*0402 DRBI*0403 DRBI*0404 DRBl*0405

DR4 DR4 DR4 DR4 DR4

Dw4 DwlO Dwl3 Dwl4 Dwl5

(19) (19) (9) (9,19) (19)

DRB3*0101 DRB3*0201 DRB3*0301

DRw52a DRw52b DRw52c

Dw24 Dw25 Dw26

(33) (33) (33)

DRB4*0101

DRw53

Dw4, DwlO, Dw13, Dw14, Dw15, Dw17, Dw23 (20, 42)

THE NEW MAP OF THE HLA REGION Figure 10-1 gives a representation of the various genes in the HLA region on the short arm of chromosome no. 6. In the class I region between HLA-A and HLA-C, a new gene locus has been defined with methods of molecular biology.P It is, however, not yet clear, whether this gene locus shows a polymorphism and whether its products are expressed and on which cells. In the class II region, it has been shown that there may be, depending on the haplotype, between one and four different genes for DR-beta-chains. There is, until now, no proof that more than two of these beta-chain genes on one haplotype are expressed. In fact, on some haplotypes the HLA-DRB2 gene is a pseudogene. In the DQ-region we find two alpha- and two beta-chain genes of which there is only one pair expressed (at least on the haplotypes which have been investigated so far). In the DQ-region, the alpha-chain genes are polymorphic and this leads in heterozygote individuals to the theoretical possibility of the formation of hybrid antigens formed by an alpha-chain of one parental haplotype combining with a betachain of the other parental haplotype. It has been demonstrated, that such hybrid antigens do indeed exist;'! and evidence from the mouse shows that even alpha- and beta-chains coded for in different regions can combine to form a functional dimer. This, however, has not been shown in man so far. Between the HLA-DQ and the -DP region, there is a single alpha-chain locus (HLADNA) and a single beta-chain locus, HLA-DOB. It is presently unknown, whether these chains are expressed and whether they form a dimer. In the DP region, there are again two alpha-chain genes and two beta-chain genes and only a pair of these appears to be expressed (DPAI and DPBl). In the region between HLA-DR and HLA-B, there are a number of genes coding for complement components: C2, Bf, and the duplicated loci C4A and C4B. In very close proximity to the C4A and C48 loci we find the loci for C21-Hydroxylase: C21OHA and C21OH-B. Present knowledge indicates, that the C21OH-A gene is not expressed.

HLA-OP

Gene:

Product:

82 A2 !ll

Al

I

I

I

02 ta

ON

CXJ

A

B

H.A-CQ B2 A2

B1 A1

IlA-OO

ill

B2

8J

£l4 A

C4 B

C4 A Bf C2

rtF A 8

HLA-

B C

E:

A

I I I I

01 IX.!

-------------------------------------- Class II -----------

Figure 10·1.

Genetic organization of the HLA complex on chromosome 6.

-- Class I --

HLA in 1988

213

Table 10-4 New Provisional Designations of HLA-A,B and C Specificities29 New

Previous Equivalents

Associated with

Aw74

Th

Bw75 Bw76 Bw77

Bw62.1(15), SH7, STI ISS, 15.4 15T,15.2

Bw6 Bw6 Bw4

Cw9 CwlO CwlI

Cw3.1 Cw3.2 CX46, Cwl +3, Cwl x3

8w55 Bw60 Bw46

This may however be different on different haplotypes. In general, the entire region between C2 and C21OH-B is characterized by a high frequency of duplications and/or deletions involving one or more genes and DNA-sequence between the genes. The orientation of the block of complement genes between HLA-B and HLA-DR has been subject of considerable controversy. Investigations with pulsed field gel electrophoresis-I-" have now confirmed the prediction of Marshall et aI. 1984,26 that the C2-gene is closer to the HLA-B locus. The most recent addition to the HLA map are the two loci for tumornecrosis factor alpha (cachectin) and beta (lymphotoxin). These genes code for mediators, which play an important role in the interaction of immune cells. The TNF genes show some kind of regulatory polymorphism in the mouse" and therefore it is quite likely, that these genes are polymorphic also in man and it is possible that such a polymorphism plays an important role in the regulation of the immune response, in transplantation and disease association.

NEW CLASS I SPECIFICITIES The designations for new HLA-A, -B and -C specificities are listed in Table lOA. The only new specificity of the HLA-A series is Aw74, previously known as Th, defined by reactivity with some long Awl9 antisera. This antigen is found mainly in black populations. The three new HLA-B locus specificities are HLA-Bw75, Bw76 and Bw77. All three are splits of B15. Bw75, previously known as Bw62.1, SH7 or TSI is a 'short' variant of Bw62 (Le. reacting with some but not all anti-Bw62 antisera) found in Caucasians and Orientals and exhibiting strong cross-reactivity with anti B35 antisera. HLA-Bw76, formerly BI5S, is characterized by cross-reactivity with anti-B45 sera. This antigen is found mainly in the Thai-population. HLA-Bw77, previously called BI5T, cross-reacts with anti-Bw53 sera and is included in Bw4, while Bw75 and Bw76are included in Bw6. The new HLA-C locus specificities are Cw9, CwIO and Cwl l , Cw9 and Cw l O are splits of Cw3. HLA-Cw9 formerly Cw3.1 is associated with Bw55 while CwlO, previously called Cw3.2 is associated with Bw60. Bw62 is found in association with both, Cw9 and CwlO.

214

Albert

Table 10·5' New Provisional Designations of HLA-DR and DQ Specificiries" New

Previous Designations

Associated with

DRwl5 DRwl6 DRwl7 DRwl8

DR2Iong DR2short, FT31 DR310ng DR3short

Bw42

DQw4 DQw5 DQw6 DQw7 DQw8 DQw9

DQ'Wa' DQ'I.I' DQ'1.2' DQ'3.I', TAIO +, IIB3-, DQ'3.2', TAIO-, 11B3+, DQ'3.3', TAIO-, IIB3+,

DRw8, Dwl5 DRI, DRwlO, DRwl4, DRwl6 DRwl3, DRwl5 DRwll, DRwl2, DR4 DR4 DR7, DR9

Cwll is the new official name for the C-locus antigen associated with Bw46, formerly known as Cwl x 3. This is an antigen, which one had formerly believed to represent a C-locus duplication, consisting of a Cwl gene and a Cw3 gene on the same haplotype. Recent sequence data show however, that this antigen is coded for by a single gene, which carries both sequences common to Cwl and Cw3. Cwll is found almost exclusively in Chinese or Southeast Asian populations and is strongly associated with Bw46 and A2.

NEW CLASS II SPECIFICITIES (Table 10·5) HLA·DR

New official designations have been given to the splits of DR2 and DR3. DRwl5 is the common variant of DR2 ('DR2 long') while DRwl6 is the new designation for 'DR2 short' (the term 'short' is laboratory jargon referring to the fact that, cells with this antigen in this case the antigen DRwI6, are negative with some anti-DR2 antisera, which are however positive with DRwI5). HLA-DR3 was split into HLA·DRw17, which is the common form of DR3 in Caucasoids and DRwl8, which is defined by a 'short' reaction pattern with DR3 antisera and which is found in association with Bw42 in Black populations. Due to the high quality of serological definition, the antigen DRw9 was upgraded to DR9, dropping the 'w' designation according to previously established criteria for the Nomenclature of HLA Factors.

HlA-DQ

Six new provisional DQ-designations have been assigned. DQw4, formerly 'WA' is a new allele of DQwl, DQw2 and DQw3 and is identified by a monoclonal antibody and alloantisera also reacting with DQwl and DQw8. DQw4 is found in linkage disequilibrium with DRw8, DRwl8 and a subset of DR4 (the Dwl5 positive one).

215

HLA in 1988 Table 10-6 New Provisional HLA-D (T cell defined) Specificlties" New

Previous Designations

Associated with

Dw20 Dw21 Dw22 DW23 Dw24 Dw25

LDI4, LVA LD2s, I\1N2, FlO, AZH DB9, LD5a DB5 52a, LB-Q4, /3111-3 52b, LB-QI, /3111-1, BO-I

Dw26

52c, /3111-2

DRI, DQw5, Bl4 DRwI6, DQw5 DRwl6, DQw7 DR9, DQw9 B8, DR3, DRw13, Dwl8, DRwl4, Dwl6 BI8, DR3; DRwII, Dw5; DRwI2, DB6; DRw13, Dwl8, DRwl4, Dw9 DRw13, Dwl9

Table 10·7 HLA-D (T cell defined) and DR Relationships" HLA-O Specificities

Associated OR Specificities

Owl,Ow20 Ow2,Owl2 Ow21,Ow22 Ow3 Ow4, OwlO, Owl3, Owl4, Dwl5 Ow5 Ow6, Ow18, Dwl9 Ow9, Owl6 Ow7, Owll, Owl7 Dw8 Dw24, Ow25, Dw26

DRI ORwI5(2) DRw I6(2) DR3 DR4 ORwll(5) DRw13(w6) DRwI4(w6) DR7 DRw8 DRw52

DQwI was split into DQw5 and DQw6. DQw5, formerly DQwl.l is associated with DRI, DRwlO, DRwI4 and DRwI6. DQw6, formerly DQ'I.2', the other split of DQwI, is found in linkage disequilibrium with DRw13 and DRwI5. DQw3 has been split into DQw7, DQw8 and DQw9. DQw7, formerly TAlO or DQ'3.I', is identified by monoclonal antibodies (TAlO positive, 11B3 negative). DQw7 is found on most DRwII and DRwI2 haplotypes and on the majority of the DRw8 haplotypes, which are not DQw4 positive. DQw8, formerly DQ'3.2', (TAW negative and 11B3 positive) is the second split of DQw3 in linkage disequilibrium with DR4. DQw9 is the third split of DQw3 (also TAlO negative and 11B3 positive) and is found on DQw2 negative haplotypes carrying DR9 and DR7. It should be stressed again, that one of the most important findings of the Xth International Histocompatibility Workshop was, that all of the above discussed new specificities and most of the already established ones can now be defined or confirmed using one or more techniques other than serology. This is particularly true for the alleles of the class 11 region, where cloned T cells, 2D-gel electrophoresis and especially RFLP analysis have greatly helped in identifying new subdivisions. Once a subdivision

Albe

216 Table 10-8 Complete Listing of Recognized HLA Specificities-? HLAA

B

C

D

DR

DQ

DP

Al A2 A3 A9 AIO All Awl9 A23(9) A24(9) A25(10) A26(10) A28 A29(wI9) A30(wI9) A31(wI9) A32(wI9) Aw33(wI9) Aw34(10) A\\'36 A\\'43 A\\'66(10) A\\'68(28) A\\'69(28) Aw74(wI9)

B5 B7 B8 BI2 BI3 BI4 BI5 BI6 BI7 BI8 B21 Bw22 B27 B35 B37 B38(16) B39(16) B40 Bw41 Bw42 B44(12) B45(12) Bw46 Bw47 Bw48 B49(21) Bw50(21) B5I(5) Bw52(5) Bw53 Bw54(w22) Bw55(w22) Bw56(w22) Bw57(17) Bw58(17) Bw59 B\\'60(40) B\\61(40) B\\'62(15) B\\63(15) B\\'64(14) Bw65(14) B\\67 Bw70 Bw71(w70) Bw72(w70) Bw73 Bw75(15) Bw76(15) Bw77(15) Bw4 B\\'6

Cwl Cw2 Cw3 Cw4 Cw5 Cw6 Cw7 Cw8 Cw9(3) CwIO(3) Cw11

Dwl Dw2 Dw3 Dw4 Dw5 Dw6 Dw7 Dw8 Dw9 DwIO Dw11(w7) Dwl2 DwI3 Dwl4 Dwl5 Dwl6 DwI7(w7) DwI8(\\'6) DwI9(\\'6) Dw20 Dw21 Dw22 Dw23 Dw24 Dw25 Dw26

DRI DR2 DR3 DR4 DR5 DR\\6 DR7 DRw8 DR9 DRwlO DRw11(5) DRwI2(5) DRw13(\\6) DRwI4(\\6) DRwI5(2) DRwI6(2) DRwI7(3) DRwI8(3)

DQwl DQw2 DQw3 DQw4 DQw5(wl) DQw6(wl) DQw7(w3) DQw8(w3) DQ\\9(w3)

DPwl DPw2 DPw3 DPw4 DPw5 DPw6

DRw52 DRw53

HLA in 1988

217

is defined in a panel of cells, it will also be possible to find or produce the appropriate serological reagents for the definition of these specificities.

HLA·DP No new HLA·DP specificities have been identified in this workshop. It should however be pointed out, that the DP-polymorphism can now be analysed on the DNA level using RFLP'S,28 which circumvenes the great difficulties encountered in production and maintenance of DP specific primed lymphocytes.

HLA-Dw Traditionally, HLA-specificities defined in Mixed Leucocyte Culture using HLAD region homozygous typing cells, have been given HLA-Dw designations. In the Xth International Histocompatibility Workshop, cytotoxic or proliferative T cell clones have been used for the definition of HLA-class II specificities. It was therefore decided, to extend the definition of Dw specificities to include determinants defined by cloned T cells. The new HLA-Dw specificities are listed in Table 10-6. The relationship between HLA-Dw and -DR specificities are presented in Table 10-7. A compl ete listing of recogniz ed HLA-specificities is given in Table 10-8.

REFERENCES Albert ED, Baur MP, Mayr WR: Histocompatibility Testing 1984. Sprin ger Verlag, Heidelberg, 1984. 2. Bidwell JL, Jarrold EA: HLA-DR allogenotyping using exon-specific cDNA probes and application of rapid minige1 methods. Molec Immunol 23(10):1111-1116,1986. 3. Bidwell JL, Bidwell EA, Laundy GJ, Klouda PT, Bradley BA: Allogenotyped definition by short DQalpha and DQbeta cDNA probes correlate with and defined splits of HLA DQ serological specificities. Molec Immunol 24(5):513-522, 1987. 4. Biro PA, Pan J, Sood AK, Kole R, Reddy VB, Weissman SM: The human major histocompatibility complex. Cold Spring Harbor Symp Quant BioI 47:1079-1086, 1983. 5. Bjorkman PJ, Saper MA, Samraoui D et al: Nature 329:506-512, 1987. 6. Bjorkman PJ , Saper MA, Samraoui Bet al: Nature 329:512-518, 1987. 7. Brenner l\IB , McLean J, Yang SY, van der Poel JJ, Pious D, Strorninger JL : Clonal T lymphoc yte recognition of the fine structure of the HLA-A2 molecule. J Immunol 135:394-390, 1985. 8. Dreur-Vriesendorp BS, Neefjes JC, Huis B, van Seventer GA, Ploegh HL, Ivanyi P: Identifi cat ion of new B27 subtypes (B27C and D27D) prevalent in Oriental populations. Hum Immunol 16:163-168, 1986. 9. Cairns JS, Cursinger JM, Dahl CA, Freeman S, Alter BJ, Bach F: Sequence polymorphism of HLA·DR{3I chain alleles relating to T-cell-rccognised determinants. Nature 317:166-168, 1985. 10. Carrolll\IC, Katzman P, Alicot El\I, Koller BH, Geraghty DE, Orr HT, Strominger JL , Spies T: Linkage map of the human major histocompatibility complex including the tumo r necrosis factor genes. PNAS USA, 84:8535-8539, 1987. I.

218

Albert

11. Charron D, Lotteau V, Turme1 P: Hybrid HLA-DQ antigens: molecular expression, in: Histocompatibility Testing 1984, Albert ED et al. (eds): Heidelberg, Springer Verlag, 1985, pp. 539-543. . 12. Choo SY, Antonelli P, Nisperos B, Nepom GT, Hansen JA: Six variants of HLA-B27 identified by isoelectric focusing. Immunogenetics 23:24-29, 1986. 13. Choo SY, St John T, Orr HT, Hansen JA: Molecular analysis of the variant alloantigen HLA-B27d identifies a unique single amino acid substitution (submitted). 14. Dunham I, Sargent CA, Trowsdale J, Campbell RD: Molecular mapping of the human major histocompatibility complex by pulsed-field gel electrophoresis. PNAS USA, 84:7237-7241, 1987. 15. Dupont B (ed): Histocompatibility Testing 1987, New York, Springer Verlag, 1988. 16. Ezquerra A, Domenech N, van der Poel JJ, Strominger JL, Vega MA, Lopez de Castro JA: Molecular analysis of an HLA-A2 functional variant, CLA, defined by cytotoxic T lymphocytes. J Immunol 137:1642-1649, 1986. 17. Flomenberg N et al: Joint report: T-cel! clones, in: Histocompatibility Testing 1987, Dupont B (ed): New York, Springer Verlag, 1988, in press. 18. Gorski J, Rollini P, Mach B: Structural comparison of the genes of two HLA-DR supertypic groups: the loci encoding DRw52 and DRw53 are not truly allelic. Immunogenetics 25:397-402, 1987. 19. Gregersen PK, Shen 1\1, Song Y, Merryman P, Degar S, Seki T, Maccari J, Goldberg D, Murphy H, Schwenzer J, Wang CY, Winchester RJ, Nepom GT, Silver J: Molecular diversity of HLA-DR4 haplotypes, PNAS USA, 83:2642-2646, 1986. 20. Gregersen PK, Moriuchi T, Karr RW, Obata F, Moriuchi J, Maccari J, Goldberg D, Winchester RJ, Silver J: Polymorphism of HLA-DR,B chains in DR4, -7 and -9 haplotypes: Implications for the mechanisms of allelic variation. PNAS USA, 83,9149-9153, 1986. 21. Inoko H, Tsuji K, Groves V, Trowsdale J: Mapping of HLA region genes by pulsed field gel electrophoresis and comid walking, in: Histocompatibility Workshop 1987, Dupont B (ed): New York, Springer Verlag, 1988, in press. 22. Jacob ChO, McDevitt HO: Tumor necrosis factor-alpha in murine autoimmune 'lupus' nephritis. Nature 331:356-358, 1988. 23. Knowles R et al: Joint report: Class II Biochemistry, in: Histocompatibility Testing 1987, Dupont B (ed): New York, Springer Verlag, 1988, in press. 24. Koller BH, Geraghty D, Orr HT, Shimizu Y, Dextars R: Organisation of the human class I major histocompatibility complex genes. Immunol Res 6:1-10, 1987. 25. Lechler RI: MHC Class II molecular structure-permitted pairs? Immunology Today 9(3):76-78, 1988. 26. Marshall WH, Neugebauer M, Baur MP, Albert ED: The second-component of complement in the 9th Workshop, in: Histocompatibility Testing 1984,Albert ED et al (eds): Heidelberg, Springer Verlag, 1984, pp. 313-317. 27. Mattson DH, Handy DE, Bradley DA, Coligan JE, Cowan EP, Biddison WE: DNA sequences of the genes that encode the CTL-defined HLA-A2 variants 1\17 and DKI. Immunogenetics 26:190-192, 1987. 28. Mitsuishi Y, Urlacher A, Tongio MM, Mayer S: Restriction fragment length polymorphism of DP genes defines three new DP alleles. Immunogenetics 26:383-388, 1987. 29. Nomenclature for Factors of the HLA-System 1988. Bull WHO, Basel, in press. 30. Parham Pet al: in: Histocompatibility Testing 1987, Dupont B (ed): New York, Springer Verlag, 1988, in press. 31. Rojo S, Aparicio P, Choo SY, Hansen JA, Lopez de Castro JA: Structural analysis of an HLA-B27 population variant, B27f. Multiple patterns of amino acid changes within a single polypeptide segment generate polymorphism in HLA-B27. J Immunol 139:831-836, 1987.

HLA in 1988 32.

33. 34. 35.

36.

37.

38.

39.

40.

41. 42. 43.

219

Rojo S, Aparicio P, Hansen JA, Choo SY, Lopez de Castro JA: Structural analysis of an HLA-B27 functional variant, B27d, detected in American Blacks. J Immunol 139:3396-3401, 1987. Rollini P, Mach B, Gorski J: Linkage map of three HLA-DR-I3-chain-genes: evidence for a recent duplication event. PNAS USA, 82:7197-7201, 1985. Seemann GHA, Rein RS, Brown CS, Ploegh HL: Gene conversion-like mechanisms may generate polymorphism in human class I genes. El\IBO J 5:547-552, 1986. Shows TB, Alpher CA, Bootsma D, Dorf M, Douglas T, Huisman T, Kit S, Klinger HP, Kozak C, Lalley PA, Lindsley D,l\1cAlphine PJ,McDougall JK,l\leera Khan P, Meisler M, Morton NE, Opitz Jl\l, Partridge CW, Payne R, Roderick TH, Rubinstein P, Ruddle FH, Shaw M, Spranger JW, Weiss K: International System for Human Gene Nomenclature (1979). Cytogenet Cell Genet 25:96-116, 1979. Taketani S, KrangelMS, Spits H, de Vriees J, Strominger JL: Structural analysis of an HLA-B7 antigen variant detected by cytotoxic T lymphocytes. J Immunol 133:816-821, 1984. Toubert A, Gromard E, Grurnet FC, Amor B, Muller JY, Levy JP: Identification of several functional subgroups of HLA-B27 by restrictioni of the activity of antiviral T killer lymphocyte. Immunogenetics 20:513-525, 1984. Vega MA, Wallace L, Rojo S, Bragado R, Aparicio P, Lopez de Castro JA: Delineation of functional sites in HLA-B27 antigens. Molecular analysis of HLA-B27 variant We\\:ak I defined by cytotoxic T lymphocytes. J Immunol 135:3323-3332, 1985. Vega MA, Bragado R, Ivanyi P, Pelaez JL, Lopez de Castro JA: Molecular analysis of a functional subtype of HLA-B27. A possible evolutionary pathway for HLA-B27 polymorphism. J Immunol 137:3557-3565, 1986. Weiss EH, Kuon W, Dorner C, Lang 1\1, Riethmiiller G: Organization, sequence and expression of the HLA-B27 gene: A molecular approach to analyze HLA and disease associations. Immunobiol 170:367-380, 1985. Yang SY et al: Joint report: Class I Biochemistry, in: Histocompatibility Testing 1987, Dupont B (ed): New York, Springer Verlag, 1988, in press. Young JAT, Wilkinson D, Bodmer WF, Trowsdale J: Sequence and evolution of HLADR7- and -DRw53-associated l3-chain genes. PNAS USA, 84:4929-4933, 1987. Ziegler A, Schneider P, Trowsdale J, Weiss E, Ragoussis J: Towards a physical map of the HLA complex, in: Histocompatibility Testing 1987, Dupont B (ed): New York: Springer Verlag, 1988, in press.