The MHC: relationship between linkage and function John Trowsdale and Stephen H. Powis Imperial C a n c e r Research Fund, L o n d o n It is intriguing that several genes with associated functions, including all of class I and class II genes, as well as some genes affecting antigen presentation of both class I and class II pathways, are linked in the MHC. Recent observations have led to speculation that there may be a functional explanation for keeping these related genes together. Current Opinion in Genetics and Development 1992, 2:492-497

Introduction: the MHC map The major histocompatibility complex (~@IC) has been the subject of intense study for several decades and the detailed physical map that has resulted provides a model for other regions of the mammalian genome. Close to 4 Mb of MHC DNA has now been cloned and mapped, encompassing some 80 genes. In the class III region, a gene has been found every 20 kb, indicating that there is still room for many more genes within other regions [1]. Most MHC genes are present in humans and rodents in similar positions [2,3,4]. The purpose of this review is to outline some of the novel genes that hm,e been found in the MHC during file past year and to speculate on any possible functional relationships.

The interesting genetics of the MHC

or to avoid cemdn combinations of polymorphic alleles. Third, exchanges of sequences can take place between related but different loci within the region, by gene conversion or non-homologous recombination [10]. Finally, a large number of mostly autoimmune diseases are associated with the MHC although it has been difficult to assign these associations to one particular locus [11]. Certain of these features are consistent with the hypothesis that the MHC does not simply contain a random scattering of genes with unrelated functions although some MHC loci do fall into this category [3,12,13]. For example, the RING3gene in the class II region is a ubiquitously expressed gene highly homologous to the Drosophila sequence female sterile homeotic and is unlikely to have a function in the immune system [14].

Linkage of related genes

The MHC is particularly interesting for several reasons. First, it contains the most highly polymorphic expressed loci in mammalian genomes, the class I and II genes, which are clustered together in gene fanlilies. New class I- and class II-related genes are still being uncovered in the MHC. For example, the class II regions of both mice and man encode a novel class II heterodimer, human leukocyte antigen (HLA)-DM [5,6]. By sequence comparison, this molecule is equidistant from class I and II and may have predated them in evolution. Its function is not known although some of the many odd class I and II sequences could in theory be specialized in their functions. A precedent for this is the class I M region product which may be dedicated to presenting bacterial f-Met peptides (Fig. 1)[7]. Second, there is evidence of linkage disequilibrium, both over short distances (DQ-DR) and over large extended haplotypes [8], as well as of highly non-random recombination in several regions [9], indicative of selective pressures to maintain

There are hints that some MHC genes enjoy a selective advantage by being linked. The most conspicuous members of the MHC are tile sequence-related class I and II genes. It is striking that except for distantly related members of the Ig-gene family, as well as the genes located on chromosome 1 that encode the CD1 antigens, there are no class I genes, or pseudogenes, outside the MHC. Class I and II sequences appear to have been maintained together in a variety of species, including chickens. An attractive explanation for the continued linkage of class I and II is that it is functionally advantageous for shaping the T-ceU repertoire, as products from both regions are involved in positive and negative T-cell selection [15]. Until recently, there was little evidence for any other functional relationships in the MHC cluster, although the finding within the region of an occasional new gene with possible immunological functions related to autoimmunity - - for example, tumour necrosis factor (TNF)-~x

Abbreviations ABC--ATP-binding cassette; cim--class I modifier; ER--endoplasmic reticulum; HLA--human leukocyte antigen; Hsp~heat-shock protein; IDDM--insulin-dependent diabetes mellitus; MHC--major histocompatibility complex; NK--natural killer; TAP--transporter associated with antigen processing; TNF~tumour necrosis factor.

492

~)-Current Biology Ltd ISSN 0959-437X

The MHC: relationship between linkage and function Trowsdale, Powis

Antigen-processing

and -13, and heat-shock protein (Hsp)-70 has stimulated much interest [16,17,18]. A recent report claimed that the Hsp70 molecule contains a putative peptide-binding site [19]. It could thus be acting to chaperone peptides during antigen processing and may also be displayed on the cell surface [20]. Another provocative observation is the finding that susceptibility to lysis by alloreactive natural killer (NK) cells is governed by a gene at the class I end of the MHC [21]. The most compelling illustration of functional linkage concerns the recent, exciting discovery of antigen processing genes that are involved in the assembly of class I molecules and which are located within the class II region (for reviews see [22-24]).

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Cell lines with mutations in the MHC and associated defects in the pathway for processing endogenous antigens have provided the stimulus for some exciting new observations ([25-28] and references therein). The mutants have facilitated the identification of two genes in the class II regions of humans and rodents with sequence identity to members of the ATP-binding cassette (ABC) superfamily. Members of the ABC family transport a wide variety of substrates, including oligopeptides, across cell membranes, The transporters associated with antigen processing (TAPs) are encoded by the new MHC trans-

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Fig. 1. Possible inter-relationship of genes and functions in the human MHC. (a) The main divisions of the MHC are shown (Classes I, II and III). Linkage disequilibrium (indicated by the dotted line) is a feature of many pairs of polymorphic loci in the MHC (e.g. see [8]). A gene that affects the expression of certain class II epitopes has recently been localized to the class I1-111region (Class II conformation factor)J54.]. Gene conversion, or other sequence exchange mechanisms, are hypothesised to take place (e.g. see [10]). The other genes indicated are described in the text (see also [7, 16-21]). Where known, the functions of the corresponding genes are shown. (b) The main components of the class 1 processing and presentation pathway encoded in the MHC. Antigen is processed in the cytoplasm by the proteasome, a large protein complex, to yield peptides that are then transported into the lumen of the endoplasmic reticulum. Here the peptides can cooperate in the assembly of the class I molecules, for subsequent presentation on the plasma membrane. For details, see the text and [22-24]. Some mouse class I genes in the H-D to H-2L region appear to afffect expression of HLA-B27 transgenes by an obscure mechanism [61]. The location of the class I genes has recently been clarified [62]. M-region genes have not been described in humans. In this figure their position is thus inferred from their location in the mouse H-2 region (see [7] and references therein). For nomenclature, see [63].

493

494 Mammaliangenetics porter genes, which are termed TAP1 and TAP2, and may function to digest protein antigens to yield peptides and subsequently transport them into the endoplasmic reticulum (ER) [29-32,33"]. The peptides can then take part in the assembly of class I molecules in the lumen of the ER, for subsequent transport to the cell surface [33"-37"]. Some reports show that ATP is apparently not required for the transport of short peptides into the microsomes in vitro but that it is required for class I assembly; this discrepancy has yet to be resolved [38,39,40]. In the class II region, two genes, LMP2 and LMP7, encode products related to a large cytoplasmic protein complex called the proteasome (or prosome, multi-catalytic protease, macropain) [41-45]. The proteasome is involved in the degradation of intracellular proteins. Biochemical evidence indicates that the two MHC-encoded gene products are bound to a subset of proteasome structures within the cytoplasm [24] which may function, in this case, to produce peptides (one of nine amino acids [46,47]) for subsequent transport into the ER. It is possible that LMP2 and LMP7 bind to file proteasome complex and subvert its function towards the supply of peptide for the TAP1-TAP2 complex [24]. The identification of this cassette of proteasome and transporter genes within file MHC has some fascinating implications, as there is compelling evidence for functional polymorphism in antigen processing• For example, rat class 1 modifier (c#n) strains with normal RTI.A class I sequences direr in their ability to stimulate T cells through RTI_&, as compared with other strains [33,48"]• The cim locus has been mapped to the /VlHC and is likely to be one of the TAP or I~¢P genes [49"]. There is evidence for similar MHC-linked, trans-acting effects in humans, as indicated by the measurement of differing abilities of B27-identical individuals to present HLA-B27-restricted epitopes to T cells [50"]• These phenotypes could be related to the LMP-TAP gene cluster (Fig. 1). There is also a suggestion of functional relevance of file transporter genes to insulin-dependent diabetes (IDDM) in both man and mouse [51,52]. Both LMP genes are polymorphic in mice and there is preliminary evidence of two alleles of I.MP2 in man [42]• The transporter genes have been shown to be polymorphic [52,53]. As well as involvement of MHC-encoded products in the endogenous antigen-processing pathway, studies with other deletion mutants have led to the conclusion that a gene in the class II MHC region is involved in the maturation of class II molecules through the exogenous processing pathway. Mutations in this gene result in unstable class II molecules at the cell surface [54].

MHC disease associations For an excellent recent review of this topic see [ 11]. It is well known that the MHC is associated with a variety of diseases, as illustrated by the skewed distribution of certain alleles in disease populations. Many of these diseases are of autoimmune aetiology, although others, such as narcolepsy, show no obvious immune component. Two recently described associations deserve mention. Risk of

squamous cell cervical carcinoma has been shown to be associated with DQw3 [55]• This is the first evidence of defense against a tumour-associated virus (human papilloma virus type 16) mediated by the immune system in humans, although such defense is well known in animals. Although it is generally assumed that polymorphism of the MHC products is driven by natural selection against infectious pathogens, evidence has been difficult to obtain. The recent report of an association of various class I and II alleles with protection against malaria in West Africa has corroborated this idea [56"]. New data on mating preference in mice have confirmed the extraordinary observation that females tend to mate with MHC-disparate males [57]• This phenomenon may well be related to enhanced fitness for disease resistance detem~ined through the MHC and it further underlines the paramount importance of the MHC in this regard [58].

Advantages of linkage Some of the recent work described above calls for the evolution of tile MHC as a unit, or cluster, of interdependent genes that are interspersed with a random assortment of other 'third party' loci. What advantages may be gained by keeping these MHC genes together? First, the concept of co-regulation. Although little is "known about gene regulation on tile macro-scale it would make sense if at least some coordinately regulated genes were located in similar areas of chromatJn so as to be open to transcription at the same time. On a smaller scale, the transporter and proteasome-related genes are expressed in similar circumstances and are all inducible by interferon. Preliminary genomic DNA sequencing shows that they may share interferon-response elements [59]. Second, the co-evolution of polymorphic genes may be the result of a functional relationship. Tile arguments for association between the class I and II regions can be applied to genes involved in antigen processing. It may be advantageous to link particular processing functions with particular polymorphic class I or class II molecules. Obviously, similar genes will be expressed from the other chromosome in a heterozygote and most MHC genes are co-dominant. Therefore, although it is possible to imagine that linkage may provide a significant evolutionary advantage in the long term, the presence of the other haplotype may thwart the short term advantage. Third, the co-evolution of polymorphic subunits - - structural relationship. A good example of this is the DQ region of the MHC. Class II molecules are heterodimers and the genes encoding the cz and [3 chains of the DQ product are polymorphic. Various studies have shown that the particular DQ cx and ]3 products encoded on one chromosome may be better adapted to form heterodimers with each other than with the subunits encoded from the other chromosome, that is, the cis-association is more effective than the trans. Fourth, the exchange of sequences• Another advantage of linkage that is enjoyed by the MHC genes is that

The MHC: relationship between linkage and function Trowsdale, Powis their placement together means that they are in a position to exchange sequences by non-homologous mechanisms (gene conversion, non-homologous recombination etc.). There is strong evidence for this occurring in the mouse, and circumstantial evidence that sequence exchanges have participated in generating some of the polymorphism of class I genes in humans [10]. Finally, it is theoretically possible that it may be beneficial to place a particular gene within the MHC even though it is non-polymorphic and not co-regulated. Genes like the proteasome-related components, for example, may have originated by duplication of genes on other chromosomes. Imagine that one such duplicate carries a mutation that makes it particularly suitable for a role in antigen processing. The transferal of this version of the gene to the MHC by chromosome rearrangement would ensure its maintenance in combination with genes also involved in similar processes.

8.

DEGLI-EsPOSTIMA, ANDREAS A, CHRISTIANSEN FT, SCHALKE B, ALBERT E, DAWKINS RL: An Approach to the Localization of the Susceptibility Genes for Generalized Myasthenia gravis by Mapping Recombinant Ancestral Haplotypes. Immun(> genetics 1991, 35:355-364.

9.

SHIROSHIT, SAGAO T, HANZAWAN, GOTOH H, MOPdWAKJ K: Genetic Control of Sex-dependent Meiotic Recombination in the Major Histocompatibility C o m p l e x of the Mouse. ~ I B O J 1991, 10:681-686.

10.

BEUCH MP, MADGRALJA, LUZ R, PETZL-ERLER ML PARHAM P: Unusual HLA-B Alleles in T w o Tribes of Brazilian Indians. Nature 1992, in press.

11.

KOSTYUDD: The HLA Gene C o m p l e x and Genetic Susceptibility to Disease. Cutv" Opin Genet Dev 1991, 1:40-47.

12.

MATSUMOTOK, ARAIM, ISHIHARAN, ANDO A, INOKO H, IKEMURA T: Cluster of Fibronectin Type-III RepeaLs Found in the H u m a n Major Histocompatibility C o m p l e x Class Ill Region Shows the Highest Homology with the Repeats in an Extracellular Matrix Protein, Tenascin. Genomics 1992, 12:485-491.

13.

HSIEH SL, CAMPBELL RE): Evidence that Gene G7a in the H u m a n Major Histocompatibility C o m p l e x is Valyl-tRNA Synthetase. Biochem J 1991, 278:809-816.

14.

BECKS, HANSONI, KELLYA, PAPPIN DJC, TROWSDALEJ: A HomoIogue of the Drosophila Female Sterile Homeotic (fsh) Gene in the Class II Region of t h e H u m a n MHC. DNA Sequence 1992, 2:203-210.

15.

LAXXq.ORDA, ZEMMOURJ, ENNIS PD, PARHAM P: Evolution of Class-I MHC Genes and Proteins: From Natural Selection to Thymic Selection. A n n u Rev Immunol 1990, 8:23-63.

16.

MIIMERCM, CAMPBELLRD: Structure and Expression of the Three MHC-linked HSP70 Genes. Immunogenetics 1990, 32:242-251.

17.

YOUNGRA: Stress Proteins and Immunology. Annu Rev Immunol 1990, 8:401-420.

18.

KAUFM&'4NSHE (ED): Heat Shock Proteins and the I m m u n e Response. In Current Topics in Microbiolog), and Immunology. Berlin: Springer-Verlag; 1991, 167:214.

19.

RIPPMANNF, TAYLORXY/R, ROTHBARDJB, GREEN NM: A Hypothetical Model for the Peptide Binding Domain of hsp70 Based on the Peptide Binding Domain of HI.A. EMBO J 1991, 10:1053-1059.

20.

VANBUSKIRKAM, DENAGEL DC, GUAGLIARDI IF., BRODSKY FM, PIERCE SK: Cellular and SubceUular Distribution of PBP72/74, a Peptide Binding Protein that Plays a Role in Antigen Processing. J Imraunol 1991, 146:500-506.

21.

CICCIONE E, COLONNA M, VIALE O, PENDE D, Dl DONATO C, REINHA~ D, AblOROSO A, JEAIxrNETM, GUARDIOLAJ, MORETrAA, e r A&: Susceptibility or Resistance to Lysis by Alloreactive Natural Killer Cells is Governed by a Gene in the H u m a n Major Histocompatibility C o m p l e x Between Bf and HLA-B. Proc Natl Acad Sci U S A 1990, 87:9794-9797. Erratum, Proc Nail Acad Sci U S A 1990, 88:5477.

22.

PARHAMP: Antigen Processing. Transporters of Delight. Nature 1990, 348:674-5.

23.

ROBERTSONM: Proteasomes in the Pathway. Nature 1991, 353:300-301.

24.

MONACOJJ: A Molecular Model of MHC Class 1-Restricted Antigen Processing. Immunol Today 1992, 13:173-179.

25.

ELLIOTT, CERUNDOLO V, ELVIN J, TOWNSEND A: Peptide-ind u c e d Conformational Change of the Class I Heavy Chain. Nature 1991, 351:402-406.

26.

ROCK KL, GP,~l~t C, BENACERRAFB: LOW T e m p e r a t u r e and Peptides Favor the Formation of Class I Heterodimers on RMA-S Cells at t h e Ceil Surface. Proc Nail Acad Sci U S A 1991, 88:4200-4294.

Conclusion Intriguing as some of the apparent relationships between MHC genes are, there is no direct evidence that their linkage is significant. There are examples where the position of the gene in mammals seems to be immaterial: [32-microglobulin , which associates with all class I molecules (although some free heavy chains may exist at the cell surface [60]), is located on a different chromosome. Transgenic experiments show that some genes can function in a variety of chromosomal locations. Finally, it must be remembered that, given the propensity for MHC class I and II genes (and other MI--ICgenes, including HSP, TNF, LlVlP, TAP) to duplicate, some clustering may simply be a reflection of relatives that have not yet managed to find a home of their own.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: • of special interest •, of outstanding interest 1.

TROWSDALE J, RAGOUSSlSJ, CAMPBELLRE): Map of the H u m a n MHC. Immunol Today 1991, 12:443-446.

2.

HANSONIM, TROWSOALEJ: Colinearity o f Novel G e n e s in the Class II Regions of the MHC in Mouse and Human. hnmunogenetics 1991, 34:5-11.

3.

CHO S, ATTAYA M, BROWN MG, MONACO JJ: A Cluster of Transcribed Sequences Between the Pb and Ob G e n e s of the Murine Major Histocompatibility Complex. Proc Natl Acad Sci U S A 1991, 88:5197-5201.

4.

YEOM YI, ABE K, BENNETT D, ARTZT K: Testis-/Embryo-expressed Genes are Clustered in the Mouse H-2K Region. Proc Naa Acad Sci U S A 1992, 89:773-777.

5.

KELLY AP, MONACOJJ, CHO S, TRO'CC~DALEJ: A New H u m a n HLA Class ll-related Locus, DM. Nature 1991, 353:571-573.

6.

CHO S, ATrAYA M, MONACOJJ: New Class ll-like G e n e s in the Murine MHC. Nature 1991, 353:573-576.

7.

SHAWARSM, COOK RG, RODGERSJR, RICH RR: Specialised Functions of MHC Class I Molecules: I. An N-Formyl Peptide Receptor is Required for Construction of the Class I Antigen Mta. J E:xp Med 1990, 171:897-912.

495

496

Mammalian genetics 27.

28.

29.

30.

31.

32.

ESQOrCEL F, YEWDELL J, BENNINK J: RMA/S CeUs Present Endogenously Synthesized Cytosolic Proteins to Class I -Restricted Cytotoxic T Lymphocytes. J ~xp Med 1992, 175:163-168.

GLYNNER, Po\xqS SH, BECK S, KELLYA, KERR L-A, TROWSDALEJ: A Proteasome.related Gene Between the Two ABC Transporter Loci in the Class I1 Region of the H u m a n MHC. Nature 1991, 353:357-360.

42.

KELLYA, POW1SSH, GLYNNE R, RADLEYE, BECK S, TROWSDALEJ: Second Proteasome-related Gene in the H u m a n MHC Class II Region. Nature 1991, 353:667-668.

43.

BROWNMG, DedSCOLLJ, MONACOJJ: Structural and Serological Similarity of MHC-linked LMP and Proteasome (Multicatalytic Proteinase) Complexes. Nature 1991, 353:355-357.

44.

TROWSDALEJ, HANSON I, MOCKRIDGE I, BECK S, TOWNSEND A, KELLY A: Sequences Encoded in the Class II Region of the MHC Related to the 'ABC" Superfamily of Transporters. Nature 1990, 348:741-4.

MART1NEZCK, MONACOJJ: Homology of Proteasome Subunits to a Major Histocompatibility Complex-lined LMP Gene. Nature 1991, 353:664-667.

45.

SPIEST, BRESNAH&NM, BAHRAMS, ARNOLDD, BD'~NCKG, MELI.INS E, PIOUS D, DEMAI~5 R: A Gene in the Human Major Histocompatibility C o m p l e x Class It Region Controlling the Class I Antigen Presentation Pathway [see Comments]. Nature 1990, 348:744-747.

ORT1Z-NAVARETTE V, SEEUG A, GERNOLD M, FRENTZEI. S, KI.OETZEL PM, I-{AMMERLINGGJ: Subunit of the '20S' Proteasome (Multicatalytic Proteinase) Encoded by the Major Histocompatibility Complex. Nature 1991, 353:662-664.

46.

DICK LR, MOOMAWCR, DEMARTINOGN, SI.AUGHTERC: Degradation of Oxidized Insulin B Chain by the Multiproteinase C o m p l e x Macropain (Proteasome). BiocbemistO, 1991, 30:272%2734.

MONACOJJ, CHO S, ATTAYA M: Transport Protein Genes in the Murine MHC. Science 1990, 250:1723-1726.

47.

MADDENDR, GORGAJC, STROMINGERJL, Wtl.~' DC: T h e Structure of HLA-B27 Reveals N o n a m e r Self-peptides Bound in an Extended Conformation. Nature 1991, 353:321-325.

48.

LIVINGSTONEAM, Powls SJ, GUNTHER E, CRAMERDV, HOWARD JC, BUTCHER GW: Cim: an MHC Class It-linked Alielism Affecting the Antigenicity of a Classical Class I Molecule for T Lymphocytes. hnmunogenetics 1991, 34:157-163.

ANDERSONK, CRESSWELLP, GAMMON M, HERMESJ, WILLIAMSON A, ZWEEPdNKH: Endogenously Synthesized Peptide with an Endoplasmic Reticulum Signal Sequence Sensitizes Antigen Processing Mutant Cells to Class I-restricted Cell - - Mediated Lysis. J E.xp Med 1991, 174:489-492. DEVERSONEV, COW IR, COADWELLXVJ, MONACOJJ, BUTCHER GW, HOWARDJC: MHC Class II Region Encoding Proteins Related to the Multidrug Resistance Family of Transm e m b r a n e Transporters [see Comments]. Nature 1990, 348:738-741.

Po~xqsSJ, HOWARDJC, BUTCHER GW: The Major Histocompatibility C o m p l e x Class ll-hnked cim Locus Controls the Kinetics of Intracellular Transport of a Classical Class I Molecule. J E.xp Med 1991, 173:913-921. This paper describes the cim phenotype in rat that, :is shown in [49••], is controlled by variation in the IVIHC-linked ABC transporters. 34. •

SPIEST, DEMARS R: Restored Expression of Major Histocompatibility Class 1 Molecules by Gene Transfer of a Putative Peptide Transporter. Nature 1991, 351:323-324. See [37•].

35.

Po~xqsSJ, TOWNSEND ARM, DEVERSON EV, BASTINJ, BtrI'CHER GW, HOWARO JC: Restoration of Antigen Presentation to the Mutant Cell Line RMA-S by an MHC-linked Transporter. Nature 1991, 354:528-531. See [37°]. •

36.

SPIEST, CERUNDOLOV, COI.ONNA M, CRE.CxS',XrELLP, TOWNSEND

•

A, DEMARs R: Presentation of Endogenous Viral Antigen De-

p e n d e n t on Putative Peptide Transporter Heterodimer. Nature 1992, 355:644-645. See [37*]. 37. •

KELLYA, POW1S SH, KERR LA, MOCKRIDGE l, ELUOTr T, BAS'nN J, UCHANSKA-ZIEGLERB, ZIEGLER A, TROWSDALEJ, TOWNSEND A: Assembly and Function of the Two ABC Transporter Proteins Encoded in the H u m a n Major Histocompatibility Complex. Nature 1992, 355:641-644. Together with [34" -36*], provides a direct demonstration that the phenotype of mutant cell lines with low class I expression at the cell surface is the result of defects in the ABC-transporter genes in the/vlHC. 38. •

LEVY F, GABATHUtERR, LAP6SON R, KVaST S: ATP is Required for in Vitro Assembly o f MHC Class 1 Antigens but not for Transfer Across the ER Membrane. Cell 1991, 67:265-274. See [40-]. KVlSTS, WIMAN K, CLAESSONL, PETERSON PA, DOBBERSTEIN B: Membrane Insertion and Oligomeric Assembly of HLA-DR Histocompatibility Antigens. Cell 1982, 29:61-69.

See 140"]. 40. •

to resoh,e this issue. 41.

33. •

39. •

News a n d Views 1992, 355:109-110). Further experiments am needed

KOPPELMANB, ZIMMEPa~,N DL, WALTER P, BRODSKY FM: Evidence for Peptide T r ~ s p o r t Across Microsomal Membranes. Proc Natl Acad Sci U S A 1992, in press. Together with [38",39•], suggests that short peptides may traverse microsome membranes in vitrowithout the need for ATP, thus obviating the need for the ATP transporters in the process (for discussion of this issue, see DOBBERSTEINB: W h o Needs Peptide Transporters? Nature,

49. ""

Po~xqsSJ, DEVERSON EV, COADWELLWJ, CIRUED\ A, HUSKISSON NS, SMITH H. BUTCHER GW, HOWARDJC: Effect of Polymorphism of an MHC-linked Transporter on the Peptides Assembled in the Class I Molecule. Nature 1992, 357:211-215. This paper shows that rat TAP2 alleles have remarkably different sequences. The sequence of the TAP allele appears to determine the profile of peptides in the groove of the class 1 molecule, RT1.A. 50. •

PA72..IANYL, ROkXq.M~ID-JONES S, HUET S, HILL A, SU'VrON J, MURRAYR, BROOKSJ, McMICHAEL A~: Genetic Modulation of Antigen Presentation by HLA B27 Molecules..1 E.x7) Meal 1992, 175:361-369. This paper provides evidence for polymorphic, MHC-linked genes that affect antigen presentation by HLA class I to c3¢otoxic T cells. 51.

FAUSTb~uND, LI X, LIN HY, FU Y, EISENBARTHG, AVRUCHJ, GUO

•

J: Linkage of Faulty Major Histocompatibility Complex Class I to A u t o i m m u n e Diabetes. Science 1991, 254:1756-1761.

This paper claims to link diabetes to variation in the TAP transporters in non-obese diabetic (nod) mice. Apparently, human IDDM patients express lower class 1 levels. Confirmation of these findings is still needed (see editorial in Science 1992, 255:531-534). 52.

COLONNAM, BRESNAHANM, BAHRAMS, STROMINGERJL, SPIES T: Alielic Variants of the H u m a n Putative Peptide Transporter Involved in Antigen Processing. Proc Nail A ca d Sci U S A 1992, 89:3932-3936.

53.

PowIs SH, MOCKPdDGE I, KELLYA, KERR L-A, GLYNNE R, GILEADI U, BECK S, TROWSDALEJ: Polymorphism in a Second ABC Transporter Gene Located Within the Class II Region of the H u m a n MHC. Proc Nail Acad Sci U S A 1992, 891463-1467.

54. •

MELLINSE, KEMPIN S, SMITH L, MONJI T, PIOUS D: A Gene Required for Class ll-restricted Antigen Presentation Maps to the Major Histocompatibility Complex. J E.xp Med 1991, 174:1607-1615. Shows that there may be additional antigen-processing genes within the MHC, mutations of which affect class LI conformation and antigen presentation. 55.

WANKR, THOMSSEN C: High Risk of Squamous Cell Carcin o m a of t h e Cervix for W o m e n with HLA-DQw3. Nature 1991, 352:723-725.

The MHC: relationship between linkage and function Trowsdale, Powis 56. •

HILL AVS, ALLSOP CEM, KWIATKOWSKID, ANSTEY NM, TWUMASt P, ROWE PA, BENNETT S, BREWSTER D, McMICHAEL AJ, GREENWOOD BM: C o m m o n W e s t African HLA Antigens are Associated with Protection from Severe Malaria. Nature 1991, 352:595-600.

phic Antigen (LA45) of Free HLA-A and -B Heavy Chains Found on the Surfaces of Activated B and T Cells. J E.xp Med 1991, 174:1085--1095. 61.

NtCKERSON-NU'Iq'ERCL, HUGEN KL, DAVID CS: Expression of HLA-B27 in Transgenic Mice is Controlled by Gene(s) Mapping Between H-2D and H-2L Loci. hnmtmogenetics 1992, 35:199-204.

62.

GERAGHTYDE, PEI J, LIPSKY B, HANDSEN JA, TAILLON-MILLER P, BRONSON SK, CHAPLIN DD: Cloning and Physical Mapping of the HLA-E to HLA-F Interval by Using Yeast Artificial Chromosomes. Proc Natl Ac ad Sci U S A 1992, 89:2669-2673.

63.

BODMERJG, MARSH SGE, ALBERT ED, BOOMER XX/F, DuPoNT B, ERLICH HA, MACH B, MAYRWR, PAP,H~t P, SASAZUFUT, ET AL: Nomenclature for Factors of the HLA System. Tissue Antigens 1992, 39:161-173.

see 158.]. POTTS~Q~(/, MANNING CJ, WAKELANDEK: Mating Patterns in Seminatural Populations of Mice Influenced by MHC Genotype. Nature 1991, 352:619-621. See 158"]. 57. •

58. HOWARD JC: Disease and Evolution. Nature 1991, 352: • 565-567. Together with [56",57•], relates to the development and maintenance of the extreme polymorphism of the MHC products. 59.

BECK S, ALDERTON R, KEtLY A, KHURSHID F, RADLEY E, TROWSDALEJ: DNA Sequence Analysis of 65kbp of the Human MHC Class II Region Encoding a Cluster of G e n e s for Antigen Processing. 1992, in press.

60.

MADRIGALJA, BELICH M, BENJAMIN RJ, LrrrLE AM, HILDEBRAND WH, MANNDL, PARHAMF: Molecular Definition of a Polymor-

J Trowsdale, SH Powis, Human Immunogenetics Laboratory, Imperial Cancer Research Fund, Lincoln's Inn Fields, Hobom, London WC2A 3PX, UK.

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