The major histocompatibility complex of ruminants

Rev sci tech Off int Epiz 1 9 9 8 1 7 (1) 108-120

The major histocompatibility complex of ruminants

M Ami l ls V Ramiya J Nonmine amp HA Lewin

Department of Animal Sciences University of Illinois at Urbana-Champaign 210 Edward R Madigan Laboratory 1201 West Gregory Drive Urbana Illinois 61801 United States of America

Summary Studies of the major h is tocompat ib i l i ty c o m p l e x ( M H C ) of cat t le over t h e past t w e n t y y e a r s have r e v e a l e d a r e a s o n a b l y de ta i led p ic ture of t h e genet ic organisat ion and funct ion of t h e g e n e s w i th in th is gene t ic sys tem S e r o l o g i c a l and b i o c h e m i c a l analys is of l ymphocy te cel l s u r f a c e an t igens prov ided t h e first e v i d e n c e for highly po lymorphic M H C g e n e s in cat t le and other r u m i n a n t s p e c i e s T h e M H C of cat t le w a s thus n a m e d t h e bovine l e u c o c y t e an t igen (BoLA) sys tem Dur ing t h e past 10 y e a r s too ls of m o l e c u l a r biology h a v e b e e n used to c h a r a c t e r i s e t h e n u m b e r of M H C g e n e s the i r s e q u e n c e and f ine s t ruc tu re in a n u m b e r of r u m i n a n t s p e c i e s A l though individual M H C g e n e s w e r e f o u n d to have c lea r or tho logues a m o n g ruminants and other m a m m a l i a n s p e c i e s t h e M H C of ca t t l e and probably t h a t of s h e e p and goa ts has a unique gene t ic organ isa t ion Catt le h a v e a c lass II g e n e c luster (c lass lib reg ion) w h i c h is physica l ly distant f rom all t h e other M H C g e n e s on t h e s a m e c h r o m o s o m e M o r e o v e r g e n e s involved in ant igen p r o c e s s i n g such as t h e p r o t e o s o m e subuni t locus LMP2 are also found in the c lass IIb reg ion demonst ra t ing t h a t t h e s e g e n e s n e e d not be in close proximity to o ther M H C g e n e s to func t ion normal ly T h e M H C c lass I and class II g e n e products of ruminants p r e s e n t p r o c e s s e d pept ides to T l y m p h o c y t e s w h i c h m e d i a t e he lper and cytotox ic funct ions Ident i f ica t ion of pept ide binding motifs of cat t le M H C c lass I m o l e c u l e s ind icates t h a t r u m i n a n t M H C m o l e c u l e s func t ion in a simi lar m a n n e r to t h o s e of m i c e and h u m a n s T h e s e funct iona l s tudies provide a f i rm m o l e c u l a r basis for a n u m b e r of w e l l - d o c u m e n t e d assoc ia t ions w i t h in fect ious d i s e a s e s a l t h o u g h a deta i led unders tand ing of the i m m u n o g e n e t i c m e c h a n i s m s under ly ing t h e s e assoc ia t ions has y e t to be e l u c i d a t e d

Keywords Bovine leucocyte antigen - Cattle - Disease resistance - Genetics - Major histocompatibility complex - Ruminants - Sheep

Introduction The major histocompatibility complex (MHC) class 1 genes encode proteins which are chiefly involved in presentation of intracellularly-derived peptides to cytotoxic T cells The class I molecules comprise an a-chain that is non-covalently associated with szlig2 microglobulin The a1 and a 2 domains form a cleft that accommodates antigenic peptides which are primarily presented to cytotoxic T cells bearing the C D 8 +

(cluster of differentiation antigen) marker (Fig 1) The class II genes encode proteins that present processed peptides

derived from extracellular antigens to helper T cells bearing the C D 4 + differentiation marker The class II molecules are formed by non-covalent association of a- and (3-chains encoded by distinct genes within the MHC For the MHC class II molecules the a1 and domains form the antigen binding site This review will discuss current knowledge of the structural and functional features of MHC genes in cattle (Bos taunts) sheep (Ovis aries) and goats (Capra hircus) Emerging information on the MHC in wild ruminants such as red deer (Cervus elaphus) and moose (Alces alces) will also be presented

Rev sci tech Off int Epiz 17 (1)

Genomic organisation of the MHC region

109

Peptide-binding groove

Alpha 1 domain Alpha 2 domain

Alpha 3 domain

Beta 2-microglobulin

Fig 1 The HLA-A2 cristallographic structure The HLA-A2 crystallography structure (14) data were obtained from the Protein Data Bank (12) and viewed using RasMol software

Linkage and physical map The MHC region contains a diverse array of genes which are crucial for the initiation of adaptive immune responses The MHC encompasses a large chromosomal region that maps to chromosome 2 3 in both cattle and goats (35 9 0 ) and to chromosome 20 in sheep (54) The bovine MHC is designated as BoLA (bovine leucocyte antigen complex) whereas in other ruminants the MHC is named according to the nomenclature proposed by Klein et al (47) Thus the MHCs of sheep and goats are referred to as Ovar and Coki respectively

The general structure of the MHC is relatively conserved among mammalian species and is divided into three main regions with different functional roles (Fig 2 ) However as more DNA sequence data accumulate these boundaries appear artificial because genes with many different functions have been found dispersed among the class I class 11 and class III regions For the purpose of this review however these regional designations will be maintained so that comparisons between species can be made more easily

Physical mapping of bovine chromosome 23 (BTA23) has demonstrated that the class I region encompasses approximately 1550 kilobases (kb) of DNA and that there

are two tightly linked expressed loci (BoLA-A and BoLA-B) (11) The class III region is constituted by a heterogeneous set of genes related to immunological and other functions such as the complement factors BF and C4 steroid 21-hydroxylase (CYP21) heat shock protein 70 (HSP70) and tumour necrosis factor a and (3 (TNFA and TNFB) (49 66 76) One of the most notable differences in the genomic organisation of the MHCs of ruminants compared with humans and mice is the splitting of the class II region into two subregions which are separated by at least 15 cM (centiMorgans) (4 93 ) The class Ila subregion comprises two clusters of genes DR and D Q Physical and genetic mapping have shown that the bovine and ovine DR and D Q genes lie in close proximity (3 77) The class IIb region includes the DMA DMB LMP2 LMP7 and TAP genes (23 4 9 72) which are involved in antigen processing and transpon and other class Il-like genes such as DNA DOB DIacuteB DYA and DYB whose function is unknown (49) On the basis of linkage analysis the bovine class II region lies near the centromere of BTA23 whereas the class I region is distal to the class lla genes (44 93) A similar organisation is expected for sheep and goats which are closely related artiodactyls (66 76) Hybridisation of BTA23 with fluorescence-labelled DYA and class I probes has demonstrated that these two regions physically map at different positions with DYA centromeric to the class 1 loci (83) Interestingly the distance between the class IIa and class IIb subregions varies among individuals as demonstrated by comparison of the recombination rate using single sperm typing of different bulls (67) Variation in the recombination rate might be due to the existence of a polymorphic recombinational hotspot ( 4 4 4 6 7 )

Major histocompatibility complex class I genes and molecules In cattle the class I region contains about 10 to 2 0 class 1 genes (11 52) whereas the estimated number of class I genes in goats is approximately 10 to 13 (17) At least three class I genes are transcribed in cattle (11 2 3 3 7 3 8 ) and sheep (41) The class I genes are polymorphic with 21 distinct BoLA class I sequences (23) and five sheep class I sequences (41) identified to date The length of the transmembrane domain (37 or 35 residues) is the major criterion for assigning the available BoLA class I sequences to specific loci Analysis of class 1 molecules by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) isoelectric focusing (IEF) and peptide mapping also gives strong support for the existence of up to three expressed class 1 loci in cattle (1 45 ) Similarly the serological available data for sheep suggest that at least three different class 1 molecules are expressed by lymphocytes ( 3 9 6 0 ) while in goats there is evidence for only two distinct class I molecules (46 66)

The major histocompatibility complex class II region The class II region in cattle has been characterised using cloned heterologous and homologous class II probes Restriction fragment length polymorphism (RFLP) analysis

110 Rev sci tech Off int Epiz 17 (1)

Fig 2 Genetic linkage map of the major histocompatibility complex region in cattle (1053) sheep (2082) and goats (90)

has allowed the determination of the number of class II genes the existence of DQ and DR alleles in strong linkage phase disequilibrium the probable absence of DP orthologues in mice and humans and the splitting of the class II region into two distantly linked subregions (23 49 ) Complete information on the molecular features of the BoLA class II genes can be found in the last report of the International Society of Animal Genetics BoLA Nomenclature Committee (23 72) and on the BoLA website (http www2ribbsrcacukbolabolaframhtm) In sheep the class II region was elucidated using RFLP analysis (L9 3 2 4 0 77) The ovine class II region has at least seven and ten different a-chain and [szlig-chain genes respectively and 14 |3-chain related sequences (24) As in other species RFLP analysis of the goat class II region suggests the existence of multiple polymorphic class II loci (17)

The major histocompatibi l i ty complex class Ila subregion DR genes The DRA gene encodes the a-chain of the DR molecule Only one BoLA-DRA allele has been identified on the basis of sequence data (Table I) By contrast the genes that encode the (3-chain of the DR molecule are highly polymorphic Polymorphism is mainly concentrated in the second exon which encodes the variable portion of the peptide binding site

(Fig 2) The second exon of one highly polymorphic DRB gene has been characterised in cattle (72) sheep (76) goats (2 73) red deer (88) and other wild ruminant species (50 58) (Table II)

The number of DRB genes varies in cattle and sheep In cattle there are at least three DRB loci but only one DRB gene (DRB3) is functional In sheep there may be six different DRB genes of which at least two are expressed (76) In the red deer and fallow deer (Dama dama) two different DRB genes are transcribed (57 88) The existence of several |3-chain genes increases the possibility of eliciting an effective immune response against pathogen-derived peptides that markedly differ in their structural characteristics

The analysis of DRB polymorphism has been particularly useful for inferring the evolutionary history of the MHC in ruminant species The low level of polymorphism in some wild ruminants such as moose (57 59) and the considerable differences in allelic frequencies between European and African cattle breeds (58) suggest that selection genetic drift and population bottlenecks have played an important role in determining the repertoire of ruminant MHC class I and II alleles In addition evidence in ruminants suggests that interallelic exchange of short sequence motifs has been of importance in the generation of allelic variability (57 73 74)

Rev sci tech Off int Epiz 17 (1) 111

Table I Molecular features of the bovine and ovine DR genes

Species Name Molecular features References

Bos taurus BoLA-DRA Encodes a mature protein of 230 amino acids Monomorphic(a) (2372 91) BoLA-DRBl Pseudogene (stop codons in the B1 and transmembrane domains)

Low polymorphism (2 alleles) (23 6372)

BoLA-DRB2 Expressed at low levels Lacks the glycosylation site at position 19 of the R1 domain Monomorphic

(23 64 72)

BoLA-DRB3 Expressed at high levels Encodes a mature protein of 238 amino acids Highly polymorphic (63 alleles)

(162372)

Ovis aries Ovar-DRA Expressed Low polymorphism (2 alleles) (3376) Ovar-DRB 1 Expressed Functionally equivalent to BoLA-DRB3 Highly polymorphic

with 74 alleles (7 76 79)

0var-DRB2 Psetidogene (lacks the exon 1 and exon 2 and has two premature stop codons and other mutations that render it non-functional)

(7 76 79)

a) Polymorphism defined on the basis of sequence data only

In the future considerably more will be learnt about the

evolution of ruminants from the sequencing of different MHC

genes

DQ genes

In cattle and sheep some individuals carry a single copy of

DQA and DQB genes whereas others have duplicated

haplotypes (Table III) (5 78 79 8 1 101) By contrast with

the DRA genes DQA genes are highly polymorphic This

increases significantly the number of different DQ molecules

Table II Polymorphism of DRB genes in several ruminant species

a) BoLA-ORB3 qene b) Ovar-DRBI gene c) Cahi-DRB1 gene

d) Number of alleles from two amplified loci

that can be expressed on the cell surface in a given individual

thus expanding antigen presentation capability In cattle there

are two or possibly three DQA genes (8) whereas there are

four different DQB genes (81) The DQB1 gene is the most

frequent whereas the DQB2 DQB3 and DQB4 genes can only

be found in duplicated haplotypes DQB1 DQB2 and DQB3

have been shown to be transcriptionally active in animals with

duplicated DQ haplotypes (56 103)

The ovine DQ region encompasses 130 kb with the DQ1 and

DQ2 subregions located 22 kb apart (97) Like cattle the

number of DQA and DQB genes in sheep varies depending on

the haplotype (33 76 78 79) and both Ovar-DQA genes are

transcribed (78) Phylogenetic analysis of ovine DQB exon 2

sequences shows that they belong to at least two different

allelic lineages (95) The DQB genes are also duplicated in the

red deer (Cervus elaphus) (89)

DR and D Q molecules

In cattle the surface expression of DR and DQ molecules has

been demonstrated using locus-specific monoclonal

antibodies and IEF (13 3 0 4 9 ) The expression of MHC class

II molecules in freshly isolated bovine T cells has also been

reported (85) In sheep four different subsets of class II

molecules co-expressed on B lymphocytes have been

identified using monoclonal antibodies (68) Three of these

subsets showed allelic variation restricted to the szlig-chain

while in the fourth subset there was also polymorphism in the

a-chain (68 69)

There is evidence suggesting that at least two different sheep

DR |3-chain molecules are expressed (29) In sheep C D 4 +

helper C D 8 + cytotoxic and yograve T cells express variable levels

of DQ and DR molecules (28 43 ) In general the expression

of DQ is lower than DR and there are also expression

differences depending on the age of the animal and the

immunological compartment being analysed (28 43 ) In

goats six different class II DR-like products (BeBl-BeB6) have

been identified by IEF (66 70) These products may

correspond to the codominant expression of two loci (66)

Species Family DRB alleles References

Bos taurus (cattle] Bovidae 63( a ) (234972)

Ovis aries (sheep) Bovidae 7 4 (b) (76)

Capra hircus (goats) Bovidae 2 8 (0 (26673)

Ovibos moschatus (musk ox) Bovidae 1 (57)

Bison bison (American bison) Bovidae 13 (50 57 62) Gazella dama ruficolis

(Dama or Addra gazelle) Bovidae 9 (50)

Damaliscus dorcas phillipsi (blesbok)

Bovidae 1 (50)

Connochaetes taurinus (white bearded wildebeest)

Bovidae 3 (50)

Addax nasomaculatus (addax) Bovidae 8 (50) Oryx dammah

(scimitar-horned oryx) Bovidae 9 (50)

Oryxleucoryx (Arabian oryx) Bovidae 3 (50) Giraffa camelopardalis reticulata

(reticulated giraffe) Giraffidae 2 (50)

Alces alces (moose) Cervidae 11 (57)

Capreolus capreolus (roe deer) Cervidae 4 (57) Rangifer tarandus (reindeer) Cervidae 11 (57)

Dama dama (fallow deer) Cervidae 1 + 1 H I (57) Cervus elaphus (red deer) Cervidae 49(d) (57 88)


Table III Molecular features of the bovine and ovine genes

Species Gene Molecular features References

Bos taurus BolA-DQA 1 BoLA-DQA2 BoLA-DQA3

Encode a mature protein of 233 amino acids Highly polymorphic (39 DQA alleles) (8 237291)

BoLA-DQBI BoLA-DQB2 BoLA-DQB3 BoLA-DQB4

Encode a mature protein of 230 amino acids The DQB genes are highly polymorphic (37 DQB alleles) (237281)

Ovis aries Ovar-DOA1 0var-DQA2

Both 004and DQA2 are transcribed There are 7 DQA1 alleles and 11 DQA2 alleles (337678)

Ovar-DQBi 0var-DQB2 0var-D0B3

There are at least two DQB genes which are transcribed and highly polymorphic (16 DQB sequences) (7679)

T h e m a j o r h i s t o c o m p a t i b i l i t y c o m p l e x c l a s s Mb s u b r e g i o n

In humans the DMA and DMB genes encode a molecule that plays a role in the complexing of peptides with class II molecules (84) whereas DNA and DOB encode a protein that might regulate the function of the DM molecule (51) The DMADMB and DNADOB orthologues have been identified in cattle (65) and sheep (99 100) respectively (Table IV)

The DY genes and the DIB gene have only been found in ruminants and exhibit a low level of polymorphism The DYA gene was sequenced in cattle (91) and sheep (98) whereas DYB has only been sequenced from sheep (98) Transcription of the Ovar-DYA gene was detected in transfected mouse L cells (98) but its expression on sheep lymphocytes has not been demonstrated The BoLA-DYA gene has similarity (69 to 79) with BoLA-DQA and probably arose by duplication and divergence from a pair of DQ genes (91)

Similar to the DY genes the DIB gene has a restricted species distribution (86 87 ) DIB has been found in several members of the Bovidae (cattle sheep gaur [Bos gaurus] American

bison [Bison bison] and sand gazelle [Gazella leptoceros]) Cervidae (wapiti [Cervus elaphus] serow [Capricornis sumatraensis] and muntjak [Muntiacus muntjak]) and Giraffidae (87) DIB displays similarity of 67 to 7 0 with the bovine Yl and Q1 DQB clones It has not been possible thus far to detect DIB expression by Northern blot analysis The cattlee class IIb region also contains genes encoding the LMP2 and LMP7 proteasome subunits and the TAP genes which encode molecules involved in the transport of peptides from the cytosol to the lumen of the endoplasmic reticulum (23 49)

Peptides bound to bovine major histocompatibility complex molecules As discussed above a major funcdon of MHC molecules is to present processed peptide antigens to T cells and thereby initiate an adaptive immune response to specific pathogens

Table IV Molecular features of bovine and ovine major histocompatibility complex class IIb genes


Bos taurus BoLA-DMA BoLA-DMB BoLA-DYA BoLA-DYB BoLA-DIB

Encodes a mature protein of 235 amino acids Transcriptionally active and monomorphic Encodes a mature protein of 245 amino acids Transcriptionally active and monomorphic Expression not detected Low polymorphism (3 alleles) Expression not detected Monomorphic Expression not detected Monomorphic

(23 6572) (23 6572) (2472 91) (2372) (2372 86)

Ovis aries Ovar-DMA Ovar-DMB Ovar-DYA Ovar-DYB Ovar-DNA Ovar-DOB

Partial sequence (exons 2 and 3) Partial sequence (exons 2 and 3) Transcriptionally active Monomorphic Not expressed in transfected mouse L cells Monomorphic Transcribed at low levels Monomorphic Transcription not detectable Monomorphic

(76) (76) (7698) (76 98) (76100) (76 99)


The MHC molecules exhibit a high degree of polymorphism that enables presentation of a wide array of peptides which usually differ in their length and sequence The efficiency of interaction between peptide and MHC molecules may determine the nature and strength of the immune response elicited by T cells and thus may influence disease progression

Crystallographic analysis of class I molecules has demonstrated that the peptides bound to the antigen binding site are predominantly nonamers whose amino- and carboxy-terminal residues bind to specific pockets located at the ends of the antigen binding groove (31) Studies have been carried out in cattle to define the structural motifs of peptides that bind to class I molecules ( 9 3 6 4 2 ) Hedge et al have shown that almost all the peptides bound to class 1 BoLA-A11 are nonamers and that position 2 is preferentially occupied by a proline residue (42) Bamford et al have analysed the repertoire of peptides presented by the BoLA-A20 allele in bovine muscle-derived fibroblast cells infected by the parainfluenza type-3 virus (9) The sequenced peptides are generally nonamers and have a common motif containing lysine and arginine at positions P2 and P9 respectively Van Lierop et al studied the presentation of three foot and mouth disease viral peptides by different class I haplotypes and showed that each haplotype has specific selectivity for peptides (94) The magnitude of the response measured by proliferation and cytokine assays also depends largely on the haplotype Taken together these results suggest that an MHC-based selection of peptides also occurs in cattle

In contrast to class I molecules the antigen binding groove of class II molecules is open at both ends and thus is able to accomodate peptides of increased length (10 to 26 residues) In addition the main binding interactions involve the central part of the peptide To date no information is available on the sequences of peptides bound to class II molecules in ruminants

The major histocompatibility complex genes and their association wi th disease resistance and productivity Major histocompatibility complex molecules as receptors for pathogens Intracellular micro-organisms invade host cells by attaching to proteins that are normally expressed on the cell surface Involvement of MHC molecules as pathogen receptors has been demonstrated in several cases Monoclonal antibodies against monomorphic determinants of bovine class I molecules inhibit the binding and entry of Theileria sporozoites into cattle lymphocytes (80) Moreover in cattle cell lines class I expression and the rate of sporozoite

infection are closely related (80) However sporozoites only infect lymphocytes while all nucleated cells express class I molecules Thus other cell surface components are probably involved in sporozoite attachment It is also possible that the actual receptor is masked by the binding of antibodies to MHC class-I molecules In sheep several polypeptides that interact with the maedi-visna virus have been isolated by virus protein overlay assay and blocking of this interaction by MHC-class II specific antibodies has been demonstrated (22) Additionally the pre-incubation of the virus with MHC class II proteins digested with papain inhibits syncytium formation (22) However both B and T cells express MHC class II molecules in sheep while only macrophages are infected by the virus Thus other co-receptors are probably involved in viral entry and infection

Disease associations The MHC genes are particularly interesting to animal breeders and veterinary geneticists because they are associated with genetic resistance and susceptibility to a wide array of diseases The molecular characterisation of MHC polyshymorphism and the implementation of fast reliable typing methods (92) constitute a very powerful tool in the design of breeding schemes that may diminish the appearance and severity of diseases in domestic animal species Understanding of the mechanisms that explain genetic variation in resistance and susceptibility may also be very valuable in the design of efficient peptide vaccines The description of MHC associations with diseases in ruminants is very broad (49 66 76) For this reason only a few well characterised and representative models will be presented here

Polymorphism in BoLA-DRB3 is closely related to resistance to bovine leukaemia virus (BLV) infection (102) The bovine leukaemia virus primarily infects B cells The majority of the infected animals remain asymptomatic Only one-third of infected animals develop persistent lymphocytosis a polyclonal expansion of B cells and about 1 to 5 of infected cattle present tumours (34) Bovine leukaemia virus has a worldwide distribution that results in the loss of millions of dollars each year due to the elimination of animals with the clinical symptoms condemnation of carcasses with tumours and the decrease of fat and milk yields (21) Resistance and susceptibility to BLV has been mapped to specific regions of the szlig-chain of the DR molecule The two amino-acid-motif glutamic acid-arginine at positions 70 and 71 of the szlig1 domain have been associated with increased resistance to BLV whereas the amino acid motif valine-aspartate-threonine-tyrosine at positions 75-78 is associated with susceptibility (102) Individuals carrying the resistance motif also show a significant reduction in BLV provirai load (61) There have been suggestions that resistance-associated alleles may promote the early development of a specific subset of T helper cells (Th l ) that secrete interferon-y and interleukin-2 (48) thus contributing to resistance to the early spread of infection in vivo

114 Rev sci tech Off int Epiz 17(1)

Dermatophilosis is another disease that has been mapped to specific amino acid motifs of the BoLA DR molecule This is an infectious disease which occurs mainly in tropical and subtropical regions is caused by the actinomycete Dermatophilus congolensis and has a strong economic impact by reducing ruminant productivity dramatically The analysis of MHC class I and DRB3 polymorphism in Brahman cattle of the Martinique Islands has led to the identification of the B 0 L A - A 8 specificity and the DRB3 motif glutamic acid-isoleucine-alanine-tyrosine at positions 66 67 74 and 78 together with the lack of serine at position 30 as factors associated with increased resistance to dermatophilosis (55)

Mastitis is the most economically important disease of dairy cattle world-wide Mastitis is a multifactorial disease that is caused by a great variety of different micro-organisms Multiple associations between MHC polymorphism and resistance and susceptibility to mastitis have been described (49 96) A locus associated with somatic cell score in Holstein cattle has recently been mapped to BTA23 (6) Dietz et al have shown that the DRB3 alleles that are associated with increased resistance to BLV are also linked to a higher resistance against mastitis (25 26) Despite the fact that there have been a number of studies often with conflicting results the frequency with which BoLA alleles have been associated with mastitis resistance suggests that at least one gene within or closely-linked to the MHC influences the outcome of udder infections If future studies can define more precisely the effect(s) associated with this gene(s) BoLA may be a useful tool for selecting cows with natural resistance to mastitis

In sheep the influence of MHC genes on resistance to pathogens has been investigated primarily for parasitic diseases The increasing resistance of nematodes to anthelmintics has given a strong impetus to this field of research The studies of Douch and Outteridge defined an association of the class I allele SY1 with a higher resistance to Trichostrongylus colubriformis (27) More recent studies have focused on class II MHC genes and resistance to Ostertagia circumcincta (15 75) The Ovar-DRBl locus accounts for 1 1 of the variation of faecal egg count and Ovar-DRBl02031512 appears to be associated with resistance In fact the substitution of DRB1 01011526 which is the most frequent allele in the analysed population results in a 58-fold reduction of faecal egg count in six month-old lambs (75) In Ostertagia infection analysis of the polymorphism of two microsatellites located in the class I and class IIb DY regions revealed that the substitution of the most frequently occurring alleles with resistance-associated alleles yields an 8- and 218-fold reduction in the faecal egg counts respectively (15)

The caprine arthritis-encephalitis (CAE) virus causes a neural disorder in young kids usually associated with loss of co-ordination and progressive paralysis while in adults CAE is associated with arthritis and lameness and in some cases with mastitis and pneumonia The class I allele Be7 was associated with resistance to CAE whereas the class I specificities Bel and B e l 4 have been associated with increased susceptibility (71) Similarly the class II BeD2 and BeD5 were weakly associated with increased susceptibility to CAE The genetic resistance to heartwater (cowdriosis) in Creole goats has been associated with the class I CLY and Bel variants whereas susceptibility has been associated with Be9 Be22 and Be23 (18)

Conclusion The molecular analysis and fine mapping of disease associations will probably play a central role in animal genetics and veterinary medicine for many years to come The increasing resistance of pathogenic micro-organisms to antibiotics and other drugs underlines the importance of understanding the molecular genetic bases underlying resistance to infectious diseases The combination of marker-assisted selection for resistance to specific diseases and peptide vaccines that use information on binding motifs will probably contribute to improved animal health in the future

Acknowledgements The authors are grateful to Roger Sayle for providing the RasMol software and to Paul Crisostomo for help in the preparation of the manuscript Marcel Amills was granted a post-doctoral fellowship from the Spanish Education and Culture Ministry

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Le complexe majeur dhistocompatibiliteacute des ruminants M Ami l ls V Ramiya J Nonmine amp HA Lewin

Reacutesumeacute Les eacute t u d e s m e n eacute e s sur le c o m p l e x e m a j e u r d h is tocompat ib i l i teacute ( C M H ) d e s

bov ins au cours des v ingt d e r n i egrave r e s a n n eacute e s ont about i agrave une descr ip t ion

r e l a t i v e m e n t deacute ta i l l eacutee de l organisat ion g eacute n eacute t i q u e et des fonc t ions des g egrave n e s au

se in du s y s t egrave m e g eacute n eacute t i q u e L analyse seacute ro log ique et b ioch imique des a n t i g egrave n e s

de s u r f a c e des l y m p h o c y t e s a mis en eacute v i d e n c e pour la p r e m i egrave r e fois le

p o l y m o r p h i s m e eacute l e v eacute des g egrave n e s du C M H des bovins e t d au t res e s p egrave c e s de

ruminants Le C M H des bovins a ainsi eacute teacute a p p e l eacute s y s t egrave m e BoLA (bovine leucocyte

antigen system)

A u cours des dix d e r n i egrave r e s a n n eacute e s les t e c h n i q u e s de la b iologie m o l eacute c u l a i r e ont

permis de d eacute t e r m i n e r le n o m b r e de g egrave n e s du C M H et de c a r a c t eacute r i s e r leur

s eacute q u e n c e e t leur s t ruc ture f ine c h e z c e r t a i n e s e s p egrave c e s de ruminants M ecirc m e sil

s est a v eacute r eacute que les g egrave n e s du C M H ont des o r tho logues eacutev idents c h e z les

ruminants e t d a n s d aut res e s p egrave c e s de m a m m i f egrave r e s le C M H des bovins e t

p r o b a b l e m e n t ce lu i des ovins e t des c a p r i n s p r eacute s e n t e n t une organ isa t ion

g eacute n eacute t i q u e un ique Les bovins p o s s egrave d e n t un g r o u p e de g egrave n e s de c lasse II ( reacuteg ion

de la c lasse IIb) p h y s i q u e m e n t eacute lo igneacute de t o u s les a u t r e s g egrave n e s du C M H sur le

m ecirc m e c h r o m o s o m e De plus des g egrave n e s i n t e r v e n a n t d a n s le t r a i t e m e n t des

a n t i g egrave n e s c o m m e le locus LMP2 de sous -un i teacute de p r o t eacute o s o m e se t r o u v e n t

eacute g a l e m e n t d a n s la reacuteg ion de la c lasse IIb ce qui m o n t r e q u e c e s g egrave n e s nont pas

besoin d ecirctre t r egrave s p r o c h e s des au t res g egrave n e s du C M H pour f o n c t i o n n e r

n o r m a l e m e n t

Les produi ts des g egrave n e s du C M H des c lasses I et II des ruminan ts p r eacute s e n t e n t aux

l y m p h o c y t e s T d e s p e p t i d e s t r a i t eacute s e t c e s l y m p h o c y t e s s o n t les a g e n t s d e la

fonc t ion d auxi l ia i re (helper) e t de la fonc t ion cy to tox ique L ident i f icat ion des

s t ruc tu res de l iaison pept id ique des m o l eacute c u l e s de la c lasse I du C M H des bovins

m o n t r e que les m o l eacute c u l e s du C M H des ruminants f o n c t i o n n e n t de la m ecirc m e

m a n i egrave r e que ce l l es de la sour is e t de l homme Ces eacute t u d e s f o n c t i o n n e l l e s

p e r m e t t e n t une b o n n e exp l ica t ion m o l eacute c u l a i r e dun ce r ta in n o m b r e d assoc ia t ions

bien c o n n u e s a v e c des m a l a d i e s i n f e c t i e u s e s m ecirc m e si les m eacute c a n i s m e s

i m m u n o g eacute n eacute t i q u e s qui s o u s - t e n d e n t c e s assoc ia t ions res ten t agrave eacute lucider

Mots-cleacutes An t i gegravene leucocyta i re bovin - Bovins - Complexe majeur d h i s tocompat ib i l i t eacute - Geacuteneacutet ique

- Ovins - Reacutesistance aux malad ies - Ruminants

bull

El complejo mayor de histocompatibilidad de los rumiantes M Ami l l s V Ramiya J Nor imine amp HA Lewin

Resumen Los estud ios rea l i zados d u r a n t e los uacutel t imos ve in te antildeos sobre el c o m p l e j o m a y o r

de h is tocompat ib i l idad (major histocompatibility complex M H C ) del g a n a d o

v a c u n o han ido t r a z a n d o una i m a g e n r a z o n a b l e m e n t e d e t a l l a d a de la

o r g a n i z a c i oacute n g e n eacute t i c a y las f u n c i o n e s de los g e n e s que c o n f i g u r a n d icho s i s t e m a

g e n eacute t i c o El anaacutel is is sero loacuteg ico y b ioquiacutemico de los a n t iacute g e n o s de super f i c ie de los

l infocitos br indoacute las p r i m e r a s p r u e b a s de la ex is tenc ia de g e n e s M H C

e x t r e m a d a m e n t e po l imoacuter f icos en los bovinos y otras e s p e c i e s de r u m i a n t e s De

ahiacute que el M H C de los bovinos rec ib ie ra el n o m b r e de s is tema de a n t iacute g e n o s

l eucoc i ta r ios bovinos (bovine leucocyte antigen system BoLA)


D u r a n t e los uacutelt imos diez antildeos han venido u s aacute n d o s e t eacute c n i c a s de biologiacutea m o l e c u l a r para d e t e r m i n a r el nuacutemero de g e n e s del M H C c a r a c t e r i z a r su s e c u e n c i a y e luc idar su es t ruc tura f ina en d iversas e s p e c i e s de r u m i a n t e s A u n q u e se descubr ioacute q u e d e t e r m i n a d o s g e n e s M H C p o s e e n c la ros or toacute logos en t re los rumian tes y otras e s p e c i e s de m a m iacute f e r o s el M H C de los bovinos y pos ib lemente el de los ovinos y los capr inos exh ibe una o r g a n i z a c i oacute n g e n eacute t i c a c a r a c t e r iacute s t i c a Los bovinos p o s e e n un rac imo (cluster) de g e n e s de la c lase II ( regioacuten de la c lase IIb) ub icado f iacute s i c a m e n t e a c ier ta d is tanc ia del resto de g e n e s M H C a u n q u e en el mismo c r o m o s o m a que eacutestos Por otra p a r t e a lgunos g e n e s impl icados en el p r o c e s a m i e n t o de los a n t iacute g e n o s c o m o el locus LMP2 de subunidad de p r o t e o s o m a t a m b i eacute n se e n c u e n t r a n en la reg ioacuten de la c lase iib lo que v i e n e a d e m o s t r a r que estos g e n e s p u e d e n f u n c i o n a r n o r m a l m e n t e sin n e c e s i d a d de una gran prox imidad f iacutes ica con otros g e n e s M H C Los productos de los g e n e s M H C de las c lases I y II de los r u m i a n t e s p r e s e n t a n peacutept idos p r o c e s a d o s a los l infocitos T que m e d i a n en f u n c i o n e s c o a d y u v a n t e s (helper) y c i to toacutex icas La ident i f icac ioacuten de las es t ruc tu ras de e n l a c e pept iacuted ico de las m o l eacute c u l a s de M H C de los bovinos de la c lase I reve la que las m o l eacute c u l a s M H C de los rumian tes f u n c i o n a n de m a n e r a muy similar a las del ra toacuten y el ser h u m a n o Estos estudios f u n c i o n a l e s p r o p o r c i o n a n una soacutel ida e x p l i c a c i oacute n m o l e c u l a r a d iversas a s o c i a c i o n e s con e n f e r m e d a d e s i n f e c c i o s a s de las que ex is t iacutean ya a b u n d a n t e s p r u e b a s Sin e m b a r g o auacuten no se c o m p r e n d e n en deta l le los m e c a n i s m o s i n m u n o g e n eacute t i c o s que s u b y a c e n a d ichas a s o c i a c i o n e s

Palabras clave Ant iacutegeno leucoci tar io bovino - Bovinos - Comple jo mayor de h is tocompat ib i l i dad -

Geneacutet ica - Ovinos - Resistencia a la en fe rmedad - Rumiantes

References

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5 Andersson L amp Rask L (1988) - Characterization of the MHC class II region in cattle The number of DQ genes varies between haplotypes Immunogenetics 27 (2) 110-120

2 Amills M Francino O amp Sanchez A (1995) - Nested PCR allows the characterization of Taql and PstI RFLPs in the second exon of the caprine MHC class II DRB gene Vet Immunol Immunopathol 48 (3-4) 313-321

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bull histocompatibility complex class I genes on bovine peripheral blood mononuclear cells Anim Genet 23 (2) 113-123

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100 Wright H Redmond J Wright F amp Ballingall KT (1995) - The nucleotide sequence of the sheep MHC class II DNA gene Immunogenetics 41 (2-3) 131-133

101 Xu A McKenna K amp Lewin HA (1993) - Sequencing and genetic analysis of a bovine DQ cDNA clone Immunogenetics 37 (3) 231-234

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Rev sci tech Off int Epiz 17 (1)

Genomic organisation of the MHC region

109

Peptide-binding groove

Alpha 1 domain Alpha 2 domain

Alpha 3 domain

Beta 2-microglobulin

Fig 1 The HLA-A2 cristallographic structure The HLA-A2 crystallography structure (14) data were obtained from the Protein Data Bank (12) and viewed using RasMol software

Linkage and physical map The MHC region contains a diverse array of genes which are crucial for the initiation of adaptive immune responses The MHC encompasses a large chromosomal region that maps to chromosome 2 3 in both cattle and goats (35 9 0 ) and to chromosome 20 in sheep (54) The bovine MHC is designated as BoLA (bovine leucocyte antigen complex) whereas in other ruminants the MHC is named according to the nomenclature proposed by Klein et al (47) Thus the MHCs of sheep and goats are referred to as Ovar and Coki respectively

The general structure of the MHC is relatively conserved among mammalian species and is divided into three main regions with different functional roles (Fig 2 ) However as more DNA sequence data accumulate these boundaries appear artificial because genes with many different functions have been found dispersed among the class I class 11 and class III regions For the purpose of this review however these regional designations will be maintained so that comparisons between species can be made more easily

Physical mapping of bovine chromosome 23 (BTA23) has demonstrated that the class I region encompasses approximately 1550 kilobases (kb) of DNA and that there

are two tightly linked expressed loci (BoLA-A and BoLA-B) (11) The class III region is constituted by a heterogeneous set of genes related to immunological and other functions such as the complement factors BF and C4 steroid 21-hydroxylase (CYP21) heat shock protein 70 (HSP70) and tumour necrosis factor a and (3 (TNFA and TNFB) (49 66 76) One of the most notable differences in the genomic organisation of the MHCs of ruminants compared with humans and mice is the splitting of the class II region into two subregions which are separated by at least 15 cM (centiMorgans) (4 93 ) The class Ila subregion comprises two clusters of genes DR and D Q Physical and genetic mapping have shown that the bovine and ovine DR and D Q genes lie in close proximity (3 77) The class IIb region includes the DMA DMB LMP2 LMP7 and TAP genes (23 4 9 72) which are involved in antigen processing and transpon and other class Il-like genes such as DNA DOB DIacuteB DYA and DYB whose function is unknown (49) On the basis of linkage analysis the bovine class II region lies near the centromere of BTA23 whereas the class I region is distal to the class lla genes (44 93) A similar organisation is expected for sheep and goats which are closely related artiodactyls (66 76) Hybridisation of BTA23 with fluorescence-labelled DYA and class I probes has demonstrated that these two regions physically map at different positions with DYA centromeric to the class 1 loci (83) Interestingly the distance between the class IIa and class IIb subregions varies among individuals as demonstrated by comparison of the recombination rate using single sperm typing of different bulls (67) Variation in the recombination rate might be due to the existence of a polymorphic recombinational hotspot ( 4 4 4 6 7 )

Major histocompatibility complex class I genes and molecules In cattle the class I region contains about 10 to 2 0 class 1 genes (11 52) whereas the estimated number of class I genes in goats is approximately 10 to 13 (17) At least three class I genes are transcribed in cattle (11 2 3 3 7 3 8 ) and sheep (41) The class I genes are polymorphic with 21 distinct BoLA class I sequences (23) and five sheep class I sequences (41) identified to date The length of the transmembrane domain (37 or 35 residues) is the major criterion for assigning the available BoLA class I sequences to specific loci Analysis of class 1 molecules by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) isoelectric focusing (IEF) and peptide mapping also gives strong support for the existence of up to three expressed class 1 loci in cattle (1 45 ) Similarly the serological available data for sheep suggest that at least three different class 1 molecules are expressed by lymphocytes ( 3 9 6 0 ) while in goats there is evidence for only two distinct class I molecules (46 66)

The major histocompatibility complex class II region The class II region in cattle has been characterised using cloned heterologous and homologous class II probes Restriction fragment length polymorphism (RFLP) analysis














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The major histocompatibility complex of ruminants

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