Kemp, Stephen J.

Teale, A.J.

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  44 - The bovine MHC and trypanotoleranceA. J. TEALE and S. J. KEMPIntroductionMHC typing of cattleMHC studies in N'Dama cattleMaterials and methodsResultsConclusionReferencesIntroductionThe MHC comprises a series of genes encoding glycoproteins which are expressed on thesurface of cells. The genes are physically associated on a single chromosome and tend to beinherited as a group. In most mammalian species there is a considerable number of suchgenes, although not all have detectable products at the cell surface.The genes and their products can be placed into two distinct groups. Class I gene productsare expressed on the surface of all nucleated cells, whereas class II gene product expressionis largely limited to the surface of some cells of the immune system with rather specializedfunctions. Class I and class II gene products can also be distinguished on the basis of theirbiochemical nature.An important feature of the MHC is its extreme polymorphism; i.e., the degree to which theindividual genes and their products vary between unrelated individuals of a species. Thenumber of loci and alleles at the different loci in man for instance, is such that on theoreticalgrounds no two unrelated people will have an identical set of MHC-encoded glycoproteins onthe surface of their cells. Moreover, expression of MHC genes is codominant, and so eachindividual expresses one set, or haplotype, inherited from the mother and one haplotypeinherited from the father.The function of MHC glycoproteins is to bind and present foreign antigens (proteins of non-selforigin to which an immune response is mounted) to cells of the immune system so that anappropriate immune response can be generated. Parts of proteins (peptides), of viruses,bacteria and protozoa, for instance, physically associate with MHC glycoproteins and thenbecome recognizable by the immune system cells. Once these cells encounter the foreignpeptide/MHC glycoprotein complex antigen, they become functionally activated and proliferateand, through various mechanisms eliminate the invading pathogen. However, a given MHCglycoprotein will not be able to associate with, and so present, all of the potentiallyimmunogenic peptides which may be generated within an animal during its lifetime.Consequently, the MHC profile of an individual can have a major effect on the immuneresponse repertoire. Further, the MHC profile can result in the failure of the immune responseas a consequence of mimicry of a particular peptide/MHC molecule combination by a secondMHC molecule, per se, within the same animal. As animals are "tolerant" (a state in whichimmune responses are not mounted) of their own proteins, which include their MHCmolecules, in this circumstance there can be no immune recognition of the peptide concerned.In view of the influential nature of the MHC in generation of immune responses, it might beexpected that disease susceptibility may be associated with the MHC profiles, or "types" ofindividuals within a species; that is, that individuals with certain MHC types exist which areeither more or less likely than the average of the species to suffer a given disease. In man, forinstance, there is now an impressive list of diseases which show significant associations withMHC type (Tiwari and Terasaki 1985). Although many such associations involve non-fatalchronic diseases, associations with important infectious diseases have been reported,including malaria (Piazza et al., 1976), typhoid and yellow fever (De Vries et al., 1979),poliomyelitis (Van Eden et al., 1983) and leprosy (Van Eden et al., 1982).MHC typing of cattleClearly, in order to make strong associations in the first instance, an ability to characterize theMHC in all its diversity is a prerequisite. It is now possible to define polymorphism in both theclass I and class II regions in cattle. In the case of class I products, these are universallycharacterized in a standard microlymphocytotoxicity test which is based on the reactivity of thecells of an animal to be typed with panels of antisera and monoclonal antibodies. When aclass I gene product is recognized by an antibody in a panel, the cell carrying the MHCmolecule is killed and the cytotoxicity measured. The overall pattern of reactivity of the cells ofan individual animal with the panel of typing reagents gives the class I phenotype of theanimal concerned. Through international collaborative efforts the definition of the bovine MHChas advanced to the point where more than 20 bovine class I gene products are nowrecognized by all laboratories working in this area. Over the past few years, in collaborationwith scientists at the AFRC Institute of Animal Physiology and Genetics Research, Edinburgh,we have been working at ILRAD to improve the MHC typing of African cattle breeds inparticular. Now, in addition to those MHC types recognized internationally, we are able todefine MHC gene products which are apparently characteristic of African breeds (Kemp et al.,1988).We and others are also able to characterise class I and II gene products with other techniqueswhich include biochemical and cellular methods. The class II region is proving definable at thelevel of the DNA of the genes themselves, using the technique of restriction fragment lengthpolymorphism (RFLP) analysis. All of these non-serological approaches are somewhat moretedious and technically demanding than the standard microlymphocytotoxicity assay, which istherefore likely to remain the most widely applied for some considerable time.Although several class I loci are defined in man and laboratory animals, it is still not clearwhether all of the class I types now recognized in cattle are encoded by a single locus or bymultiple loci. However, this ignorance of the complexity of bovine MHC haplotypes need notnecessarily delay searches for associations between MHC type and diseaseresistance/susceptibility. This is because, given that there is a considerable degree of linkageover the length of the MHC, identification of any of the products of an haplotype and itsdifferentiation from the products of other haplotypes in a study population, is all that is requiredto follow MHC inheritance.MHC studies in N'Dama cattleThe trypanotolerant trait of some West African races of Bos taurus cattle is well documentedbut the genetic control is unclear. We have begun a study of the MHC of N'Dama in TheGambia which involves collecting sufficient typing data to enable a valid comparison of theMHC profiles of these cattle with those of unrelated "susceptible" breeds. In addition, we haveattempted to identify extremes within the N'Dama population, with respect to trypanotolerance,to enable a within-breed comparison. The overall objective is to reveal haplotypes which maybe associated with trypanotolerance for further study in laboratory challenge experiments priorto detailed analysis of the individual genes carried on such haplotypes.Materials and methodsMHC typingThis was performed essentially as reported previously (Teale et al. 1983) with modificationsrequired by an automated reading system (Kemp and Teale, 1987).Cattle populationsAll of the N'Dama animals are under study at the ITC in The Gambia. The population samplefor typing is made up of two groups:A. Cattle in the Livestock Development Project (LDP) herds at Kerr-Serigne andKeneba. These animals may be considered to be representative of the Gambianpopulation of N'Damas as they were acquired from a number of different herds invarious parts of the country. They will form the nucleus of the LDP breedingprogramme. This group consists of approximately 270 cows, calves and bulls.B. Approximately 50 present and future breeding bulls in 4 village locations. Thebulls can be considered to be representative of the 2500 or so cattle beingmonitored for various production/performance characteristics under villagemanagement systems. Disease data are also being collected in this population.The bulls were specifically chosen because they may be expected to have a majorimpact on the future MHC structures of the village herds.Sample preparationPeripheral blood mononuclear cells (PBM) for typing were either separated from whole bloodsamples and placed into liquid nitrogen at the ITC using a standard method ofcryopreservation, or aliquots of whole blood samples were cryopreserved as previouslydescribed (Kemp and Teale, 1984) for subsequent preparation of PBM at ILRAD.ResultsTo date, the cells of more than 300 N'Damas have been tested with our panel of 180 class Ityping reagents. Antigen frequencies have been compared with those in other populations ofcattle. The frequencies for a number of them and including all those which show significantfrequency differences between breeds, are shown in Figure 1. The frequency of the null allele(i.e., genes for which no product is detected) in the European, Boran and N'Dama populationsis 0.58, 0.44 and 0.54, respectively.Figure 1. Frequencies of BoLA class I antigens in three races of cattle.With respect to features of the MHC profiles which seem characteristic of the N'Damapopulation, the most striking involves the KN18 antigen which is present in 21% of the N'Damacattle but in only 1.5% of the Borans and in only one of the European animals. This is a verywell characterized antigen and such a difference in its frequency between N'Dama and othercattle breeds is worthy of further investigation.Another well-defined specificity is w10 which has been shown to have two subgroups, KN3and KN104 (Kemp et al., 1988). These subgroups have never been observed in Europeancattle but are common in African Boran and Zebu breeds. Most N'Dama w10 animals werefound to have both of these subgroups and so could be considered to possess typical"African" w10 antigens. However, individuals with w10 but lacking both subgroups were foundamong the N'Dama. This is typical of the w10 antigen in European cattle and is extremely rarein Bos indicus animals.Like Boran cattle, the N'Dama were found to have a low frequency of w2, an antigen which iscommon in European breeds.Other striking features of the N'Dama BoLA profile are the relatively high frequency of KN4and the low frequency of KN8 and w8. The N'Dama also appeared to have a very highfrequency of w3 and w5. However, we believe that the w3 and w5 antigens are not beingreliably detected in the N'Dama. Therefore, although the differences in the frequency of theantigens detected is real and possibly significant, the w3 and w5 nomenclature should not betaken to mean that the differences are in fact in frequencies of internationally-agreed antigens.ConclusionRecently we have reported a detailed comparative analysis of the MHC gene products ofEuropean taurine and African zebu types (Kemp et al., 1988). It is now apparent that there areclear differences in the BoLA profiles of the Gambian N'Dama by comparison with theEuropean and East African animals and each of the major breed groups described thereforehas some unique features in its BoLA profile. Thus the high frequency of KN18 is a particularfeature of the N'Dama population whereas high frequencies of KN8 and KN12 are more typicalof the East African Zebus. In some respects however, there are indications of similaritiesbetween the N'Dama population and the Zebu population on the one hand and between theN'Damas and the European cattle, on the other. This is illustrated by the occurrence of theKN104 gene in both the N'Dama and Zebu populations but not in the European breeds and bythe occurrence of a particular w10 subtype in the N'Dama and European cattle which is notseen in the Zebus. In some cases there are no significant differences in frequencies within thethree groups.Differences where they are seen between distinct populations within a species are notunexpected and have been well documented in human races, for example (Baur and Danilovs,1980). Whether the differences seen in the cattle populations are the result of selection foradvantageous types in the different environments or whether they are the result of randomdrift is not clear at the present time.Nevertheless, these results are of value in that they make it possible to select haplotypes forfurther studies of the involvement of the MHC in trypanotolerance, on a logical rather than ona random basis. The segregation of selected haplotypes would be followed in animals in whichresponse to parasite challenge is monitored. Bulls carrying typically N'Dama haplotypes (e.g.,KN18) and haplotypes with low frequency in the population as a whole would be used toproduce half-sibling families in matings with cows chosen on the same basis. In this waycalves with various combinations of "N'Dama" and "non-N'Dama" haplotypes would be madeavailable for field and laboratory challenge studies.Bulls selected for heterozygosity as described would also be obvious choices for matings withcows of non-trypanotolerant type, producing F1 and ultimately F2 animals which could beused in challenge experiments to further investigate whether or not the bovine MHC has aninfluence on the trypanotolerance trait.AcknowledgementsWe would like to thank our colleagues and staff at the ITC for their help in planning, collectionand transportation of the Gambian samples and for the hospitality shown to us during our visitsto the Gambia. In particular, we would like to mention Ron Dwinger, Alistair Grieve, PhillipeJeannin, Kwaku Agyemang, Derek Clifford and the Director of the ITC, Professor Ian McIntyre.This is ILRAD publication number 595.ReferencesBaur M.P. and J.A. Danilovs. 1980. Population analysis of HLA-A, B. C, and/or other geneticmarkers. In: Histocompatibility Testing. P.I. Terasaki, ed. UCLA Tissue Typing Laboratory, LosAngeles, pp. 955-993.De Vries R.R.P., P. Meera Khan, L.F. Bernini, E. van Loghem and J.J. van Rood. 1979.Genetic control of survival in epidemics. J. Immunogen. 6: 271-287.Kemp S.J. and A.J. Teale. 1987. An assay for the fully automated reading of thelymphocytotoxicity test and its application to the detection of Bovine Class I and Class II MHCantigens. Animal Genetics 18: (suppl. 1), 15-16.Kemp, S.J. and A.J. Teale. 1984. Cryopreservation of lymphocytes in whole cattle blood: Amethod suited to the field collection of large numbers of samples. Animal Blood Groups andBiochemical Genetics 15: 219-222.Kemp S.J., R.L. Spooner and A.J. Teale. 1988. A comparative study of majorhistocompatibility complex antigens in East African and European cattle breeds. AnimalGenetics. 19: 17-29.Piazza A., M.C. Belvedere, D. Bernoco D, C. Conighi, L. Contu, E.S. Curtoni, P.L. Mattiuz, W.Mayr, P. Richiardi, G. Scudeller and R. Ceppellini. 1973. In: Histocompatibility Testing 1972. J.Dausset and J. Colombani, eds., Copenhagen: Munksgaard, pp. 73-84.Teale, A.J., S.J. Kemp, F. Young and R.L. Spooner. 1983. Selection by majorhistocompatibility lyre (BoLA), of lymphoid cells derived from a bovine chimard andtransformed by Theileria parasites. Parasite Immunology 5: 329-336.Tiwari J.L. and P.I. Terasaki. 1985. HLA and Disease Associations. New York: Springer-Verlag.Van Eden W., R.R.P. De Vries, J. D'Amaro, G.M.Th. Schreuder, D.L. Leiker and J.J. vanRood. 1982. HLA-DR associated genetic control of the type of leprosy in a population fromSurinam. Human Immunology 4: 343-350.Van Eden W., G.G. Persijn., H. Bijkerk, R.R.P. de Vries, R.K.B. Schuurman and J.J. vanRood. 1983. Differential resistance to paralytic poliomyelitis controlled by histocompatibilityleukocyte antigens. J. Infect. Dis. 147: 422-426.  

The bovine MHC and trypanotolerance

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The bovine MHC and trypanotolerance

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