UNPRECEDENTED DRB HAPLOTYPE POLYMORPHISM IN THE RHESUS MACAQUE
Gaby G M Doxiadis, Nel Otting, Natasja G de Groot, and Ronald E Bontrop Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
The rhesus macaque is an important model in clinical and biomedical research in transplantation and in investigations of chronic and infectious diseases as EAE, rheumatoid arthritis, and AIDS. Therefore a well characterized rhesus macaque major histocompatibility complex (MhcMamu) is important. Molecular typing of the exon 2 sequence of Mamu-DRB by DGGE (Denaturant Gradient Gel Electrophoresis) and subsequent sequencing allowed the detection of a total of 120 Mamu-DRB alleles. Most of the alleles belong to loci/lineages which are orthologues to human ones as -DRB1*03, -DRB1*10, -DRB1*04, -DRB1*07, -DRB3, -DRB4, -DRB5, and -DRB6. For some loci/lineages no human equivalents have been identified. These are designated by workshop numbers, namely DRB*W1 till DRB*W7, DRB*W20, DRB*W21, DRB*W25 till DRB*W28, and DRBW*31. Within a panel of 200 pedigreed rhesus macaques and/or homozygous animals from consanguineous origin at least 43 different DRB haplotypes could be distinguished. Ignoring allelic polymorphism, within these haplotypes 26 DRB region configurations can be observed which differ in their composition with regard to the number of DRB loci/lineages and -content. In humans, only 5 DRB haplotypes are known. The number of DRB genes present per haplotype can vary from 2 to 6 in the rhesus macaque, whereas it ranges from 2 to 5 in humans. In contrast to humans, the Mamu-DRB1 locus can be absent or duplicated as in DRB1*03/DRB1*10, DRB1*03/DRB1*04, or DRB1*03/DRB1*07. Other loci than DRB1 can also be duplicated as DRB6. There are DRB haplotypes composed only by macaque specific loci/lineages.. Most of the Mamu-DRB haplotype configurations contain one or two DRB6 loci/lineage members, which do not encode a functional Mhc class II gene product. Although most of the Mamu-DRB alleles belong to loci/lineages shared by both species, there is neither sharing of Mhc-DRB alleles themselves nor haplotypes between humans and rhesus macaques. Such a MHC diversity of the class II region must have offered the rhesus macaque an evolutionary advantage in the immune respone against a variety of pathogens.