Ronald E. Bontrop

Nomenclature for factors of the HLA system, 2002

This chapter provides the nomenclature for factors of the HLA system, 2002. A number of previously described class I and II gene fragments within the HLA region are named in this system. Official designations are given to these gene fragments. The names LMP2 and LMP7 used previously for the two proteasome genes in the HLA class II region have been renamed by the Human Genome Nomenclature committee (HGNC) as PSMB9 and PSMB8, respectively. This system introduces the additional digit for synonymous variation and all allele names that are currently five digits or above are renamed accordingly. The use of an optional “N’” or “L” suffix to an allele name to indicate either “Null” or “Low” expression was introduced in previous Nomenclature Reports. Three new suffixes are introduced in this system. An “S” to denote an allele specifying a protein that is expressed as a soluble “Secreted” molecule but is not present on the cell surface; a “C” to indicate an allele product that is present in the “Cytoplasm” but not at the cell surface; an “A” to indicate “Aberrant” expression where there is some doubt as to whether a protein is expressed or not. There is evidence of differential splicing of HLA-G that leads to the production of both membrane-bound and soluble forms of the same allele. The IMGT/HLA Sequence Database contains sequences for all HLA alleles officially recognized by the WHO Nomenclature Committee for Factors of the HLA System and, provides users with online tools and facilities for their retrieval and analysis.

Nomenclature for factors of the HLA system, 2002.

This chapter provides the nomenclature for factors of the HLA system, 2002. A number of previously described class I and II gene fragments within the HLA region are named in this system. Official designations are given to these gene fragments. The names LMP2 and LMP7 used previously for the two proteasome genes in the HLA class II region have been renamed by the Human Genome Nomenclature committee (HGNC) as PSMB9 and PSMB8, respectively. This system introduces the additional digit for synonymous variation and all allele names that are currently five digits or above are renamed accordingly. The use of an optional “N’” or “L” suffix to an allele name to indicate either “Null” or “Low” expression was introduced in previous Nomenclature Reports. Three new suffixes are introduced in this system. An “S” to denote an allele specifying a protein that is expressed as a soluble “Secreted” molecule but is not present on the cell surface; a “C” to indicate an allele product that is present in the “Cytoplasm” but not at the cell surface; an “A” to indicate “Aberrant” expression where there is some doubt as to whether a protein is expressed or not. There is evidence of differential splicing of HLA-G that leads to the production of both membrane-bound and soluble forms of the same allele. The IMGT/HLA Sequence Database contains sequences for all HLA alleles officially recognized by the WHO Nomenclature Committee for Factors of the HLA System and, provides users with online tools and facilities for their retrieval and analysis.

Complete withdrawal of immunosuppression in kidney allograft recipients: a prospective study in rhesus monkeys.

Background. We previously reported the successful withdrawal of immunosuppression in kidney-allografted rhesus monkeys. Recipients had received pretransplant blood transfusions and cyclosporine (CsA) immunosupression for 6 to 12 months. One animal is still alive at more than 15 years after transplantation. Our hypothesis was that the sharing of a single DR antigen between blood donor and recipient, and the sharing of the same DR antigen with the kidney donor, may be beneficial to allograft survival. We now report on the results from a prospective study. Methods. The animals received three pretransplant blood transfusions from a single donor sharing one DR antigen with the recipient. Subsequently, a life-supporting kidney from a donor sharing the same DR antigen was transplanted. CsA was given for at least 6 months after transplantation. Results. Two animals rejected their graft at 5-8 weeks after cessation of CsA treatment. One animal is still alive at 700 days after transplantation. This animal showed MLR nonreactivity to its kidney donor, similar to the animal at more than 15 years after transplantation. Conclusion. These results demonstrate that withdrawal of immunosuppression may be a realistic option in kidney graft patients under careful immunological monitoring of donor-specific immunity.

Molecular Diversity of HLA-DQ

HLA-DQ molecules were isolated from a panel of HLA-DR-DQ homozygous cell lines, partially of consanguineous origin, derived by the use of monoclonal antibody SPV-L3, and subsequently analyzed by gel electrophoretic techniques. It is demonstrated that both the DQ alpha and beta chain exhibit an extensive isoelectric point polymorphism. Within a panel of 29 B-cell lines tested, at least 5 distinct alpha and 6 distinct DQ beta chain gene products were observed. Of the 30 theoretically possible DQ alpha-beta dimers, only 10 could be identified within the panel: 5 different dimers are associated with the DQw1 allospecificity; HLA-DQw2 and -DQw3 are associated with 2 types of dimers, whereas another DQ alpha-beta combination was expressed by a cell line with a so-called DQ-blank specificity. The relation between the specificities 2B3 and TA10 appeared to be complicated as far as DQ beta chain isoelectric point differences are concerned: monoclonal antibody IIB3 seems to be reactive with four distinct DQ beta chain alleles whereas monoclonal antibody TA10 only reacted with one type of DQ beta chain. These results suggest that the polymorphic DQ alpha and beta chains may both contribute to the definition of the HLA-DQ allospecificity. A particular DQ beta chain was present in two types of HLA-DQw1 molecules, as well as in one type of HLA-DQw2 and -DQw3 (2133 positive) molecule, and formed dimers with electrophoretic distinct DQ alpha chains. On the other hand, HLA-DQw2 molecules isolated from HLA-DR3-positive cells and one type of HLA-DQw3 (TA10 positive) molecule were found to be constructed of identical alpha chains but appeared to differ in the composition of their DQ beta chain gene products. The implications of these findings will be discussed.

Patterns of Diversity in HIV-Related Loci among Subspecies of Chimpanzee: Concordance at CCR5 and Differences at CXCR4 and CX3CR1

Human immunodeficiency virus type 1 (HIV-1) arose in humans via zoonotic transmissions of simian immunodeficiency viruses (SIV(cpz)) from common chimpanzees, Pan troglodytes. Despite the close relatedness of the two viruses and their hosts, we do not yet understand what causes SIV(cpz) to be nonpathogenic in chimpanzees, and HIV/AIDS to be one of the most devastating infectious diseases to have emerged in humans. There have been a number of genes identified in humans that confer disease resistance/susceptibility toward HIV-1, but little is known about the evolution and diversity of most of these chemokine receptor genes in chimpanzees. Here we show that genetic variation in chimpanzees differs across the various loci related to HIV-1, and that the pattern of variation differs among the chimpanzee subspecies. For all three subspecies, low diversity at CCR5 is confined to a small area of chromosome 3, suggesting that a selective sweep at this locus may have predated subspeciation. In contrast, diversity and neutrality tests suggest differing evolutionary forces among subspecies at CXCR4 and CX(3)CR1, with directional selection (in Pan troglodytes vellerosus) and demographic expansion (Pan troglodytes troglodytes) offering the most likely scenarios. These are some of the first data demonstrating differentiation in functional loci among chimpanzee subspecies.

The action of falciparum malaria on the human and chimpanzee genomes compared: absence of evidence for a genomic signature of malaria at HBB and G6PD in three subspecies of chimpanzee.

The historical association between Plasmodium and primates has meant that many Plasmodium species have coevolved with specific primate hosts. However, unlike humans that are infected by species such as P. falciparum that cause severe malaria, many non-human primates are infected by Plasmodium species that only cause mild disease. Here we investigate whether the genomic signatures of plasmodial infection found in humans are also present in chimpanzees. We find no evidence of the major deleterious mutations at HBB (beta-globin) and G6PD in chimpanzees that confer resistance to malaria caused by P. falciparum nor evidence of long-term balancing selection at these loci. Our knowledge of malaria prevalence and pathogenesis in wild chimpanzees is severely limited, but it may be the case that beta-globin and G6PD variation are not adaptive in chimpanzees because malaria is rare and/or less detrimental in this species. Alternatively, chimpanzees may utilise mechanisms that are different from those of humans to protect against malaria.

DQw1 (DQw5, DQw6): 2-D Gel Patterns

The HLA-DQw1 specificity was the first supertypic specificity recognized and was described at the 7th Workshop(1). Structural differences have been demonstrated between DQ molecules associated with DR1, DR2, and DRw6(2). These differences have also been distinguished in vitro by CTL lines(3) and clones(4) and monoclonal antibodies such as Genox 3.53 (5).

Nomenclature for Factors of the HLA System, 1995

The WHO Nomenclature Committee for factors of the HLA system met in Brighton in March 1995 at the joint meeting of the European Foundation for Immunogenetics and British Society for Histocompatibility and Immunogenetics to consider additions and revisions to the nomenclature of specificities defined by both molecular and serological techniques following the principles established in previous reports [l-121. sociated with the incorrect sequence is deleted. Names deleted on this basis are given in 2b. In some cases errors are suspected on the basis that they contain unexpected substitutions in normally conserved regions, but no material of the original sample is available for resequencing. As indicated in 2b, the names A*2401 and B*0701 have been deleted for this reason.

DR5 (DRw11, DRw12): 2-D Gel Patterns

HLA-DR5 was subdivided after the 9th Workshop into two specificities, HLA-DRw11 and HLA-DRwl2 (1). Despite some discussion in the 10th Workshop (2), it was finally agreed to retain both DRw11 and DRw12 as splits of DR5(3). The biochemical characteristics of the class II molecules expressed by the DRwll and DRwl2 cell lines are described in this report.

Selective Inactivation of the Primate Mhc-DQA2 Locus

Based on sequence analyses, phylogenetic studies and Southern blot data, a model for the evolution of the primate Mhc-DQA1 and DQA2 loci is presented. The data suggest the existence of two primate Mhc-DQA1 allele families (i.e. DQA1-I and II) before the separation of the ancestors of the old world monkeys and hominoids (approximately 22–28 million years ago). The primate Mhc-DQA2 locus probably originates from a gene duplication that occurred before this separation. After the separation of the two primate lineages, the DQA2 locus was deleted along the old world monkey evolutionary line and was inactivated in the hominoid lineages. These findings suggest the presence of selective forces against a functional primate Mhc-DQA2 locus.