A large case-control study of malaria in West African children shows that a human leucocyte class I antigen (HLA-Bw53) and an HLA class II haplotype (DRB1*1302-DQB1*0501), common in West Africans but rare in other racial groups, are independently associated with protection from severe malaria. In this population they account for as great a reduction in disease incidence as the sickle-cell haemoglobin variant. These data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.

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Common West African HLA antigens are associated with protection from severe malaria

Human Diversity in Killer Cell Inhibitory Receptor Genes

Analysis of a successful immune response against hepatitis C virus

Functionally and Structurally Distinct NK Cell Receptor Repertoires in the Peripheral Blood of Two Human Donors

Although inhibition of natural killer (NK) cell-mediated lysis by the class I HLA molecules of target cells is an established phenomenon, knowledge of the features of class I molecules which induce this effect remains rudimentary. Using class I alleles HLA-B*1502 and B*1513 which differ only at residues 77-83 which define the Bw4 and Bw6 serological epitopes, we tested the hypothesis that the presence of the Bw4 epitope on class I molecules determines recognition by NKB1+ NK cells. HLA-B*1513 possesses the Bw4 epitope, whereas B*1502 has the Bw6 epitope. Lysis by NKB1+ NK cell clones of transfected target cells expressing B*1513 as the only HLA-A, -B, or -C molecule was inhibited, whereas killing of transfectants expressing B*1502 was not. Addition of an an anti-NKB1 monoclonal antibody reconstituted lysis of the targets expressing B*1513, but did not affect killing of targets bearing B*1502. The inhibitory effect of B*1513 could be similarly prevented by the addition of an anti-class I monoclonal antibody. These results show that the presence of the Bw4 epitope influences recognition of HLA-B molecules by NK cells that express NKB1, and suggest that the NKB1 molecule may act as a receptor for Bw4+ HLA-B alleles. Sequences outside of the Bw4 region must also affect recognition by NKB1+ NK cells, because lysis of transfectants expressing HLA-A*2403 or A*2501, which possess the Bw4 epitope but are in other ways substantially different from HLA-B molecules, was not increased by addition of the anti-NKB1 antibody. Asparagine 86, the single site of N-linked glycosylation on class I molecules, is in close proximity to the Bw4/Bw6 region. The glycosylation site of the Bw4-positive molecule B*5801 was mutated, and the mutant molecules tested for inhibition of NKB1+ NK cells. Inhibition that could be reversed by addition of the anti-NKB1 monoclonal antibody was observed, showing the presence of the carbohydrate moiety is not essential for class I recognition by NKB1+ NK cell clones.

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The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor

Although the B70 antigen exhibits allele frequencies of 8-23% in African and American black populations, it remains poorly defined. Cloning and sequencing of cDNA encoding B70 antigens from six cell lines has identified a group of three closely related alleles: B*1503, B*1509 and B*1510, that form a subgroup of the B15 family. The sequences of these alleles and, in particular, B*1503, are close to that of the HLA-B consensus consistent with the difficulty in their serological definition. The products of the three alleles correspond to three electrophoretically detected variants of the B70 antigen and some correlation with the B71 and B72 subspecificities of the B70 antigen can be made. A fourth allele, B*7901, previously described by Choo et al. (J. Immunol. 147: 174-180, 1991) that was not serologically typed as B70, differs by a single nucleotide substitution from B*1510. The sensitivity of alloantibodies to single differences in peptide binding residues suggest a role for bound peptides in the HLA-B70 alloantigenic specificities. The heavy chains encoded by the four alleles differ at four peptide binding residues of the antigen recognition site, the evolutionary modification of which can be explained in terms of interallelic recombination events.

Structural heterogeneity in HLA‐B70, a high‐frequency antigen of black populations *

The HLA class I and II phenotypes of the three popuation groups in the Cape Province of South Africa were determined. The HLA-A, B, and C antigens were tested in 1027 South African Negroes (Xhosa), 3716 Cape Coloureds and 1059 South African Caucasoids. This is the first study which has also included the class II antigens in the Southern African Negroes (Xhosa). The numbers tested for the DR and DQ antigens were smaller, as only typings done after the 8th Histocompatibility Workshop were included. A comparison was made between the frequencies in the Xhosa, the Cape Coloureds and the South African Caucasoids as well as the Nigerians, another group who also belong to the Bantu-speaking division of African Negroes and who were recently studied. The antigen, gene and haplotype frequencies were estimated in all three groups, and the genetic distances calculated. Striking differences in gene and haplotype frequencies between the various populations were seen. For example, Bw42 had a phenotype frequency of 0.062 in the Cape Coloureds, 0.213 in the Xhosa and 0.004 in the South African Caucasoids. The Xhosa showed marked differences in HLA distribution compared to the other Negro group (Nigerians), which can be attributed to a Khoisan admixture, e.g. HLA-DR4 had a phenotype frequency of 0.134 in the Xhosa and only 0.010 in the Nigerians. The haplotype B8, DR3, seen in association with many autoimmune diseases, had a significant delta value in all three populations.

HLA-A, B, C, DR and DQ polymorphisms in three South African population groups: South African Negroes, Cape Coloureds and South African Caucasoids.

DR51, a protein encoded by the DRB5 gene, was shown to be present in almost all DR2-positive haplotypes. Exceptions were reported, some DR2-negative samples were shown to be DR51 positive and in a number of DR2-positive samples no DR51 antigen could be demonstrated. In some of them lack of the DRB5 gene was the cause of the absence of DR51 but in others the DRB5 gene was present without resulting in a detectable gene product. Many of these variants were studied in detail in previous international workshops. One of them was DR2ES from our laboratory. She is a DR15-positive DR51-negative individual of oriental origin with a clearly demonstrable DRB5*01 allele when typed by molecular techniques. To unravel the molecular mechanism responsible for the defect in expression, cDNA and DNA encoding the defective DRB5 allele were analyzed. Nucleotide sequence analysis of exon 2 showed no differences from the sequence of DRB5*0102. However, when exon 3 was examined a difference in length was noticed due to a deletion of 19 nucleotides between codon 161 and 168. The deletion caused a frameshift and a premature stopcodon resulting in a null allele. The same allele could be demonstrated in 6 other unrelated individuals of oriental origin as well as in 5 individuals from South Africa. The absence of the DR51 protein was explained by the presence of an alteration in the DRB5 allele resulting in a null allele. The allele has been officially named DRB5*0108N. This is the first description of a null allele of the DRB5 gene.

The absence of DR51 in a DRB5‐positive individual DR2ES is caused by a null allele (DRB5*0108N)

Alleles encoding five HLA-A and B Ag characteristic of black populations have been isolated and their nucleotide sequences determined. In each case, the "black" allele is similar to a "related" allele found in caucasoid populations. The primary differences between these pairs of alleles are localized clusters of nucleotide substitutions that change two to five residues of the Ag recognition site. The pattern of differences indicates that the pairs of black and caucasoid alleles diverged primarily as a result of interallelic conversion events.

Distinctive HLA-A,B antigens of black populations formed by interallelic conversion.

HLA-A, B, C, DR and DQ typing was done on 26 black Zimbabweans with rheumatoid arthritis and the respective antigen frequencies were compared with those in a group of 119 normal individuals from the same ethnic background. Only the DR4 antigen was significantly increased in frequency in the patients, confirming the association with this disease seen in other Black African populations.

E. D. du Toit

Papers

Structural heterogeneity in HLA‐B70, a high‐frequency antigen of black populations *

HLA-A, B, C, DR and DQ polymorphisms in three South African population groups: South African Negroes, Cape Coloureds and South African Caucasoids.

The absence of DR51 in a DRB5‐positive individual DR2ES is caused by a null allele (DRB5*0108N)

Distinctive HLA-A,B antigens of black populations formed by interallelic conversion.

The association between HLA and rheumatoid arthritis in Zimbabwean blacks.