Search

We have analyzed a series of HLA region markers in 207 UK Caucasoids with early-onset myasthenia gravis (EOMG, onset before age 40), where there is a strong female bias. The well known associations with HLA-DR3 and -B8 have now proved to be significantly stronger in the 165 females than in the 42 males. In patients (of either sex) lacking -DR3, there was also a significant increase in HLA-DR2. Although the muscle weakness in EOMG is clearly mediated by autoantibodies, the associations are consistently stronger with HLA-B8 (in class I) than with HLA-DR3 (in class II), as confirmed here. We therefore typed 87–137 cases for polymorphisms at four loci in the intervening class III region, and also at three in the adjacent stretch of class I. At each locus, one allele tended to co-occur with HLA-B8 and showed strong and highly significant associations in the patients. There appeared to be a region of maximal susceptibility extending from HSP70 (in class III) past HLA-B and HLA-C at least 600kb telomerically into the class I region, which is now being mapped in detail. Any candidate genes here that act shortly after puberty may allow more precise localization of susceptibility.

Human killer cell inhibitory receptors (KIR) are novel members of the immunoglobulin superfamily of cell surface glycoproteins, which are expressed by lymphocytes with natural killer (NK) and cytotoxic T-cell (CTL) phenotypes. These receptors have specificity for relatively conserved epitopes of HLA-A, -B, and -C class I antigens. Recent studies have identified KIR as being involved in the transmission of negative, inhibitory signaling events to the cytotoxic cell which prevent or diminish target cell lysis. KIR are thus likely to play an important role in the responses of alloreactive NK cells and CTL to allogeneic HLA antigens. In this article, we review the known structural and functional characteristics of KIR, suggest a possible mechanism for the transmission of intracellular negative signaling by these receptors, and discuss the relevance of KIR function and HLA specificity to the clinical transplantation of allogeneic tissues.

Cw*1602, a novel HLA-C allele belonging to the newly assigned Cw*16 group, has been cloned and sequenced from a Spanish Caucasoid cell expressing a "Cw6.2" phenotype. Some of the polymorphic substitutions of the new allele, and linkage disequilibrium to B51, had been predicted on the basis of previously published studies. The primary structure of Cw*1602 is in agreement with its serologic reactivity and, in comparison with that of Cw*1601, underlines the dimorphism of HLA-C molecules at residues 77 and 80 of the alpha 1-domain alpha helix.

Molecular genotyping of HLA class II genes using group-specific DNA amplification by the PCR followed by probing with (PCR-SSO) probes is too time consuming for the typing of cadaveric organ donors. Recently, amplification of DNA using PCR-SSP has proved a reliable and rapid method for typing HLA-DRB1 genes. PCR-SSP takes 2 hours to perform and is therefore suitable for the genotyping of cadaveric donors. We have designed a set of primers that in eight PCR reactions will positively identify the HLA-DQB1 alleles corresponding to the serologically defined series HLA-DQ2, DQ4, DQ5, DQ6, DQ7, DQ8, and DQ9. Presently, 30 homozygous cell lines and 138 individuals have been typed by the DQB1 PCR-SSP technique and compared with a combination of serology and RFLP with 100% concordance. No false-negative or false-positive amplifications were recorded. All combinations of DQB1 can be readily identified. DQB1 PCR-SSP can take as little as 130 minutes from start to finish, including DNA preparation.

In the West African population of the Gambia the class I antigen HLA-Bw53 is found at high frequency. We used the polymerase chain reaction to amplify cDNA from an individual homozygous for this allele and determined the nucleotide sequence of the polymorphic alpha 1 and alpha 2 domains. The HLA-Bw53 sequence is identical to HLA-B35 except for a short sequence at the 3' end of exon 2 (encoding the alpha 1 domain) which specifies a Bw4 rather than a Bw6 motif. This suggests an origin for HLA-Bw53 involving a gene conversion of HLA-B35 by an allele containing this Bw4 sequence. The alpha 2 domain shared by HLA-Bw53, -B35, and -Bw58 is particularly common in sub-Saharan Africans.