Mechanisms for genetically predetermined differential quantitative expression of HLA-A and -B antigens.

Previous studies showed that different HLA-A and -B antigens are differentially expressed in cells. Their relative quantities are genetically predetermined and inherited according to Mendelian laws. To investigate mechanisms responsible for this differential expression, a correlation study between the relative quantities of different HLA-A and -B proteins and their mRNA levels in eight different HLA-phenotyped lymphoblastoid cell lines (LCLs) were performed. The results show proportional correlation in all the studied cell lines except those that are positive for HLA-A24. Study of the turnover of HLA antigens reveals that different HLA-A and -B antigens are proportionally degraded. Measurement of the relative quantities of HLA-A and -B mRNAs in six LCLs before and after treatment with 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), an inhibitor of RNA polymerase II, demonstrates that HLA-A and -B mRNAs are proportionally degraded except slight differences in two LCLs. Measurement of the relative quantities of different HLA-A and -B pre-mRNAs in nuclei shows that they are not proportional to the relative quantities of their respective mature mRNAs in cytoplasm in four of six LCLs. These results indicate that combinations of different regulatory steps which include gene transcription, pre-mRNA splicing and mRNA degradation are involved in the genetically predetermined quantitative differential expression of HLA-A and -B antigens. Transcription of HLA genes and splicing of HLA pre-mRNAs appear to be the dominant regulatory steps.