The ever-expanding list of HLA alleles: changing HLA nomenclature and its relevance to clinical transplantation.

Since the discovery of the HLA system 51 years ago, both the techniques for the detection of HLA antigens and the method of nomenclature for cataloguing them have changed dramatically. Initially serology was the sole technological tool available to describe the polymorphism of the class 1 and later the class 2 loci. Numbers were assigned to antigens as they were described and as serologic techniques that improved "subtypes" of the original antigens were described. With sequencing of HLA alleles, further polymorphisms were described, and it became evident that the degree of polymorphism was much greater than had hitherto been realized. Sequence differences were detected between alleles, which did not appear to provoke antibody responses but were clearly recognized by responding T cells. A new method of nomenclature was devised, which assigned 2 sets of numbers to each allele. The first 2 numbers indicated the serologic group to which the allele belonged, whereas the second set of 2 numbers was assigned in a numerical progression as each new allele was described. In addition, letters were introduced at the end of each allele where they were known to be nonexpressed or have low levels of cell expression. The limitation of this system is that it only caters for 99 alleles in each serologic group, and this has now been exceeded in some cases. The World Health Organization Nomenclature Committee for factors of the HLA system introduced a modification of the current nomenclature in April 2010 which uses colons to separate the numbers that has the effect of delimiting the number of alleles, which can be assigned to each serologic group. Due to the extensive polymorphism of the HLA genes, sequencing frequently results in ambiguous combinations of alleles and also "strings" of possible alleles due to polymorphisms in nonsequenced gene locations. The reporting in such instances has been simplified to some extent by the introduction of a lettering system to indicate a particular "string." The nomenclature of the HLA system can be confusing to those outside the HLA scientific community. It is important, however, that physicians, particularly those involved in transplantation, have a working knowledge of the nomenclature. It is important in solid organ transplantation in terms of interpreting the relevance of HLA antibodies in cases where there are clear demonstrations in patients of allele-specific antibodies. It is critical in hematopoietic stem cell transplantation where allele level matching is imperative and where decisions have to be made regarding the likelihood of possible sequence mismatches and the clinical relevance of nonexpression or low expression of HLA allelic products.