History of HLA Nomenclature: The 1970s

Class I is full of parent antigen specificities and their associated subtypic splits.

But what are splits?

Here is an official way of defining HLA splits⁵:

“The subdivision of an original specificity through the subsequent discovery of newer, more specific reagents.”

HLA Beyond Tears (2nd Ed.) by Glenn Rodey

As the development of reagents for HLA specificities progressed, so did the ability to target increasingly discrete aspects of a specificity. Researchers were discovering that known antigen specificities (already approved and named by the Committee) were showing cross-reactivity. This was because they were targeting a more specific aspect of the antigen specificities.

For example, the HL-A9 specificity was cross-reacting. This meant that cells identified as A9 were reacting with reagents that identify it as A9 (as expected), but A9 cells were also reacting to new reagents (unexpectedly). Because the reactivity was consistent, the Committee elected to give these split reactivities the next sequential numbers in the HLA naming convention. At the time of discussion and discovery, the numbers 23 and 24 were the next available numbers, thus W23 and W24 became the next specificities listed in the nomenclature. This means that A9 had reactivity that split further into W23 and W24. These splits are also known as ‘subtypic’ specificities, subgroups, or subpopulations.

A9 showed reactivity that split into the subtypes W23 and W24 (’W’ = working/workshop).

Because A9 had these subtypic specificities, A9 became known as a ‘parent’, ‘broad’, or ‘supertypic’ specificity.

Once the subtypes were confirmed, they were given full status, which meant removing the W and replacing it with the ‘A’ designation. The numbers don’t change; those numbers are specific identifiers. What changes is our surety of them as an antigen specificity. (You can see the answer to the next question: “What is the Purpose of the ‘w’ in HLA Specificity Nomenclature” for more information).

What were the reagents detecting?

The reagents were detecting epitopes, which are clusters of amino acids situated closely together on the HLA molecule, creating a target for antibodies. The A9 antibody reagent was detecting the A9 public epitope. The A23 and A24 antibody reagents were detecting private epitopes.

Here are two patient cells. One cell has A23 antigen specificities on its surface. The other has A24 antigen specificities on its surface. But you might notice that there’s the same cyan-colored spot on both A23 and A24 antigens.

Public epitopes are present on multiple different antigen specificities. In this case, the A9 epitope/amino acid cluster is present on both the A23 and A24 specificities. This is what the original A9 reagent was detecting.

Private epitopes are present on only one antigen specificity. There is a private epitope specific to A23 and a private epitope specific to A24 that help distinguish the two specificities. The more specific reagents allow the A9 cells to be further distinguished as either A23 or A24.

So how are splits notated?

In current nomenclature, splits are sometimes marked with the parent specificity in parentheses. We now know that A9 splits into A23 and A24. This can be notated in official nomenclature as A23(9) or as A23. Similarly, A24(9) and A24 are referencing the same antigen specificity. One form identifies the parent of the split (A9) while the other does not. Both notations are acceptable. If a cell is typed as A9, this means that it could be an A23 or an A24 subtype. This type of result likely meant that the laboratory performing the typing didn’t have reagents available to clarify whether the A9 cells were more specifically A23 or A24.

This method of giving splits the next numbers in the sequence as they’re discovered also explains why so many splits share a running number sequence (ex: A28 splitting into A68 and A69, B22 splitting into B54, B55, and B56, etc), though not all do. Interestingly, this also means you can identify the order the splits were encountered in the A and B loci when specificities are placed in numerical order, because the A and B locus were named as a single running sequence. In this case, A9 and A10 subtypes were the first identified, followed by A19, some more A10, and then B16 as we can see below. This was organized purely for fun and serves no other real purpose beyond curiosity.

Some shorthand nomenclature methods were also used to identify subtypes/splits, though these are unofficial names. Some easy examples are present with the B17 that split into Bw57 and Bw58. There were a few different alternative shorthand naming methods. For example:

There are also ‘long’ and ‘short’ designations that will be discussed more in the 1990’s.

You’ll see these shorthand versions in historical HLA articles but this is not common practice today.

The W’s, however, they stuck.

But what are the ‘W’s doing there?