HLA null alleles are alleles for which no HLA products are expressed at the cell surface. Over 190 null alleles have been described across HLA class I and II. Examples include A*01:04N and A*01:11N. The nomenclature for null alleles includes the ‘N’ suffix symbolising null. Other alleles which are alternatively expressed have the suffixes ‘L’ for low expression of HLA product, ‘S’ for products which are secreted rather than being expressed on the cell surface, ‘C’ for product found only in the cytoplasm, ‘A’ for product with aberrant expression where there is some doubt about the cell surface expression and ‘Q’ for products with questionable expression, where the mutation in the allele has previously been shown to affect normal expression.
Mutations in allele sequences which lead to null alleles include insertions, deletions and point mutation many of which lead to the introduction of stop codons, though some lead to the development of incorrectly spliced products. Many of these mutations are located outside of exons 2 and 3 for class I and outside of exon 2 for class II. DNA based HLA typing techniques that do not inspect the gemone outside of these regions therefore run a significant risk of misidentifying null alleles. Misidentifying a null allele for its fully expressed counterpart poses a significant risk in stem cell transplantation.
If a stem cell donor null allele is misidentified as a fully expressed product and therefore transplanted into a patient bearing the expressed antigen, the patient’s antigen will be allogeneic for the donor’s T cells and can lead to severe acute GvHD. In the reverse scenario, if a patient null allele is misidentified as a fully expressed product and therefore transplanted with a donor bearing the expressed antigen, the donors’ antigen will be allogeneic for the patients’ T cells and can lead to destruction of the donor stem cells and graft failure.
Various studies have shown that low expressed alleles are expressed in sufficient numbers to result in T cell tolerance which means that in a stem cell transplant, misidentification of low expressed alleles in either the donor or the patient is likely to be tolerated.
Compared to the impact in stem cell transplantation, misidentification of null alleles in solid organ transplantation has a much reduced clinical impact. If a patient null allele is misidentified as a fully expressed product and therefore transplanted with a donor bearing the expressed antigen, this results in a mismatch which is not life threatening, though the patient does have a risk of developing donor specific antibodies for that mismatch. A donor null allele misidentified as a fully expressed product and therefore transplanted into a patient bearing the expressed antigen results in no humoral rejection and is well tolerated. In the case of low expressed alleles, misidentifying a low expressed allele for its fully expressed variant presents very little risk to the transplant. Even overlooking a low expressed allele such as HLA-A*24:01:01:02L in a donor carries only a small risk of humoral rejection by preformed anti-A24 antibodies due to the low expression.
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