MHC polymorphism: Coping with the allele explosion

Abstract

Definition of alleles of genes within the human major histocompatibility complex is ongoing with more than 1400 alleles currently recognized. Clinically, human leukocyte antigen (HLA) typing is performed primarily for solid organ and hematopoietic stem cell transplantation. Typing is becoming increasingly complex as the number of recognized alleles increases. Molecular typing techniques are sensitive, accurate and reproducible, but are also compromised by inconsistencies with serological reactivity and ambiguous allele assignments. Inconsistent correlation of some alleles with the antigenic reactivity of their broad allele group can result from sharing of an antigenic motif with another allele group, as well as by null or low expression alleles. Typing ambiguities can result from two or more alleles sharing identical sequences in the regions of the HLA genes amplified, probed or sequenced. Ambiguities also occur in sequencing based typing when heterozygous typing results could be accounted for by two or more combinations of different alleles. It is vital for the histocompatibility specialist to be aware of these problems. Failure to recognize alleles with inconsistent antigen specificity could result in potentially serious mismatches in a transplant recipient. The histocompatibility specialist must also know how to resolve typing ambiguities and recognize the clinical situations for which resolution is critical. A phased approach to typing, from low to high, or allele level, resolution permits use of different techniques, maximizing typing information that may be helpful in resolving ambiguities, while minimizing costs.