HLA dictionary 2004: Summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ antigens
Introduction
Several years ago, the World Marrow Donor Association initiated a study aimed at identifying the serological types associated with each human leukocyte antigen (HLA)-A, -B, -DRB allelic product. This work resulted in a “serology to DNA equivalents dictionary” first published in 1997 with updates in 1999 and 2001 [1, 2, 3]. The dictionary is a resource to aid searches for unrelated hematopoietic stem cell donors in adult volunteer and umbilical cord blood banks. Although most patients in need of hematopoietic stem cell transplantation are HLA typed by DNA-based methods at medium or high resolution, substantial parts of the donor registries predominantly provide only serologically based HLA typings, at least for HLA class I. In this respect, the dictionary can help in the search for donors whose HLA phenotypes closely resemble that of the patient even though these typings are determined by different methods [4]. Once identified, molecular class I typing of patient and selected donor can be performed to confirm the match. Since the publication of the 2001 dictionary [3] based on the alleles listed in the 2000 World Health Organization (WHO) Nomenclature report [5], a large number of additional alleles have received official allele designations [6]. The International Cell Exchange (UCLA), with its primary emphasis on recruitment of cells with new or rare alleles, contributed updated equivalent information for a number of specificities. Moreover, a reanalysis of the HLA typings in the National Marrow Donor Program (NMDP) volunteer donor database provided more reliable serologic equivalents for the DNA typed samples. Serologic equivalents have also been studied as a project of the 13th International Histocompatibility Workshop. For this project, a large number of cell samples with rare and newly identified HLA-A, -B, and -C alleles were collected worldwide and tested with well-defined sets of serologic reagents. A summary of those results has been included in this dictionary [7]. A new development is the serologic predictions by use of neural network (NN) analysis [8]. A summary of these predictions, updated to include newly defined alleles, has been implemented in this report. The serologic equivalents that are presented in the regular updates of the WHO nomenclature report form a matter of debate. For that reason, we now include a serologic equivalent termed expert assigned type, which summarizes our view on the most probable serologic equivalent for the alleles, which may differ from the WHO HLA assigned type. For completeness, all known alleles (four digits only) as included in the IMGT/HLA database [9] as of October 2003 have been included in TABLE 1, TABLE 2, TABLE 3, TABLE 4, TABLE 5, TABLE 6.
Although serological typing of HLA-C and -DQ antigens is notoriously difficult, often incomplete, and unreliable, the information, when available for a donor, may help in the selection procedure. For that reason, we have included HLA-C and -DQB1 serologic equivalents. Although HLA-DQ molecules are heterodimers combining polymorphic α- and β-chains, the DQ serologic patterns correlate strongly with DQB1, but not with DQA1 polymorphisms. For that reason, Table 6 gives equivalents between DQB1 alleles and DQ antigens.
Section snippets
WHO nomenclature: allele and serologic assignments
This update includes all presently identified alleles as included in the most recent nomenclature report [6] extended with the IMGT/HLA database update from October 2003. Alleles are presented with their four-digit number designation because silent substitutions (represented by the fifth and sixth digits) do not influence the antigenic expression. Nonexpressed (N-(ull))-alleles are included for completeness. This disregards the fact that some null alleles are actually rare subtypes of
International cell exchange, UCLA
The International Cell Exchange (UCLA) provided serologic equivalents for 43 HLA-A, 108 HLA-B, 33 HLA-C, 82 HLA-DRB1, 6 HLA-DRB3, 3 HLA-DRB4, 4 HLA-DRB5, and 17 HLA-DQB1 alleles. The HLA class I analysis included 120 new samples, cells 1065–1184, from healthy individuals, characterized between February 2001 and November 2003. In addition, two cells typed outside the above cell range were included to provide information for the rare alleles, B*2709 and Cw*1509, in TABLE 2, TABLE 3, respectively.
National marrow donor program
Cells from unrelated donors from the United States were HLA typed by means of serological and molecular methods by NMDP-affiliated laboratories. The NMDP data set is based on the typing information from 58,407 individuals for HLA-A; 95,764 individuals for HLA-B; 6234 individuals for HLA-C; 68,188 individuals for HLA-DRB1; and 51,382 individuals for HLA-DQB1. TABLE 1, TABLE 2, TABLE 3, TABLE 4, TABLE 6 present the number of individuals carrying a certain allele, together with the most frequent
NN
An artificial NN was used to predict serologic assignments for alleles lacking this information [8] and to support serologic assignments from other sources. The NN was trained with the polymorphic amino acid residues from the sequences of HLA-A, -B, and -DRB1 allelic products with well-established reference serologic types. The WHO HLA Nomenclature Committee-assigned serologic specificities, including most broad and split specificities, were included in the training set. After training of five
Serology-allele phenotype component of the 13th International Histocompatibility Workshop
One of the goals of this 13th International Histocompatibility Workshop (IHWG) component was to determine the serological assignment of HLA-A and -B and -C alleles whose serological reactivity was unknown or lacked complete characterization [10]. Cell samples including these alleles were made available by a number of laboratories and were tested with a common set of well-characterized reagents including mainly monoclonal antibodies and supplementary alloantisera. Twelve international
Information obtained from other sources
The comments column in the tables indicates references to recent publications that included remarks on the serologic expression of newly described alleles. Expression of alleles tested in the HLA-Club Cell Exchange is indicated in the tables as well. Also, personal communications to and local observations in the Leiden laboratory are included, but it should be realized that such observations are often based on very few samples tested in only one laboratory.
Expert assigned type
It was considered that the use of the dictionary would greatly improve if as many serologic equivalents could be provided as possible. Therefore, we include now an expert assigned type for HLA-A, -B, -C, -DRB1, -DRB3/4/5, and -DQB1, in which all possible information is combined. This expert assigned type may in some cases differ from the WHO nomenclature assignment. In cases where multiple assignments are possible (hybrid molecules), more antigen assignments are provided (see, e.g., A*3108 and
Use of dictionary in a hematopoietic stem cell donor search
The dictionary can be used to develop unrelated donor search strategies. First, the number of individuals tested as carrying a particular allele by the NMDP laboratories provides a rough estimate of allele frequency. For example, 10,841 individuals carried B*0702 compared with the smaller number of individuals who carried other B*07 alleles (e.g., 44 individuals carried B*0704). This suggests that a potential donor typed as B*07 (or B7) is most likely to carry B*0702. It also suggests that it
Serologic specificities lacking official WHO nomenclature designations
As the tables illustrate, a number of alleles appear with several common serologic assignments, indicating that their serologic reaction patterns are not well characterized. For example, the molecule encoded by B*4416 exhibits both B47 and B44 reactivity. A description of some of these variant reaction patterns for HLA allelic products is provided in the comments columns of the tables.
The majority of typing laboratories cannot readily identify a number of officially named HLA specificities.
Future reports of the links between alleles and serologic assignments
With the use of the serologic reagents of the 13th IHWG, a computational analysis was developed to map the amino acid residues that determine the epitopes in the different HLA alleles [11]. Through this analysis, the serologic reactivity of each HLA class I allele is analyzed with the complete 13th IHWG serum set, and the most likely serotype can be predicted. The assignment of likely serotypes obtained by this approach is underway, and future dictionary versions will include these results that
Acknowledgments
The efforts from the participants of the UCLA International Cell Exchange are acknowledged. We thank the typing laboratories in the Netherlands, Belgium, and Luxembourg, which participated in the HLA-Club Cell Exchange, for submitting, typing, and commenting on the samples with new and rare HLA alleles. This work was supported in part by the J.A. Cohen Institute for Radiopathology and Radioprotection (IRS), by the Dutch National Reference Center for Histocompatibility, and by the U.S. Office of
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