HLA MHC Genetics Evolution
Biostatistics Glossary Homepage
HLA-DR53 Fact File
M.Tevfik Dorak, M.D., Ph.D.
Dorak MT et al: Conserved Extended Haplotypes Update. Genes &
Immunity, Sept 2006
Contents:
Brief
review of HLA-DR53
Disease
Associations
Sequences
References
PowerPoint
presentation on MHC & Leukemia Associations in Humans
HLA-DR53
specificity is exclusively found in association with haplotypes encoding the
DR4, DR7 and DR9 specificities. It was originally called BR4x7, Hon7, MT3 and
DRw53 1. HLA-DR53 is an HLA class II supertypic
antigen expressed at somewhat lower level than the private HLA-DR antigens 2-6. The HLA-DRB4 promoter polymorphism is associated with differential
expression of this locus 4 and this occurs at the level of mRNA production 3. No such difference between the transcripts of the HLA-DRB1 and
HLA-DRB3 genes were found for the HLA-DR52 haplotypes 7 which shows the highest transcriptional activity 6-8. The same studies suggest that the HLA-DRB1 and -DRB4 genes have the
lowest level of transcription among all HLA-DRB genes 6-8.
HLA-DR53 is not expressed on the
HLA-B57DR7Dw11DQ9 (DQA1*0201, DQB1*03032) haplotype (as in the cell line DBB (IHW
9052) representing the ancestral haplotype 57.1) due to a base substitution at
the 3' end of the first intron of the gene 9;10. In fact, the null allele of the HLA-DRB4 gene (DRB4*0103102N)
is transcribed, but it is an aberrant protein due to the lack of splicing out
of the first exon 11. An exception has been reported as an unexpected expression of
HLA-DR53 in a DR7 (Dw11) : DQ9 - positive leukemia
patient 12. More recently, further unusual associations have also been reported.
The null allele DRB4*0103102N
has been found on HLA-DRB1*0401, *0402 and *0404 haplotypes 13;14. The reference cell lines for this allele are DBB and
JHO2821 15;16.
The gene encoding the HLA-DR53 antigen is HLA-DRB4 which exists only on DR4, DR7 and DR9 haplotypes. In HLA-DRB4, allelic differences occur and are not limited to exon 2 (b1 domain) but involve exon 3 (b2 domain) too. All expressed alleles belong to the DRB4*01 allelic series (see the Table below). The three main alleles (DRB4*0101101 [MOU-MANN, LKT3, LBUF-LBF, BSM and PRIESS cell lines]; *0102 [CML cell line], and *0103101 [BOLETH, JHAF, DKB and SUD cell lines]) differ by one amino acid substitution. DRB4*0102 differs from the others in codon 76 of the b1 domain (Asp to Gly substitution - creating a Bsp1286 I (or SduI) site), and DRB4*0103101 differs from the others in codon 135 of the b2 domain (Ser to Gly substitution - creating an EaeI (or CfrI) site). The rare alleles DRB4*0104 and DRB4*0105 have also been recognized 17-22. The null alleles which are not expressed are: DRB4*0103102N [DBB and 12762 cell lines], DRB4*0201N [GN016 cell line] and DRB4*0301N [GN017 cell line] 16;17;20;21. For the alignment of DRB4 allelic sequences, see the IMGT/HLA Sequence Database alignment page. The latest list of officially recognized HLA-DRB alleles can be found at the ANRC site.
Serological
equivalents of HLA-DRB4 alleles
(From
HLA
Dictionary (Refs. 20, 21) and Nomenclature
Reports 1998, 2000
(Ref.22), 2002):
DRB4*01
DRB4*0101101 [DR53]
DRB4*0102 [DR53]
DRB4*0103101 [DR53]
DRB4*0103102N [null]
DRB4*01032 [DR53] [cell line W778R]
DRB4*01033 [equivalent to DRB4*0103101; Ref. 23]
DRB4*0104 [No serological equivalent is defined]
DRB4*0105 [DR53]
DRB4*02
DRB4*0201N [null]
DRB4*03
DRB4*0301N [null]
There is a high degree of diversity in the DRB1-DRB4 haplotypes 24. This is not surprising as these two genes have different evolutionary histories (see below). Some DRB1 alleles are associated with more than one DRB4 allele. This is exemplified by the association of DRB1*0401 with either DRB4*0101101 or DRB4*0103101 (as in the cell lines BOLETH and SUD). In Caucasians and also in patients with rheumatoid arthritis, the commonest DRB4 allele is DRB4*0103 25.
Common
HLA-DRB4 haplotypes
|
Ancestral Haplotype |
B/DRB1/DQB1 |