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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

 

 

DRB4

 

Bw4/6

 

BF

 

TNFB

 

HSP70-2

 

Frequency

(%)

 

44.1

44/0401/0301

0101

4

S

1

183

5.1

44.2

44/07/0201

0101

4

F

2

183

3.9

57.1

57/07/03032

0103102N

4

S

2

183

2.7

60.1

60/0404/0302

0101

6

S

2

-

2.6

64.1

64/07/0201

0101

6

S

2

-

1.7

62.1

62/0401/0302

0101/0103

6

S

2

183

 

1.5

(B62.X)

62.2

62/0401/0302

0103

6

S

2

183

62.4

62/0401/0302

0103

6

S

2

183

13.1

13/07/0201

0101

4

S

2

188

1.0

38.1

38/0402/0302

0101

4

S

2

183

< 0.5

47.1

47/07/0201

0101

4

F

2

183

< 0.5

50.1

50/07/0201

0101

6

S

1

-

< 0.5

51.1

51/0404/0301

0103

4

F

2

183

< 0.5

(DKB)

40/0901/0303

0103

6

S

2

183

< 0.5

As exemplified in the cell lines BOLETH and BSM, the DRB4 may differ on the ancestral haplotype 62.1 despite identity at DRB1 and DQB1. The haplotypes are shown in decreasing frequency order (in the Welsh population, Ref. 26) and those with a frequency of > 0.5% are shown in bold. The frequency column shows the haplotype frequencies for HLA-BDRDQ parts of the ancestral haplotypes in an adult Welsh population 26. The HSP70-2 genotypes are from our own studies (Dorak et al. 2006) with confirmation from another report by Corzo et al. 27. TNF and BF genotypes are from Refs. 28, 29. Further information of the typings of IHW / 4AOH cell lines can be found at ECACC, IMGT  and  ASHI / NMDP Cell Repository  websites. See also Complete List of HLA-DR53 Homozygous Cell Lines.

 

Brief evolutionary history of the HLA-DRB haplotypes

Although there are different scenarios, the ancestor of the human HLA-DRB genes appears to have been HLA-DRB1*04-like (Figueroa, 1994; Satta, 1996a, Satta, 1996b) 30;31. Both DRB1*04- like ancestor and the ancestor of the DRB1*03 cluster have been estimated to be older than 85 mya (Figueroa, 1994) 30. This estimate derives from the fact that DRB1*04 alleles are found in Prosimian species (note that the mouse lineage separated about 75-80 mya). It is possible that DRB2 (on DR52 haplotypes), DRB4 (on DR53 haplotypes and most closely resembles DRB2), and DRB6 (on DR51 haplotypes) might be the diverged copies of a single ancestral DRB gene 32-34. Available evidence suggests that the different HLA-DRB genes arose by duplication that was followed by homogenization through gene conversions 35. The DR51 and DR52 haplotypes may share a common ancestry and the lineages separated after an ERV9 LTR insertion about 40-60 mya 33.

            The DRB4 gene may have arisen 46 mya by a deletion from the DRB1 and DRB2 genes 31. The DRB9 locus is about 58 mya old 36 and the pseudogenes DRB7 and DRB8 arose after DRB9 37. The remaining HLA-DR haplotypes, the DR1/10 and DR8 groups, probably evolved from the DR51 and DR52 haplotypes, respectively, after more recent deletion events 33. All DR53 haplotypes carry the DRB1, DRB4, DRB7, DRB8 and DRB9 genes. The DRB1 and DRB4 genes of the DR53 haplotypes have distinct evolutionary histories 38. It has to be noted that phylogenetic analysis results may vary depending on which part of the gene is analyzed. There is strong evidence that the present day HLA haplotypes derived from three main haplotypes corresponding to HLA-DR51, -DR52, and -DR53 haplotypes (Satta, 1996a) 31. This grouping is agreed by others too: an evolutionary grouping encompasses the HLA class II haplotype families characterized by the second expressed DRB genes encoding the supertypes, i.e., DRB5, DRB3 and DRB4 haplotype groups (Andersson, 1994). Since DR51 (incl. DR1/10) and DR52 (incl. DR8) haplotypes seem to share a common ancestor 33, it is possible to divide the HLA-DR haplotypes into two evolutionarily related groups: DR53 group and non-DR53 group as direct descendants of the two primordial DRB genes more than 85 mya old (but see below). In summary, two main, evolutionarily old branches of HLA-DR haplotypes exist in human population. The DR53 supertypic group represents one main branch, and the second branch consists of the DR51 and DR52 supertypic groups as well as the -DR1 and -DR8 lineages 33;39. The second branch (DR51/52 group) is characterized by the ERV9 LTR insertions at the identical position in the intron 5 of the expressed DRB genes (DRB1*01, *15, *0301, *0802; DRB3*0101) 33;39. However, note that the DRB5 lineage appears closer to the DRB3 group when intron 1 sequences are used (Hughes, 2000).

            By direct comparison of exon 2 nucleotide sequences of DRB1 alleles, two groups of HLA class II haplotypes (HLA-DRB4/DRB5 and ‑DRB3) can be distinguished (Klein, 1990; Kasahara, 1992; Ayala, 1994; Svensson, 1995; Satta, 1996). The evolutionary tree of 58 HLA-DRB1 alleles show that these alleles coalesced into 44 lineages by 1.7 million years ago (Ayala, 1994; Fig 3). They further coalesced into two ancestral lineages about 25 to 30 million years ago with the exception of HLA-DRB1*0701. One of these lineages contains all HLA-DRB1*03, *11/12, *13/14 and *08 alleles examined (the DRB3 group and DRB1*08), while the other one contains all DRB1*04, *09, *15/16, *01 and *10 alleles examined (DRB4/5group and DRB1*01/*10).

            Analysis of DRB gene sequences from primates showed that the age of polymorphism for DRB4 is very old, in fact, its age is only exceeded by DQB1 and DQA1 loci 40.  The DRB4 locus is polymorphic also in Chimpanzees but not in other primates examined, and is subject to selection 40. This is suggested by a high dn/ds ratio (number of non-synonymous substitutions / synonymous substitutions). Also in humans, the HLA-DRB4 gene shows a very high dn/ds ratio only in the peptide-binding regions but not in the remainder of the gene 41. Therefore, the appearance of polymorphism accompanied by a high dn/ds ratio supports the notion that balancing selection is the driving force behind the maintenance of the polymorphism.

            The most ancient polymorphic class II locus is likely to be HLA-DQA1 (Gyllensten & Erlich, 1989) 40;42. The polymorphism of this locus also correlates to the MHC class II supertypical groupings (Moriuchi, 1985) 43. This is most obvious in the HLA-DQA1 / TaqI RFLP patterns as used in an HLA-leukemia association study 44. The supertypes' being the ancient allelic lineages of MHC is also evident from the cross-reactivities among them in different species 45-49. Most interestingly, HLA-DR53 is cross-reactive with the corresponding supertype H‑2Ek 48;49. The HVR3 epitope of HLA-DR53 is shared by HLA-DR1 and HLA-DR10 50;51. This explains an earlier finding that an antibody specific for H-2Ek was found to be cross-reactive with HLA-DR1 when HLA-DR53 had not been recognized yet 52.

 

Extra DNA on HLA-DR53 haplotypes

One exclusive feature of the DRB4-carrying haplotypes is that they have an extra amount of DNA compared to the DR3 haplotype irrespective of the DRB1 type 53-56. It is not yet known whether this DNA contains novel genes. Although the sequencing of a human MHC haplotype is now completed 57, the haplotype used in that study is the shortest HLA-DR52 haplotype. It is understood that the Sanger Centre is also sequencing the class II region of a DR53 haplotype 57;58. This study should clarify the nature of the extra DNA in the class II region of the HLA-DR53 haplotypes. Recently, a gene (PRKRA) has been identified that is exclusive to the DR53 haplotypes 59;60. Fina verdict on the nature of the extra DNA awaits the completion of the complete sequencing of an HLA-DR53 haplotype at Sanger Institute, which is underway (MHC Haplotype Project).

 

Immunological function of HLA-DR53

The HLA-DR53 molecule has a unique peptide-binding motif and indeed binds peptides (most frequently an autoantigen calreticulin 'p278-292' involved in class I peptide presentation pathway, L-plastin 'p581-595', gliadin 'various peptides', a melanocyte antigen gp100, and a cancer antigen 'NY-ESO-1') 61-69. In a diabetic patient, an autoreactive T cell clone has been shown to recognize a fragment of HLA-DR4 presented by HLA-DR53 64. The putative peptide binding motif of HLA-DR53 is a positively charged residue (K) at position 1, a hydrophobic residue (I) at position 4, a positively charged residue (R or K) at position 8 or 9, and another hydrophobic residue (I) at position 10 (the C-terminus) 62;65; but another study found no preference for P1; while F, I, M, T are favorable residues for P4; F, A, I, T are for P6; I, T are for P9; and D for P10 67. The crucial residues on the HLA-DRb molecules are residues 86 and 57. In the HLA-DR53 molecule, b57 is D and b86 is V (the tyrosine at b81 is unique to HLA-DR53 and may indirectly alter the specificity of pocket 1 by providing a higher flexibility to the peptide 67. It is thought that the hydrophobic b86V has an influence on the HLA-DR53 binding motif composed of a positively charged residue at the N-terminus; and the negatively charged b57D (and/or b9E) interacts with the positively charged residues at the C-terminus of the peptide 62.

            Among the peptides eluted from HLA-DR4/DR9/DR53, the most interesting is calreticulin. It is a peptide-binding cytoplasmic molecular chaperone which behaves like a tumor-rejection antigen by eliciting CTL response against bound peptides 70;71. Calreticulin is also implicated in a number of autoimmune disorders 72. The peptide fragment of calreticulin found bound to HLA-DR53/DR4 61;73 is as follows:

                           (278/295) DNPEY SPDPS  IYAYD (292/309)

The residues in bold correspond to relative positions 1 and 6 of anchor residues in HLA-DR4 / HLA-DR53. This sequence is not found in any other human protein listed on the SwissPort database (as of May 2006).

            Another peptide which binds to HLA-DRB4*0101 for presentation is dihydrolipoamide acetyltransferase component of pyruvate dehydrogenase complex (PDC-E2 also known as 70 kDa mitochondrial autoantigen of primary biliary cirrhosis) peptide 65:

                            (163) GDLLAEIETDKATI (176)

The crucial amino acids in binding of this peptide to HLA-DR53 are shown in bold. This peptide sequence is not shared by another human protein in the SwissPort database either. Despite binding of these peptides to the DR53 molecule, if you do a search for DR53-specific epitopes in these sequences using the HLA-peptide binding motif scanner, it does not find any epitope that would bind to DR53.

            The peptide binding motifs of the individual HLA-DR53 family members, HLA-DR4, ‑DR7 and ‑DR9, are known 61;63;74-77.

            HLA-DR53 is immunologically functional and no different from any other HLA-DR antigen. HLA-DR53 acts as a restriction element in antigen presentation 48;64;65;78-83. Among the antigens for which it is a restriction element are Hsp70 of M. leprae (Mustafa, 1994; Adams, 1997) 81;82 (see also Joko, 1995 and White, 1997 for protective role of HLA-DR53 in leprosy), the PDC-E2 (mitochondrial autoantigen of primary biliary cirrhosis) (Shigematsu H, 2000) 65;80, a Chlamydia trachomatis antigen 78 (see also White, 1997 for protective role of HLA-DR53 in blinding trachoma), glutamic acid decarboxylase [an autoantigen in diabetes] 83, TARP (prostate and breast tumor antigen) (Kobayashi, 2005), and most interestingly the HLA-DR4 molecule 64. Beta2-glycoprotein I (beta2GPI)-specific CD4+ T cells preferentially recognize the antigenic peptide containing the major phospholipid (PL)-binding site in the context of DR53, and autoreactive CD4+ T cells to beta2-glycoprotein I (beta2GPI) that promote production of pathogenic antiphospholipid antibodies (Kuwana, 2004).

            The HLA-DR53 molecule is known to have poor interaction with CD4 which is determined by the polymorphic residues between positions beta 180 and 189 (Fleury, 1995) 84. Another feature of the HLA-DR53 molecule is its low affinity for superantigen binding (Herman, 1991; Karp & Long, 1992) 85;86. The DR53 family molecules DR4 and DR7 are associated with low IFN-g production in an MLR context (but also DR3 and DR5) 87.

            The residues 80 to 83 of HLA-DRb chain (residues 80 RHNY 83) control the post-Golgi entry of class II molecules into endosomes 88. This sequence is highly conserved among all HLA-DRB alleles except HLA-DRB4*01 (80 RYNY 83). It is not known what effect this may have on the intracellular transport of the HLA-DRb4 chain. Although the effect of this difference has not been studied specifically, it is known that a single amino acid change at position 81 (where HLA-DRB4*01 differs from the rest) severely affects the intracellular transport of the mutant HLA-DRb chain and possibly also its peptide presentation ability 88. One other segment that is unique to all HLA-DRB4 alleles lies between residues 39 and 42 of b1 domain encoded by exon 2. The consensus amino acid sequence of this segment is Arg-Phe-Asp-Ser (RFDS) in all DRB1 (except *0433, *10011 and *10112), DRB3, DRB5, DQB1 and DPB1 alleles (IMGT database). It is, however, Arg-Tyr-Asn-Ser (RYNS) in all HLA-DRB4 alleles (Young, 1987) 89. The importance of this finding is that this segment may be important for T-cell recognition 90.

            The above-mentioned studies suggest that although there is no doubt that HLA-DR53 is an immunologically functional HLA molecule, the functionality of DR53 itself and that of the DR alleles who are the members of the DR53 family may be somewhat lower than other HLA-DR alleles. These features of the HLA-FR53 family of haplotypes may be the immunological mechanism of the homozygous HLA-DR53 association in CML, CLL and childhood ALL (see PowerPoint presentation on MHC & Leukemia Associations in Humans).

 

Cross-reaction with H-2Ek

Several monoclonal antibodies react with various epitopes of HLA-DR53. Among these, 17-3-3s also reacts with the mouse class II supertype H-2Ek  (r=0.88; p=10-12) 49, and 109d6 recognizes the HVR3-encoded epitope and detects it as a susceptibility marker for adult acute myeloblastic leukemia  91 and rheumatoid arthritis 92. The cross-reaction with H-2Ek may be of functional significance as H-2k haplotype is invariably associated with increased risk for spontaneous and virus induced mouse leukemia 93-95.

 

Molecular mimicry

The HVR3-encoded epitope is mimicked in its entirety (67 LLERRRA 74, exon 2) by the E3-14.7K protein of adenovirus and the large tegument protein of EBV 96. The HVR3 epitope is identical in all DRB4 variants. The following DRB1 alleles also share this epitope: DRB1*0101, 0102, 0104, 0105, 0106, 0404, 0405, 0408, 0410, 0419, 0423, 0428, 0430, 0440, 0442, 1134, 1344, 1402, 1406, 1409, 1413, 1420, 1429, 1430, 1433. DRB1*1001 shares the epitope with the exception of a single conservative amino acid change in position 70 (Q70R). A large group of DRB1*14 alleles show the same conservative amino acid change from the DR53 HVR3 epitope. These are 1401, 1407, 1408, 1410, 1411, 1414, 1418, 1423, 1426, 1428, 1431, 1432, 1434, 1435, 1436, 1438 and 1439. Therefore, it 4can be said that the mimicry by several oncogenic viruses of the HVR3 epitope of DR53 extends to DRB1*01, *10 and *14 alleles.

This is the greatest molecular mimicry ever reported between an HLA molecule and a non-HLA protein. Given the fact that HLA-DR53 or HLA-DR4/7/9 are associated with a number of diseases including all major leukemias and several other malignancies, it is likely that this molecular mimicry is operative in the pathogenesis of these diseases. It has been proposed that molecular mimicry with adenovirus, together with other features of HLA-DR53, may play a role in the development of childhood acute lymphoblastic leukemia 97. A recent study has shown an increased frequency of antibodies against EBV in childhood acute lymphoblastic leukemia, which suggests the involvement of EBV in the development of this leukemia 98.

 

Disease associations

A number of autoimmune, viral and malignant diseases are associated with HLA-DR53 or HLA-DR4/7/9:

* Rheumatoid arthritis (DRB1*04 and DRB4*01 susceptibility; DRB1*07 protection) 92;99-111 (homozygosity for HLA-DR4 in young males 110;111; HLA-DR4,7 genotype more frequent in males 112; association with ancestral HLA-DR haplotypes in males only 99)

* Felty syndrome (DR4) 113

* Early-onset psoriatic arthritis (DR4, DR53) 114

* Pemphigus  vulgaris (DRB1*04) 115

* Polymyalgia rheumatica 116

* Giant cell arteritis 117-119, in one study HLA-DR7 association in males only 120

* Primary antiphospholipid syndrome (DRB1*07 and DRB4*01) 121-124 (see also Kuwana, 2004 for the molecular mechanism)

* Recurrent spontaneous abortion associated with the presence of anticardiolipin (antiphospholipid) antibodies 125

* Recurrent spontaneous abortions (DR4) 126, and pre-eclampsia (DR4) 127;128 or B44DR7 129;130

* Intrauterine growth retardation (B4DR7) 129

* IDDM (DRB1*04 and DRB1*03) 131. Under 13 yr, an excess of females in the DR3+/DR4- group; and an excess of males in DR3-/DR4+ group 132;133.

* Myasthenia gravis in Japan (DR53 in early-onset disease in females) 134

* Hashimoto thyroiditis 135;136

* Graves' disease (DR9) (in China and in males only) 137;138

* Crohn's disease in Japan: DRB1*0402, *0405, *0410 139-141

* Celiac disease 66

* Vogt-Koyanagi-Harada syndrome 142-146

* 70kd U1-snRNP antibody-positive connective tissue disease 147;148 

* HTLV-1-associated HAM/TSP: B*54,DRB1*0405 149

* Rheumatic fever 150;151

* Protection from multiple sclerosis (together with HLA-DR1) 152

* Protection from ulcerative colitis: DRB4*0101 140

* Erythema multiforme [herpes virus related] 153-155

* CMV infections in AIDS: (B44)DR7 156;157

* Persistence of hepatitis C infection 158;159, lack of response to interferon treatment in hepatitis C infection 160 (B*54,DRB1*0405 in Japan)

* Unresponsiveness to hepatitis B surface antigen: B*54,DRB1*0405 haplotype in the Japanese 161, DRB1*07 in Caucasians 162

* Autoimmune hepatitis in Japan (HLA-B54, DRB1*0405) 163

* Actinic prurigo (DRB1*0407) 164

* Atopy (DR4, DR7) 165

* Drug reaction to Abacavir 166

* Rapidly progressing periodontitis (DR4) 167

* Long-QT syndrome (DR7, in males only) 168

* Autism (the HVR3 shared epitope of HLA-DRB1*0401 and *0404) 169

* Anti-glomerular basement membrane disease (DRB1*04 susceptibility / DRB1*07 protection)  170

* Thrombotic thrombocytopenic purpura/adult hemolytic uremic syndrome (protective) 171

* Immune thrombocytopenic purpura: DRB1*0410 in Japan 172

* Vitiligo (in blacks) 173

* Creutzfeldt-Jakob disease (CJD) in Japan 174

* Longevity: negative association with homozygosity for DR53 in males only 175; increased DR7 and decreased DR4 in the elderly (above 75 years) 176; increased DR7 in male centenarians 177.

* Protective association in leprosy (Joko, 1995 & White, 1997) and blinding trachoma (White, 1997).

 

Malignancies

* Lymph node metastasis in gastric cancer (DR4) 178;179

* Gall bladder cancer (DR4) 180

* Breast cancer in Russia (DR4) 181

* Skin cancer (DR7) 182;183, in post-transplant patients 184

* Melanoma (DR4) 185

* Thyroid cancer (DR7) 186

* Germ-cell testis tumors (obviously in males only) (DR7) 187-189 and DR4 190;191

* Burkitt's lymphoma (DR7) 192

* Cervical cancer in HPV-16-positive patients (DR7) 193;194

* Protective effect from renal cell carcinoma in the Japanese (DRB1*0405 and *0101) 195

 

Leukemias (PPT)

* Adult acute myeloblastic leukemia (DR53 HVR3 epitope) 91

* Childhood acute lymphoblastic leukemia (homozygosity for DR53 in males only) 196;197 (Dorak et al, 1999)

* Childhood acute lymphoblastic leukemia (homozygosity for DR7) 198

* Chronic myeloid leukemia (DR53) 44 (Oguz FS et al, 2003)

* Chronic lymphoid leukemia (A2B44DR7) 199 and (DR53) 200;201

* Large granular lymphocyte leukemia with arthritis (DRB1*04) [Coakley G et al., BSHI98 abstract]

* Worse prognosis following BMT 202.

 

 

                                                   Appendix

 

          The aa sequence of DRB4*0103 (accession number: NP_068818; GI: 18641373)
        1 MVCLKLPGGS CMAALTVTLT VLSSPLALAG DTQPRFLEQA KCECHFLNGT ERVWNLIRYI
       61 YNQEEYARYN SDLGEYQAVT ELGRPDAEYW NSQKDLLERR RAEVDTYCRY NYGVVESFTV
      121 QRRVQPKVTV YPSKTQPLQH HNLLVCSVNG FYPGSIEVRW FRNSQEEKAG VVSTGLIQNG
      181 DWTFQTLVML ETVPRSGEVY TCQVEHPSMM SPLTVQWSAR SESAQSKMLS GVGGFVLGLL
      241 FLGTGLFIYF RNQKGHSGLQ PTGLLS
 

 

   
          The mRNA sequence of DRB4 (accession number: NM_021983; GI: 52630343)

        1 ggggggccat agttctccct gattgagact tgcctgctgc tgtgaccact ggtcttgtcc

       61 tcttctccag catggtgtgt ctgaagctcc ctggaggctc ctgtatggca gcgctgacag

      121 tgacattgac ggtgctgagc tccccactgg ctttggctgg ggacacccaa ccacgtttct

      181 tggagcaggc taagtgtgag tgtcatttcc tcaatgggac ggagcgagtg tggaacctga

      241 tcagatacat ctataaccaa gaggagtacg cgcgctacaa cagtgacctg ggggagtacc

      301 aggcggtgac ggagctgggg cggcctgacg ctgagtactg gaacagccag aaggacctcc

      361 tggagcggag gcgggccgag gtggacacct actgcagata caactacggg gttgtggaga

      421 gcttcacagt gcagcggcga gtccaaccta aggtgactgt gtatccttca aagacccagc

      481 ccctgcagca ccacaacctc ctggtctgct ctgtgaatgg tttctatcca ggcagcattg

      541 aagtcaggtg gttccggaac ggccaggaag agaaggctgg ggtggtgtcc acaggcctga

      601 tccagaatgg agactggacc ttccagaccc tggtgatgct ggaaacagtt cctcggagtg

      661 gagaggttta cacctgccaa gtggagcatc caagcatgat gagccctctc acggtgcaat

      721 ggagtgcacg gtctgaatct gcacagagca agatgctgag tggagtcggg ggctttgtgc

      781 tgggcctgct cttccttggg acagggctgt tcatctactt caggaatcag aaaggacact

      841 ctggacttca gccaacagga ctcttgagct gaagtgcaga tgaccacatt caaggaagaa

      901 ccttctgccc cagctttgca agatgaaaag ctttcccact tggctcttat tcttccacaa

      961 gagctttgtc aggaccaggt tgttactggt tcagcaactc tgcagaaaat gtcctccctt

     1021 gtggcttcct tagctcctgt tcttggcctg aagcctcaca gctttgatgg cagtgcctca

     1081 tcttcaactt ttgtgcttcc ctttacctaa actgtcctgc ctcccgtgca tctgtactcc

     1141 ccttgtgcca cacattgcat tattaaatgt ttctcaaaca tggagttaaa aaa

 
 
 
Genomic sequence of DRB4 (accession number: M20555; GI: 188433): The polymorphic exons 2 and 3 are nt 878-1147 and nt 3888-4160, respectively. See also a chromosome 6 draft sequence which includes the DRB4 gene (GI:29804596).
 
Genomic sequence of the DR subregion of the DR53 haplotype (DRA to DRB1; 150447 bp): accession number: NG_002433.1; GI:28212470. Compare DR53 with DR51 and DR52 haplotypes using PAIRWISE BLAST.
 

 

References

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