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HLA-DR53 Fact File

M.Tevfik Dorak, M.D., Ph.D.



 Brief review of HLA-DR53

Disease Associations



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*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*0201N  [null]


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






































































































< 0.5








< 0.5








< 0.5








< 0.5








< 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).



* 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.





          The aa sequence of DRB4*0103 (accession number: NP_068818; GI: 18641373)


          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.



         1.    Mukai R, Suzuki M, Yabe T, Hamaguchi H, Maeda H. Identification of the MT3 molecule from HLA-DR4, 7, and w9 homozygous cell lines.  Journal of Immunology 1984; 133 : 3211-3219.

         2.    Bell JI, Denney D, Jr., Foster L, Belt T, Todd JA, McDevitt HO. Allelic variation in the DR subregion of the human major histocompatibility complex.  Proceedings of the National Academy of Sciences USA 1987; 84: 6234-6238.

         3.    Stunz LL, Karr RW, Anderson RA. HLA-DRB1 and -DRB4 genes are differentially regulated at the transcriptional level.  Journal of Immunology 1989; 143: 3081-3086.

         4.    Leen MP, Gorski J. DRB4 promoter polymorphism in DR7 individuals: correlation with DRB4 pre-mRNA and mRNA levels.  Immunogenetics 1997; 45: 371-378.

         5.    Czerwony G, Alten R, Gromnica-Ihle E, et al. Differential surface expression of HLA-DRB1 and HLA-DRB4 among peripheral blood cells of DR4 positive individuals.  Human Immunology 1999; 60: 1-9.

         6.    Vincent R, Louis-Plence P, Gaillard F, Clot J, Eliaou JF. Qualitative and quantitative analysis of HLA-DRB gene expression.  Journal of Rheumatology 1997; 24: 225-226.

         7.    Vincent R, Louis P, Gongora C, Papa I, Clot J, Eliaou JF. Quantitative analysis of the expression of the HLA-DRB genes at the transcriptional level by competitive polymerase chain reaction.  Journal of Immunology 1996; 156: 603-610.

         8.    Louis P, Vincent R, Cavadore P, Clot J, Eliaou JF. Differential transcriptional activities of HLA-DR genes in the various haplotypes.  Journal of Immunology 1994; 153: 5059-5067.

         9.    Knowles RW, Flomenberg N, Horibe K, Winchester R, Radka SF, Dupont B. Complexity of the supertypic HLA-DRw53 specificity: two distinct epitopes differentially expressed on one or all of the DR beta-chains depending on the HLA-DR allotype.  Journal of Immunology 1986; 137: 2618-2626.

      10.    Sutton VR, Kienzle BK, Knowles RW. An altered splice site is found in the DRB4 gene that is not expressed in HLA-DR7,Dw11 individuals.  Immunogenetics 1989; 29: 317-322.

      11.    Sutton VR, Knowles RW. An aberrant DRB4 null gene transcript is found that could encode a novel HLA-DR beta chain.  Immunogenetics 1990; 31: 112-117.

      12.    Lardy NM, van der Horst AR, van de Weerd MJ, de Waal LP, Bontrop RE. HLA-DRB4 gene encoded HLA-DR53 specificity segregating with the HLA-DR7, -DQ9 haplotype: unusual association.  Human Immunology 1998; 59: 115-118.

      13.    Gassner C, Ellemunter H, Zahn R, Albert ED, Blasczyk R, Schonitzer D. Unusual association of the DRB4 null allele, DRB4*0103102N, with HLA DRB1*0402 in a sample of Austrian patients.  Tissue Antigens 1999; 54: 307-309.

      14.    Voorter CE, Lardy NM, van den Berg-Loonen EM. Presence of the DRB4*0103102N null allele in different DRB1*04-positive individuals.  Tissue Antigens 2000; 55: 37-43.

      15.    Inoko H, Naruse T, Ota M, et al. AHS#16: HLA-DR7, DR9, DR53. In: Charron D, ed. Genetic Diversity of HLA: Functional and Medical Implications, Paris: EDK, 1997: 119-128.

      16.    Marsh SG, Parham P, Barber LD. The HLA Facts Book. San Diego: Academic Press, 2000;

      17.    Bodmer JG, Marsh SG, Albert ED, et al. Nomenclature for factors of the HLA system, 1996.  Tissue Antigens 1997; 49: 297-321.

      18.    Voorter CE, Emonds MP, van den Berg-Loonen EM. Identification of a new DRB4 allele (DRB4*0105) by sequence- based typing.  Tissue Antigens 1997; 49: 662-664.

      19.    De Canck I, Demanet C, Mersch G, et al. Characterization of a new DRB4 allele (DRB4*0104).  Tissue Antigens 1996; 48: 213-216.

      20.    Schreuder GM, Hurley CK, Marsh SG, et al. The HLA dictionary 1999: A 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.  Human Immunology 1999; 60: 1157-1181.

      21.    Schreuder GM, Hurley CK, Marsh SG, et al. The HLA dictionary 2001: a 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.  Human Immunology 2001; 62: 826-849 (HLA Dictionary 2004: http://www.anthonynolan.com/HIG/nomen/dictionary/dictionary2004.html)

      22.    Marsh SG, Bodmer JG, Albert ED, et al. Nomenclature for the factors of the HLA system, 2000.  Tissue Antigens 2001; 57: 236-283.

      23.    Palou E, Nogues N, Gil J, Ribera A. Identification of a new HLA-DRB4 allele (DRB4*01033) by PCR-SSP and direct sequencing.  Tissue Antigens 2000; 56: 279-281.

      24.    Naruse TK, Ando R, Nose Y, et al. HLA-DRB4 genotyping by PCR-RFLP: diversity in the associations between HLA-DRB4 and DRB1 alleles.  Tissue Antigens 1997; 49: 152-159.

      25.    Voorter CE, de Bruyn-Geraets D, van den Berg-Loonen M. High-resolution HLA typing for the DRB3/4/5 genes by sequence-based typing.  Tissue Antigens 1997; 50: 283-290.

      26.    Darke C, Guttridge MG, Thompson J, McNamara S, Street J, Thomas M. HLA class I (A, B) and II (DR, DQ) gene and haplotype frequencies in blood donors from Wales.  Experimental & Clinical Immunogenetics 1998; 15: 69-83.

      27.    Corzo D, Yunis JJ, Yunis EJ, Howard A, Lieberman JA. HSP70-2 9.0 kb variant is in linkage disequilibrium with the HLA-B and DRB1* alleles associated with clozapine-induced agranulocytosis.  Journal of Clinical Psychiatry 1994; 55 Suppl B: 149-152.

      28.    Cross SJ, Tonks S, Trowsdale J, Campbell RD. Novel detection of restriction fragment length polymorphisms in the human major histocompatibility complex.  Immunogenetics 1991; 34: 376-384.

      29.    Degli-Esposti MA, Leelayuwat C, Daly LN, et al. Updated characterization of ancestral haplotypes using the Fourth Asia-Oceania Histocompatibility Workshop panel.  Human Immunology 1995; 44: 12-18.

      30.    Figueroa F, O'hUigin C, Tichy H, Klein J. The origin of the primate Mhc-DRB genes and allelic lineages as deduced from the study of prosimians.  Journal of Immunology 1994; 152: 4455-4465 (full-text)

      31.    Satta Y, Mayer WE, Klein J. HLA-DRB intron 1 sequences: implications for the evolution of HLA-DRB genes and haplotypes.  Human Immunology 1996a; 51: 1-12 (full-text)

      32.    Vincek V, Klein D, Figueroa F, et al. The evolutionary origin of the HLA-DR3 haplotype.  Immunogenetics 1992; 35: 263-271.

      33.    Svensson AC, Setterblad N, Pihlgren U, Rask L, Andersson G. Evolutionary relationship between human major histocompatibility complex HLA-DR haplotypes.  Immunogenetics 1996; 43: 304-314.

      34.    Svensson AC, Setterblad N, Sigurdardottir S, Rask L, Andersson G. Primate DRB genes from the DR3 and DR8 haplotypes contain ERV9 LTR elements at identical positions.  Immunogenetics 1995; 41: 74-82.

      35.    Andersson G, Larhammar D, Widmark E, Servenius B, Peterson PA, Rask L. Class II genes of the human major histocompatibility complex. Organization and evolutionary relationship of the DR beta genes.  Journal of Biological Chemistry 1987; 262: 8748-8758.

      36.    Gongora R, Figueroa F, Klein J. The HLA-DRB9 gene and the origin of HLA-DR haplotypes.  Human Immunology 1996; 51: 23-31.

      37.    Arvidsson AK, Svensson AC, Widmark E, Andersson G, Rask L, Larhammar D. Characterization of three separated exons in the HLA class II DR region of the human major histocompatibility complex.  Human Immunology 1995; 42: 254-264.

      38.    Gorski J, Rollini P, Mach B. Structural comparison of the genes of two HLA-DR supertypic groups: the loci encoding DRw52 and DRw53 are not truly allelic.  Immunogenetics 1987;  25: 397-402.

      39.    Svensson AC, Andersson G. Presence of retroelements reveal the evolutionary history of the human DR haplotypes.  Hereditas 1997; 127: 113-124.

      40.    Bergstrom T, Gyllensten U. Evolution of Mhc class II polymorphism: the rise and fall of class II gene function in primates [Review].  Immunological Reviews 1995; 143: 13-31.

      41.    Hughes AL. Evolution of the HLA complex. In: Jackson M, Strachan T, Dover G, eds. Human Genome Evolution, Oxford: Bios Scientific Publishers, 1996: 73-92.

      42.    Gyllensten UB & Erlich HA. Ancient roots for polymorphism at the HLA-DQ alpha locus in primates.  Proceedings of the National Academy of Sciences USA 1989; 86: 9986-9990 (full-text)

      43.    Moriuchi J, Moriuchi T, Silver J. Nucleotide sequence of an HLA-DQ alpha chain derived from a DRw9 cell line: genetic and evolutionary implications.  Proceedings of the National Academy of Sciences USA 1985; 82: 3420-3424 (full-text)

      44.    Dorak MT, Chalmers EA, Gaffney D, et al. Human major histocompatibility complex contains several leukemia susceptibility genes.  Leukemia & Lymphoma 1994; 12: 211-222.

      45.    Lawlor DA, Warren E, Ward FE, Parham P. Comparison of class I MHC alleles in humans and apes [Review].  Immunological Reviews 1990; 113: 147-185.

      46.    Bontrop RE, Elferink DG, Otting N, Jonker M, de Vries RR. Major histocompatibility complex class II-restricted antigen presentation across a species barrier: conservation of restriction determinants in evolution.  Journal of Experimental Medicine 1990; 172: 53-59.

      47.    Pierres M, Mercier P, Madsen M, Mawas C, Kristensen T. Monoclonal mouse anti-I-Ak and anti-I-Ek antibodies cross-reacting with HLA-DR supertypic and subtypic determinants rather than classical DR allelic specificities.  Tissue Antigens 1982; 19: 289-300.

      48.    Waters SJ, Winchester RJ, Nagase F, Thorbecke GJ, Bona CA. Antigen presentation by murine and human cells to a murine T-cell hybridoma: demonstration of a restriction element associated with a major histocompatibility complex class II determinant(s) shared by both species.  Proceedings of the National Academy of Sciences USA 1984; 81: 7559-7563.

      49.    Matsuyama T, Schwenzer J, Silver J, Winchester R. Structural relationships between the DR beta 1 and DR beta 2 subunits in DR4, 7, and w9 haplotypes and the DRw53 (MT3) specificity.  Journal of Immunology 1986; 137: 934-940.

      50.    Seyfried CE, Mickelson E, Hansen JA, Nepom GT. A specific nucleotide sequence defines a functional T-cell recognition epitope shared by diverse HLA-DR specificities.  Human Immunology 1988; 21: 289-299.

      51.    Auger I, Roudier J. Influence of the QKRAA/QRRAA/RRRAA motifs of the third hypervariable region of HLA-DRB1 in the development of rheumatoid arthritis.  Journal of Rheumatology 1997; 24: 227-228.

      52.    Birnbaum D, Dosseto M, Bourgue F, Pierres M, Kourilsky FM. A cross-reactive mouse anti-I-Ek monoclonal antibody detects an HLA-DR polymorphism linked to HLA-DR1.  Molecular Immunology 1982; 19: 755-764.

      53.    Dunham I, Sargent CA, Dawkins RL, Campbell RD. An analysis of variation in the long-range genomic organization of the human major histocompatibility complex class II region by pulsed-field gel electrophoresis.  Genomics 1989; 5: 787-796.

      54.    Inoko H, Ando A, Kawai J, Trowsdale J, Tsuji K. Mapping of the HLA-D region by pulsed-field gel electrophoresis: size variation in subregion intervals. In: Silver J, ed. Molecular Biology of HLA Class II Antigens, Florida: CRC Press, 1990: 1-17.

      55.    Niven MJ, Hitman GA, Pearce H, Marshall B, Sachs JA. Large haplotype-specific differences in inter-genic distances in human MHC shown by pulsed field electrophoresis mapping of healthy and type 1 diabetic subjects.  Tissue Antigens 1990; 36: 19-24.

      56.    Kendall E, Todd JA, Campbell RD. Molecular analysis of the MHC class II region in DR4, DR7, and DR9 haplotypes.  Immunogenetics 1991; 34: 349-357.

      57.    The MHC sequencing consortium. Complete sequence and gene map of a human major histocompatibility complex.  Nature 1999; 401: 921-923.

      58.    Beck S, Trowsdale J. Sequence organisation of the class II region of the human MHC.  Immunological Reviews 1999; 167: 201-210.

      59.    Chida S, Hohjoh H, Tokunaga K. Molecular analyses of the possible RNA-binding protein gene located in the human leukocyte antigen (HLA)--DR subregion.  Gene 1999; 240: 124-132.

      60.    Chida S, Hohjoh H, Hirai M, Tokunaga K. Haplotype-specific sequence encoding the protein kinase, interferon-inducible double-stranded RNA-dependent activator in the human leukocyte antigen class II region.  Immunogenetics 2001; 52: 186-194.

      61.    Verreck FA, Elferink D, Vermeulen CJ, et al. DR4Dw4/DR53 molecules contain a peptide from the autoantigen calreticulin.  Tissue Antigens 1995; 45: 270-275.

      62.    Kobayashi H, Kokubo T, Abe Y, et al. Analysis of anchor residues in a naturally processed HLA-DR53 ligand.  Immunogenetics 1996; 44: 366-371.

      63.    Kinouchi R, Kobayasi H, Sato K, Kimura S, Katagiri M. Peptide motifs of HLA-DR4/DR53 (DRB1*0405/DRB4*0101) molecules.  Immunogenetics 1994; 40: 376-378.

      64.    Miller G, Nepom GT, Reich MB, Thomas JW. Autoreactive T cells from a type I diabetic recognize multiple class II products.  Human Immunology 1993; 36: 219-226.

      65.    Shimoda S, Nakamura M, Ishibashi H, Hayashida K, Niho Y. HLA DRB4*0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases.  Journal of Experimental Medicine 1995; 181: 1835-1845.

      66.    Clot F, Gianfrani C, Babron MC, et al. HLA-DR53 molecules are associated with susceptibility to celiac disease and selectively bind gliadin-derived peptides.  Immunogenetics 1999; 49: 800-807.

      67.    Texier C, Pouvelle-Moratille S, Busson M, Charron D, Menez A, Maillere B. Complementarity and redundancy of the binding specificity of HLA-DRB1, -DRB3, -DRB4 and -DRB5 molecules.  European Journal of Immunology 2001; 31: 1837-1846.

      68.    Jager E, Jager D, Karbach J, et al. Identification of NY-ESO-1 epitopes presented by human histocompatibility antigen (HLA)-DRB4*0101-0103 and recognized by CD4(+) T lymphocytes of patients with NY-ESO-1-expressing melanoma.  Journal of Experimental Medicine 2000; 191: 625-630.

      69.    Kobayashi H, Lu J, Celis E. Identification of Helper T-Cell Epitopes That Encompass or Lie Proximal to Cytotoxic T-Cell Epitopes in the gp100 Melanoma Tumor Antigen.  Cancer Research 2001; 61: 7577-7584.

      70.    Nair S, Wearsch PA, Mitchell DA, Wassenberg JJ, Gilboa E, Nicchitta CV. Calreticulin displays in vivo peptide-binding activity and can elicit CTL responses against bound peptides.  Journal of Immunology 1999; 162: 6426-6432.

      71.    Basu S, Srivastava PK. Calreticulin, a peptide-binding chaperone of the endoplasmic reticulum, elicits tumor- and peptide-specific immunity.  Journal of Experimental Medicine 1999; 189: 797-802.

      72.    Eggleton P, Llewellyn DH. Pathopysiological roles of calreticulin in autoimmune disease.  Scandinavian Journal of Immunology 1999; 49: 466-473.

      73.    Max H, Halder T, Kalbus M, Gnau V, Jung G, Kalbacher H. A 16mer peptide of the human autoantigen calreticulin is a most prominent HLA-DR4Dw4-associated self-peptide.  Human Immunology 1994; 41: 39-45.

      74.    Krieger JI, Karr RW, Grey HM, et al. Single amino acid changes in DR and antigen define residues critical for peptide-MHC binding and T cell recognition.  Journal of Immunology 1991; 146: 2331-2340.

      75.    Futaki G, Kobayashi H, Sato K, Taneichi M, Katagiri M. Naturally processed HLA-DR9/DR53 (DRB1*0901/DRB4*0101)-bound peptides.  Immunogenetics 1995; 42: 299-301.

      76.    Fujisao S, Matsushita S, Nishi T, Nishimura Y. Identification of HLA-DR9 (DRB1*0901)-binding peptide motifs using a phage fUSE5 random peptide library.  Human Immunology 1996;  45: 131-136.

      77.    Matsushita S, Fujisao S, Nishimura Y. The N-terminal six residues of peptide core sequences suffice for binding to HLA-DR4 (DRB1*0405) and DR9 (DRB1*0901) molecules.  Immunology Letters 1997; 58: 89-93.

      78.    Paulsen G, Qvigstad E, Gaudernack G, Rask L, Winchester R, Thorsby E. Identification, at the genomic level, of an HLA-DR restriction element for cloned antigen-specific T4 cells.  Journal of Experimental Medicine 1985; 161: 1569-1574.

      79.    Qvigstad E, Gaudernack G, Thorsby E. Antigen-specific T cell clones restricted by DR, DRw53 (MT), or DP (SB) class II HLA molecules. Inhibition studies with monoclonal HLA-specific antibodies.  Human Immunology 1984; 11: 207-217.

      80.    Ichiki Y, Shimoda S, Hara H, et al. Analysis of T-cell receptor beta of the T-cell clones reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53 in patients with primary biliary cirrhosis.  Hepatology 1997; 26: 728-733.

      81.    Mustafa AS, Deggerdal A, Lundin KE, Meloen RM, Shinnick TM, Oftung F. An HLA-DRw53-restricted T-cell epitope from a novel Mycobacterium leprae protein antigen important to the human memory T-cell repertoire against M. leprae.  Infection & Immunity 1994; 62: 5595-5602 (Full-text)

      82.    Adams E, Basten A, Rodda S, Britton WJ. Human T-cell clones to the 70-kilodalton heat shock protein of Mycobacterium leprae define mycobacterium-specific epitopes rather than shared epitopes.  Infection & Immunity 1997; 65: 1061-1070 (full-text)

      83.    Huck C, Endl J, Walk T, et al. HLA-DR53 molecules restrict glutamic acid decarboxylase peptide presentation to T cells of a Type I diabetes patient: specification of the trimolecular HLA-peptide/T-cell receptor complex.  Diabetologia 2001; 44: 70-80.

      84.    Fleury S, Thibodeau J, Croteau G, et al. HLA-DR polymorphism affects the interaction with CD4.  Journal of Experimental Medicine 1995; 182: 733-741 (full-text)

      85.    Herman A, Labrecque N, Thibodeau J, Marrack P, Kappler JW, Sekaly RP. Identification of the staphylococcal enterotoxin A superantigen binding site in the beta 1 domain of the human histocompatibility antigen HLA-DR.  Proceedings of the National Academy of Sciences USA 1991; 88: 9954-9958 (full-text)

      86.    Karp DR & Long EO. Identification of HLA-DR1 beta chain residues critical for binding staphylococcal enterotoxins A and E.  Journal of Experimental Medicine 1992; 175: 415-424 (full-text)

      87.    Petrovsky N, Harrison LC. HLA class II-associated polymorphism of interferon-gamma production. Implications for HLA-disease association.  Human Immunology 1997; 53: 12-16.

      88.    Chervonsky AV, Gordon L, Sant AJ. A segment of the MHC class II beta chain plays a critical role in targeting class II molecules to the endocytic pathway.  International Immunology 1994; 6: 973-982.

      89.    Young JA, Wilkinson D, Bodmer WF, Trowsdale J. Sequence and evolution of HLA-DR7- and -DRw53-associated beta- chain genes.  Proceedings of the National Academy of Sciences USA 1987; 84: 4929-4933 (full-text)

      90.    Auffray C, Novotny J. Speculations on sequence homologies between the fibronectin cell-attachment site, major histocompatibility antigens, and a putative AIDS virus polypeptide.  Human Immunology 1986; 15: 381-390.

      91.    Seremetis S, Cuttner J, Winchester R. Definition of a possible genetic basis for susceptibility to acute myelogenous leukemia associated with the presence of a polymorphic Ia epitope.  Journal of Clinical Investigation 1985; 76: 1391-1397.

      92.    Lee SH, Gregersen PK, Shen HH, Nunez Roldan A, Silver J, Winchester RJ. Strong association of rheumatoid arthritis with the presence of a polymorphic Ia epitope defined by a monoclonal antibody: comparison with the allodeterminant DR4.  Rheumatology International 1984; 4 Suppl: 17-23.

      93.    Lilly F, Boyse EA, Old LJ. Genetic basis of susceptibility to viral leukaemogenesis.  Lancet 1964; ii: 1207-1209.

      94.    Boyse EA, Old LJ, Stockert E. The relation of linkage group IX to leukemogenesis in the mouse. In: Emmelot P, Bentvelzen P, eds. RNA Viruses and Host Genome in Oncogenesis, Amsterdam: North Holland Publishers Co., 1972: 171-185.

      95.    Vasmel WL, Zijlstra M, Radaszkiewicz T, Leupers CJ, de Goede RE, Melief CJ. Major histocompatibility complex class II-regulated immunity to murine leukemia virus protects against early T- but not late B- cell lymphomas.  Journal of Virology 1988; 62: 3156-3166.

      96.    Dorak MT, Burnett AK. Molecular mimicry of an HLA-DR53 epitope by viruses [letter].  Immunology Today 1994; 15: 138-139.

      97.    Dorak MT. The implications for childhood leukemia of infection with adenovirus.  Trends in Microbiology 1996; 4: 60-63.

      98.    Schlehofer B, Blettner M, Geletneky K, et al. Sero-epidemiological analysis of the risk of virus infections for childhood leukaemia.  International Journal of Cancer 1996; 65: 584-590.

      99.    Jaraquemada D, Ollier W, Awad J, et al. HLA and rheumatoid arthritis: a combined analysis of 440 British patients.  Annals of the Rheumatic Diseases 1986; 45: 627-636.

    100.    Puttick A, Briggs D, Welsh K, Jacoby R, Williamson E, Jones V. Extended haplotypes in rheumatoid arthritis and preliminary evidence for an interaction with immunoglobulin genes.  Disease Markers 1986; 4: 139-144.

    101.    Raum D, Awdeh Z, Glass D, et al. Extended haplotypes of chromosome 6 in adult rheumatoid arthritis.  Arthritis & Rheumatism 1984; 27: 516-521.

    102.    Fraser PA, Stern S, Larson MG, et al. HLA extended haplotypes in childhood and adult onset HLA-DR4-associated arthropathies.  Tissue Antigens 1990; 35: 56-59.

    103.    van Zeben D, Hazes JM, Zwinderman AH, et al. Association of HLA-DR4 with a more progressive disease course in patients with rheumatoid arthritis. Results of a followup study.  Arthritis & Rheumatism 1991; 34: 822-830.

    104.    Haberhauer G, Peichl P. The effect of HLA-DRB4 on the clinical picture of chronic polyarthritis [German].  Zeitschrift Fur Rheumatologie 1989; 48: 129-131.

    105.    Auger I, Escola JM, Gorvel JP, Roudier J. HLA-DR4 and HLA-DR10 motifs that carry susceptibility to rheumatoid arthritis bind 70-kD heat shock proteins.  Nature Medicine 1996;  2: 306-310.

    106.    Wagner U, Kaltenhauser S, Sauer H, et al. HLA markers and prediction of clinical course and outcome in rheumatoid arthritis.  Arthritis & Rheumatism 1997; 40: 341-351.

    107.    Seidl C, Koch U, Buhleier T, et al. HLA-DRB1*04 subtypes are associated with increased inflammatory activity in early rheumatoid arthritis.  British Journal of Rheumatology 1997; 36: 941-944.

    108.    Rowley MJ, Stockman A, Brand CA, et al. The effect of HLA-DRB1 disease susceptibility markers on the expression of RA.  Scandinavian Journal of Rheumatology 1997; 26: 448-455.

    109.    McDonagh JE, Dunn A, Ollier WE, Walker DJ. Compound heterozygosity for the shared epitope and the risk and severity of rheumatoid arthritis in extended pedigrees.  British Journal of Rheumatology 1997; 36: 322-327.

    110.    Weyand CM, Hicok KC, Conn DL, Goronzy JJ. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis.  Annals of Internal Medicine 1992; 117: 801-806.

    111.    MacGregor A, Ollier W, Thomson W, Jawaheer D, Silman A. HLA-DRB1*0401/0404 genotype and rheumatoid arthritis: increased association in men, young age at onset, and disease severity.  Journal of Rheumatology 1995; 22: 1032-1036.

    112.    Larsen B, King CA, Simms M, Skanes VM. Major histocompatibility complex phenotypes influence serum testosterone concentration.  Rheumatology (Oxford) 2000; 39: 758-763.

    113.    McMahon MJ, Hillarby MC, Clarkson RW, Hollis S, Grennan DM. Major histocompatibility complex variants and articular disease severity in rheumatoid arthritis.  British Journal of Rheumatology 1993; 32: 899-902.

    114.    Salvarani C, Macchioni PL, Zizzi F, et al. Clinical subgroups and HLA antigens in Italian patients with psoriatic arthritis.  Clinical & Experimental Rheumatology 1989; 7: 391-396.

    115.    Ahmed AR, Park MS, Tiwari JL, Terasaki PI. Association of DR4 with pemphigus.  Experimental & Clinical Immunogenetics 1987; 4: 8-16.

    116.    Haworth S, Ridgeway J, Stewart I, Dyer PA, Pepper L, Ollier W. Polymyalgia rheumatica is associated with both HLA-DRB1*0401 and DRB1*0404.  British Journal of Rheumatology 1996; 35: 632-635.

    117.    Bignon JD, Barrier J, Soulillou JP, Martin P, Grolleau JY. HLA DR4 and giant cell arteritis.  Tissue Antigens  1984; 24: 60-62.

    118.    Weyand CM, Hicok KC, Hunder GG, Goronzy JJ. The HLA-DRB1 locus as a genetic component in giant cell arteritis. Mapping of a disease-linked sequence motif to the antigen binding site of the HLA-DR molecule.  Journal of Clinical Investigation 1992; 90: 2355-2361.

    119.    Dababneh A, Gonzales-Gay MA, Garcia-Porrua C, Hajeer A, Thomson W, Ollier W. Giant cell arteritis and polymyalgia rheumatica can be differentiated by distinct patterns of HLA class II association.  Journal of Rheumatology 1988; 25: 2140-2145.

    120.    Salavarani C. HLA-DRB1, DQA1, and DQB1 alleles associated with giant cell arteritis in northern Italy.  Journal of Rheumatology 1999; 26: 2395-2399.

    121.    Asherson RA, Doherty DG, Vergani D, Khamashta MA, Hughes GR. Major histocompatibility complex associations with primary antiphospholipid syndrome.  Arthritis & Rheumatism 1992; 35: 124-125.

    122.    Camps MT, Cuadrado MJ, Ocon P, et al. Association between HLA class II antigens and primary antiphospholipid syndrome from the south of Spain.  Lupus 1995; 4: 51-55.

    123.    Sebastiani GD, Galeazzi M, Morozzi G, Marcolongo R. The immunogenetics of the antiphospholipid syndrome, anticardiolipin antibodies, and lupus anticoagulant [Review].  Seminars in Arthritis & Rheumatism 1996; 25: 414-420.

    124.    Goldstein R, Moulds JM, Smith CD, Sengar DP. MHC studies of the primary antiphospholipid antibody syndrome and of antiphospholipid antibodies in systemic lupus erythematosus.  Journal of Rheumatology 1996; 23: 1173-1179.

    125.    Trabace S, Nicotra M, Cappellacci S, et al. HLA-DR and DQ antigens and anticardiolipin antibodies in women with recurrent spontaneous abortions.  American Journal of Reproductive Immunology  1991; 26: 147-149.

    126.    Sasaki T, Yamada H, Kato EH, et al. Increased frequency of HLA-DR4 allele in women with unexplained recurrent spontaneous abortions, detected by the method of PCR-SSP.  Journal of Reproductive Immunology 1997; 32: 273-279.

    127.    Liston WA, Kilpatrick DC. Is genetic susceptibility to pre-eclampsia conferred by homozygosity for the same single recessive gene in mother and fetus?  British Journal of Obstetrics & Gynaecology 1991; 98: 1079-1086.

    128.    Kilpatrick DC, Gibson F, Livingston J, Liston WA. Pre-eclampsia is associated with HLA-DR4 sharing between mother and fetus.  Tissue Antigens 1990; 35: 178-181.

    129.    Peterson RD, Tuck-Muller CM, Spinnato JA, Peevy K, Giattina K, Hoff C. An HLA-haplotype associated with preeclampsia and intrauterine growth retardation.  American Journal of Reproductive Immunology 1994; 31: 177-179.

    130.    Kilpatrick DC. Influence of human leukocyte antigen and tumour necrosis factor genes on the development of pre-eclampsia.  Human Reproduction Update 1999; 5: 94-102.

    131.    Undlien DE, Friede T, Rammensee HG, et al. HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection.  Diabetes 1997; 46: 143-149.

    132.    Tait BD, Harrison LC, Drummond BP, Stewart V, Varney MD, Honeyman MC. HLA antigens and age at diagnosis of insulin-dependent diabetes mellitus.  Human Immunology 1995; 42: 116-122.

    133.    Chan SH, Thai AC, Lin YN, Liu KF, Wee GB. Influence of gender and age at onset on the HLA associations in Chinese with insulin-dependent diabetes mellitus.  Human Immunology 1995; 44: 175-180.

    134.    Morita K, Moriuchi J, Inoko H, Tsuji K, Arimori S. HLA class II antigens and DNA restriction fragment length polymorphism in myasthenia gravis in Japan.  Annals of Neurology 1991; 29: 168-174.

    135.    Onuma H, Ota M, Sugenoya A, Fukushima H, Inoko H, Iida F. Association of HLA-DR53 and lack of association of DPB1 alleles with Hashimoto's thyroiditis in Japanese.  Tissue Antigens 1993; 42: 150-152.

    136.    Wan XL, Kimura A, Dong RP, Honda K, Tamai H, Sasazuki T. HLA-A and -DRB4 genes in controlling the susceptibility to Hashimoto's thyroiditis.  Human Immunology 1995; 42: 131-136.

    137.    Yeo PP, Chan SH, Thai AC, et al. HLA Bw46 and DR9 associations in Graves' disease of Chinese patients are age- and sex-related.  Tissue Antigens 1989; 34: 179-184.

    138.    Cavan DA, Penny MA, Jacobs KH, et al. The HLA association with Graves' disease is sex-specific in Hong Kong Chinese subjects.  Clinical Endocrinology (Oxf) 1994; 40: 63-66.

    139.    Kobayashi K, Atoh M, Yagita A, et al. Crohn's disease in the Japanese is associated with the HLA-DRw53.  Experimental & Clinical Immunogenetics 1990; 7: 101-108.

    140.    Yoshitake H, Kimura A, Okada M, Yao T, Sasazuki T. HLA class II alleles in Japanese patients with inflammatory bowel disease.  Tissue Antigens 1999; 53: 350-358.

    141.    Kawasaki A, Tsuchiya N, Hagiwara K, Takazoe M, Tokunaga K. Independent contribution of HLA-DRB1 and TNF alpha promoter polymorphisms to the susceptibility to Crohn's disease.  Genes & Immunity 2000; 1: 351-357.

    142.    Shindo Y, Inoko H, Yamamoto T, Ohno S. HLA-DRB1 typing of Vogt-Koyanagi-Harada's disease by PCR-RFLP and the strong association with DRB1*0405 and DRB1*0410.  British Journal of Ophthalmology 1994; 78: 223-226.

    143.    Zhao M, Jiang Y, Abrahams IW. Association of HLA antigens with Vogt-Koyanagi-Harada syndrome in a Han Chinese population.  Archives of Ophthalmology 1991; 109: 368-370.

    144.    Weisz JM, Holland GN, Roer LN, et al. Association between Vogt-Koyanagi-Harada syndrome and HLA-DR1 and -DR4 in Hispanic patients living in southern California.  Ophthalmology 1995; 102: 1012-1015.

    145.    Alaez C, del Pilar Mora M, Arellanes L, et al. Strong association of HLA class II sequences in Mexicans with Vogt-Koyanagi-Harada's disease.  Human Immunology 1999; 60: 875-882.

    146.    Kim MH, Seong MC, Kwak NH, et al. Association of HLA with Vogt-Koyanagi-Harada syndrome in Koreans.  American Journal of Ophthalmology 1992; 129: 173-177.

    147.    Hoffman RW, Rettenmaier LJ, Takeda Y, et al. Human autoantibodies against the 70-kd polypeptide of U1 small nuclear RNP are associated with HLA-DR4 among connective tissue disease patients.  Arthritis & Rheumatism 1990; 33: 666-673.

    148.    Genth E, Zarnowski H, Mierau R, Wohltmann D, Hartl PW. HLA-DR4 and Gm(1,3;5,21) are associated with U1-nRNP antibody positive connective tissue disease.  Annals of the Rheumatic Diseases 1987; 46: 189-196.

    149.    Usuku K, Sonoda S, Osame M, et al. HLA haplotype-linked high immune responsiveness against HTLV-I in HTLV-I-associated myelopathy: comparison with adult T-cell leukemia/lymphoma.  Annals of Neurology 1988; 23 Suppl: S143-S150

    150.    Guilherme L, Weidebach W, Kiss MH, Snitcowsky R, Kalil J. Association of human leukocyte class II antigens with rheumatic fever or rheumatic heart disease in a Brazilian population.  Circulation 1991; 83: 1995-1998.

    151.    Visentainer JE, Pereira FC, Dalalio MM, Tsuneto LT, Donadio PR, Moliterno RA. Association of HLA-DR7 with rheumatic fever in the Brazilian population.  Journal of Rheumatology 1992; 27: 1518-1520.

    152.    Luomala M, Elovaara I, Ukkonen M, Koivula T, Lehtimaki T. The combination of HLA-DR1 and HLA-DR53 protects against MS.  Neurology 2001; 56: 383-385.

    153.    Kampgen E, Burg G, Wank R. Association of herpes simplex virus-induced erythema multiforme with the human leukocyte antigen DQw3.  Archives of Dermatology 1988; 124: 1372-1375.

    154.    Lepage V, Douay C, Mallet C, et al. Erythema multiforme is associated to HLA-Aw33 and DRw53.  Tissue Antigens  1988; 32: 170-175.

    155.    Schofield JK, Tatnall FM, Brown J, McCloskey D, Navarrete C, Leigh IM. Recurrent erythema multiforme: tissue typing in a large series of patients.  British Journal of Dermatology 1994; 131: 532-535.

    156.    Schrier RD, Freeman WR, Wiley CA, McCutchan JA. Immune predispositions for cytomegalovirus retinitis in AIDS. The HNRC Group.  Journal of Clinical Investigation 1995; 95: 1741-1746.

    157.    Price P, Keane NM, Stone SF, Cheong KY, French MA. MHC haplotypes affect the expression of opportunistic infections in HIV patients.  Human Immunology 2001; 62: 157-164.

    158.    Kuzushita N, Hayashi N, Moribe T, et al. Influence of HLA haplotypes on the clinical courses of individuals infected with hepatitis C virus.  Hepatology 1998; 27: 240-244.

    159.    Thursz M, Yallop R, Goldin R, Trepo C, Thomas HC. Influence of MHC class II genotype on outcome of infection with hepatitis C virus. The HENCORE group. Hepatitis C European Network for Cooperative Research.  Lancet 1999; 354: 2119-2124.

    160.    Kikuchi I, Ueda A, Mihara K, et al. The effect of HLA alleles on response to interferon therapy in patients with chronic hepatitis C.  European Journal of Gastroenterology & Hepatology 1998; 10: 859-863.

    161.    Watanabe H, Okumura M, Hirayama K, Sasazuki T. HLA-Bw54-DR4-DRw53-DQw4 haplotype controls nonresponsiveness to hepatitis-B surface antigen via CD8-positive suppressor T cells.  Tissue Antigens 1990; 36: 69-74.

    162.    McDermott AB, Zuckerman JN, Sabin CA, Marsh SG, Madrigal JA. Contribution of human leukocyte antigens to the antibody response to hepatitis B vaccination.  Tissue Antigens 1997; 50: 8-14.

    163.    Seki T, Ota M, Furuta S, et al. HLA class II molecules and autoimmune hepatitis susceptibility in Japanese patients.  Gastroenterology 1992; 103: 1041-1047.

    164.    Menage Hd, Vaughan RW, Baker CS, et al. HLA-DR4 may determine expression of actinic prurigo in British patients.  Journal of Investigative Dermatology 1996; 106: 362-367.

    165.    Aron Y, Desmazes-Dufeu N, Matran R, et al. Evidence of a strong, positive association between atopy and the HLA class II alleles DR4 and DR7.  Clinical & Experimental Allergy 1996; 26: 821-828.

    166.    Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  Lancet 2002; 359: 727-732.

    167.    Katz J, Goultschin J, Benoliel R, Brautbar C. Human leukocyte antigen (HLA) DR4. Positive association with rapidly progressing periodontitis.  Journal of Periodontology 1987;  58: 607-610.

    168.    Weitkamp LR, Moss AJ, Lewis RA, et al. Analysis of HLA and disease susceptibility: chromosome 6 genes and sex influence long-QT phenotype.  American Journal of Human Genetics 1994; 55: 1230-1241.

    169.    Warren RP, Odell JD, Warren WL, et al. Strong association of the third hypervariable region of HLA-DR beta 1 with autism.  Journal of Neuroimmunology 1996; 67: 97-102.

    170.    Owens IP, Rowe C, Thomas AL. Sexual selection, speciation and imprinting: separating the sheep from the goats.  Trends in Ecology and Evolution 1999; 16: 131-132.

    171.    Joseph G, Smith KJ, Hadley TJ, et al. HLA-DR53 protects against thrombotic thrombocytopenic purpura/adult hemolytic uremic syndrome.  American Journal of Hematology 1994; 47: 189-193.

    172.    Nomura S, Matsuzaki T, Ozaki Y, et al. Clinical significance of HLA-DRB1*0410 in Japanese patients with idiopathic thrombocytopenic purpura.  Blood 1998; 91: 3616-3622.

    173.    Dunston GM, Halder RM. Vitiligo is associated with HLA-DR4 in black patients. A preliminary report.  Archives of Dermatology 1990; 126: 56-60.

    174.    Kuroda Y, Kaneoka H, Shibasaki H, Kume S, Yamaguchi M. HLA study of Japanese patients with Creutzfeldt-Jakob disease: significant association with HLA-DQw3.  Annals of Neurology 1986; 20: 356-359.

    175.    Dorak MT, Mills KI, Gaffney D, et al. Homozygous MHC genotypes and longevity.  Human Heredity 1994; 44: 271-278.

    176.    Papasteriades C, Boki K, Pappa H, Aedonopoulos S, Papasteriadis E, Economidou J. HLA phenotypes in healthy aged subjects.  Gerontology 1997; 43: 176-181.

    177.    Ivanova R, Henon N, Lepage V, Charron D, Vicaut E, Schachter F. HLA-DR alleles display sex-dependent effects on survival and discriminate between individual and familial longevity.  Human Molecular Genetics 1998; 7: 187-194.

    178.    Ogoshi K, Tajima T, Mitomi T, Tsuji K. HLA-DR4 antigen and lymph node metastases in poorly differentiated adenocarcinoma of the stomach.  Cancer 1994; 73: 2250-2252.

    179.    Ogoshi K, Tajima T, Mitomi T, Tsuji K. HLA antigens are candidate markers for prediction of lymph node metastasis in gastric cancer.  Clinical & Experimental Metastasis 1996;  14: 277-281.

    180.    Yamamoto M, Haga M, Takagi S, et al. HLA antigens in cancer of the gallbladder.  Tohoku Journal of Experimental Medicine 1990; 161: 69-71.

    181.    Iarygin LM, Malyshev VS, Polianskaia IS, et al. The clinical significance of determining the HLA-DR4 antigen in patients with breast cancer. [Russian].  Voprosy Onkologii 1991; 37: 796-800.

    182.    Czarnecki D, Watkins F, Leahy S, et al. Skin cancers and HLA frequencies in renal transplant recipients.  Dermatology 1992; 185: 9-11.

    183.    Czarnecki DB, Lewis A, Nicholson I, Tait B. Multiple nonmelanoma skin cancer associated with HLA DR7 in southern Australia.  Cancer 1991; 68: 439-440.

    184.    Bavinck JN, Gissmann L, Claas FH, et al. Relation between skin cancer, humoral responses to human papillomaviruses, and HLA class II molecules in renal transplant recipients.  Journal of Immunology 1993; 151: 1579-1586.

    185.    Barger BO, Acton RT, Soong SJ, Roseman J, Balch C. Increase of HLA-DR4 in melanoma patients from Alabama.  Cancer Research 1982; 42: 4276-4279.

    186.    Sridama V, Hara Y, Fauchet R, DeGroot LJ. Association of differentiated thyroid carcinoma with HLA-DR7.  Cancer 1985; 56: 1086-1088.

    187.    DeWolf WC, Lange PH, Einarson ME, Yunis EJ. HLA and testicular cancer.  Nature 1979; 277: 216-217.

    188.    Oliver RT, Stephenson CA, Parkinson MC, et al. Germ cell tumours of the testicle as a model of MHC influence on human malignancy [letter].  Lancet 1986; 1: 1506-1506.

    189.    Aiginger P, Kuzmits R, Kratzik C, et al. HLA antigens and germ-cell tumours [letter].  Lancet 1987; i: 276-277.

    190.    Nishimura K, Miura H, Yasunaga Y, et al. [HLA antigens in patients with testicular germ cell tumors] [Japanese].  Hinyokika Kiyo 1996; 42: 95-99.

    191.    Ozdemir E, Kakehi Y, Mishina M, et al. High-resolution HLA-DRB1 and DQB1 genotyping in Japanese patients with testicular germ cell carcinoma.  British Journal of Cancer 1997;  76: 1348-1352.

    192.    Jones EH, Biggar RJ, Nkrumah FK, Lawler SD. Study of the HLA system in Burkitt's lymphoma.  Human Immunology 1980; 1: 207-210.

    193.    Bontkes H, van Duin M, de Gruijl TD, et al. HPV 16 infection and progression of cervical intra-epithelial neoplasia: analysis of HLA polymorphism and HPV 16 E6 sequence variants.  International Journal of Cancer 1998; 78: 166-171.

    194.    Stern PL. Immunity to human papillomavirus-associated cervical neoplasia [Review].  Advances in Cancer Research 1996; 69: 175-211.

    195.    Ozdemir E, Kakehi Y, Nakamura E, et al. HLA-DRB1*0101 and *0405 as protective alleles in Japanese patients with renal cell carcinoma.  Cancer Research 1997; 57: 742-746.

    196.    Dorak MT, Owen G, Galbraith I, et al. Nature of HLA-associated predisposition to childhood acute lymphoblastic leukemia.  Leukemia 1995; 9: 875-878.

    197.    Dorak MT, Lawson T, Machulla HKG, Darke C, Mills KI, Burnett AK. Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia.  Blood 1999; 94: 694-700.

    198.    Von Fliedner VE, Sultan-Khan Z, Jeannet M. HLA-DRw antigens associated with acute leukemia.  Tissue Antigens 1980; 16: 399-404.

    199.    Dyer PA, Ridway JC, Flanagan NG. HLA-A,B and DR antigens in chronic lymphocytic leukaemia.  Disease Markers 1986; 4: 231-237.

    200.    Dorak MT, Machulla HK, Hentschel M, Mills KI, Langner J, Burnett AK. Influence of the major histocompatibility complex on age at onset of chronic lymphoid leukemia.  International Journal of Cancer 1996; 65: 134-139.

    201.    Machulla HK, Muller LP, Schaaf A, Kujat G, Schonermarck U, Langner J. Association of chronic lymphocytic leukemia with specific alleles of the HLA-DR4:DR53:DQ8 haplotype in German patients.  International Journal of Cancer 2001; 92: 203-207.

    202.    Honeyman M, Doran T, Rouse S. The relevance of HLA in survival following bone marrow transplantation.  Transplantation Proceedings 1989; 21: 3062-3063.


Frequently Asked Questions about HLA-DR53 and Leukemia


HLA-related Links


SNP analysis of HLA-DRB4    Entrez-Gene: HLA-DRB4   dbSNP: HLA-DRB4


UniGene- HLA-DRB4: Hs.696211    Protein Database: HLA-DRB4   



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M.Tevfik Dorak, M.D., Ph.D.


Last updated on 25 February 2008


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