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Illustration of an HLA-DR (Human MHC class II) antigen receptor with bound antigen
human major histocompatibility complex, class II, DR4
Haplotypes groups DRA*01:DRB1*0401 to DRA*01:DRB1*0413
Structure (See HLA-DR)
alpha *0101
Symbol(s) HLA-DRA
beta 1 *0401 to *0413
Symbol(s) HLA-DRB1
Shared data
Locus chr.6 6p21.31

HLA-DR4 (DR4) is an HLA-DR serotype that recognizes the DRB1*04 gene products. The DR4 serogroup is large and has a number of moderate frequency alleles spread over large regions of the world.


DR4 serological recognition of the gene products of some DRB1*04 alleles[1]
DRB1* DR4 Sample
allele % size (N)
04:01 98 5118
04:02 92 1029
04:03 92 748
04:04 89 2164
04:05 91 505
04:06 89 83
04:07 86 846
04:08 86 258
04:09 95 13
04:10 84 29
04:11 93 76
04:12 >50 1
04:13 >30 3

The serological identification of DR4 is good. The serology of DRB1*04:17 to *04:60 is unknown.

Disease associations

By serotype

DR4 is associated with extraarticular[2] rheumatoid arthritis,[3] hydralazine-induced female systemic lupus erythematosus,[4] pemphigoid gestationis,[5] pemphigus foliaceus,[6] obstructive hypertrophic cardiomyopathy,[7] IgA nephropathy,[8] 'shared syndrome'-systemic sclerosis/rheumatoid arthritis[9] and polymyalgia rheumatica.[10]

By allele

DRB1*04 is associated with increased risk for alopecia areata.[11]

DRB1*04:01 is associated with multiple sclerosis,[12] rheumatoid arthritis,[13] type 1 diabetes,[14][15] lyme disease induced arthritis.[16]

DRB1*04:02: drug-triggered[17]/idiopathic pemphigus vulgaris,[18][19] type 1 diabetes,[15] SLE associated anti-cardiolipin and anti-β2 glycoprotein I.[20]

DRB1*04:03: polycystic ovary syndrome,[21] SLE associated anti-cardiolipin and anti-β2 glycoprotein I.[22]

DRB1*04:04: anti-citrullinated fibrinogen[23] in rheumatoid arthritis,[13] autoimmune hepatitis.[24]

DRB1*04:05: rheumatoid arthritis,[25] Autoimmune hepatitis,[26] type 1 diabetes.[14][15]

DRB1*04:06: caspase-8 autoantibodies silicosis-systemic sclerosis (SSc)-systemic lupus erythematosus (SLE).[27]

DRB1*04:09: T. cruzi infection with cardiomyopathy.[28]

By haplotype

DR4-DQ8 is a risk factor for papillary thyroid carcinoma,[29] juvenile diabetes, coeliac disease and rheumatoid arthritis.[30]

DRB1*04:DQA1*03:03-DQB1*04:01 haplotype: type III autoimmune polyglandular syndrome,[31] autoimmune hepatitis,[32] autoimmune pancreatitis.[33]

DRB1*04:DQA1*03-DQB1*03:02 haplotype: Type 1 diabetes[34][35] with DRB1*04:01, *04:05, *04:02 increasing risk when DQ8 is present.[36]

By genotype

DRB1*01:01/*04:04 and *01:01/*04:01 increases risk of mortality in rheumatoid arthritis, with ischemic heart disease and smoking.[37] these same genotypes are associated with rheumatoid vasculitis.[38]

Genetic linkage

DR4 Haplotypes
Serotypes DRA DRB1 DRB4
DR4-DR53 *0101 *0401 *0103
*0101 *0402 *01
*0101 *0403 *01
*0101 *0404 *01
*0101 *0405 *01
Serotypes DQA1 DQB1 DRB1
DR4-DQ7 (7.3, 3) *0303 *0301 *0401
DR4-DQ7 (8.1, 3) *0301 *0302 *0401
*0301 *0302 *0402
*0301 *0302 *0404
DR4-DQ4 (4.3) *0303 *0401 *0405
Serotypes HLA-A HLA-C HLA-B DRB1
A2-Cw10-B62(15)-DR4 *0201 *0304 *1501 *0401
A2-Cw10-B60(40)-DR4 *0201 *0304 *4001 *0402
A2-Cw5-B44(16)-DR4 *0201 *0501 *4402 *0401


  1. ^ derived from IMGT/HLA
  2. ^ Roudier J (2006). "HLA-DRB1 genes and extraarticular rheumatoid arthritis". Arthritis Research & Therapy. 8 (1): 103. doi:10.1186/ar1886. PMC 1526581. PMID 16542468.
  3. ^ Winchester R (1981). "Genetic aspects of rheumatoid arthritis". Springer Semin Immunopathol. 4 (2): 89–102. doi:10.1007/BF01857089. PMID 6459655.
  4. ^ Batchelor J, Welsh K, Tinoco R, Dollery C, Hughes G, Bernstein R, Ryan P, Naish P, Aber G, Bing R, Russell G (1980). "Hydralazine-induced systemic lupus erythematosus: influence of HLA-DR and sex on susceptibility". Lancet. 1 (8178): 1107–9. doi:10.1016/S0140-6736(80)91554-8. PMID 6103441.
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  7. ^ Sakurami T, Ueno Y, Iwaki Y, Park M, Terasaki P, Saji H (1982). "HLA-DR specificities among Japanese with several autoimmune diseases". Tissue Antigens. 19 (2): 129–33. doi:10.1111/j.1399-0039.1982.tb01428.x. PMID 6954729.
  8. ^ Kashiwabara H, Shishido H, Tomura S, Tuchida H, Miyajima T (1982). "Strong association between IgA nephropathy and HLA-DR4 antigen". Kidney Int. 22 (4): 377–82. doi:10.1038/ki.1982.185. PMID 6217371.
  9. ^ Szücs G, Szekanecz Z, Zilahi E, et al. (2007). "Systemic sclerosis-rheumatoid arthritis overlap syndrome: a unique combination of features suggests a distinct genetic, serological and clinical entity". Rheumatology (Oxford, England). 46 (6): 989–93. doi:10.1093/rheumatology/kem021. PMID 17384178.
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  14. ^ a b Fernandez-Viña M, Ramirez L, Raskin P, Stastny P (1993). "Genes for insulin-dependent diabetes mellitus (IDDM) in the major histocompatibility complex (MHC) of African-Americans". Tissue Antigens. 41 (2): 57–64. doi:10.1111/j.1399-0039.1993.tb01980.x. PMID 8475491.
  15. ^ a b c Undlien D, Friede T, Rammensee H, Joner G, Dahl-Jørgensen K, Søvik O, Akselsen H, Knutsen I, Rønningen K, Thorsby E (1997). "HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection". Diabetes. 46 (1): 143–9. doi:10.2337/diabetes.46.1.143. PMID 8971095.
  16. ^ Gross D, Forsthuber T, Tary-Lehmann M, Etling C, Ito K, Nagy Z, Field J, Steere A, Huber B (1998). "Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis". Science. 281 (5377): 703–6. doi:10.1126/science.281.5377.703. PMID 9685265.
  17. ^ Matzner Y, Erlich H, Brautbar C, Sanilevitch A, Landau M, Brenner S, Friedmann A (1995). "Identical HLA class II alleles predispose to drug-triggered and idiopathic pemphigus vulgaris". Acta Derm Venereol. 75 (1): 12–4. PMID 7747528.
  18. ^ Sáenz-Cantele AM, Fernández-Mestre M, Montagnani S, Calebotta A, Balbas O, Layrisse Z (2007). "HLA-DRB1*0402 haplotypes without DQB1*0302 in Venezuelan patients with pemphigus vulgaris". Tissue Antigens. 69 (4): 318–325. doi:10.1111/j.1399-0039.2007.00826.x. PMID 17389015.
  19. ^ Lee E, Lendas K, Chow S, Pirani Y, Gordon D, Dionisio R, Nguyen D, Spizuoco A, Fotino M, Zhang Y, Sinha A (2006). "Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris". Hum Immunol. 67 (1–2): 125–39. doi:10.1016/j.humimm.2005.09.003. PMID 16698434.
  20. ^ Galeazzi M, Sebastiani G, Tincani A, Piette J, Allegri F, Morozzi G, Bellisai F, Scorza R, Ferrara G, Carcassi C, Font J, Passiu G, Smolen J, Papasteriades C, Houssiau F, Nebro A, Ramon Garrido E, Jedryka-Goral A, Marcolongo R (2000). "HLA class II alleles associations of anticardiolipin antibodies". Lupus. 9 (1): 47–55. doi:10.1177/096120330000900109. PMID 10715100.
  21. ^ Kaibe M, Takakuwa K, Murakawa H, Ishii K, Tamura M, Tanaka K (2006). "Studies on the human leukocyte antigens in patients with polycystic ovary syndrome in a Japanese population--possible susceptibility of HLA-A11 and -DRB1*0403 to patient population with polycystic ovary syndrome". Am J Reprod Immunol. 55 (4): 301–6. doi:10.1111/j.1600-0897.2006.00369.x. PMID 16533342.
  22. ^ Galeazzi M, Sebastiani G, Tincani A, Piette J, Allegri F, Morozzi G, Bellisai F, Scorza R, Ferrara G, Carcassi C, Font J, Passiu G, Smolen J, Papasteriades C, Houssiau F, Nebro A, Ramon Garrido E, Jedryka-Goral A, Marcolongo R (2000). "HLA class II alleles associations of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus". Lupus. 9 (1): 47–55. doi:10.1177/096120330000900109. PMID 10715100.
  23. ^ Auger I, Sebbag M, Vincent C, Balandraud N, Guis S, Nogueira L, Svensson B, Cantagrel A, Serre G, Roudier J (2005). "Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen". Arthritis Rheum. 52 (11): 3424–32. doi:10.1002/art.21391. PMID 16255019.
  24. ^ Vázquez-García M, Aláez C, Olivo A, Debaz H, Pérez-Luque E, Burguete A, Cano S, de la Rosa G, Bautista N, Hernández A, Bandera J, Torres L, Kershenobich D, Alvarez F, Gorodezky C (1998). "MHC class II sequences of susceptibility and protection in Mexicans with autoimmune hepatitis". J Hepatol. 28 (6): 985–90. doi:10.1016/S0168-8278(98)80347-4. PMID 9672174.
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  30. ^ Singal D, Green D, Reid B, Gladman D, Buchanan W (1992). "HLA-D region genes and rheumatoid arthritis (RA): importance of DR and DQ genes in conferring susceptibility to RA". Ann Rheum Dis. 51 (1): 23–8. doi:10.1136/ard.51.1.23. PMC 1004612. PMID 1371662.
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