HLA DR3-DQ2: Difference between revisions

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'''DR3''' and/or '''DQ2.5''' are linked to the following diseases: Moreen's ulceration<ref>{{cite journal | author = Taylor C, Smith S, Morgan C, Stephenson S, Key T, Srinivasan M, Cunningham E, Watson P | title = HLA and Mooren's ulceration. | journal = Br J Ophthalmol | volume = 84 | issue = 1 | pages = 72-5 | year = 2000 | id = PMID 10611103}}</ref>, "bout onset" multiple schlerosis<ref>{{cite journal | author = Weinshenker B, Santrach P, Bissonet A, McDonnell S, Schaid D, Moore S, Rodriguez M | title = Major histocompatibility complex class II alleles and the course and outcome of MS: a population-based study. | journal = Neurology | volume = 51 | issue = 3 | pages = 742-7 | year = 1998 | id = PMID 9748020}}</ref>, [[Grave's disease]]<ref>{{cite journal | author = Ratanachaiyavong S, Lloyd L, Darke C, McGregor A | title = MHC-extended haplotypes in families of patients with Graves' disease. | journal = Hum Immunol | volume = 36 | issue = 2 | pages = 99-111 | year = 1993 | id = PMID 8096501}}</ref> and [[systemic lupus erythematosus]]<ref>{{cite journal | author = Tjernström F, Hellmer G, Nived O, Truedsson L, Sturfelt G | title = Synergetic effect between interleukin-1 receptor antagonist allele (IL1RN*2) and MHC class II (DR17,DQ2) in determining susceptibility to systemic lupus erythematosus. | journal = Lupus | volume = 8 | issue = 2 | pages = 103-8 | year = 1999 | id = PMID 10192503}}</ref>
'''DR3''' and/or '''DQ2.5''' are linked to the following diseases: Moreen's ulceration<ref>{{cite journal | author = Taylor C, Smith S, Morgan C, Stephenson S, Key T, Srinivasan M, Cunningham E, Watson P | title = HLA and Mooren's ulceration. | journal = Br J Ophthalmol | volume = 84 | issue = 1 | pages = 72-5 | year = 2000 | id = PMID 10611103}}</ref>, "bout onset" multiple schlerosis<ref>{{cite journal | author = Weinshenker B, Santrach P, Bissonet A, McDonnell S, Schaid D, Moore S, Rodriguez M | title = Major histocompatibility complex class II alleles and the course and outcome of MS: a population-based study. | journal = Neurology | volume = 51 | issue = 3 | pages = 742-7 | year = 1998 | id = PMID 9748020}}</ref>, [[Grave's disease]]<ref>{{cite journal | author = Ratanachaiyavong S, Lloyd L, Darke C, McGregor A | title = MHC-extended haplotypes in families of patients with Graves' disease. | journal = Hum Immunol | volume = 36 | issue = 2 | pages = 99-111 | year = 1993 | id = PMID 8096501}}</ref> and [[systemic lupus erythematosus]]<ref>{{cite journal | author = Tjernström F, Hellmer G, Nived O, Truedsson L, Sturfelt G | title = Synergetic effect between interleukin-1 receptor antagonist allele (IL1RN*2) and MHC class II (DR17,DQ2) in determining susceptibility to systemic lupus erythematosus. | journal = Lupus | volume = 8 | issue = 2 | pages = 103-8 | year = 1999 | id = PMID 10192503}}</ref>


'''Genetic Linkage'''
'''Genetic Linkage''' of DR3-DQ2.5 can be established to other genes like TNF-305A (TNF2) which may also increase the risk of autoimmune disease in both Coeliac Disease and Type 1 diabetes. In systemic lupus erythematosus (SLE) patients HLA DR3-DQ2.5-C4AQ0, which was strongly associated with SLE (odds ratio [OR] 2.8, 95% CI 1.7-4.5). A more recent paper shows that Inositol triphosphate receptor 3 gene which is ~ 1 million base pairs from DQ2.5 is also associated with Type 1 diabetes. DQ2.5 is also linked to the IgA-less phenotype which may or may not increase susceptibility to diseases. This posses a problem for understanding autoimmunity in DQ2.5, since many genes linked to disease with partial contributions are some degree of disequilibration with DQ2.5 loci and thus DQ2.5 masks genetic association via it positive association with some many diseases.

*DR3-DQ2.5 can be established to other genes like TNF-305A (TNF2) which may also increase the risk of autoimmune disease in both Coeliac Disease and Type 1 diabetes. In systemic lupus erythematosus (SLE) patients HLA DR3-DQ2.5-C4AQ0, which was strongly associated with SLE (odds ratio [OR] 2.8, 95% CI 1.7-4.5)<ref>{{cite journal | author = Jönsen A, Bengtsson A, Sturfelt G, Truedsson L | title = Analysis of HLA DR, HLA DQ, C4A, FcgammaRIIa, FcgammaRIIIa, MBL, and IL-1Ra allelic variants in Caucasian systemic lupus erythematosus patients suggests an effect of the combined FcgammaRIIa R/R and IL-1Ra 2/2 genotypes on disease susceptibility. | journal = Arthritis Res Ther | volume = 6 | issue = 6 | pages = R557-62 | year = 2004 | id = PMID 15535834}}</ref>.

* A more recent paper shows that Inositol triphosphate receptor 3 gene which is ~ 1 million base pairs from DQ2.5 is also associated with Type 1 diabetes<ref>{{cite journal | author = Roach J, Deutsch K, Li S, Siegel A, Bekris L, Einhaus D, Sheridan C, Glusman G, Hood L, Lernmark A, Janer M | title = Genetic mapping at 3-kilobase resolution reveals inositol 1,4,5-triphosphate receptor 3 as a risk factor for type 1 diabetes in Sweden. | journal = Am J Hum Genet | volume = 79 | issue = 4 | pages = 614-27 | year = 2006 | id = PMID 16960798}}</ref>.

* DQ2.5 is also linked to the IgA-less phenotype which may or may not increase susceptibility to diseases<ref>{{cite journal | author = Schaffer F, Palermos J, Zhu Z, Barger B, Cooper M, Volanakis J | title = Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes. | journal = Proc Natl Acad Sci U S A | volume = 86 | issue = 20 | pages = 8015-9 | year = 1989 | id = PMID 2573059}}</ref><ref>{{cite journal | author = Klemola T, Savilahti E, Koskimies S, Pelkonen P | title = HLA antigens in IgA deficient paediatric patients. | journal = Tissue Antigens | volume = 32 | issue = 4 | pages = 218-23 | year = 1988 | id = PMID 3217938}}</ref>. This imposes a problem for understanding autoimmunity in DQ2.5, since many genes linked to disease with partial contributions are some degree of disequilibration with DQ2.5 loci and thus DQ2.5 masks genetic association via it positive association with some many diseases.


===DR17===
===DR17===

Revision as of 23:39, 1 November 2006

DQ2.5 ligand (gliadin peptide:lqpfpqpelpy) within the binding pocket of DQ α5β2,
DQ2.5 binding pocket with ligand PDB: 1S9V​
major histocompatibility complex, class II, DQ
Haplotype DQA1*0501:DQB1*0201
Structure
Type Cell surface receptor
Quartenary αβ-heterodimer, ligand
Ligand polypeptides, >9 residues DQ type restricted
MMDB 26620
Identifiers
alpha 1 *0501
Symbol(s) HLA-DQA1 CELIAC1
Entrez 3117
OMIM 146880
EBI-HLA DQA1*050101
Identifiers
beta 1 *0201
Symbol(s) HLA-DQB1
Entrez 3119
OMIM 604305
EBI-HLA DQB1*020201
Shared data
Locus chr.6 6p21.31

HLA DR3-DQ2 is the serotypic representation of a HLA-DRB1: DQA1 :DQB1 haplotype. DR3-DQ2 represents the haplotype DRB1*0301: DQA1*0501: DQB1*0201. This haplotype is associated with some of the most common autoimmune disease known. It is relatively abundant in western hemisphere. DR3-DQ2 is an ambiguous designation except for the fact that linkage clarifies both the DR3 and DQ2. Less ambiguous is DR17-DQ2.5 which describes the DRB1*0301/0304 alleles and DQ2.5 which defines the alpha as A1*05 and beta as B1*0201 in an overwhelming majority of instances. DR3-DQ2 nomenclature is useful because many older population studies did not use DR17 antibodies or did not assay for DQA1*05, but did show haplotype linkage. In most cases DQ2.5 defines the abundance of DR17 and DR17 defines the abundance of DQ2.5 in any given population. The irony is that DQA1*0501 and DQB1*0201, often, do not, because older typing kits define DQA1*0505 and DQA1*0501 as DQA1*0501, and many older DQB1*0201 typing kites define DQB1*0201 and DQB1*0202 as DQB1*0201. Only haplotype analysis reveals actual DQ2.5 haplotype and linkage to DR3 or DQA1*05 generally suffices.

DR3-DQ2 (DQ2.5) Distribution

DQ2.5 Spread Late in Human Evolution

DR3-DQ2 probably originated from Central or West Africa. DQ2.5 the second highest frequency haplotype in the Aka (N. Congo) and several other surrounding groups it is virtually absent in the !Kung[1]. DQ2.5 primarily spread to the northwest and appears to have spread late in global spread of anatomically modern humans. The !Kung and Austronesians[2] are reasonable marker populations for spread out of Africa and those that spread rapidly, since the ancestors of the !Kung appear to have come from East Africa and share many Cw_B types in common with Austronesians and Northern Eurasians. DQ2.5 is at low frequencies in both of these populations, and it did not spread to Japan or the New World in pre-Columbian times. There is the possibility it spread to Arabia, but through stepwise expansion of small groups was lost from the DQ genetic repertoire. Based on frequencies in Central and East Asia DR3_DQ2 appears to have spread eastward recently. Of particular interest to the West African/Central Asian comparison, not only is DQ3-DQ2.5 elevated in both places, but a linked HLA A-B haplotype, A33-B58[1], is found in West Africans and both the A33 and B58 alleles show more allelic and haplotype diversity in West Africa. This similarity would be remarkable if this haplotype came with migrations 50 to 130,000 years ago, since considerable equilibration is expected over this time frame. There is no convincing route of travel between West Africa and Central Asia suggested by gene frequencies in the peoples between the two.

Table 2.1.1 DR3 and DQ2.5 levels in Africans (given as frequency in %)
h Reference DRB1 DQA1 DQB1 Haplo. Estimated
h Population 0301 0501 0201 DR3-DQ2 DQ2.5
[3] Suoss (Morocco) 17.3 28.6* 37.8* 17.3 17.3
[4] Berbers 14.8 27.3* 29.7* 14.3 14.3
[5] Tunis (Tunisia) 15.1 15.9 14.1
[6] Bubi (Gabon) 12.5 12.5
[7] Aka pygmy (Congo) 11.2 11.2
[8] Algeria 11.8 35.3* 11.3 11.3
[1] Senegal 9.6 9.6
[9] Amhara (Ethiopia) 6.5 20.9* 30.1* 7.7 7.7
[7] Bantu (Congo) 6.5 17.1 35.3* 6.5 6.5
[1] !Kung (Namibia) 1.9 11.9* 1.9
h * = Allele stated contains 2 or more alleles.

One problem with the African origin for this type and many others, many African HLA haplotypes types appear to have a common recent ancestral population (crescent shaped distribution), which points toward the Central Saharan or Central Sahel. No representative population in those areas exists, suggesting a possible complete dispersion of some past subpopulation and modern replacement in those areas. The other corroborating fact is that DQ2.2, from which DQ2.5 evolved (DQ2.2 has undergone more linkage equilibration), is also at high frequencies in these Central/west African populations and DQA1*0505, a potential ancestral allele to DQA1*0501 is found at elevated frequencies in Western Africa. Recent studies do point to ancient settling of Iberia from West Africa by mitochondrial DNA. [10]. The descrepancy between mtDNA and Y chromosome time-to-most recent-common-ancestor (TMRCA) and the placement (PMRCA) of the Eurasian Y ancestor in East- Central Asia and global ancestor in Africa spreading from Africa ~30 kya might explain this. However, the Africa Y PMRCA tends to place the source population in southern and eastern africa, not Western Africa. The problem with HLA evolution is two fold. First, HLA is diploid in the population, and the heterozygous selection acts to preserve diversity, whereas mtDNA and Y tend to rapidly loose diversity in smaller groups. As a result HLA frequency and haplotypes can preserve information lost at other loci. However, since HLA are also functional loci in which variable selection acts, one could also argue that frequencies deviated over time as a result of selection for DR3-DQ2. Better mitochondrial, HLA, X-linked and Y chromosomal studies can resolve these discrepancies between different loci.

DR2.5 is Nodal in Sardinia and Western Ireland.

Although not every western populations have been type for DQ2.5., since DQ2.5 is in tight linkage disequilibrium with DRB1*0301 (majority of DR3) in many parts of NW Europe it is therefore possible to estimate DQ2.5 or DR3 in many parts of Western Eurasia. B8 frequency also tends to be similar to DQ2.5 in most parts of Europe and also correlates. DQB1*0201 may be available, but most often it is given incorrectly (DQB1*0201 = DQB1*0201 + DQB1*0202 + DQB1*0203). DQA1*0501 is often given incorrectly (DQB1*0501 = DQB1*0501 + DQB1*0505). As a result, when using older studies it is often better to rely on DR3 and B8 frequencies to correctly estimate DQ2.5 if a DR-DQ or DQA1*-DQB1* haplotype is not given. DR3 also represents DRB1*0302 which has a different linkage and is more prominent outside of Europe. Also, as one moves south and east from the Northwestern Europe B8 linkage gives way to B18, B44 and B45 linkage. Therefore, as one moves east and southward B8 and DR3 become less predictive and DRB1*0301 and DQB1*0201 (if DQB1*0202 is also given) can be relied upon. From direct determinations and these estimates, the argument can be made that DR3-DQ2 is elevated in the western regions of Europe and is based on dozens of population studies.

B8, DR3 and DQ2.5 levels in Europeans (given as frequency in %)
Reference B8 DR17 DRB1 Haplo. Estimated
Population (&A30B18) (DR3) 0301 DR3DQ2 DQ2.5
[1] Sardinian (20.0) 25.7 21.9 22.0
[1] Basque (Spain) (15) 19.2 21.9 22.0
[11] Western Irish [12] 20.8 21.5
[13] Irish[14][15] 17.7 (17.4) 17.0
[1] Swedish 16.0 15.9 15.9
[16] Arratia (Spain) (15.3) 17.3 12.0 12.0
[17] Wales 16.5 16.6 14.7 14.7
[18] Dutch 12.1 (13.2) 14.4 13.2
[1] Belgium[19] 5.5 (15.7) 14.2 14.2
[1] England 13.7 (12.4) 12.4
[1] Yugoslavia 10.7 (11.5) 12.0 12.0
[1] Cornish 11.4 (11.4) 11.4 11.4
[1] Danish 8.9 (11.3) 11.3 11.3
[20] Swiss 10.3 (11.6) 10.3
[21] Poland[22] 10.3 (10.7) 10.7 10.7
[23] Paris (7.7) (10.1) 9.7 9.7
[24] Arab Israeli 9.6 9.6
[25] Turk 9.6 9.2 9.2
[26] Finn[27] 8.9 6.0 9.2 9.0
[28] Russian 9.5 9.0 9.0
[29] Svanetian 6.8 8.7 8.7
[30] Croatian 6.4 8.3 8.3
[31] Bulgarian 18.2 8.2 8.0
[32] Greek 3.6 6.5 6.3 6.3
[33] NE. Turk 3.4 5.6 5.4
[34] Macedonian 6.8 6.8 5.0 5.0
[35] non-Ashk Jew. 7.8 4.4 4.4

In Europe, DQ3-DQ2 is a constituent of the ' 'Super B8' ' haplotype and is also genetically linked to A30-B18 in the Western Mediterranean along with A2-B44 and A2-B35 haplotypes in the Western and Eastern Mediterranean regions, respectively. European DQ2.5 is likely derived from Africa via Southwestern Europe. There two directions of DQ2.5 propagation; the first appear from the south to north and follows largely the western extreme of Europe and appears to be constituitive to all Western European peoples. A30-B18-DR3 spread appears to be more recent and directly from North Africa into the Sardinian and Iberian populations, but also has a presence in Northern France. A2-B44 is also constituitive to Western Europeans and appears to have a center of diversity in Iberia and recombination between Super B8 and A2-B44-DR7-DQ2.2 appears to explain this haplotype, particularly given its presence in the Basque (appears to be enriched in recombinants of the most anceint Europeans), A1-B8-DR3-DQ2.5 itself appears to have arrived from Northern Africa. A homolog ' 'B8-DR3-DQ2.5' ' exists in the NW African region.

Anti-node in Western Europe. Although DR3-DQ2 is the highest frequency haplotype in France, France is the western anti-node for the type and is surrounded by higher frequencies on just about every side except the western (Atlantic) side (even so the US and Canada are higher in frequency). This trough in frequency suggests a more East and Central Mediterranean admixture in France, particularly in the Paris region (but more study of France's regional groups is needed), separating the node in N. Iberia from the node in Northern Europe, which is elongated, and remains high from Denmark to the NW black Sea and on into Slovenia and Yugoslavia. It may link these peoples to the ancient 'Gothic' peoples historically reported to have lived in Eastern Europe. To the east the frequency declines slowly past the Ukraine and the B8 haplotype is identified as far east as Manchuria and possible strands of ancient western eurasain migrants in the east (e.g. Tarim basin culture). There are western haplotypes such as A2-B8 and A3-B8 which may represent eastward migrations through Europe during the last interglacial period, peoples who established themselves within the refuges in Romania and Southeastern Europe and later migrated eastward. A1-B8 haplotype that was once the most abundant haplotype in Western Europe however is not observed in the Far East except in the context of historic migrations and admixture.

DQ3-DR2 East of the Urals

DR3 and DQ2.5 levels in Asians (given as frequency in %)
Reference DR17 DRB1 Haplo. Estimated
Population (DR3) 0301 DR3DQ2 DQ2.5
[36] Kazahk 13.1 13.1
[37] Uygar (China) 14.0 12.6 12.6
[38] Tsaatan (Mongolia) 12.5 12.5
[38] Khalka (Mongolia) [39] 9.0 11.5 11.5
[40] Australo (N.S.Wales) 11.4 11.4
[41] Iranian 10.0 10.0 10.0
[1] Muong (Viet Nam) 12.7 9.8 9.8
[38] Oold (Mongolia) 8.7 8.7
[42] Jing (China) 8.1 8.1
[37] N.W. Han (China) 7.6 7.6 7.6
[43] Mansi (Russia) 7.4 7.4 7.4
[44] N.India 7.4 7.4 7.4
[45] Iran (Yadz) 5.4 5.4 5.4
[46] Hanoi (Viet Nam) 4.4 4.0 4.0
[43] Buryat (Siberia) 4.0 4.0 4.0
[47] Shangdong (China) 3.6 3.6
[48] Korean 2.9 2.9 2.9
[2] Nusa Ten. (Indonesia) 2.4 2.4 2.4
[43] Ulchi 1.4 1.4 1.4
[49] Ryukyu (Japan) 0.0 0.0 0.0
[50] Japanese 0.7 0.3 0.3
[51] Ainu(Japan) 0.0 0.0 0.0
[52] ket(Russia) 0.0 0.0 0.0
[52] Ngasan(Siberia) 0.0 0.0 0.0
[43] Negidal(Siberia) 0.0 0.0 0.0
[2] Molacca(Indonesia) 0.0 0.0 0.0

The other node in Eurasia is more intriguing, it is associated with, specifically the high in Western Mongolia, Kazahkstan and Western China. However this is the likely result of the blending of two sources, the western, "Super B8" source and an unknown source. The eastern Haplotype is "A33-B58" and has some punctuated distribution in Western Europe at relatively low levels, and is also in extreme disequilibrium where it is found, elsewhere. In Thailand it is elevated, particularly in the Thai Chinese, but in the south and most parts of Indonesia its frequency is zero. Elevated DR3-DQ2 levles in the Muong suggest a similar North to South spread. Similar alleles are found in Western India in populations of recent migration but from unknown sources.

DR3-DQ2 presence in the Koreans and lack thereof in the Japanese suggest a recent spread into Eastern Asia. By HLA, Y chromosome, or mitochondrial DNA the Japanese are about 60-85% of post-Jomon period Korean origin, and the level in Japanese is about 1/10th that of Koreans suggesting that DR3-DQ2 did not spread in the Yayoi and that it spread recently with Mongol spread in Eastern Asia, it is rare both east and south of China, rare in Indigenous Austronesians, and isolated Indigeonous American groups. Three haplotype, A3303: Cw*1403: B*4403: DRB1*07: DQA1*0201: DQB1*0202, A3303: Cw*0302: B*5801: DRB1*1302: DQA1*0102: DQB1*0609, and A3303: Cw*0302: B*5801: DRB1*0301: DQA1*0501: DQB1*0201 seem more suitable for Iberia or W. Africa than Eastern Asia, these are not found in the Ainu, Ryukyuans, or Japanese. There is archaeology in support of early migrations from central asia to East Asia starting as the Last glacial maximum began to ebb 18,300 years ago. However the absence of DQ2.5 in the Ainu is remarkable, it is also low in the Orochon and Negidal, suggesting that it arrived in eastern asia much later. There is high enough frequency close Chinese/Burman border to suggest this is proximally where it might have been displaced from; however its path into the region may be a reversal of previous settlement from the west, possibly Arabia, Iran or Western India. Interestingly, some of the cultivars used by the ancient Chinese appear to have been domesticated originally in eastern or western Africa, so that there may be an expansion associated with early agriculture in Southern China, this migration would have been about 8 to 12 ky years in age, and could explain the lack of DQ2.5 the ancestors to indigenous Americans, who migrated into Northeastern Siberias or New World prior to this time.

The importance of the estimates

Currently, in assessing diseases like Coeliac disease a definite diagnosis is often not possible and statistical considerations are relied upon. The knowledge of frequencies in populations, particularly among ancestors of immigrants can aid patient and physician as to what potential risks are. A case in point, one publication states that the western regions of Ireland have the highest coeliac disease rate in the world[53]. Plotting the frequency of DQ2.5 from any part of Western Europe to the Irish one sees the frequency gradient progressing toward the north and west of Ireland; therefore, a high rate of coeliac disease is not unexpected in Western Ireland. In fact, when the markers used in these studies were corrected for linkage, Western Ireland becomes the nodal center of DQ2.5 frequency distribution. Presently however if one lives in Western Ireland and has Coeliac Disease or Type 1 Diabetes, the medical professionals are aware of the increased risk of disease; however, if one is of Irish descent living in Canada or the U.S. the individual and physician may be completely unaware of the elevated risk within the Irish, Britain and Scandinavian derived populations. The same pitfalls have been noted with Type 1 diabetes. Recent studies indicated that late onset type 1 diabetes is frequently confused as Type 2 diabetes and in some instances evidence for both conditions is present. In these ambiguous cases, DQ2.5/DQ8 is elevated, but the physicians may be unaware that the individuals come from at risk populations. In some cases risk is high because of high levels of DQ2.5 and modest levels DQ8 (Scandinavia) or in parts of Mexico because DQ8 is high and DQ2.5 levels are modest.

DR3-DQ2 and Selection

Studies of DQ2.5 indicate that the receptor is an 'acid-peptide' presenter and this may determine whether selection is positive or negative in different populations. The super B8 haplotype which it is commonly associated with in Northwest Europe A1-Cw7-B8-DR3-DQ2.5 links it to one of two probable early settling groups in europe, possibly the earliest of settlers along the Atlantic coast of Europe. Based on the level of shellfish middens found in Epipaleolithic and Mesolithic Europe, Super B8 may have been selective for a diet rich in seafood or shellfish. While there is some equilibration of this haplotype the rate of equilibration lags that predicted by inter-locus genetic distances, and the very high levels of this haplotype are enigmatic. This has created the notion that the 5 gene chain was under repeated selection. An alternative explanation is that climate instability in Northwest Europe prior to the Holocene caused constant collapses with certain groups constantly re-fixing the most abundant type and eliminated minor recombinants. Still, since the end of the Holocene adequate time has elapsed for equilibration with alleles A2, A3 and B7, B44, so that if population size fluxes diminished variability at one time, during recent times Super B8 appears to be evolving much slower toward equilibration than expected for unclear reasons.

Associated Diseases

DQ2.5

DR3-DQ2 is associated with probably the greatest frequency of autoimmune occurrence relative to any other haplotype. The DQA1*0501:DQB1*0201 (DQ2.5) locus confers susceptibility to Gluten Sensitive Enteropathy (GSE)and (Type 1 Diabetes ) but has also been linked to other rarer autoimmune diseases like myasthenia gravis.

In Coeliac Disease DQ2.5 presents peptides of Triticeae glutens (prolamines and glutelins) to the immune system. This presentation is improved by the host enzyme tissue transglutaminase(tTG) which deamidates the gluten peptides making them more acidic. Since DQ2.5 is an acid peptide presenter it improves the immunogenecity increasing the level of activation. The tTG also links itself to prolamine peptides and the prolamine motif can be bound to T-cell receptors presenting tTG to the immune system creating autoantibodies. Autoantibodies and a prolamine peptide (α-2 gliadin 31-45) appear to activate tTG and mobilize it from cell surfaces. The tTG then cross linkes food and self peptides to gliadin eliciting antibodies to food proteins and self proteins causing an increased occurrence of food allergies and secondary autoimmune conditions. crossreactive antibodies to tTG also bind epidermal Transglutaminase and are involved in Dermatitis herpetiformis (majority of incidences attributable to GSE), but glutens in soaps and skin care products can likewise react. Crossreactive IgG and IgA to food proteins can also bind host tissues. As a result DR3-DQ2.5 is linked via gluten consumption is associated from weakly to strongly a variety of autoimmune diseases. Some of the most commonly note are autoimmune thyroiditis (Graves Disease and Hashimoto's thyroiditis), Rheumatoid Arthritis, Sjögren's Syndrome, Addison's Disease and many others. In addition to autoimmune conditions, DQ2.5 can be linked via GSE to pernecious anemia (female) irratable bowel disease, small gut lymphoma, cancers of the upper GI, Gastroesophageal reflux disease (GIRD), asthma, dementia and anaphalaxis. Most GSE cases are mediated by DQ2.5, however, a minority are linked to DQ8 and rarely DQ2.2. About 1:40 individuals who have DQ2.5 and consume Triticeae gluten will have GSE within their lifetime, most will go undiagnosed.

Juvenile diabetes (T1D) has a high association with DQ2.5 and there appears to be link between GSE and early onset male T1D. Anti-tTG antibodies are found elevated in a 1/3rd of T1D pateints[54][55] and there are indicators that Triticeae may be involved but the gluten protein is a type of globulin (Glb1)[56]. Recent studies indicate a combination of DQ2.5 and DQ8 (both acid peptide presenters) greatly increase the risk of adult onset Type 1 Diabetes and ambiguous type I/II Diabetes[57][58].

Other autoimmune diseases with associated with DQ2.5 are Lambert-Eaton myasthenic syndrome (LEMS), Sjögren's Syndrome, and autoimmune hepatitis although significant proportion of the risk is secondary to Coeliac Disease. DR3 and/or DQ2.5 are linked to the following diseases: Moreen's ulceration[59], "bout onset" multiple schlerosis[60], Grave's disease[61] and systemic lupus erythematosus[62]

Genetic Linkage

  • DR3-DQ2.5 can be established to other genes like TNF-305A (TNF2) which may also increase the risk of autoimmune disease in both Coeliac Disease and Type 1 diabetes. In systemic lupus erythematosus (SLE) patients HLA DR3-DQ2.5-C4AQ0, which was strongly associated with SLE (odds ratio [OR] 2.8, 95% CI 1.7-4.5)[63].
  • A more recent paper shows that Inositol triphosphate receptor 3 gene which is ~ 1 million base pairs from DQ2.5 is also associated with Type 1 diabetes[64].
  • DQ2.5 is also linked to the IgA-less phenotype which may or may not increase susceptibility to diseases[65][66]. This imposes a problem for understanding autoimmunity in DQ2.5, since many genes linked to disease with partial contributions are some degree of disequilibration with DQ2.5 loci and thus DQ2.5 masks genetic association via it positive association with some many diseases.

DR17

The diseases associated with DR17(3) are covered within the HLA-DR page.

References

  1. ^ a b c d e f g h i j k l Kimiyoshi, Tsuji (1992 location = Oxford). Proceedings of the Eleventh International Histocompatibility Workshop and Conference Held in Yokohoma, Japan, 6-13 November, 1991. Oxford University Press. ISBN 0192623907. {{cite book}}: Check date values in: |date= (help); Missing pipe in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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