HLA A1-B8 haplotype

Philosophically, A1-B8 is more than just two gene-alleles. These gene-alleles are markers for a haplotype, a stretch of chromosome 6 that contains many gene alleles. In its natural history this haplotype underwent some atypical selection, at the end of the period of evolution it became the predominant haplotypes in North/Western European ancestors. Today however the collection of genes is associated with increased incidences of certain diseases. Despite the fact that the associations have been known almost as long as A1 and "A8" were known, the role of factors affecting disease are still not clear.

A1-B8 serotype was associated with a number of diseases as "HL-A"' antigens were first being described. Among these were coeliac disease, autoimmune active chronic hepatitis, myasthenia gravis, Adrenocortical hyperfunction-Cushing's syndrome, primary biliary cirrhosis.{{cite journal |vauthors=Clarke AK, Galbraith RM, Hamilton EB, Williams R |title=Rheumatic disorders in primary biliary cirrhosis |journal=Ann. Rheum. Dis. |volume=37 |issue=1 |pages=42–7 |date=February 1978 |pmid=305233 |pmc=1000187 |doi= 10.1136/ard.37.1.42|url=}}{{cite journal |vauthors=Lada G, Gyódi E, Gláz E |title=HLA antigens in patients with adrenocortical hyperfunction |journal=Acta Med Acad Sci Hung |volume=34 |issue=4 |pages=213–26 |year=1977 |pmid=618054 }}{{cite journal |vauthors=Ludwig H, Polymenidis Z, Granditsch G, Wick G |title=[Association of HL-A1 and HL-A8 with childhood celiac disease] |language=de |journal=Z Immunitatsforsch Exp Klin Immunol |volume=146 |issue=2 |pages=158–67 |date=November 1973 |pmid=4282973 }}{{cite journal |vauthors=Mackay IR, Morris PJ |title=Association of autoimmune active chronic hepatitis with HL-A1,8 |journal=Lancet |volume=2 |issue=7781 |pages=793–5 |date=October 1972 |pmid=4116233 |doi= 10.1016/S0140-6736(72)92149-6}}{{cite journal |vauthors=Feltkamp TE, van den Berg-Loonen PN, Engelfriet CP, etal |title=[HL-A typing and autoantibodies in patients with myasthenia gravis] |language=nl |journal=Ned Tijdschr Geneeskd |volume=118 |issue=23 |pages=895–6 |date=June 1974 |pmid=4839444 }}{{cite journal |vauthors=Hammarström L, Smith E, Möller E, Franksson C, Matell G, Von Reis G |title=Myasthenia gravis: studies on HL-A antigens and lymphocyte subpopulations in patients with myasthenia gravis |journal=Clin. Exp. Immunol. |volume=21 |issue=2 |pages=202–15 |date=August 1975 |pmid=1081023 |pmc=1538268 }}File:PBB Protein LTA image.jpg is encoded with HLA A-B region]] However, as study sizes increased and D serotypes were described in more detail, the association of these loci moved from the MHC class I loci to the MHC class II loci. Underlying this move was the HLA A1-B8-DR3-DQ2 haplotype, a haplotype that is in acute linkage disequilibrium in the European population.{{cite journal |vauthors=Gazit E, Sartani A, Mizrachi Y, Ravid M |title=HLA antigen in Jewish patients with juvenile diabetes mellitus |journal=Diabete Metab |volume=3 |issue=1 |pages=55–8 |date=March 1977 |pmid=858444 }}{{cite journal |vauthors=Vogten AJ, Shorter RG, Opelz G |title=HLA and cell-mediated immunity in HBsAg negative chronic active hepatitis |journal=Gut |volume=20 |issue=6 |pages=523–5 |date=June 1979 |pmid=89064 |pmc=1412459 |doi= 10.1136/gut.20.6.523|url=}}{{cite journal |vauthors=Ercilla G, Parés A, Arriaga F, etal |title=Primary biliary cirrhosis associated with HLA-DRw3 |journal=Tissue Antigens |volume=14 |issue=5 |pages=449–52 |date=November 1979 |pmid=12731577 |doi= 10.1111/j.1399-0039.1979.tb00874.x}}{{cite journal |vauthors=Robinson BN, Roberts DF, Mather BA, Nelson R, Rowlatt AS |title=Coeliac disease and HLA: a family study |journal=European Journal of Immunogenetics |volume=7 |issue=5 |pages=381–91 |date=October 1980 |pmid=7430678 |doi= 10.1111/j.1744-313X.1980.tb00732.x}}{{cite journal |vauthors=Tosi R, Vismara D, Tanigaki N, etal |title=Evidence that celiac disease is primarily associated with a DC locus allelic specificity |journal=Clin. Immunol. Immunopathol. |volume=28 |issue=3 |pages=395–404 |date=September 1983 |pmid=6192959 |doi= 10.1016/0090-1229(83)90106-X}} This disequilibrium made it appear that A1 and other class I gene-alleles were disease factors, when these alleles were only attached to a long segment of conserved DNA that had disease associated genes on the other end. In at least 2 diseases, the risk of autoimmune disease extends beyond the class II region of the haplotype.

The "HL-A1,8 phenotype" was found to be associated with severe systemic lupus erythematosus (SLE) (renal and central nervous system involvement) in Caucasian patients.{{cite journal |vauthors=Goldberg MA, Arnett FC, Bias WB, Shulman LE |title=Histocompatibility antigens in systemic lupus erythematosus |journal=Arthritis Rheum. |volume=19 |issue=2 |pages=129–32 |year=1976 |pmid=1259797 |doi= 10.1002/art.1780190201|doi-access= }} Two-point haplotype analysis between TNFB(B*01 allele) and HLA show that the allele is in linkage disequilibrium with HLA-A1, Cw7, B8, C4A(Null), DR3, DQ2.5.{{cite journal |vauthors=Parks CG, Pandey JP, Dooley MA, etal |title=Genetic polymorphisms in tumor necrosis factor (TNF)-alpha and TNF-beta in a population-based study of systemic lupus erythematosus: associations and interaction with the interleukin-1alpha-889 C/T polymorphism |journal=Hum. Immunol. |volume=65 |issue=6 |pages=622–31 |date=June 2004 |pmid=15219382 |doi=10.1016/j.humimm.2004.03.001 |url=https://zenodo.org/record/1259007}}

While type 1 diabetes shows an extended association on the HLA A1-B8-DR3-DQ2 haplotype, the association appears not to extend beyond the HLA-B locus.{{cite journal |vauthors=Noble JA, Martin A, Valdes AM, etal |title=Type 1 diabetes risk for human leukocyte antigen (HLA)-DR3 haplotypes depends on genotypic context: association of DPB1 and HLA class I loci among DR3- and DR4-matched Italian patients and controls |journal=Hum. Immunol. |volume=69 |issue=4–5 |pages=291–300 |year=2008 |pmid=18486765 |pmc=2505335 |doi=10.1016/j.humimm.2008.02.003 }} A recent study of DR3-DQ2/DR4-DQ8 phenotype found that A1-cw7-B8 was actually lower than expected relative to other A-B types, indicating that risk associated genes are located between B8 and DR3. A*0101 appears to alter risk for type 1 diabetes but not Cw7-B8.{{cite journal |vauthors=Noble J, Valdes A, Bugawan T, Apple R, Thomson G, Erlich H | title = The HLA class I A locus affects susceptibility to type 1 diabetes. | journal = Hum Immunol | volume = 63 | issue = 8 | pages = 657–64 | year = 2002 | pmid = 12121673 | doi = 10.1016/S0198-8859(02)00421-4| pmc = 4049513 }} The type 1 diabetes example shows the inherent difficulty in the use of linkage analysis alone to cipher risk.

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In allergic disease A1,B8 were found to associate with allergic reactions in new-borns.{{cite journal |vauthors=Soothill JF, Stokes CR, Turner MW, Norman AP, Taylor B |title=Predisposing factors and the development of reaginic allergy in infancy |journal=Clinical & Experimental Allergy |volume=6 |issue=4 |pages=305–19 |date=July 1976 |pmid=963861 |doi= 10.1111/j.1365-2222.1976.tb01911.x}} A1, B8 was found increased in children with bronchial asthma and low IgA.{{cite journal |vauthors=Ostergaard PA, Eriksen J |title=Association between HLA-A1,B8 in children with extrinsic asthma and IgA deficiency |journal=Eur. J. Pediatr. |volume=131 |issue=4 |pages=263–70 |date=August 1979 |pmid=477683 |doi= 10.1007/BF00444347}} However, some of this reaction can be attributed to the linkage of the HLA A1-B8-DR3-DQ2 haplotype to the IgA-less phenotype.{{cite journal |vauthors=Ambrus M, Hernádi E, Bajtai G |title=Prevalence of HLA-A1 and HLA-B8 antigens in selective IgA deficiency |journal=Clin. Immunol. Immunopathol. |volume=7 |issue=3 |pages=311–4 |date=May 1977 |pmid=872455 |doi= 10.1016/0090-1229(77)90062-9}} A firmer association was found with atopies.{{cite journal |vauthors=Dasgupta A, Misri N, Bala S |title=Population and family studies to demonstrate Ir genes: HLA haplotype in atopic allergy |journal=Monogr Allergy |volume=11 |pages=75–9 |year=1977 |pmid=327293 }}{{cite journal |vauthors=MacKie RM, Dick HM |title=A study of HLA antigen distribution in families with atopic dermatitis |journal=Allergy |volume=34 |issue=1 |pages=19–23 |date=February 1979 |pmid=453484 |doi= 10.1111/j.1398-9995.1979.tb01996.x}}{{cite journal |vauthors=Heikkilä M, Koistinen J, Lohman M, Koskimies S |title=Increased frequency of HLA-A1 and -B8 in association with total lack, but not with deficiency of serum IgA |journal=Tissue Antigens |volume=23 |issue=5 |pages=280–3 |date=May 1984 |pmid=6611606 |doi= 10.1111/j.1399-0039.1984.tb00046.x}} A1,B8 where found more frequently in hay fever complicated by asthma or atopia relative to just hay fever.{{cite journal |vauthors=Turner MW, Brostoff TJ, Wells RS, Stokes CR, Soothill JF |title=HLA in eczema and hay fever |journal=Clin. Exp. Immunol. |volume=27 |issue=1 |pages=43–7 |date=January 1977 |pmid=849649 |pmc=1540890 }}{{cite journal |vauthors=Jeannet M, Girard JP, Varonier HS, Mirimanoff P, Joye P |title=HLA antigens in grass pollinosis |journal=Monogr Allergy |volume=11 |pages=69–73 |year=1977 |pmid=876128 }}{{cite journal |vauthors=Oehling A, Baena-Cagnani CE, Sanz ML, Crisci CD |title=HLA and pollinosis |journal=Allergol Immunopathol (Madr) |volume=7 |issue=6 |pages=423–6 |year=1979 |pmid=539526 }} Further asthmatic patients with negative skin tests tended toward higher A1,B8 serotypes.{{cite journal |vauthors=Morris MJ, Vaughan H, Lane DJ, Morris PJ |title=HLA in asthma |journal=Monogr Allergy |volume=11 |pages=30–4 |year=1977 |pmid=876121 }}

File:PBB Protein C4A image.jpg gene is deleted within A1-B8]]

In the mid-1980s the association with A1-B8-DR3 and HIV progression appeared shortly after the discover of the virus.{{cite journal |vauthors=Steel CM, Ludlam CA, Beatson D, etal |title=HLA haplotype A1 B8 DR3 as a risk factor for HIV-related disease |journal=Lancet |volume=1 |issue=8596 |pages=1185–8 |date=May 1988 |pmid=2897006 |doi= 10.1016/S0140-6736(88)92009-0}} A1-B8 associated with more rapid progression to seropositivity, and was strongly associated with a rapid decline in T4 cells and development of HIV-related symptoms within four years of infection.{{cite journal |vauthors=Kaslow RA, Duquesnoy R, VanRaden M, etal |title=A1, Cw7, B8, DR3 HLA antigen combination associated with rapid decline of T-helper lymphocytes in HIV-1 infection. A report from the Multicenter AIDS Cohort Study |journal=Lancet |volume=335 |issue=8695 |pages=927–30 |date=April 1990 |pmid=1970024 |doi= 10.1016/0140-6736(90)90995-H}} The strongest associations were seen with A1-Cw7-B8 haplotype. C4 (complement 4) produces a null allele at on locus C4AQ. This locus in part of the HLA A1-B8-DR3-DQ2 haplotype (markers are A1, CW7, B8, BfS, C4AQ0, C4B1, DR3, DQ2) therefore one study concluded that C4AQ0 could explain the increased infectivity to HIV.{{cite journal |vauthors=Cameron PU, Mallal SA, French MA, Dawkins RL |title=Major histocompatibility complex genes influence the outcome of HIV infection. Ancestral haplotypes with C4 null alleles explain diverse HLA associations |journal=Hum. Immunol. |volume=29 |issue=4 |pages=282–95 |date=December 1990 |pmid=1981061 |doi= 10.1016/0198-8859(90)90042-N}} The haplotype was further linked to false-tumor splenomegaly, CD8 lymphocytosis, and high IgG.{{cite journal |vauthors=Oksenhendler E, Autran B, Gorochov G, D'Agay MF, Seligmann M, Clauvel JP |title=CD8 lymphocytosis and pseudotumoral splenomegaly in HIV infection |journal=Lancet |volume=340 |issue=8813 |pages=207–8 |date=July 1992 |pmid=1353138 |doi= 10.1016/0140-6736(92)90471-E}}

An association was seen between viral hepatitis and HLA-A1.{{cite journal |author=Hug G |title=Genetic factors and autoimmunity in viral hepatitis |journal=Am. J. Clin. Pathol. |volume=65 |issue=5 Suppl |pages=870–5 |date=May 1976 |pmid=218441 }}{{cite journal |vauthors=Descamps B, Jungers P, Naret C, Degott C, Zingraff J, Bach JF |title=HLA-A1, B8-phenotype association and HBs antigenemia evolution in 440 hemodialyzed patients |journal=Digestion |volume=15 |issue=4 |pages=271–7 |year=1977 |pmid=67978 |doi= 10.1159/000198012}} Though, the association of A1 with autoimmune hepatitis with no anti-viral antibody was stronger than with chronic active hepatitis with anti-viral titer.{{cite journal |vauthors=Freudenberg J, Baumann H, Arnold W, Berger J, Büschenfelde KH |title=HLA in different forms of chronic active hepatitis. A comparison between adult patients and children |journal=Digestion |volume=15 |issue=4 |pages=260–70 |year=1977 |pmid=863130 |doi= 10.1159/000198011}} The association with viral hepatitis was subsequently demonstrated and patients with antinuclear antibodies were more likely to have A1-B8-DR3.{{cite journal |vauthors=Czaja AJ, Carpenter HA, Santrach PJ, Moore SB |title=Immunologic features and HLA associations in chronic viral hepatitis |journal=Gastroenterology |volume=108 |issue=1 |pages=157–64 |date=January 1995 |pmid=7806037 |doi= 10.1016/0016-5085(95)90020-9|doi-access=free }} Currently studies point to association proximal the Cw*0702-B*0801 loci.

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Category:Human MHC haplogroups

Category:Human MHC mediated diseases