DNA Polymorphism of HLA Class I and Class II Regions

Cohen, Daniel; Paul, Pascale; Gall, Isabelle Le; Marcadet, A.; Font, Marie-Pierre; Cohen-Haguenauer, Odile; Sayagh, Brigitte; Cann, Howard M.; Lalouel, Jean-Marc; Dausset, J

doi:10.1111/j.1600-065x.1985.tb01131.x

Cited by 59 publications

(30 citation statements)

References 26 publications

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“…Recent studies have shown that DQ genes have a higher level of polymorphism than is currently recognized by serological methods (28,29). Restriction fragment length polymorphism has been demonstrated within the same DQwl and DR2 specificities (28, 29).…”

Section: Discussionmentioning

confidence: 99%

Human histocompatibility leukocyte antigen (HLA) haplotype frequencies estimated from the data on HLA class I, II, and III antigens in 111 Japanese narcoleptics.

Matsuki¹,

Juji²,

Tokunaga³

et al. 1985

J. Clin. Invest.

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In order to deduce the predominant haplotypes in Japanese narcoleptics, we have studied a total of 111 Japanese patients with narcolepsy and six multiple-case families for HLA class I and class II antigens, and for class III HLA-linked complement markers. In Japanese narcoleptics, the most frequent haplotypes were B35-DR2, B15-DR2, and B51-DR2. These haplotypes were rare in normal Japanese population. In contrast, the most frequent haplotype of HLA-DR2 in normal Japanese, A24-C blankBw52-C4A*2 B*QO-BF *S-C2*C-DR2-DQwl, had a decreased frequency to one-third of the normal controls. Haplotypes B35-DR2, B15-DR2, and B51-DR2, which were more frequent among Japanese narcoleptics, were different from the haplotype found more frequently among Caucasoid narcoleptics, A3-Cw7-B7-DR2-DQwl. Haplotype analysis on six families showed that B35-DR2 and other rare haplotypes in normal Japanese were associated with narcolepsy. There were four cases without any signs of narcolepsy among 19 subjects with the disease susceptibility haplotypes. This finding suggests an incomplete penetrance of hepersomnia. Haplotype analysis of family members was also useful for the early detection of the high risk children to narcolepsy.

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Section: Discussionmentioning

confidence: 99%

Human histocompatibility leukocyte antigen (HLA) haplotype frequencies estimated from the data on HLA class I, II, and III antigens in 111 Japanese narcoleptics.

Matsuki¹,

Juji²,

Tokunaga³

et al. 1985

J. Clin. Invest.

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“…Almost no polymorphism was observed for DRa; limited polymorphism was noted for DXa, DPa, and DP/3; in contrast DRf3, DQa, and DQP3 yielded extensive polymorphism (3,12). Generally, the majority of RFLPs correlate with supertypic specificities whereas fewer fragments are found with single DR specificities (12,13). Nevertheless, RFLPs specific for DR-associated subtypes have been reported (3,11,13,14).…”

mentioning

confidence: 96%

HLA-DR2, -DR5, and DRw6 associated Dw subtypes correlate with HLA-DR beta and -DQ beta restriction fragment length polymorphisms.

Font¹,

Gebuhrer²,

Bétuel³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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DNAs extracted from peripheral blood leukocytes of 24 individuals, selected for their HLA-DR types, -DR2, -DR5, and -DRw6, were analyzed with four restriction enzymes, BamHI, EcoRV, HindIll, and Taq (al, a2) and 2(3 ((31, /32). In addition DZa and DO/3 genes have been characterized but not yet located (2, 3). The numerous antigens encoded by these loci were initially characterized by alloantisera against DR and DQ, homozygous typing cells (HTC), and by primed lymphocytes for D and DP determinants.The specificities recognized by T-cell proliferation in response to allogeneic stimulation by B cells were initially thought to be controlled by the HLA-D locus (4). When serological methods allowed the recognition of B-cell antigens coded by the HLA region, these antigens were correlated with their cellular counterpart. The similarity was sufficient to warrant the existence of DR locus (D related), and the same nomenclature was applied to the specificities defined by two different procedures (5). Subsequently, this position was no longer tenable as new D specificities had no DR equivalent or were included in broader DR reagents. With this approach, it was demonstrated that HTCs typed as DR4 could be resolved in five different clusters by the level oftheir proliferative response when tested against each other (6). Availability of proper alloantisera can lead to the recognition of some Dw types by serology. For example, subtypes of DR2, such as FJO or AZH defined by HTCs, can be serologically recognized (7). An alloantiserum has permitted the distinction of a variant of DRw6 (now DRw14) corresponding to Dw9 (8). However, there still remain Dw subtypes like Dw18 and Dwl9 (subtypes of Dw6), which evade serological recognition. Alleles at the DQ locus (formerly MB) are found in strong linkage disequilibrium with DR antigens. DQwl is usually associated with DR1, DR2, DRw6 (DRw13 and DRw14), and DRw10; DQw2 with DR3 and DR7; DQw3 with DR4, DR5, and DRw9 (20). The rare associations such as DRw13-DQw3 and DRw14-DQw3 raise different cellular response(s) when compared to DRw13-DQwl or DRw14-DQwl. This dissociation has led to the assumption that Dw specificities could correspond to the summation of epitopes present on DR, DQ, and other molecules (9).The obtention and use of class II cDNA probes represent an approach to unravel the complexity of this region through restriction fragment length polymorphism (RFLP) studies (10, 11). The degree of polymorphism depends on the locus explored. Almost no polymorphism was observed for DRa; limited polymorphism was noted for DXa, DPa, and DP/3; in contrast DRf3, DQa, and DQP3 yielded extensive polymorphism (3,12). Generally, the majority of RFLPs correlate with supertypic specificities whereas fewer fragments are found with single DR specificities (12,13). Nevertheless, RFLPs specific for DR-associated subtypes have been reported (3,11,13,14). The aim of the present study was to investigate DRI and DQP RFLP in various subtypes of HLA-DR2, -DR5, and -DRw6. These subtypes selected f...

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“…2, the polymorphic 4.8-kb DQa gene fragment, characteristic of the HLA-DR4 haplotype (ref. 4, H. Erlich, unpublished data), and the invariant 2.5-kb fragment, derived from the DXa locus (18), can be easily seen in as little as 0.5 1ig of total human DNA. A faint 0.8-kb band is also seen in the lanes with 4.0 and 2.0 ug ofhuman DNA.…”

Section: Methodsmentioning

confidence: 95%

Use of nonisotopic M13 probes for genetic analysis: application to HLA class II loci.

Sheldon¹,

Kellogg²,

Watson³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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Previously, DNA polymorphisms in the HLA gene cluster have been analyzed using radioactive probes in Southern blot experiments; the restriction fragment length polymorphisms (RFLPs) revealed by this analysis are capable of subdividing HLA serological types. Here, we report the use of DNA probes labeled with biotinylated psoralen to provide nonisotopic detection of HLA class H RFLP patterns. These biotinylated probes contain cDNA sequences encoding the a and 13 chains of DP, DQ, and DR HLA class II genes as inserts in M13 vectors. The recombinant M13 molecules are partially double-stranded with single-stranded HLA cDNA regions and contain biotinylated psoralen covalently linked to duplex DNA by UV irradiation. Following hybridization, the presence of biotinylated probe bound to target DNA is detected using a streptavidin-horseradish peroxidase conjugate, which converts the colorless substrate 3,3',5,5'-tetramethylbenzidine to a blue precipitate in less than 1 hr. The probe and detection system described here can detect single-copy genes in less than 0.5 jug of total human DNA on Southern blots and generates the same specific RFLP patterns as do probes labeled with 32P by nick-translation. These biotinylated HLA class II probes have been applied to tissue typing for bone marrow transplantation and the study of insulin-dependent diabetes susceptibility, revealing in each case relevant polymorphisms not detected by serologic typing.The specificity and sensitivity of DNA hybridization have made possible the application of radioactively labeled DNA probes for the diagnosis of genetic (1) and infectious (2) disease. In addition, specific probes have been used to reveal DNA polymorphisms in the HLA region for use in HLA typing (reviewed in refs. 3 and 4). The HLA region consists of the class I loci, which encode the heavy chain of the classic transplantation antigens, the class II loci, which encode a 33-to 34-kDa a chain and a 28-to 29-kDa ,3 chain that form a cell surface heterodimer, and the class III loci, which encode components of the complement pathway. The HLA class II glycopeptides include three distinct groups of cell surface antigens called HLA-DR, -DQ, and -DP. Both the class I and class II antigens are highly polymorphic cell surface molecules that function as recognition elements for T lymphocytes. Probes derived from the class II genes have identified restriction fragment length polymorphisms (RFLPs) that are correlated with HLA specificities and, in many cases, can subdivide these serologically defined types. These probes have been used for tissue typing as well as for the analysis of disease susceptibility in family and population studies. Based on the high degree of polymorphism revealed by RFLP analysis, another area of potential use for HLA DNA probes is in paternity determination.

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DNA Polymorphism of HLA Class I and Class II Regions

Cited by 59 publications

References 26 publications

Human histocompatibility leukocyte antigen (HLA) haplotype frequencies estimated from the data on HLA class I, II, and III antigens in 111 Japanese narcoleptics.

Human histocompatibility leukocyte antigen (HLA) haplotype frequencies estimated from the data on HLA class I, II, and III antigens in 111 Japanese narcoleptics.

HLA-DR2, -DR5, and DRw6 associated Dw subtypes correlate with HLA-DR beta and -DQ beta restriction fragment length polymorphisms.

Use of nonisotopic M13 probes for genetic analysis: application to HLA class II loci.

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