HLA‐DR restriction‐fragment‐length polymorphisms in narcolepsy

Holloman, J. D.; Bell, John I.; Kilduff, Thomas S.; Dement, William C.; Guilleminault, Christian; Ho, McDevitt

doi:10.1002/jnr.490180134

Cited by 11 publications

(7 citation statements)

References 18 publications

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“…Studies of DR,DQ haplotypes in different racial groups, with different DR,DQ associations, may make possible the definition of disease markers of pathogenetic significance. For example, narcolepsy is associated with DR2,Dw2 haplotype, but not with DR2,Dw12 haplotype (36)(37)(38). This very strong association is also present in Japanese patients, although in a normal population DR2 is associated with Dwl2 (39).…”

Section: Discussionmentioning

confidence: 92%

Polymorphism of HLA‐DR2,DQwl haplotypes in Asian Indians

Singal

Sood

1990

Tissue Antigens

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We examined the polymorphism of DR2,DQw1 haplotypes in Epstein-Barr virus-transformed B-lymphoblastoid cell lines (HTCs) and unrelated (32 Canadian Caucasians and 24 Asian Indians) individuals by restriction fragment length polymorphism (RFLP) and oligonucleotide typing. The data demonstrate that three subtypes of DR2,DQw1 haplotypes, DRw15(B1.1501).DQw6a(A1.0102,B1.0602),DRw15(B1.1502). DQw6b(A1.0103,B1.0601), DRw16(B1.1601).DQw5(A1.0102,B1.0502) are present in HTCs and Canadian Caucasians. Of these, DRw15(B1.1501).DQw6a (A1.0102,B1.0602) haplotype was present in majority (81.3%) of Caucasians. Among Asian Indians, this haplotype was present only in one DR2,DQw1-positive individual. In addition, three new haplotypes representing different combinations of DRB1, DQA1 and DQB1 genes were demonstrable in Asian Indians. These new haplotypes are DRw15(B1.1501).DQw6b(A1.0103,B1.0601),DRw15(B1.1501). DQw5(A1.0102,B1.0502), and DRw15(B1.1501).DQw6c(A1.0102, B1.0601). The most frequent haplotypes among Asian Indians were DRw15(B1.1502).DQw6b(A1.0103,B1.0601) and DRw15(B1.1501). DQw6b(A1.0103,B1.0601). The distribution of subtypes of DR2,DQw1 haplotypes in Asian Indians was significantly different from that in Canadian Caucasians. The results in the present study have important implications for HLA and for HLA-disease associations.

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Section: Discussionmentioning

confidence: 92%

Polymorphism of HLA‐DR2,DQwl haplotypes in Asian Indians

Singal

Sood

1990

Tissue Antigens

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“…In an attempt to confirm this observation at the DNA level and to discover whether various allele-specific RFLPs are preferentially associated with MS, DR-unmatched Caucasian MS patients were studied by sequential RFLP analysis using DRP, DQP, and DQa probes. Seventeen of these patients were DR2+ with the DRP probe pRTVl com- Holloman et al, 1987). The nucleic acid sequences of DRP chains from Dw2, Dw12, and AZH have recently been compared and the structural basis for the differences in cellular typing appears to lie within the PI chain between amino acid residues 30 and 38 (Lee et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

“…Pst 1 digests also provide definitive detection of DR2/Dw2 at the DNA level with the DRP probe (Jacobson et a]., 1986) and the Pst 1 RFLP patterns from the DR2/Dw2 cell line PGF and the 26 DR2+ patients were identical. However, DR2 heterogeneity is well recognized and mixed lymphocyte cultures have defined a number of DR2 subtypes, which include Dw2, Dw12, and a group of non-Dw2, nonDw12 types including AZH, FJO, tb24, MN2, and REM (reviewed in Holloman et al, 1987). The nucleic acid sequences of DRP chains from Dw2, Dw12, and AZH have recently been compared and the structural basis for the differences in cellular typing appears to lie within the PI chain between amino acid residues 30 and 38 (Lee et al, 1987).…”

Section: Hla Polymorphism In Multiple Sclerosis 51mentioning

confidence: 99%

HLA‐DRβ, ‐DQα, and ‐DQβ restriction fragment length polymorphisms in multiple sclerosis

Haegert

Michaud

Schwab

et al. 1989

J of Neuroscience Research

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Restriction fragment length polymorphism (RFLP) studies were performed on DNA from unrelated Caucasian patients with multiple sclerosis (MS) using cDNA probes to the HLA class II genes DR beta, DQ alpha, and DQ beta. In a study of 34 patients and 34 controls who were not matched for DR type, we found that the DQ beta allele-specific RFLP or allogenotype, termed DQ beta lb, which corresponds at the molecular level to the DQwl serotype, is preferentially associated with MS. A significant disease association with DR2 was demonstrated by serology but this was not confirmed using DR2/Dw2-specific RFLPs. We suggest that DQ beta lb is largely responsible for HLA-associated susceptibility to MS and that the apparent MS-DR2 serological association is due to the strong linkage disequilibrium between DR2 and DQ beta lb. Homozygosity of one of the two allelic bands of the DX alpha gene, usually termed the DX alpha lower (DX alpha L) band (which cross-hybridizes with the DQ alpha probe), correlated with reduced susceptibility to MS. Similarly a 5.3 kb band identified by the DQ alpha probe in Mspl digests showed a negative correlation with MS. In an analysis of 27 DR2+ controls and 26 DR2+ patients it was found that these individuals all had DR2/Dw2-specific RFLPs and all had identical DR2/Dw2-associated DQ beta (DQ beta lb) and DQ alpha (DQ alpha lb) allogenotypes. We detected no polymorphisms of DR beta, DQ alpha, or DQ beta genes among the DR2+ MS patients which distinguished them from normals.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…All Japanese patients carried Dw2, which is the dominant DR2 subtype in Caucasians (25 %), but a more minor antigen in Japanese (8–10 %), where Dw12 is more common [44, 45]. Restriction fragment length polymorphism (RFLP) studies with DQ probes performed in the laboratory of Hugh McDevitt also confirmed this finding, showing a unique pattern of association correlating with Dw2 but not Dw12 [46, 47]. As will be seen later, this pattern differentiates DRB1*15:01, DQA1*01:02, DQB1*06:02 versus DRB1*15:02, DQA1*01:03, DQB1*06:01, the two major DR2 and DQ1 haplotypes in the Japanese population [48].…”

Section: First Hla Association Studies In Narcolepsy and Early Immunomentioning

confidence: 92%

History of narcolepsy at Stanford University

Mignot

2014

Immunol Res

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Although narcolepsy was first described in the late nineteenth century in Germany and France, much of the research on this disorder has been conducted at Stanford University, starting with Drs. William C. Dement and Christian Guilleminault in the 1970s. The prevalence of narcolepsy was established, and a canine model discovered. Following the finding in Japan that almost all patients with narcolepsy carry a specific HLA subtype, HLA-DR2, Hugh Mac Devitt, F. Carl Grumet, and Larry Steinman initiated immunological studies, but results were generally negative. Using the narcoleptic canines, Dr. Nishino and I established that stimulants increased wakefulness by stimulating dopaminergic transmission while antidepressants suppress cataplexy via adrenergic reuptake inhibition. A linkage study was initiated with Dr. Grumet in 1988, and after 10 years of work, the canine narcolepsy gene was cloned by in 1999 and identified as the hypocretin (orexin) receptor 2. In 1992, studying African Americans, we also found that DQ0602 rather than DR2 was a better marker for narcolepsy across all ethnic groups. In 2000, Dr. Nishino and I, in collaboration with Dr. Lammers in the Netherlands, found that hypocretin 1 levels in the cerebrospinal fluid (CSF) were undetectable in most cases, establishing hypocretin deficiency as the cause of narcolepsy. Pursuing this research, our and Dr. Siegel’s group, examining postmortem brains, found that the decreased CSF hypocretin 1 was secondary to the loss the 70,000 neurons producing hypocretin in the hypothalamus. This finding revived the autoimmune hypothesis but attempts at demonstrating immune targeting of hypocretin cells failed until 2013. At this date, Dr. Elisabeth Mellins and I discovered that narcolepsy is characterized by the presence of autoreactive CD4+ T cells to hypocretin fragments when presented by DQ0602. Following reports that narcolepsy cases were triggered by vaccinations and infections against influenza A 2009 pH1N1, a new pandemic strain that erupted in 2009, our groups also established that a small epitope of pH1N1 resembles hypocretin and is likely involved in molecular mimicry. Although much remains to be done, these achievements, establishing hypocretin deficiency as the cause of narcolepsy, demonstrating its autoimmune basis, and showing molecular mimicry between hypocretin and sequences derived from a pandemic strain of influenza, are likely to remain classics in human immunology.

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HLA‐DR restriction‐fragment‐length polymorphisms in narcolepsy

Cited by 11 publications

References 18 publications

Polymorphism of HLA‐DR2,DQwl haplotypes in Asian Indians

Polymorphism of HLA‐DR2,DQwl haplotypes in Asian Indians

HLA‐DRβ, ‐DQα, and ‐DQβ restriction fragment length polymorphisms in multiple sclerosis

History of narcolepsy at Stanford University

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