HLA-DR2 association with excessive somnolence in narcolepsy does not generalize to sleep apnea and is not accompanied by systemic autoimmune abnormalities

Rubin, Robert L.; Hajdukovich, Roza; Mitler, Merrill M.

doi:10.1016/0090-1229(88)90104-3

Cited by 43 publications

(23 citation statements)

References 29 publications

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“…3,4 HLA-DR2 has been described as closely associated with anti-glomerular basement membrane disease, 32 multiple sclerosis, 36 and narcolepsy. 37 In general, HLA linkage to autoimmune disease is believed to arise from an HLA haplotype-determined ability to present pathogenic peptides derived from self-antigens or foreign antigens. In addition, HLA-derived peptides themselves may serve as autoantigens.…”

Section: Discussionmentioning

confidence: 99%

Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome

Maciejewski

Follmann

Nakamura

et al. 2001

Blood

138

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Many autoimmune diseases are associated with HLA alleles, and such a relationship also has been reported for aplastic anemia (AA). AA and paroxysmal nocturnal hemoglobinuria (PNH) are related clinically, and glycophosphoinositol (GPI)-anchored protein (AP)-deficient cells can be found in many patients with AA. The hypothesis was considered that expansion of a PNH clone may be a marker of immune-mediated disease and its association with HLA alleles was examined. The study involved patients with a primary diagnosis of AA, patients with myelodysplastic syndrome (MDS), and patients with primary PNH. Tests of proportions were used to compare allelic frequencies. For patients with a PNH clone (defined by the presence of GPI-APdeficient granulocytes), regardless of clinical manifestations, there was a higher than normal incidence of HLA-DR2 (58% versus 28%; z ‫؍‬ 4.05). The increased presence of HLA-DR2 was found in all frankly hemolytic PNH and in PNH associated with bone marrow failure (AA/PNH and MDS/PNH). HLA-DR2 was more frequent in AA/PNH (56%) than in AA without a PNH clone (37%; z ‫؍‬ 3.36). Analysis of a second cohort of patients with bone marrow failure treated with immunosuppression showed that HLA-DR2 was associated with a hematologic response (50% of responders versus 34% of nonresponders; z ‫؍‬ 2.69). IntroductionIdiopathic aplastic anemia (AA) shows striking similarities to diseases of other organ systems with classically established autoimmune pathophysiology: AA frequently affects younger individuals, there is laboratory evidence for immune activation and destruction of the target organ by autoreactive T cells, 1 and patients often respond to immunosuppressive therapies. 2 Many autoimmune diseases have clear associations with particular HLA alleles: ankylosing spondylitis with HLA-B27 is the classical example, but similar relationships have been found in psoriasis (HLA-B13, HLA-B17-Cw6), rheumatoid arthritis (HLA-DR1 and HLA-DR4), juvenile diabetes mellitus (HLA-B8, HLA-B15, and HLA-B54), and multiple sclerosis (HLA-B7 and HLA-DR2). In hematology, agranulocytosis secondary to clozapine (HLA-B38, HLA-DR4, and DQw3) or methimazole (HLA-DR8) and mixed cryoglobulinemia in hepatitis C virus-infected patients (HLA-B8 and HLA-DR3) exemplify links between immunogenetics and pathophysiology. [3][4][5][6] Fundamentally, the presence of particular HLA alleles likely allows for preferential presentation of particular peptides, perhaps derived from autoantigens, to specific T cells, driving the autoimmune process.In AA, HLA associations have also been examined. [7][8][9][10][11][12][13][14][15][16][17][18][19] An increased frequency of HLA-DR2 has been reported in some but not all studies. [9][10][11][12][13]16 An association with class I alleles (especially HLA-A2) has been inconsistently identified. 7,10,[13][14][15] The presence of HLA-DR15 (split of DR2) was associated with good response to cyclosporine therapy, suggesting that this allele may be a specific predisposing factor for the development of immune-med...

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Section: Discussionmentioning

confidence: 99%

Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome

Maciejewski

Follmann

Nakamura

et al. 2001

Blood

138

View full text Add to dashboard Cite

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“…Subject 3N was atypical from the other narcoleptics only in that she carried the DR4 antigen rather than the DRw15 antigen. Caucasian narcoleptics with this antigen and without the DRw15 antigen do exist and have been described by other authors and by our group (24,25). This narcoleptic was typical in all other respects, including a clinical history of cataplexy.…”

Section: Subjectsmentioning

confidence: 77%

“…As part of the characterization of our narcoleptic subjects we performed histocompatibility leukocycle antigen (HLA) typing. Seropositivity for HLA DRw15 and DQw6 in Caucasians and Orientals, or seropositivity for HLA DQw6 in African Americans is strongly (but not invariably) associated with narcolepsy (7,(23)(24)(25). Subject 3N was atypical from the other narcoleptics only in that she carried the DR4 antigen rather than the DRw15 antigen.…”

Section: Subjectsmentioning

confidence: 98%

Treatment of Narcolepsy with Methamphetamine

Mitler

Erman

1993

Sleep

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SummaryEight pairs of subjects (each consisting of a narcoleptic and a control matched on the basis of age, sex, educational background and job) were evaluated under the following double-blind, randomized treatment conditions: baseline, placebo, low dose and high dose methamphetamine. Subjects were drug-free for 2 weeks prior to beginning the protocol. Methamphetamine was the only drug taken during the protocol and was given in a single morning dose of 0, 20 or 40-60 mg to narcoleptics and 0, 5 or 10 mg to controls. The protocol was 28 days long, with each of the four treatment conditions lasting 4 days followed by 3 days of washout. Nighttime polysomnography and daytime testing were done during the last 24 hours of each treatment condition. Daytime sleep tendency was assessed with the multiple sleep latency test (MSLT). Daytime performance was assessed with performance tests including a simple, computer-based driving task. Narcoleptics' mean MSLT sleep latency increased from 4.3 minutes on placebo to 9.3 minutes on high dose, compared with an increase from 10.4 to 17.1 minutes for controls. Narcoleptics' error rate on the driving task decreased from 2.53% on placebo to 0.33% on high dose, compared with a decrease from 0.22% to 0.16% for controls. The effects of methamphetamine on nocturnal sleep were generally dose-dependent and affected sleep continuity and rapid eye movement (REM) sleep. Elimination half life was estimated to be between 15.9 and 22.0 hours. Mild side effects emerged in a dose-dependent fashion and most often involved the central nervous system and gastrointestinal tract. We concluded that methamphetamine caused a dose-dependent decrease in daytime sleep tendency and improvement in performance in both narcoleptics and controls. Methamphetamine at doses of 40-60 mg allowed narcoleptics to function at levels comparable to those of unmedicated controls. KeywordsNarcolepsy; CNS stimulants; Methamphetamine; MSLT; Polysomnography; Driving task Narcolepsy is a neurological disorder affecting some 250,000-350,000 individuals in the United States, a prevalence rate similar to that for multiple sclerosis (1-4). Narcolepsy is thought to stem from genetic or early developmental abnormalities in catecholamine regulation within the brain (5,6). The disorder is characterized by a pentad of symptoms: daytime somnolence, cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep (7,8). The etiology of daytime somnolence in narcolepsy is poorly understood, but seems to stem from dysregulation of the sleep/wake cycle, rather than from an excessive need for sleep (9,10). Hypnagogic hallucinations, sleep paralysis and cataplexy are manifestations of an underlying dysfunction in the control and organization of rapid eye movement (REM) sleep (7). Pathological somnolence is by far the most disabling and potentially dangerous symptom of narcolepsy. Pathological somnolence, whether from narcolepsy or from other causes such Note: This article was planned for the April issue, which included artic...

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“…In many of these diseases, the role of a specific HLA DR and DQ heterodimer is well documented in disease predisposition. A similar autoimmune mechanism was thus suggested for narcolepsy (Parkes et al 1986), but all attempts have failed to substantiate this hypothesis (Rubin et al 1988;Carlander et al 1993;Mignot et al 1995a). As a general rule, HLA class II-associated autoimmune diseases show a female preponderance, but no sex difference is observed in narcolepsy (Bassetti and Aldrich 1996).…”

Section: Is Narcolepsy An Autoimmune Disorder?mentioning

confidence: 93%

“…Lymphocyte subpopulations, erythrocyte sedimentation ratio, complement levels, and C-reactive protein are all within the normal range even in very early stages of the disease (Matsuki et al 1988b). Rheumatoid factor, anti-nuclear antibodies, and all other attempts at demonstrating systemic autoimmune abnormalities have shown negative results (Rubin et al 1988). Similarly, cerebrospinal fluid analysis also did not show increased frequency of oligoclonal IgG bands (Fredrikson et al 1990).…”

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confidence: 92%

Genetic Studies in the Sleep Disorder Narcolepsy

Kadotani¹,

Faraco²,

Mignot³

1998

Genome Res.

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Narcolepsy is a chronic neurologic disorder characterized by excessive daytime sleepiness and abnormal manifestations of REM sleep including cataplexy, sleep paralysis, and hypnagogic hallucinations. Narcolepsy is both a significant medical problem and a unique disease model for the study of sleep. Research in human narcolepsy has led to the identification of specific HLA alleles (DQB1*0602 and DQA1*0102) that predispose to the disorder. This has suggested the possibility that narcolepsy may be an autoimmune disorder, a hypothesis that has not been confirmed to date. Genetic factors other than HLA are also likely to be involved. In a canine model of narcolepsy, the disorder is transmitted as a non-MHC single autosomal recessive trait with full penetrance (canarc-1). A tightly linked marker for canarc-1 has been identified, and positional cloning studies are under way to isolate canarc-1 from a newly developed canine genomic BAC library. The molecular cloning of this gene may lead to a better understanding of sleep mechanisms, as has been the case for circadian rhythms following the cloning of frq, per, and Clock.Sleep consumes almost one-third of any human lifetime, yet its biological function remains unknown. Electrophysiological studies have shown that sleep is physiologically heterogeneous. Sleep onset is first characterized by light nonrapid eye movement (NREM) sleep (stage I and II), followed by deep NREM sleep or slow-wave sleep (stage III and IV) and finally rapid eye movement (REM) sleep. This sleep cycle is ∼90 min long and is repeated multiple times during nocturnal sleep. REM sleep, also called paradoxical sleep, is characterized by low-voltage fast electroencephalogram activity, increased brain metabolism, skeletal muscle atonia, rapid eye movements, and dreaming. Total sleep deprivation and/ or REM sleep deprivation are both lethal in animals.NREM and REM sleep are mainly regulated by circadian and homeostatic processes. Recent studies have suggested that across the animal kingdom, circadian rhythms are regulated by similar negative feedback loops involving the rhythmic expression of RNAs encoding proteins that act to shut off the genes encoding them (Hall 1995;Dunlap 1996;Rosbash et al. 1996;Young et al. 1996). From a genetic perspective, much less progress has been made in the noncircadian aspects of sleep regulation. This review demonstrates that a genetic approach to narcolepsy will in time provide a novel insight into the molecular basis of sleep control. Narcolepsy, a Disorder of REM Sleep RegulationNarcolepsy most often begins in the second decade of life but may be observed at the age of 5 or younger (Honda 1988). The cardinal symptom in narcolepsy is a persistent and disabling excessive daytime sleepiness. Sleep attacks are unpredictable, irresistible, and may lead to continuing activities in a semiconscious manner, a phenomenon referred to as automatic behavior. Naps are usually refreshing, but the restorative effect vanishes quickly.Sleepiness is not sufficient to diagnose the disorder. N...

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HLA-DR2 association with excessive somnolence in narcolepsy does not generalize to sleep apnea and is not accompanied by systemic autoimmune abnormalities

Cited by 43 publications

References 29 publications

Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome

Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome

Treatment of Narcolepsy with Methamphetamine

Genetic Studies in the Sleep Disorder Narcolepsy

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