Narcolepsy with Cataplexy: An Autoimmune Phenomenon

Transcription

1 Fall 2014 Meeting October 3-4, 2014 Narcolepsy with Cataplexy: An Autoimmune Phenomenon Soumya C. Madala MD Mercy Health Sleep Center Grand Rapids, MI

2 Conflict of Interest Disclosures for Speakers 1. I do not have any relationships with any entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients, OR 2. I have the following relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients: Type of Potential Conflict Details of Potential Conflict Grant/Research Support Consultant Speakers Bureaus Financial support Other The material presented in this lecture has no relationship with any of these potential conflicts, OR 4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture:

3 ICSD 3 Diagnostic Criteria Narcolepsy Type 1 A.) Excessive daytime sleepiness present daily for over 3 months B.) Presence of one or both of the following: 1.) Cataplexy; mean sleep latency under 8 minutes on MSLT; 2 or more SOREMP s on MSLT; SOREMP on preceding night PSG may replace one of the SOREMP s on MSLT. 2.) CSF Hypocretin-1 concentration, measured by immunoreactivity is </= 110 pg/ml or <1/3 rd of mean values obtained in normal subjects American Academy of Sleep medicine. International Classification of Sleep Disorders. 3 rd ed. Darien, IL: American Academy of Sleep medicine;

4 Cataplexy Sudden episodes of striated muscle weakness with preserved consciousness, absent tendon reflexes Last up to 30 seconds Correlates strongly with loss of Hypocretin-1 Clinical predictor for HLA-DQBI*06:02 Onset of cataplexy at the same time as EDS or more than 15 years later In 20% cataplexy resolves spontaneously long term Partinen M, et. al Lancet Neurol 2014; 12:

5 ICSD 3 Diagnostic Criteria Narcolepsy Type 2 Criteria A E need to be met. A.) Excessive daytime sleepiness present daily for over 3 months B.) Mean sleep latency </= 8 minutes, 2 or more SOREMP s on MSLT. SOREMP on preceding night PSG can replace one SOREMP on MSLT. C.) Cataplexy is absent D.) CSF Hypocretin-1 is not obtained or CSF Hypocretin-1 is >110 pg/ml or >1/3 rd of mean values obtained from a normal subject E.) Hypersomnolence and MSLT findings are not explained by other causes (insufficient sleep, OSA, DSPS, effect of medications or substances or effect of their withdrawal.) American Academy of Sleep medicine. International Classification of Sleep Disorders. 3 rd ed. Darien, IL: American Academy of Sleep medicine;

6 History of Narcolepsy Research and Therapy 1877: First description in medical literature by Westphal and Gelineau 1880: Gelineau called the disorder narcolepsy 1902: Loewenfeld coined narcolepsy 1935: First use of amphetamines in the treatment 1960: SOREMP s were described in narcoleptics 1973: First report of canine Narcolepsy 1977: MSLT described 1983: Association of Narcolepsy with HLA-DR2 1985: Monoaminergic and cholinergic imbalance described in narcolepsy 1992: Association of HLA-DQB1*06: : Identification of hypocretin/orexin system and their receptors 1999: Hypocretin mutations caused narcolepsy in mice and dogs 2000: Human narcolepsy was associated with low CSF Hypocretin levels and loss of Hypocretin cells 2001: HLA effects additional to DQBI*06:02 in narcolepsy 2009: Genome wide association studies identify T-cell receptor as additional susceptibility loci 2010: Association of narcolepsy onset with the 2009 H1NI infections and vaccinations 2010: Allele competition explains the protective effects of some DQ1 haplotypes from narcolepsy 2013: Identification of hypocretin-autoreactive CD4 T cells 2013: Molecular mimicry between H1N1 and hypocretin autoantigen Mignot E. History of narcolepsy at Stanford University. Immunol Res (2014) 58:

7 Autoimmune Disorder Predisposition Precipitating Factors Narcolepsy Manifestation 7

8 Predisposition - HLA Human Leukocyte Antigen (HLA) genes are present on Chromosome 6 HLA genes encode Major Histocompatibilty Complex (MHC) Class 1 and Class 2 proteins MHC proteins present foreign peptides to T-cells to trigger an immune response by T-Cell Receptor activation 8

9 Predisposition - HLA HLA-DQB1*06:02 allele associated with narcolepsy in all ethnicities 98% of patients - Narcolepsy with Cataplexy & low CSF Hypocretin -identifies susceptibility for the disease -Cataplexy is therefore a positive predictor for positivity 40-60% of patient Narcolepsy without Cataplexy 12-38% of general population carries this allele Highest risk for narcolepsy: Homozygotes 2 to 3 times higher risk Heterozygous for HLA-DQB1*06:02; DQA1*01:02 9

10 Homozygous Heterozygous Normal Relative Risk 2 Relative Risk 1 Relative Risk 0.5 Mignot E. History of narcolepsy at Stanford University. Immunol Res (2014) 58:

11 Predisposition Pre-prohypocretin found to have high affinity to DQBI*0602 binding sites on MHC CD 4 T-cells react to 2 peptide molecules of the Preprohypocretin which once cleaved corresponds to Hypocretin 1 Hypocretin 2 HCRT56-68 HCRT /24/

12 APC MHC HCRT peptides TCR T-Cell Mignot E. History of narcolepsy at Stanford University. Immunol Res (2014) 58:

13 Predisposition - TCR T Cell receptor (TCR) comprised of an alpha and beta gene TCR expressed on the surface of T cells recognizes antigens bound to the MHC molecules on the Antigen Presenting Cells (APC s) Polymorphism in the TCR alpha gene has been identified in patients with Narcolepsy Polymorphism causes cross reactivity to the Hypocretin peptide leading to the autoimmune process. 13

14 Predisposition - Others Purinergic receptor subtype 2Y11 gene ATP receptor which regulates cell death, leukocyte maturation and chemotaxis Polymorphism Decreased expression of this gene can lead to reduced resistance to ATP mediated cell death Cathepsin H Lysosomal enzyme present in Antigen presenting cells Polymorphism has been identified in patients with Narcolepsy Tumor Necrosis Factor Superfamily member 4 (TNFSF4) Costimulator to promote T-cell survival Polymorphism can skew the immune response to infection DNMT 1 gene mutation DNA Methyltransferase expressed by the immune system Late onset after age 40, Narcolepsy, Cerebellar Ataxia, Deafness 14

15 Precipitating Factors - Upper Airway Infections Spanish Flu 1918; H1NI seasonal epidemic Encephalitis lethargica Sleepiness, ophthalmoplegia, residual Parkinson s Streptococcus Pyogenes ASO (anti streptolysin O) and Anti DNAse B (ADB) antibody titers elevated within 1 to 3 years of onset of Narcolepsy ASO and ADB levels drop over the course of the disease Children who developed Narcolepsy had 5 times more frequency of Streptococcal infections compared to their counterparts Narcolepsy diagnosis highest in spring versus winter months Likely triggered by the winter upper airway infections 15

16 ASO Titers and Narcolepsy Presentation High ASO titers in close association with clinical onset of Narcolepsy symptoms. Aran A; Nevsimalova S; Plazzi G; Hong SC; Weiner K; Zeitser J; Mignot E. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. SLEEP 2009;32(8):

17 Seasonality of Presentation Mignot E. History of narcolepsy at Stanford University. Immunol Res (2014) 58:

18 Precipitating Factors - Infections H1NI Influenza Pandemic Swine flu strain identified in spring 2009 Swine flu symptoms in winter 2009 Spring-Summer 2010: 6 fold increase in Narcolepsy cases noted in China Peak presentation occurred 4-6 months following the peak of H1N1 infection H1N1 vaccination rate was low in China suggesting an infectious trigger Narcolepsy cases dropped to pre-pandemic baseline in subsequent years 18

19 Yearly Trend of diagnosis in China Mignot E. History of narcolepsy at Stanford University. Immunol Res (2014) 58:

20 Precipitating Factors - Vaccination Pandemrix Manufactured by Dresden/Glaxosmithkline Used in Finland, Sweden, Norway, England, Ireland and France AS03 adjuvant high potency to stimulate CD4 T-Cell response vaccine efficacy was high; one injection sufficient 1:16,000 vaccinated children developed Narcolepsy (Vaccine Attributable Risk) Children and adolescents: 4-13 fold risk of Narcolepsy Adults: 2-4 fold risk following the vaccine; symptoms less severe 20

21 Narcolepsy risk: Unvaccinated vs. Vaccinated Nohynek H, Jokinen J, Partinen M, Vaarala O, et al. (2012) AS03 Adjuvanted AH1N1 Vaccine Associated with an Abrupt Increase in the Incidence of Childhood Narcolepsy in Finland. PLoS ONE 7(3): e doi: /journal.pone

22 Cases in Finland: Childhood Incidence Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, Hublin C, et al. (2012) Increased Incidence and Clinical Picture of Childhood Narcolepsy following the 2009 H1N1 Pandemic Vaccination Campaign in Finland. PLoS ONE 7(3): e doi: /journal.pone

23 Cases in Finland: Childhood Incidence Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, Hublin C, et al. (2012) Increased Incidence and Clinical Picture of Childhood Narcolepsy following the 2009 H1N1 Pandemic Vaccination Campaign in Finland. PLoS ONE 7(3): e doi: /journal.pone

24 Cases in Finland: Adult Presentation Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, Hublin C, et al. (2012) Increased Incidence and Clinical Picture of Childhood Narcolepsy following the 2009 H1N1 Pandemic Vaccination Campaign in Finland. PLoS ONE 7(3): e doi: /journal.pone

25 Precipitating Factors - Vaccination Arepandrix Produced by Glaxosmithkline Use in Quebec, Canada MF59 adjuvant fold risk of Narcolepsy 25

26 Role of precipitating factors Narcolepsy Adjuvants are used to trigger a stronger immune response Reactivate the narcolepsy autoimmune response Bystander Mechanism 26

27 Role of precipitating factors Narcolepsy 1.) Cross reactivity of adjuvants or H1N1 vaccine or 2.) Cross reactivity of H1N1 antigen from the flu virus With Hypocretin peptide sites (autoantigen) on the HLA-DQBI*0602 Presented to the autoantigen sensitized CD4 T-cells Molecular Mimicry 27

28 Molecular Mimicry Mahlios J, De la Herran-Arita A, Mignot E. The autoimmune basis of narcolepsy. Current Opinion in Neurobiology 2013, 23:

29 Narcolepsy Manifestation Mignot, E. History of narcolepsy at Stanford University. Immunol Res (2014) 58:

30 Conclusion Genetic predisposition triggered by environmental factors culminates in an autoimmune attack of the Hypocretin neurons Loss of Hypocretin cells results in Type 1 Narcolepsy ICSD 3 incorporated CSF- Hypocretin measurement as a diagnostic criteria for Type 1 Narcolepsy 30

31 References American Academy of Sleep medicine. International Classification of Sleep Disorders. 3 rd ed. Darien, IL: American Academy of Sleep medicine; Mignot, E. History of narcolepsy at Stanford University. Immunol Res 2014, 58: Mahlios J, De la Herran-Arita A, Mignot E. The autoimmune basis of narcolepsy. Current Opinion in Neurobiology 2013, 23: Partinen A, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol 2014, 13: Singh AK, Mahlios J, Mignot E. Genetic association, seasonal infections and autoimmune basis of narcolepsy. J Autoimmun. 2013, 43: Kornum BR, Faraco J, Mignot E. Narcolepsy with hypocretin/orexin deficiency, infections and autoimmunity of the brain. Current Opinion in Neurobiology 2011, 21: Aran A; Nevsimalova S; Plazzi G; Hong SC; Weiner K; Zeitser J; Mignot E. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. SLEEP 2009,32(8): Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, Hublin C, et al. (2012) Increased Incidence and Clinical Picture of Childhood Narcolepsy following the 2009 H1N1 Pandemic Vaccination Campaign in Finland. PLoS ONE 7(3): e doi: /journal.pone Nohynek H, Jokinen J, Partinen M, Vaarala O, et al. (2012) AS03 Adjuvanted AH1N1 Vaccine Associated with an Abrupt Increase in the Incidence of Childhood Narcolepsy in Finland. PLoS ONE 7(3): e doi: /journal.pone