AUTOIMMUNE RESPONSESTO OREXIN AND ITS RECEPTOR

Kang, Young Jin

Liu, Yi Si

PHM142 Fall 2014Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson

DISCOVERY OF OREXIN

By 2 independent groups with different techniques

- L. de Lecea et al. – via nucleotide sequencing “Clone-35 mRNA” from rat hypothalamus Pre-prohypocretin (pro-hormone) Hypocretin-1 (Hcrt-1) and Hypocretin-2 (Hcrt-2)

- Sakurai et al. – via orphan receptor cloning Also from hypothalamus of rat brain Orexin-A (Orx-A) and Orexin-B (Orx-B)

OREXIN STRUCTURES

Orexin-A Orexin-B

SITE OF OREXIN SYNTHESIS

Orexin-producing neurons (orexin neurons) - Localized exclusively to the 1) perifornical area, 2) lateral

and 3) posterior hypothalamic area in the rat brain - Same for human brain - Projection to entire brain except cerebellum, suggesting

the action takes place in multiple brain areas Many orexin neurons are glutamatergic, presenting vesicular

glutamate transporter

OREXIN RECEPTORS

Types: OX1R and OX2R Mechanism:

a) OX1R

- GPCR exclusively coupled with Gq

- PLC activation followed by IP3/DAG pathway

- Increase intracellular calcium level

b) OX2R

- GPCR coupled with either Gi or Gq

- Inhibitory or intracellular calcium regulation, respectively

Affinity: OX1R is selective for Orexin-A, whereas OX2R is non-selective

OREXIN RECEPTORS CONT’D

Distribution: a) OX1R

- Many in brain region

- e.g. Prefrontal cortex, infra-limbic cortex, Hippocampus, Amygdala, Bed nucleus of the Stria Terminalis (BST), Paraventricular thalamic nucleus, Anterior hypothalamus, Dorsal Raphe (DR), Ventral Tegmental Area (VTA), LC, and Laterodorsal Tegmental nucleus (LDT)/Pedunculopontine nucleus (PPT)

b) OX2R - Showing distinct and complementary distribution

- Only partially overlapping with OX1R

- e.g. Amygdala, BST, Paraventricular thalamic nucleus, DR, VTA, LDT/PPT, Arcuate nucleus (Arc), TMN, Dorsomedial Hypothalamic Nucleus (DMH), Paraventricular nucleus, LHA in the hypothalamus, Cornu ammonis 3 in the hippocampus, and Medial septal nucleus

FUNCTION OF OREXIN

1. Maintains consolidated sleep and wakefulness - Related to Narcolepsy

2. Reward system - Orexin activates dopaminergic neurons - Orexinergic neurons are inhibited by dopamine

3. Regulates feeding behaviour and energy homeostasis - In response to decreased blood glucose level - Increases food intake

4. Thermogenesis from brown fat and lipid metabolism - Related to Obesity

OREXIN FUNCTION – SLEEP/WAKE

AUTOIMMUNE

Lost of immunological tolerance – ability to ignore self

Two possibilities - destruction of orexin producing neurons – decrease overall orexin

level - destruction of the orexin receptor – decrease in response to orexin

Most common form is believed to be autoimmune response to orexin producing neurons (HCRT neurons)

AUTOIMMUNE

Orexin/hypocretin cell destruction will have opposing orexin effect

Most common result in Narcolepsy and brief lost in muscle tone (cataplexy)

Narcolepsy is a neurological disease resulting in: - frequent excessive daytime sleepiness - disturbed nocturnal sleep - sleep paralysis

HLA ASSOCIATION

Molecular aspect of orexin autoimmune is still unclear however,

Narcolepsy is strongly associated with human leukocyte antigen (HLA_ - DQA1*01:02/DQB1*06:02 - (DQ0602).

HLA is a locus of genes that encode for proteins responsible for regulation of immune system in humans

99% Patients affected with narcolepsy have HLA (DQ0602) variant present in their body, suggesting its association with autoimmune disease

Unique to narcolepsy is the genetic association with a polymorphism in the T-cell receptor alpha (TCR) genes – suggesting autoimmunity relevance

MOLECULAR MIMICRY

Infections are increasingly recognized as playing a role in the pathophysiology of autoimmune diseases. In the narcolepsy, two types of upper airway infections have been suggested to have an effect on narcolepsy susceptibility:

influenza A streptococcal infections

Possible reason behind its effect on narcolepsy may be due to molecular mimicry

NEW RESEARCH DISCOVERY!

CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy.

Bridge the gap between narcolepsy, orexin and autoimmunity

December 2013 paper: identified two DQ0602-binding HCRT epitopes, HCRT56-68 and HCRT87-99 activated CD4(+) T cells in narcolepsy patients but not normal individuals

In vitro stimulation of narcolepsy CD4(+) T cells with pH1N1 (H1N1) proteins increased the frequency of HCRT56-68- and HCRT87-99-reactive T cells.

SUMMARY Orexin-A and Orexin-B : Formed from proteolysis of prepro-orexin Synthesis by orexin neurons in perifornical area, lateral and posterior hypothalamus Orexin neurons project to entire brain, except cerebellum OX1R and OX2R : GPCR coupled with Gq and Gq/Gi respectively Functions of orexin: 1) Maintenance of sleep/wake status, 2) Participation to reward

system involving dopaminergic neurons, 3) Regulation of feeding behavior and homeostasis, and 4) Thermogenesis.

Orexin/hypocretin cell destruction will have opposing orexin effect Most common result in Narcolepsy and brief lost in muscle tone (cataplexy) Narcolepsy is a neurological disease resulting in: 1) Frequent excessive daytime

sleepiness, 2) disturbed nocturnal sleep, and 3) sleep paralysis 99% Patients effected with narcolepsy have HLA (DQ0602) variant present in their

body, suggesting its association with autoimmune disease In the narcolepsy, two types of upper airway infections have been suggested to

have an effect on narcolepsy susceptibility: influenza A , streptococcal infections Molecular aspect of orexin autoimmune is still unclear

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