Circadian rhythms are characterized by the physiology's adaptation to the alternation of day and night, enabling to adapt to the environment. These rhythms are generated by a molecular clock within each cell. At the molecular level, the circadian clock is based on a complex system of cell-autonomous transcription loops. These exert positive and negative feedback on themselves, generating cyclic transcriptional activity. * In the main loop, the BMAL1 transcription factor links with CLOCK or NPAS2 ( (Neuronal PAS Domain Protein 2) to activate transcription of per1,2 and 3 and cryptochrome (cry1 and cry2), which in turn repress BMAL1/CLOCK1 transcriptional activity.. The BMAL1/CLOCK complex also activates transcription of numerous target genes (per and cry, Rev-erb, etc.).. * other secondary loops refine the function of the first. Recent studies suggest that many aspects of innate immunity are controlled by circadian rhythm through inhibition of NLRP3 inflammasome activation. Nevertheless, the regulation of the NLRP3 inflammasome by the circadian clock has yet to be elucidated. Inflammasomes are molecular platforms that control caspase-1 activation and consequently the maturation of precursors of (interleukine) IL-1β, pro-IL-18, a pro-inflammatory cytokine. Since its discovery, its functions have been widely characterized as part of the innate immune response as a sensor of pathogens and danger signals (extracellular ATP (Adenosine triphosphate), atmospheric pollutants). NLRP3 (nucleotide-binding domain LRR (leucin-rich repeat ) and pyrin-containing receptor 3) has been described for its genetic association with dominant monogenic hereditary syndromes characterized by recurrent systemic inflammatory episodes in the absence of any infection or autoimmune disease, known as CAPS (cryopyrin-associated periodic syndrome) or cryopyrinopathies which is a continuum of diseases ranging from a moderate to the most severe form of the syndrome: familial cold urticaria syndrome, Muckle-Wells syndrome (MWS), and CINCA/NOMID syndrome. Interestingly, patients with Muckle-Wells syndrome show a circadian pattern of symptoms, with a recurrent, predominantly vesperal fever peak lasting a few hours, and extreme fatigue on a daily basis. However, a molecular link between the circadian clock and CAPS pathology remains to be determined. The aim of this protocol is to identify circadian rhythm dysregulation in patients with CAPS confirmed by genetic analysis of NLRP3, to demonstrate a link between circadian clock and CAPS syndrome, and to identify circadian clock regulatory pathways.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
30
Blood test for genetic analysis of NLRP3
Wear a Withings Pulse HR (heart rate) actigraphic watch 24 hours a day for 1 month to define circadian rhythm
Saliva sampling for salivary melatonin determination
Questionnaire to determine chronotype
Disease activity score using AIDAI score (only for patients in the CAPS group) AIDAI : AUTO-INFLAMMATORY DISEASE ACTIVITY INDEX
1. Inflammatory cytokines measurement : IL1-beta (Interleukin-1) and IL-18. 2. Molecular characterization of circadian clock signaling pathways
Hôpital Femme-Mère-Enfant (HCL)
Bron, France
Hôpital Claude Huriez (CHU de Lille)
Lille, France
Hôpital de la Croix-Rousse (HCL)
Lyon, France
Hôpital Edouard Herriot (HCL)
Lyon, France
Hôpital Tenon (AP-HP)
Paris, France
Hôpital Kremlin-Bicêtre (AP-HP)
Paris, France
Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3,
Concentration of the peak secretion of melatonin in both arms
Time frame: 6 months after inclusion
Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3,
Concentration of the peak secretion of melatonin in both arms
Time frame: 12 months after inclusion
Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3,
time of the peak secretion of melatonin in both arms
Time frame: 6 months after inclusion
Description of circadian rhythm deregulation in patients with cryopyrinopathy (CAPS) whose diagnosis was confirmed by genetic analysis of NLRP3,
time of the peak secretion of melatonin in both arms
Time frame: 12 months after inclusion
Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.
Determination of circadian rhythms : amplitude in both arms
Time frame: 6 th month
Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.
Determination of circadian rhythms : period in both arms
Time frame: 6 th month
Difference in circadian clock biomarkers between patients and control participants for Circadian Rhythm Characteristics.
Determination of circadian rhythms : phase in both arms
Time frame: 6 th month
Chronotype determination
Number of patients in each chronotype for the 2 arms based on the specific questionnaire in both arm
Time frame: 6 th month
sleep duration
sleep duration in both arms
Time frame: 6 th month
number of steps
Daily activity in both arms
Time frame: 6 th month
Comparison of inflammatory state
basal levels of IL1β in patient monocytes in both arms
Time frame: 6 months after inclusion
Comparison of inflammatory state
basal levels of IL1β in patient monocytes in both arms
Time frame: 12 months after inclusion
Comparison of inflammatory state
basal levels of IL18 in patient monocytes in both arms
Time frame: 6 months after inclusion
Comparison of inflammatory state
basal levels of IL18 in patient monocytes in both arms
Time frame: 12 months after inclusion
Disease activity measurement
Number of patient with active disease ie AIDAI (AUTO-INFLAMMATORY DISEASE ACTIVITY INDEX) score \>9 in CAPS patient arm
Time frame: 6 months after inclusion
Disease activity measurement
Number of patient with active disease ie AIDAI (AUTO-INFLAMMATORY DISEASE ACTIVITY INDEX) score \>9 in CAPS patient arm
Time frame: 12 months after inclusion
presence or absence of an abnormality in the NLRP3 signalling pathway in CAPS arm compared control arm
Biochemical characterization of the NLRP3 inflammasome protein regulatory pathway in both arms
Time frame: 6 months after inclusion
presence or absence of an abnormality in the NLRP3 signalling pathway in CAPS arm compared to control arm
Biochemical characterization of the NLRP3 inflammasome protein regulatory pathway in both arms
Time frame: 12 months after inclusion
presence or absence of ASC inflammasome protein regulatory pathway in CAPs arm compared to control arm
Biochemical characterization of the ASC inflammasome protein regulatory pathway in both arms
Time frame: 6 months after inclusion
presence or absence of ASC inflammasome protein regulatory pathway in CAPS arm compared to control arm
Biochemical characterization of the ASC inflammasome protein regulatory pathway in both arms
Time frame: 12 months after inclusion
presence or absence of the CASPASE-1 inflammasome protein regulatory pathway in CAPS arm compared to control arm
Biochemical characterization of the CASPASE-1 inflammasome protein regulatory pathway in both arms
Time frame: 6 months after inclusion
presence or absence of the CASPASE-1 inflammasome protein regulatory pathway in CAPS arm compared to control arm
Biochemical characterization of the CASPASE-1 inflammasome protein regulatory pathway in both arms
Time frame: 12 months after inclusion
presence or absence of REV-ERBα inflammasome protein regulatory pathway in CAPS arm compared to control arm
Biochemical characterization of the REV-ERBα inflammasome protein regulatory pathway in both arms
Time frame: 6 months after inclusion
presence or absence of REV-ERBα inflammasome protein regulatory pathway in CAPS arm compared to control arm
Biochemical characterization of the REV-ERBα inflammasome protein regulatory pathway in both arms
Time frame: 12 months after inclusion
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