The Role of Cytokines and Regulatory T Lymphocytes in Migraine Pathophysiology.
- Conditions
- EndometriosisMigraine DisordersPainAutoimmune DiseasesLupus ErythematosusRheumatoid ArthritisCrohn DiseaseMultiple Sclerosis
- Interventions
- Biological: Blood test
- Registration Number
- NCT06426316
- Lead Sponsor
- University Hospital, Clermont-Ferrand
- Brief Summary
Migraine is a frequent and debilitating neurologic disorder. It is more frequent in women, and more prevalent in patients with autoimmune and/or inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), Crohn's disease (CD), systemic lupus erythematosus (SLE) and endometriosis, whereas patients with long standing type 1 diabetes mellitus (T1DM) - an autoimmune but non inflammatory disease - seem to be less affected compared to the general population. Despite new migraine prevention treatments, a large number of patients remain unresponsive to currently available anti-migraine therapy and migraine pathophysiology remains unclear. Several peptides (calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase activating peptide-38 (PACAP-38), vasoactive intestinal polypeptide (VIP)) and hormones (estrogens, prolactin) and the immune system play an important role in migraine pathophysiology. Among T lymphocytes, regulatory T (Treg) cells suppress inflammation. Studies have evidenced higher levels of inflammatory molecules (cytokines) in migraine patients and have suggested decreased proportions of Treg cells in migraine, as well as in MS, RA, CD and SLE, whereas inflammation declines and Treg levels seem increased in long-standing T1DM. Inflammation, which participates in migraine pain, seems to be a common factor for migraine and these diseases. However, these studies display conflicting results and further investigation is required to better understand the mechanisms behind migraine.
In this study, the investigators will compare Treg levels, as well as identify Treg subpopulations and measure cytokine levels in migraine and migraine-free participants with and without an autoimmune/inflammatory disorder (MS, RA, CD, SLE, T1DM and endometriosis).
- Detailed Description
Migraine is the 6th most frequent disease (14% of the population) and the second leading cause of disability worldwide. From puberty and onward, migraine is 2 to 3 times more frequent in women, which also suffer from more severe attacks. Migraine is also up to twice as prevalent in patients suffering from autoimmune or inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), Crohn disease (CD), systemic lupus erythematosus (SLE) and endometriosis, whereas patients with long standing type 1 diabetes mellitus (T1DM) - an autoimmune but non inflammatory disease - seem to be less affected compared to the general population.
Despite the identification of the role of peptides such as CGRP in migraine pathophysiology and the development of targetted anti-CGRP treatments, many patients remain unresponsive and the mechanisms behind migraine are still unclear.
The trigemino-vascular system is involved in the perception of migraine pain. Migraine occurs with trigemino-cervical neuron sensitization, leading to peptide secretion (such as CGRP, PACAP-38 and VIP), which induce neurogenic inflammation that is responsible for vasodilation, capillary leakage, oedema and further sensitization of the trigemino-vascular system, leading to amplified perception of migraine pain. CGRP, PACAP-38 and VIP infusions all induce migraine attacks in migraine patients, and only mild or no headache in healthy volunteers.
Sex hormones, prolactin and insulin are also involved in migraine pathophysiology, and the immune system, through cytokine production and immune cell dysregulations seems to also play a role in the pathogenesis of migraine. Both are closely related as sex hormone levels may have an influence on the levels of certain immune cell subtypes. Several pro-inflammatory cytokines (tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and interleukin (IL)-6) were shown to be elevated in migraine patients but also inflammatory diseases such as MS and endometriosis compared to controls and are associated with migraine pathophysiology. Inflammation seems to be a common factor for migraine and these diseases. However, these studies provide conflicting results and further investigation is needed to better understand the role of inflammation in migraine pathophysiology.
Among T lymphocytes, regulatory T (Treg) cells regulate inflammation by suppressing effector T cells through several suppressive mechanisms such as IL-10 secretion or the hydrolysis of pro-inflammatory and nociceptive adenosine triphosphate (ATP) into anti-inflammatory and anti-nociceptive adenosine by cluster of differentiation (CD) 39 and 73 enzymes on the Treg cell surface. Recent studies have suggested decreased Treg proportions in migraine patients, particularly CD 39 and CD 73-positive Treg cells, whereas Treg cells were shown to be increased in T1DM patients. This suggests the role of Treg cells in migraine, but further studies are needed.
In this study, the investigators aim to compare Treg levels, as well as identify Treg subpopulations and measure cytokine levels in migraine and migraine-free participants with and without an autoimmune/inflammatory disorder (MS, RA, CD, SLE, T1DM and endometriosis). This will provide better understanding of migraine pathophysiology and lead to the development of targeted and personalized treatment strategies, according to the immune pain profile and associated inflammatory diseases of migraine patients.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- Female
- Target Recruitment
- 396
- female
- 18 - 50 years of age
- at least 50 kg
- menopause
- type 2 diabetes
- pregnancy (or delivery < 3 months)
- breast feeding
- hysterectomy or adnexectomy
- characterized immune deficiency
- active cancer (or remission < 1 year)
- bone marrow or solid organ transplant
- hormone therapy (other than birth control)
- migraine attack within 12 hours before or after blood test
- person under guardianship
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description No migraine - autoimmune/inflammatory disease (MS, RA, CD, SLE, T1DM, endometriosis) Blood test No migraine - autoimmune/inflammatory disease (MS, RA, CD, SLE, T1DM, endometriosis) group No migraine - no autoimmune/inflammatory disease Blood test No migraine - no autoimmune/inflammatory disease group Migraine - autoimmune/inflammatory disease (MS, RA, CD, SLE, T1DM, endometriosis) Blood test Migraine - autoimmune/inflammatory disease (MS, RA, CD, SLE, T1DM, endometriosis) group Migraine - no autoimmune/inflammatory disease Blood test Migraine - no autoimmune/inflammatory disease group
- Primary Outcome Measures
Name Time Method Date of last menstrual period as a date in the form: day/month/year Once, at inclusion Date of last menstrual period start day to measure the impact of the menstrual cycle on Treg levels
Treg cell levels in cell/microliter (cell/µL) Once, at inclusion To measure Treg cell levels in migraine and migraine-free participants, with and without autoimmune/inflammatory diseases (MS, RA, CD, SLE, endometriosis, T1DM) using flow cytometry
Number of headache days per month in days/month Once, at inclusion Number of days with a headache to determine whether migraine is episodic or chronic (average during last 3 months)
Treg cell levels in percentage (%) of white blood cells Once, at inclusion To measure Treg cell levels in migraine and migraine-free participants, with and without autoimmune/inflammatory diseases (MS, RA, CD, SLE, endometriosis, T1DM) using flow cytometry
Score on the Hospital Anxiety and Depression Scale Once, at inclusion Score to be answered at inclusion to determine anxiety and depression levels : ranges from 0 to 21 for each (anxiety and depression). A score of 11 and above ascertains anxiety or depression. Licence n° 2403391 with Mapi Research Trust.
White blood cell count in giga/liter (G/L) Once, at inclusion To measure the absolute white blood cell count to determine the percentage of Treg cells
Weight in kilograms (kg) Once, at inclusion Weight on scales during inclusion visit
Migraine diagnostic criteria from the International Classification of Headache Disorders 3rd edition (ICHD-3) Once, at inclusion To be completed at inclusion to confirm migraine diagnosis. No licence needed
Human chorionic gonadotropin subunit beta level in milli-international units per milliliter (mIU/mL) Once, at inclusion To insure exclusion of pregnant women
Body mass index (BMI) in kilogram per square meter (kg/m2) Once, at inclusion Weight in kilograms and height in meters will be combined to determine the body mass index in kilogram per square meter
Age in years Once, at inclusion Age at inclusion
Score on the Headache Impact Test Once, at inclusion Score to be answered at inclusion to determine the impact of headache on patients' daily life, ranging from 36 to 78. The higher the score, the higher the impact of headache on daily life. Licence to be signed shortly with QualityMetrics
Sex (female, male) Once, at inclusion For sex repartition
Height in meters (m) Once, at inclusion Measured at inclusion
- Secondary Outcome Measures
Name Time Method Cytokine levels in picogram per milliliter (pg/mL) Once, at inclusion To measure cytokine levels (interleukin 1b, interleukin 2, interleukin 6, interleukin 10, interleukin 12, interleukin 17, interleukin 18, interleukin 21, interleukin 23, interleukin 35, tumor necrosis factor a, interferon g and transforming growth factor b) using a LUMINEX method
Pituitary adenylate cyclase-activating polypeptide (PACAP) levels in nanogram per milliliter (ng/mL) Once, at inclusion To study association between PACAP levels and migraine
Progesterone in nanogram per milliliter (ng/mL) Once, at inclusion To determine correlation with Treg cell levels
Luteinizing hormone in international units per liter (IU/L) Once, at inclusion To determine the correlation between the menstrual cycle period and Treg cell levels
Prolactin levels in nanogram per milliliter (ng/mL) Once, at inclusion To determine the correlation between the presence of migraine and prolactin levels
Calcitonin gene-related peptide (CGRP) in picogram per milliliter (pg/mL) Once, at inclusion To study association between CGRP levels and migraine
Estrogen in picogram per milliliter (pg/mL) Once, at inclusion To determine correlation with Treg cell levels
Follicle stimulating hormone (FSH) in milli-international units per milliliter (mIU/mL) Once, at inclusion To determine the correlation between the menstrual cycle period and Treg cell levels
Fasting blood glucose concentration in gram per liter (g/L) Once, at inclusion To determine the correlation between sugar levels and Treg cell levels
Insulin levels in milligram per deciliter (mg/dL) Once, at inclusion To determine the correlation between insulin levels and Treg cell levels
Vasoactive intestinal polypeptide (VIP) in picogram per milliliter (pg/mL) Once, at inclusion To study association between VIP levels and migraine
Levels of C-reactive protein (CRP) in milligram per liter (mg/L) Once, at inclusion To measure the general level of inflammation
Trial Locations
- Locations (1)
CHU de Clermont-Ferrand - Service de Neurologie
🇫🇷Clermont-Ferrand, Aura, France