The Role of Cytokines and Regulatory T Lymphocytes in Migraine Pathophysiology.

Official title

Immune System, Inflammation, Migraine - The Role of Cytokines and Regulatory T Lymphocytes in Migraine Pathophysiology

Overview

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.

Interventions

• Biological Blood test
  1 blood test of maximum 40 millilitres per patient

Primary outcome measures

• Treg cell levels in cell/microliter (cell/µL) and percentage (%) of white blood cells [Time frame: Once, at inclusion]

Secondary outcome measures (5)

• Cytokine levels in picogram per milliliter (pg/mL) [Time frame: Once, at inclusion]
• Impact of hormones (progesterone, estrogen, testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), insulin and prolactin) levels on levels of Treg cells [Time frame: Once, at inclusion]
• Impact of hormones (progesterone, estrogen, testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), insulin and prolactin) levels on levels of cytokines [Time frame: Once, at inclusion]
• Impact of neuropeptides (calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP) on Treg cell levels [Time frame: Once, at inclusion]
• Impact of neuropeptides (calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP) on cytokine levels [Time frame: Once, at inclusion]

Eligibility criteria

Inclusion criteria

• female
• 18 - 50 years of age
• at least 50 kg
• autoimmune/inflammatory disease groups : with a diagnosis of multiple sclerosis, systemic lupus erythematous, rheumatoid arthritis, Crohn's disease, type 1 diabetes or endometriosis
• migraine group : with a diagnosis of migraine with at least 4 headache days per month

Exclusion criteria

• BMI < or = 17 ou > or = 30kg/m²
• type 2 diabetes, immune deficit, other chronic autoimmune or inflammatory disease
• non-migraine headache, except for tension type headache of less than 4 days/month
• pregnancy, delivery, miscarriage, breast-feeding, participation in a medically assisted human reproduction program (ovary stimulation/hormone therapy) < 3 months before blood sampling
• Menopause, hysterectomy, or bilateral oophorectomy
• Hormone therapy (besides contraception and treatment of endometriosis)
• bone marrow or solid organ transplant
• guardianship, curatorship, safeguard of justice or deprivation of liberty
• for patients : diagnosis of several autoimmune or inflammatory diseases
• for controls : diagnosis of an autoimmune or inflammatory disease
• for non-migraine participants : migraine

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

France · 1 center

• CHU de Clermont-Ferrand - Service de Neurologie — Clermont-Ferrand

Publications

• Al-Hassany L, Haas J, Piccininni M, Kurth T, Maassen Van Den Brink A, Rohmann JL. Giving Researchers a Headache - Sex and Gender Differences in Migraine. Front Neurol. 2020 Oct 22;11:549038. doi: 10.3389/fneur.2020.549038. eCollection 2020. PMID 33192977
• Stovner LJ, Hagen K, Linde M, Steiner TJ. The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain. 2022 Apr 12;23(1):34. doi: 10.1186/s10194-022-01402-2. PMID 35410119
• Ashina M. Migraine. N Engl J Med. 2020 Nov 5;383(19):1866-1876. doi: 10.1056/NEJMra1915327. No abstract available. PMID 33211930
• Pellesi L, Al-Karagholi MA, De Icco R, Coskun H, Elbahi FA, Lopez-Lopez C, Snellman J, Hannibal J, Amin FM, Ashina M. Effect of Vasoactive Intestinal Polypeptide on Development of Migraine Headaches: A Randomized Clinical Trial. JAMA Netw Open. 2021 Aug 2;4(8):e2118543. doi: 10.1001/jamanetworkopen.2021.18543. PMID 34357396
• Al-Karagholi MA, Kalatharan V, Ghanizada H, Gram C, Dussor G, Ashina M. Prolactin in headache and migraine: A systematic review of clinical studies. Cephalalgia. 2023 Feb;43(2):3331024221136286. doi: 10.1177/03331024221136286. PMID 36718026
• Bhoi SK, Kalita J, Misra UK. Metabolic syndrome and insulin resistance in migraine. J Headache Pain. 2012 Jun;13(4):321-6. doi: 10.1007/s10194-012-0416-y. Epub 2012 Jan 26. PMID 22278639
• Schetters STT, Gomez-Nicola D, Garcia-Vallejo JJ, Van Kooyk Y. Neuroinflammation: Microglia and T Cells Get Ready to Tango. Front Immunol. 2018 Jan 25;8:1905. doi: 10.3389/fimmu.2017.01905. eCollection 2017. PMID 29422891
• Watkins LR, Maier SF. Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov. 2003 Dec;2(12):973-85. doi: 10.1038/nrd1251. No abstract available. PMID 14654796

Identifiers

NCT: NCT06426316 · RBHP 2023 STUCHFIELD · 2023-A01503-42

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗