Immunologic aspects of migraine: A review of literature

Abstract

Migraine headaches are highly prevalent, affecting 15% of the population. However, despite many studies to determine this disease's mechanism and efficient management, its pathophysiology has not been fully elucidated. There are suggested hypotheses about the possible mediating role of mast cells, immunoglobulin E, histamine, and cytokines in this disease. A higher incidence of this disease in allergic and asthma patients, reported by several studies, indicates the possible role of brain mast cells located around the brain vessels in this disease. The mast cells are more specifically within the dura and can affect the trigeminal nerve and cervical or sphenopalatine ganglion, triggering the secretion of substances that cause migraine. Neuropeptides such as calcitonin gene-related peptide (CGRP), neurokinin-A, neurotensin (NT), pituitary adenylate-cyclase-activating peptide (PACAP), and substance P (SP) trigger mast cells, and in response, they secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) as a selective result of corticotropin-releasing hormone (CRH) secretion. This stress hormone contributes to migraine or intensifies it. Blocking these pathways using immunologic agents such as CGRP antibody, anti-CGRP receptor antibody, and interleukin-1 beta (IL-1β)/interleukin 1 receptor type 1 (IL-1R1) axis-related agents may be promising as potential prophylactic migraine treatments. This review is going to summarize the immunological aspects of migraine.

Keywords: headache; immunologic aspects; immunological: autoimmune disease; immunology; migraine.

Figure 1

Neuroinflammation and migraine. Stimulation of the trigeminal neurons causes the release of neuropeptides, including CGRP, substance P (SP), leading to mast cell degranulation, leukocyte infiltration, glial cell activation, and increased production of inflammatory TNF-α, IL-1, and IL-6 cytokines. Besides, satellite glial cells (SGCs) and trigeminal ganglions (TG) express receptors for CGRP, and CGRP can stimulate intracellular signaling molecules that are relevant to pain, such as cAMP, CREB, MAPK, and ERK. Under the influence of inflammation, activated microglia, T cells, and mast cells can boost the inflammation loop and production of cytotoxic mediators in the CNS.

Figure 2

The association between migraine and autoimmune disorders.

Figure 3

The schematic illustration of the association between MS and migraine. Migraine is a forecaster of MS. 5-hydroxytryptamine (5-HT), a compound produced in the body from the tryptophan, is diminished during migraine headaches. 5-HT induces T cell differentiation to Treg cells; therefore, 5-HT deficiency may affect T cell differentiation toward effector T cells. 5-HT deficiencies may also be responsible for increased permeability of the blood–brain barrier (BBB), resulting in the recruitment of more inflammatory immune cells to the CNS.

Figure 4

Migraine is a possible risk factor for RA, SLE, and proteus syndrome (Ps) but not T1DM.