Abstract
Dear sirSince immunological mechanisms are increasingly being considered inside various neurological diseases we read with great interest the paper by Empl and coworkers on T-cell subset variations and integrins expression in migraine (1). Our pioneering and ‘visionary’ neuroimmunological approach to cluster headache and migraine, that dates back more than a decade, tried to bring attention to some physiopathological shaded passages of these debilitating head pain syndromes.
The intriguing paper by Empl et al. contains at least two points which concerned us. The authors’ criticism is mainly focused on a recent paper from our laboratory that demonstrated a sharp decrease on monocyte of the inter-cellular adhesion molecule 1 (ICAM-1) expression and of their soluble isoform (sICAM-1), and of Interleukin-4 (IL-4) serum values in both nitric oxide (NO)-donor and spontaneous migraine (2).
Firstly, if one considers the kinetic of adhesion molecules expression, i.e. the very late antigens (VLAs), we can accept that a specific inflammatory stimulus localized at dura mater level should produce an upregulation of such integrins expression. This fact has been demonstrated in in vitro experimental models and it depends on a continuous stimulus that produces a marked VLAs expression level. The time-limited duration of migraine attacks and the restricted anatomical sites of the sterile inflammation in migraine could represent a situation very far from generating and maintaining within 2 weeks the described molecular events.
The different substrate used in the compared papers, the lymphocytes in Ebel's paper (1) and the monocytes in our paper (2), renders the matching of results as unreliable. However, it should be also stressed that the observation of the ICAM-1 downregulation may be reinforced by a similar downregulation of a very early adhesion molecule such as endothelial leukocyte adhesion molecule 1 (ELAM-1) that has been observed during migraine attack (3).
Moreover, if there is evidence that LFA-1 and ICAM-1 are downregulated on macrophage by astrocyte coculture reducing during inflammation the CNS invasion by activated macrophages/monocytes (4) we can also accept different data on the enhancement of T-cell adhesion to endothelium treated with astrocyte-conditioned medium (5).
Hence the authors' conclusions should be treated as suggestions. Probably they are right, but this was not strictly proven in the light of the conflicting information available on integrative communications between resident immune cells in CNS and those coming from the periphery.
Lastly, the molecular role of nitric oxide (NO) in migraine and its ability to downregulate the adhesion molecules expression should be reconsidered in the light of boosting data that open the debate (6).
However, the co-operation of immunological events in the microenvironment of sterile inflammation of migraine has gained increasing attention. In the future we should consider it in a more integrated picture of migraine.