J Neurol (1993) 240 : 46-50 Journal of Neurology © Springer-Verlag1993 In vivo relationship of interleukin-2 and soluble IL-2 receptor to blood-brain barrier impairment in patients with active multiple sclerosis Mohammad K. Sharief 1, Romain Hentges 2, Maria Ciardi 3, Edward J. Thompson 1 1 Department of Clinical Neurochemistry, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London WCIN 3BG, UK 2Department of Neuro-Psychiatry, Free University of Brussels, Brussels, Belgium 3 Institute of Infectious Diseases, La Sapienza University, Rome, Italy Received March 15, 1991 / Received in revised form June 7, 1991 / Accepted March 17, 1992 Abstract. Interleukin (IL)-2 has well-recognized effects on cerebral endothelial cells and, therefore, may mediate disruption of the blood-brain barrier in patients with multiple sclerosis (MS). To evaluate the in vivo relation- ship of the IL-2 system to blood-brain barrier impair- ment in MS, levels of IL-2 and soluble IL-2 receptors (sIL-2R) in cerebrospinal fluid (CSF) and serum samples from 50 patients with active MS and 49 controls were correlated with values of the CSF to serum albumin ratio. Intrathecal levels of IL-2 and sIL-2R were signifi- cantly higher in MS compared with the control groups and correlated with albumin ratios in MS patients. Intra- thecal levels of IL-2 and sIL-2R also correlated with the degree of barrier damage in these patients. It is suggest- ed that intrathecal levels of IL-2 and sIL-2R are related to barrier impairment in MS and may be important in understanding some of the pathological changes of this condition. Key words: Interleukin-2 - Soluble IL-2 receptor - Blood-brain barrier - Multiple sclerosis - Pathogenesis Introduction Multiple sclerosis (MS) is an inflammatory and de- myelinating disease of the central nervous system that is a major cause of neurological disability in young adults. The disease follows a chronic recurrent course and has several well-established immunological aberrations that involve B-lymphocytes and various subsets of T-lympho- cytes (reviewed by Tourtellotte [39]). There is considerable evidence that alterations of the blood-brain barrier might be important in the patho- genesis of MS [23, 24, 26]. A role of interleukin-2 (IL-2) has also been implicated in the pathogenesis of a number of central nervous system (CNS) diseases, including MS. Correspondence to: M. K. Sharief Evidence for this has emanated from studies on tissues from MS plaques [5, 10, 21] and on serum and cerebro- spinal fluid (CSF) samples from MS patients [1, 2, 16, 25, 40]. Pathological studies have consistently shown that administration of recombinant IL-2 (rIL-2) leads to dis- ruption of the blood-brain barrier [13, 32, 43], a finding that could be relevant in the context of pathophysiologi- cal changes seen in patients with MS. Clinical studies have also shown that administration of rIL-2 to patients with cancer who had no evidence of CNS involvement may result in disruption of the blood-brain barrier [33]. Indeed, there is now convincing evidence that human endothelial cells are directly affected by IL-2, which is based on the fact that human vascular endothelial cells express significant levels of functional IL-2 receptors, both of low and high affinity [20]. As a result, IL-2 may directly modulate human endothelial cell functions both in vitro [19] and in vivo [20]. However, the relationship between IL-2 concentrations and damage to the blood- brain barrier in patients with MS is unknown at present. IL-2 exerts a pleotrophic effect via its specific high affinity receptor [42] which is formed by the association of a 55-kDa a-(Tac antigen) and the 75-kDa 13-chains. Cell proliferation after the binding of IL-2 to its receptor leads to the release of a smaller (45-kDa) form of a- chain, the soluble IL-2 receptor (sIL-2R). To evaluate the in vivo relationship of the IL-2 system to alterations of blood-brain barrier functions in MS, concentrations of IL-2 and sIL-2R were determined in paired CSF and serum samples from 50 patients with active MS and 49 neurological control patients and normal subjects. Val- ues were then correlated with CSF to the serum ratio of albumin which is a reliable indicator of barrier damage [31, 35, 38]. Patients and methods Patients Paired CSF and serum samples were collected from 50 patients (29 females) with clinically definite MS [30]. Their mean age (SD) was