The associations between serum vascular endothelial growth factor, tumor necrosis factor and interleukin 4 with the markers of blood\u2013brain barrier breakdown in patients with paraneoplastic neurological syndromes

Slawomir Michalak,Wojciech Kozubski,Joanna Rybacka-Mossakowska,Alicja Kalinowska-Lyszczarz,Mikolaj Zaborowski

doi:10.1007/s00702-018-1950-9

Abstract

The blood–brain barrier (BBB) disruption is a critical step in paraneoplastic neurological syndrome (PNS) development. Several cytokines have been implicated in BBB breakdown. However, the exact step-by-step mechanism in which PNS develops is unknown, and the relationship between a systemic neoplasm and BBB is multilevel. The aim of the present study was to examine serum markers of BBB breakdown (S100B protein, neuron-specific enolase, NSE) and concentrations of proinflammatory (TNF-alpha, VEGF) and anti-inflammatory/immunosuppressive cytokines (IL-4), and to establish their interrelationship in patients with PNS. We analyzed 84 patients seropositive for onconeural antibodies that originated from a cohort of 250 cases with suspected PNS. Onconeural antibodies were estimated with indirect immunofluorescence and confirmed with Western blotting. Serum S-100B was estimated using electrochemiluminescence immunoassay. NSE, VEGF, TNF-alpha and IL-4 were analyzed with ELISA. We found that S-100B protein and NSE serum concentrations were elevated in PNS patients without diagnosed malignancy, and S-100B additionally in patients with peripheral nervous system manifestation of PNS. Serum VEGF levels showed several abnormalities, including a decrease in anti-Hu positive patients and increase in PNS patients with typical manifestation and/or central nervous system involvement. Increase in TNF-alpha was observed in patients with undetermined antibodies. To conclude, the presence of paraneoplastic neurological syndrome in seropositive patients does not affect serum markers of BBB breakdown, with the exception of the group without clinically demonstrated malignancy and patients with peripheral manifestation of PNS. S-100B and NSE might increase during early phase of PNS. VEGF may be involved in typical PNS pathophysiology.

Highlights

Paraneoplastic neurological syndromes (PNS) are considered to be immune-mediated pathology resulting from remote effects of systemic malignancy
One of the aspects of PNS development is the disruption of the blood–brain barrier (BBB) that may facilitate autoimmune reaction against previously sequestered central nervous system (CNS) antigens
Autoimmune cells can enter the CNS in the absence of BBB disruption once they have been activated in the periphery, which has been demonstrated for anti-Hu syndrome, BBB disintegrity may contribute to propagation of the neuroinflammatory cascade

Summary

Introduction

Paraneoplastic neurological syndromes (PNS) are considered to be immune-mediated pathology resulting from remote effects of systemic malignancy. One of the aspects of PNS development is the disruption of the blood–brain barrier (BBB) that may facilitate autoimmune reaction against previously sequestered central nervous system (CNS) antigens. Autoimmune cells can enter the CNS in the absence of BBB disruption once they have been activated in the periphery, which has been demonstrated for anti-Hu syndrome (de Jongste et al 2013), BBB disintegrity may contribute to propagation of the neuroinflammatory cascade. Such phenomenon is known for demyelinating autoimmunity in the CNS, namely for multiple sclerosis. Several observations were made, including those of a compromised tight junctions structure, enlargement of perivascular space, fenestrations in blood vessels, increased number and activity of pinocytic vacuoles and decreased expression of transporters like P-glycoprotein (PgP) in the endothelial cells (Bart et al 2000; Liebner et al 2000; Shibata 1989; Regina et al 2001)

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