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

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.

Granzyme B in peripheral blood mononuclear cells as a measure of cell-mediated immune response in paraneoplastic neurological syndromes and malignancy

“…In contrast, patients with low GrB-PBMC and no onconeural antibodies could be PNS that developed in an alternative nonimmune process. That is in line with some previous studies that failed to detect signs of the immune response in nervous tissue in some patients or animal models with PNS [38][39][40]. It is unlikely that the distinction between these subgroups comes from heterogeneity in clinical presentation since we observed no difference between PNS affecting the peripheral and central nervous system (Fig.…”

Role of Serum IL‐6 in Neuropsychiatric Systemic lupus Erythematosus

“…In fact, the correlation of serum IL‐6 and Q albumin was relatively low, although it was statistically significant. Therefore, it would be ideal to examine a variety of cytokines in sera, such as tumor necrosis factor‐α and vascular endothelial growth factor (32).…”

Targeted Temperature Management Suppresses Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Expression in a Pig Model of Cardiac Arrest

“…The NSE protein is mainly present in neuronal and peripheral neuroendocrine cells [ 45 ]; however, it is also found in small quantities in serum and cerebrospinal fluid. In the event of neuronal damage and BBB disruption, neuronal cells and the BBB become leaky, leading to an increase in NSE serum levels in the blood [ 46 , 47 ]. Serum NSE protein is a biomarker of brain injury after CA and CPR [ 46 ], and increased serum levels of NSE have been demonstrated as a useful tool for predicting neurological outcomes in survivors of CA patients treated with hypothermia [ 48 ].…”