The Role of Prolactin on B Cell Regulation in Multiple Sclerosis (P02.127)

Abstract

Objective: To evaluate the role of Prolactin in MS pathogenesis. Background Hyperprolactinemia has been associated with different autoimmune diseases in humans. Moreover, increased levels of Prolactin have been found in experimental MS models and administration of prolactin antagonists suppressed disease. Design/Methods: Ninety-two patients with relapsing remitting MS were examined, fifty-eight during remission and 32 during exacerbations. Forty healthy age and gender-matched subjects served as controls. Prolactin, JAK2, Stat1, Stat3, Stat5, BAFF, and Bcl-2 were measured by ELISA. Prolactin receptor and IRF-1 expression were assessed using RT-PCR. Anti-MOG antibodies were measured by ELISPOT. Results: Prolactin levels were higher in MS subjects compared to controls (p= 0.01). However, no differences were found in men, and no association was found between disease activity and Prolactin levels. B and T cells isolated from both MS patients and controls expressed Prolactin receptor, which were upregulated by estrogens. B cells isolated from MS patients demonstrated higher JAK2/Stat pathway activation and IRF-1 expression. Likewise, B cells stimulated in vitro with Prolactin showed increased JAK2 and IRF-1 expression, and Stat protein phosphorylation. Anti-MOG antibodies, BAFF and Bcl-2 levels were significantly higher in MS patients compared to healthy subjects, findings reproduced by culturing CD19+, and CD19+CD5+ B cells in the presence of Prolactin. Moreover, prolactin antagonists blocked these effects, suggesting Prolactin may enhance autoreactive B cells survival. Finally, Prolactin induced CD40 expression on B cells, suggesting it may rescue autoreactive B cells, possibly through recruitment of T cell support. Conclusions: Prolactin can promote B cell autoreactivity in MS through different mechanisms, mediated by the JAK2/Stat pathway. Prolactin influence over the hormonal milieu may have implications on pathogenic immune responses in MS. Disclosure: Dr. Correale has received personal compensation for activities with Merck Serono Argentina, Biogen Idec, Novartis, and from Teva Neuroscience as a speaker. Dr. Farez has nothing to disclose. Dr. Ysrraelit has nothing to disclose.