Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action

In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-gamma+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCR alpha beta- microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCR alpha beta- cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage

Plasma fractalkine is a sustained marker of disease severity and outcome in sepsis patients

INTRODUCTION: Fractalkine is a chemokine implicated as a mediator in a variety of inflammatory conditions. Knowledge of fractalkine release in patients presenting with infection to the Intensive Care Unit (ICU) is highly limited. The primary objective of this study was to establish whether plasma fractalkine levels are elevated in sepsis and associate with outcome. The secondary objective was to determine whether fractalkine can assist in the diagnosis of infection upon ICU admission. METHODS: Fractalkine was measured in 1103 consecutive sepsis patients (including 271 patients with community-acquired pneumonia (CAP)) upon ICU admission and at days 2 and 4 thereafter; in 73 ICU patients treated for suspected CAP in whom this diagnosis was refuted in retrospect; and in 5 healthy humans intravenously injected with endotoxin. RESULTS: Compared to healthy volunteers, sepsis patients had strongly elevated fractalkine levels. Fractalkine levels increased with the number of organs failing, were higher in patients presenting with shock, but did not vary by site of infection. Non-survivors had sustained elevated fractalkine levels when compared to survivors. Fractalkine was equally elevated in CAP patients and patients treated for CAP but in whom the diagnosis was retrospectively refuted. Fractalkine release induced by intravenous endotoxin followed highly similar kinetics as the endothelial cell marker E-selectin. CONCLUSIONS: Plasma fractalkine is an endothelial cell derived biomarker that, while not specific for infection, correlates with disease severity in sepsis patients admitted to the ICU