Evaluation Of Cytokines As Biomarkers In Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Background & ObjectiveAnti-N-methyl-D-aspartate Receptor (anti-NMDAR) encephalitis is the most common type of autoimmune encephalitis associated with antibodies against synaptic receptors. Patients can present with a complex series of several syndromes followed by a rapidly developing course with various severities. Researches on the pathogenesis of anti-NMDAR encephalitis recently have suggested that the formation of specific anti-GluN1 antibodies in vivo is the direct cause of this disease, while the upstream immunologic mechanism remains unclear. By now, diagnosis of anti-NMDAR encephalitis only can be made in the presence of positive anti-GluNl antibodies results in cerebrospinal fluid (CSF). Clinical assessments include evaluation of the major symptoms, modified Rankin Score (mRS). CSF antibody titers and the level of intrathecal synthesis of IgG. Our study detected the CSF and serum cytokine levels of anti-NMDAR encephalitis group and other control groups, aiming at evaluating the application possibility of cytokine detection in clinical practice.Methods52 definite anti-NMDAR encephalitis patients were recruited, as well as 13 patients with AQP4-positive NMO in inflammation control group and 6 in non-inflammation control group. CSF and serum samples were collected and stored at -60℃. Enzyme-linked immunosorbent assay was applied to detect the concentration of 5 different cytokines, including CXCL13, BAFF, APRIL, IL-6 and CXCL10. Despite compared with control groups, anti-NMDAR patients’samples also compared with their own paired CSF and serum collected during follow-up. We also tried to figure out the possible clinical factors influencing CSF cytokine concentration. Statistics were analyzed using SPSS IBM 20.0.Results(1) Serum APRIL was lower in encephalitis patient than in non-inflammation group (Sidak post hoc, P=0.004). CSF cytokine concentrations among three groups showed no significant differences, which may due to shortage of control group cases. (2) CSF Samples from encephalitis patients had different CXCL13, BAFF and IL-6 concentrations between acute and relieving stages, with P=0.050; P=0.014; P=0.041, respectively). Serum BAFF also had similar result (P=0.022). (3) Age and gender correlate with CSF CXCL13 levels. IL-6 could be influenced by pleocytosis of CSF. CXCL10 had relationship with age, mRS, and treatment, while other two cytokines, BAFF or APRIL, had nothing to do with patient’s clinical characteristics. (4) 2 patients who periodically received intrathecal injection therapy was analyzed by comparing the cytokine concentrations with the CSF antibody titer. BAFF, IL-6 ad CXCL10 seemed to match well with the changing titer. After immunotherapy, CXCL 13 could drop rapidly back to the normal level. New drugs targeting BAFF or APRIL might be able to induce apoptosis of antibody-secreting plasma cell more directly.ConclusionsB lymphocyte activation is the core of humoral immunity response, which is often helped by Th17 cells. Our study provides more evidences supporting the theory that intrathecal humoral immunity is the main immunologic mechanism during anti-NMDAR encephalitis. Despite the intrathecal inflammation process, B cell activation also exist all over the body. CSF CXCL13, BAFF and IL-6, as well as serum BAFF, are probably novel biomarkers for clinical assessment and follow-up after treatment in anti-NMDAR encephalitis. CSF IL-6 concentration could elevate if CSF pleocytosis exists. Age may influence the level of CSF CXCL13. Several cytokines showed similar tendency with CSF antibody titer during follow-up.