Cerebrospinal fluid soluble CD27 is a sensitive biomarker of inflammation in autoimmune encephalitis.

BACKGROUND: Autoimmune encephalitis (AE) comprises a group of rare, severe neuroinflammatory conditions. Current biomarkers of neuroinflammation are often normal in AE which therefore can be difficult to rule out in patients with seizures, cognitive and/or neuropsychiatric symptoms. Cerebrospinal fluid (CSF) soluble CD27 (sCD27) and soluble B-cell maturation antigen (sBCMA) have high sensitivity for neuroinflammation in other neuroinflammatory conditions. In this exploratory study we investigate the potential of sCD27 and sBCMA in CSF as biomarkers of neuroinflammation in AE. METHODS: Concentrations of sCD27 and sBCMA were measured in CSF from 40 AE patients (20 patients were untreated (12 with anti-N-Methyl-d-Aspartate receptor antibodies (NMDA) and 8 with anti-Leucine-rich Glioma-Inactivated 1 antibodies (LGI1)), and 37 symptomatic controls (SCs). RESULTS: CSF concentrations of sCD27 were increased in untreated NMDA AE patients (median 1571 pg/ml; p < 0.001) and untreated LGI1 AE patients (median 551 pg/ml; p < 0.05) compared to SCs (median 250 pg/ml). CSF sBCMA was increased in untreated NMDA AE patients (median 832 pg/ml) compared to SCs (median 429 pg/ml). CSF sCD27 and sBCMA correlated with the CSF cell count. Receiver operating characteristic curve analysis of untreated AE patients versus SCs showed an area under the curve of 0.97 for sCD27 and 0.76 for sBCMA. CONCLUSION: CSF sCD27 is a suitable biomarker of neuroinflammation in AE with an ability to discriminate patients with NMDA AE and LGI1 AE from symptomatic controls. CSF sCD27 may be suited for ruling out AE and other neuroinflammatory conditions in the early phase of the diagnostic work-up.

CD11c+ B cells in relapsing-remitting multiple sclerosis and effects of anti-CD20 therapy.

OBJECTIVES: B cells are important in the pathogenesis of multiple sclerosis. It is yet unknown which subsets may be involved, but atypical B cells have been proposed as mediators of autoimmunity. In this study, we investigated differences in B-cell subsets between controls and patients with untreated and anti-CD20-treated multiple sclerosis. METHODS: We recruited 155 participants for an exploratory cohort comprising peripheral blood and cerebrospinal fluid, and a validation cohort comprising peripheral blood. Flow cytometry was used to characterize B-cell phenotypes and effector functions of CD11c+ atypical B cells. RESULTS: There were no differences in circulating B cells between controls and untreated multiple sclerosis. As expected, anti-CD20-treated patients had a markedly lower B-cell count. Of B cells remaining after treatment, we observed higher proportions of CD11c+ B cells and plasmablasts. CD11c+ B cells were expanded in cerebrospinal fluid compared to peripheral blood in controls and untreated multiple sclerosis. Surprisingly, the proportion of CD11c+ cerebrospinal fluid B cells was higher in controls and after anti-CD20 therapy than in untreated multiple sclerosis. Apart from the presence of plasmablasts, the cerebrospinal fluid B-cell composition after anti-CD20 therapy resembled that of controls. CD11c+ B cells demonstrated a high potential for both proinflammatory and regulatory cytokine production. INTERPRETATION: The study demonstrates that CD11c+ B cells and plasmablasts are less efficiently depleted by anti-CD20 therapy, and that CD11c+ B cells comprise a phenotypically and functionally distinct, albeit heterogenous, B-cell subset with the capacity of exerting both proinflammatory and regulatory functions.

Cerebrospinal fluid soluble CD27 is associated with CD8+ T cells, B cells and biomarkers of B cell activity in relapsing-remitting multiple sclerosis.

Cerebrospinal fluid (CSF) soluble CD27 (sCD27) is a sensitive biomarker of intrathecal inflammation. Although generally considered a biomarker of T cell activation, CSF sCD27 has been shown to correlate with biomarkers of B cell activity in multiple sclerosis. We analyzed CSF from 40 patients with relapsing-remitting multiple sclerosis (RRMS) and nine symptomatic controls using flow cytometry and multiplex electrochemiluminescence immunoassays. CSF sCD27 levels were increased in RRMS and correlated with IgG index, soluble B cell maturation antigen, cell count, B cell frequency and CD8+ T cell frequency. We provide new data indicating that CSF sCD27 is associated with CD8+ T cells and B cells in RRMS.

Biomarkers of systemic inflammation, soluble IL-2Rα and the multiple sclerosis-associated IL2RA SNP rs2104286 in healthy subjects and multiple sclerosis patients.

Soluble interleukin-2 (IL-2) receptor α (sIL-2Rα) antagonizes IL-2 signaling and is involved in the pathogenesis of several immune-mediated diseases including multiple sclerosis (MS). The level of sIL-2Rα is affected by the MS-associated single nucleotide polymorphism (SNP) rs2104286. By use of ELISA and electrochemiluminescence, we investigated if 26 biomarkers of systemic inflammation were associated with sIL-2Rα and rs2104286 in cohorts of healthy subjects and MS patients in serum and heparin plasma. We found that sIL-2Rα significantly correlated with the level of tumor necrosis factor-α (TNFα) (r = 0.391, p = 0.002) in healthy subjects and the association was validated in a separate cohort. Additional, in healthy subjects we confirmed a previous report indicating that C-reactive protein (CRP) correlates with sIL-2Rα (r = 0.278, p = 0.034). None of the biomarkers of systemic inflammation were significantly associated with sIL-2Rα in MS patients. Furthermore, the MS-associated SNP rs2104286 was not significantly associated with any of the biomarkers of systemic inflammation in neither healthy subjects nor MS patients. We conclude that sIL-2Rα is associated with TNFα and CRP in healthy subjects. However, further research is required to confirm the use of sIL-2Rα as biomarker of systemic inflammation as well as to assess the mechanism underlying the observed correlation between levels of sIL-2Rα and TNFα.