#ResearchSpeak: who trumps who; the T-cell or the B or plasma cells?

Who is afraid of the big bad wolf? #ResearchSpeak #MSBlog

Every now an then a immunology paper grabs my attention. The paper below confirms that CSF levels of a soluble protein, sCD27, correlates with MS disease activity and immunoglobulin synthesis within the brain and spinal cord, is interesting. I predict this observation is important. 

T-cells vs. B-cells; who will be the winner?

For the immunologist reading this post you will recall that CD27 is a member of the tumour necrosis factor (TNF)-receptor superfamily and is part of an important pro-inflammatory cascade. The CD27 receptor is required for generation and long-term maintenance of T cell immunity. It binds to CD70 on B-cells, and plays a key role in regulating B-cell activation and immunoglobulin synthesis. 

The study below observed a correlation between sCD27 and IgG index, a marker of immunoglobulin synthesis in the spinal fluid (see figure below). The author's speculate that there may be a direct role for sCD27 released by T cells on IgG production by B cells. Interestingly, the binding of sCD27 to the CD70 on memory B cells stimulates those B cells to differentiate into IgG-secreting plasma cells. Could sCD27 be the important link between T-cells and B-cells and plasma cells? It will be very interesting if sCD27 in the spinal fluid also predicts recurrence of disease activity after an induction therapy. 

The researchers' conclude that sCD27 in the CSF of pwCIS is an activation molecule directly related to the immunopathology of the disease and that is a potential clinical marker to help in treatment decisions after a first attack of suspected MS. They imply that it is marker of T-cell activation, but could it be the downstream B-cells and plasma cells that are the real players? 

van der Vuurst et al. Soluble CD27 Levels in Cerebrospinal Fluid as a Prognostic Biomarker in Clinically Isolated Syndrome. JAMA Neurol. 2017 Jan 3. doi: 10.1001/jamaneurol.2016.4997.

IMPORTANCE: There is a growing number of therapies that could be administered after the first symptom of central nervous system demyelination. These drugs can delay multiple sclerosis (MS) diagnosis and slow down future disability. However, treatment of patients with benign course may not be needed; therefore, there is a need for biomarkers to predict long-term prognosis in patients with clinically isolated syndrome (CIS).

OBJECTIVE: To investigate whether the T-cell activation marker soluble CD27 (sCD27) measured in cerebrospinal fluid of patients at time of a first attack is associated with a subsequent diagnosis of MS and a higher relapse rate.

:This prospective study included 77 patients with CIS between March 2002 and May 2015 in a tertiary referral center for multiple sclerosis, in collaboration with several regional hospitals. Patients with CIS underwent a lumbar puncture and magnetic resonance imaging scan within 6 months after first onset of symptoms.

MAIN OUTCOMES AND MEASURES: Soluble CD27 levels were determined in cerebrospinal fluid using a commercially available enzyme-linked immunosorbent assay. Cox regression analyses was used to calculate univariate and multivariate hazard ratios for MS diagnosis. Association between sCD27 levels and relapse rate was assessed using a negative binomial regression model.

RESULTS: Among 77 patients with CIS, 50 were female (79.5%), and mean (SD) age was 32.7 (7.4) years. Mean (SD) age in the control individuals was 33.4 (9.5) years, and 20 were female (66.7%).Patients with CIS had higher cerebrospinal fluid sCD27 levels than control individuals (geometric mean, 31.3 U/mL; 95% CI, 24.0-40.9 vs mean, 4.67 U/mL; 95% CI, 2.9-7.5; P < .001). During a mean (SD) follow-up of 54.8 (35.1) months, 39 of 77 patients (50.6%) were diagnosed as having MS. In a model adjusted for magnetic resonance imaging and cerebrospinal fluid measurements, sCD27 levels were associated with a diagnosis of MS (hazard ratio, 2.4 per 100 U/mL increase in sCD27 levels; 95% CI, 1.27-4.53; P = .007). Additionally, patients with MS with high sCD27 levels (median, >31.4 U/mL) at the time of CIS had a 5.5 times higher annualized relapse rate than patients with low sCD27 levels (annualized relapse rate, 0.06 vs 0.33; P = .02).

CONCLUSIONS AND RELEVANCE: Soluble CD27 in cerebrospinal fluid of patients with CIS was associated with MS diagnosis and a high relapse rate. Therefore, sCD27 is an activation molecule directly related to the immunopathology of the disease and is a potential clinical marker to help in treatment decisions after a first attack of suspected MS.

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