This study provides new insights on the BAFF/APRIL system in pediatric OMS. Correlation of CSF BAFF with clinical severity and co-segregation of high CSF BAFF with CSF inflammatory chemokines and oligoclonal bands suggest a potential role of CSF BAFF as one of several biomarkers of disease activity in OMS. BAFF also showed promise as a treatment biomarker in its remarkable sensitivity to ACTH or corticosteroids in cross-sectional as well as longitudinal studies. APRIL was not a biomarker of disease activity in OMS, but showed a striking treatment effect of IVIg. BAFF-R expression on circulating B cells was not altered in OMS, nor is it in multiple sclerosis  or myasthenia gravis .
The fact that CSF BAFF and APRIL did not trend in the same direction in OMS is not without precedent . Although both are increased in neuropsychiatric lupus [12, 14], only CSF BAFF is increased in untreated multiple sclerosis [19, 20]. Another difference between BAFF and APRIL signaling in neuroinflammatory diseases is that both CSF and serum BAFF are elevated in neuro-Behcet’s disease , whereas only CSF BAFF is elevated in multiple sclerosis. The highest CSF BAFF concentrations in multiple sclerosis were found in patients with more than six oligoclonal bands , which is similar to the higher band counts we found in OMS. Serum BAFF and APRIL have not reflected CSF levels in other disorders [9, 13, 19] or in the present study.
Differences in APRIL and BAFF responses also may reflect differences in their functions . Both BAFF and APRIL bind to BCMA and TACI receptors, however, only BAFF binds to BAFF-R, and APRIL also binds to surface proteoglycans . The expression of these receptors differs on pre-immune B cells and antigen-experienced B cells (memory B cells and long-lived plasma cells) . BAFF and APRIL may localize to different anatomic niches, with distinctive local interactions. APRIL modulates certain aspects of B cell activation and isotype switching . Also, BAFF plays a role in T cell activation and polarization to Th1 [11, 15], and APRIL suppresses Th2 cytokine production and antibody responses in vitro.
Extraordinary differential effects of immunotherapy were found for APRIL and BAFF. To our knowledge, increased serum APRIL concentration as an effect of IVIg therapy has not been reported previously in a neurological disorder. The only previous report we encountered was of 11 children with Kawasaki disease, an acute vasculitis that responds to IVIg , in whom an IVIg dose of 2 g/kg raised APRIL (6.7-fold) but lowered BAFF (−41%) in plasma. In OMS, we found no IVIg-lowering effect on serum BAFF. Serum BAFF increased only after rituximab therapy, which we showed to be an early response to B cell depletion in OMS . Only ACTH and corticosteroids lowered CSF BAFF, but they did not affect CSF APRIL. Previously, a reduced concentration of serum BAFF has been reported in disorders with elevated BAFF, such as in Wegener’s granulomatosis . These differences might be clinically exploited should they be found to serve as response predictive biomarkers (identifying subpopulation according to response potential) or response identification (relating biological and clinical responses to treatment) biomarkers in longitudinal studies.
The clinical impact of IVIg-induced elevation in serum APRIL is difficult to predict from observational data. In diseases associated with increased APRIL in serum, APRIL is thought to have a pathologic role. However, IVIg induces clinical improvement in OMS , and APRIL is not elevated in untreated OMS, raising the possibility that boosting serum APRIL could be therapeutic in OMS. Interestingly, APRIL has been suggested to be involved in downregulation of serological and clinical activity in patients with systemic lupus erythematosus . This view is consistent with the proposed mode of IVIg action, which is thought to be immunomodulation of the cytokine network . However, modulation of APRIL may not be the mechanism involved.
Treatment-induced reduction of BAFF in the central nervous system might decrease BAFF-dependent survival of plasma cells , which express BAFF-R . In pediatric OMS, elevated CSF BAFF (not APRIL) correlated with CSF cerebellar autoantibodies , though the effect of treatment was not studied. Increased serum BAFF after rituximab, which may be important to B-cell repopulation , could also increase survival of autoreactive circulating B cells .
BAFF adds to the evolving picture of B-cell involvement in OMS, which includes CSF B-cell subset expansion , positive oligoclonal bands , intrathecal over-production of CXCL13 , selective over-expression of CXCR5 receptors on CSF memory B cells , and clinical response to adjunctive anti-CD20 monoclonal antibody rituximab . One potential limitation of CSF BAFF as a biomarker is its inter-individual variability. Moreover, only 23% of patients with untreated OMS had CSF BAFF concentration >2 SD above the control mean. This shows significant overlap of CSF BAFF values between patients and controls. Our current research explores the hypothesis that inflammatory cytokines, none of which is elevated in all patients, may have greater predictive value in OMS as a biomarker cluster than individually.
In conclusion, BAFF, not APRIL, joins a short list of other putative CSF biomarkers of disease activity in pediatric OMS that includes B cell frequency (total B cells and B-cell subsets), B-cell chemoattractants (CXCL10, CXCL13), and oligoclonal bands [2–5]. Such molecules necessary for B-cell recruitment, activation, and survival may be working together to promote neuroinflammation . Because of the exceptional sensitivity of CSF BAFF to peripherally administered ACTH or corticosteroid therapy, its potential utility as a response predictive biomarker or response identification biomarker warrants validation. The immunomodulatory effect of IVIg on APRIL signaling merits evaluation in a variety of neuroinflammatory disorders.