After all, it is a persistent virus selected to co-exist with the host rather than endanger it

After all, it is a persistent virus selected to co-exist with the host rather than endanger it. Open in a separate window Fig. EBERs were indeed released from EBV-infected cells and acted as local immunomodulators [48]. Could innate activation triggered by latent EBV infection be part of the game? Perhaps we have to think differently C EBV might be more subtle than we anticipated. After all, it is a persistent virus selected to co-exist with GPI-1046 the host rather than endanger it. Open in a separate window Fig. 2 Recruitment of B cells into active lesion in multiple sclerosis (MS). The B cell infiltrate may contain the occasional EpsteinCBarr virus (EBV)+ B cells. These cells contain EBV non-coding small RNAs (EBERs), which can be secreted in a complex with the cellular EBER binding lupus antigen (La). EBERs can bind to Toll-like receptor (TLR)-3 on neighbouring cells and elicit interferon (IFN)- production, thereby contributing to an inflammatory milieu. These processes may help to sustain an inflammatory response in the central nervous system (CNS) and contribute to demyelination and axonal injury. The success of B cell therapies in MS In a small Phase II trial with rituximab (anti-CD20), there was a dramatic reduction of disease activity in RRMS patients within 48 weeks [49]. Rituximab is a genetically engineered chimeric humanized molecule that targets CD20+ B cells and is used for treating B cell lymphoma. CD20 is present on B cells and pre-B cells but lost upon plasma cell differentiation [50, 51]. The primary end-point of this trial was mean gadolinium (Gd)-enhancing lesions (inflammatory activity) assessed by MRI from baseline to week 48. A decrease in disease activity was already noted at week 4 and most pronounced at week 12. Such very early treatment responses suggest that rituximab treatment may act directly via B cell lysis C or, indeed, on the inflammatory mechanisms C rather than by reducing GPI-1046 pathogenic autoantibody levels. Indeed, rituximab does not affect serum and CSF antibody levels [52]. Interestingly, in a trial on PPMS, the primary end-point was not reached; however, there was a suggestion of an effect in subjects with evidence of active inflammation [53]. Treatment with rituximab led to predominance of circulating naive and immature B cells. In the CSF, T and B cell numbers were decreased, and resting B cells predominated. Two additional humanized antibodies targeting different epitopes on CD20 are now being trialled in MS: ofatumumab and ocrelizumab [54]. Ocrelizumab appears to target mature B cells. It has reached Phase III for several autoimmune diseases, e.g. rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and Phase II for MS. Those for RA and SLE were halted in May 2010 because of occasional serious/fatal opportunistic infections in high-dose arms, especially in subjects with Asian ancestry. The Phase II study in RRMS in October 2010 showed statistically significant reductions at week 24 in both lesion load (as GPI-1046 measured by MRI activity) and relapse rate, compared to placebo, both doses (200 mg and 600 mg) being well tolerated. The rituximab trial data were somewhat surprising, as a positive effect was already recognized at week 12 post-treatment. This finding shows the potential for an autoantibody-independent effect of B cell depletion on MS disease activity. B cells are important antigen-presenting cells. Physical connection of B cells and T cells [major histocompatibility complex (MHC)/antigen/T cell receptor] happens in the presence of co-stimulatory molecules such as CD40/CD40ligand, B7/CD28, OX40 ligand/OX40 on the surface of B cells and T cells, respectively [55]. B cell depletion in mice was found to impact on CD4+ T cell activation and development or B cell depletion. B cell depletion may, therefore, be effective in reducing CNS swelling. However, B cells also play an important part in immunoregulation. Animal studies focus on the importance of the IL-10-generating B cell subset (B10) in the suppression of GPI-1046 autoimmunity and swelling [59], which may clarify why B cell GPI-1046 depletion led to the worsening of inflammatory disease in some EAE models, with delayed production of IL-10 and emergence of regulatory T cells [60]. B cell depletion also exacerbated disease in myelinColigodendrocyte glycoprotein peptide (MOG p35C55)-induced BM28 EAE in mice [61]. Hence, the relative contribution of B cells to EAE and MS may vary.