Virally Affected B cells are the Centre of EAE

Epub: Anwar Jagessar et al. The Different Clinical Effects of Anti-BLyS, Anti-APRIL and Anti-CD20 Antibodies Point at a Critical Pathogenic Role of γ-Herpesvirus Infected B Cells in the Marmoset EAE Model. J Neuroimmune Pharmacol. 2013 Mar 19.

Background: The robust and rapid clinical effect of depleting anti-CD20 monoclonal antibodies (mAb) in multiple sclerosis (MS) demonstrates a critical pathogenic contribution of B cells. The clinical effect of anti-CD20 mAb has been replicated in a relevant preclinical MS model, experimental autoimmune encephalomyelitis (EAE) in marmoset monkeys (Callithrix jacchus). By contrast, treatment with mAbs against two essential cytokines in B cell activation growth and survival, i.e. BlyS/BAFF and APRIL, was only partially effective. All three mAbs induced depletion of CD20+ B cells from the circulation, albeit with different kinetics and based on distinct mechanisms of action.

Objective: In the current study we analyzed whether the different clinical effect of anti-CD20 mAb or the anti-BLyS and anti-APRIL mAbs is due to different depletion of B cells infected with the EBV of marmosets, CalHV3. 

Methods & results: Employing a novel PCR-based assay, half of the colony of group-housed marmosets was tested positive for CalHV3 DNA in secondary lymphoid organs (Lymph glands). The same prevalence was observed in placebo-treated monkeys. In marmosets treated with anti-CD20 mAb the load of CalHV3 DNA in lymphoid organs was substantially reduced, while this was not observed in the monkeys treated with anti-BLyS or anti-APRIL mAbs. To examine the pathogenic role of virus-transformed B cells, we infused EBV-transformed B lymphoblastic cell (BLC) lines presenting the immunodominant MOG34-56 peptide. We observed in the recipients of MOG34-56 pulsed BLC, but not in their fraternal siblings infused with non-pulsed BLC, activation of anti-MOG34-56 T cells and meningeal inflammation. 

Conclusions: Collectively, the data show that among CD20+ B cells, the herpesvirus-transformed subset has a particularly important pathogenic role in the marmoset EAE model.

B cell activating factor (BAFF) is critical for B cell survival factor it is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. It is expressed as transmembrane protein on various cell types. The transmembrane form can be cleaved from the membrane, generating a soluble protein fragment. BAFF is the natural ligand of three unusual tumor necrosis factor receptors named BAFF-R, TACI, and BCMA. These receptors are expressed mainly on mature B lymphocytes and BCMA on plasma cells-antibody producing cells). TACI binds worst since its affinity is higher for a protein similar to BAFF, called a proliferation-inducing ligand (APRIL), which does a similar thing to BAFF.

As Prof G puts it “BAFF and APRIL are immunological fertilizer for B cells. In the presence of BAFF and APRIL B cells are more likely to survive, proliferate and make antibodies.” In MS, anti-CD20 and ati-CD19 inhibit relapses but BAFF-inhibitors did not appear to work belimumab a BAFF inhibitor failed in trials. Atacicept is a recombinant fusion protein that combined the binding site for two cytokines that regulate maturation, function, and survival of B cells, B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), with the constant region of immunoglobin. This made MS worse.

As shown previously Anti-BLys and Anti-APPRIL antibodies ameliorated but did not stop EAE developing, so not quite the same as in MS. This relative lack of efficacy of ant-BAFF treatment compared to anti-CD20 was related in this study to the relative lack of effect of removing B cells infected with a virus. This study implicates virally infected B cells as important mediators in the development of autoimmunity. Should this not mean that half the marmosets in the colony not get EAE if this is the case? Could this be the same in multiple sclerosis and maybe treatments that inhibit viruses may be beneficial in MS? The hypothesis is being tested in the Charcot Project.

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