Abstract
The success of ocrelizumab in reducing confirmed disability accumulation in primary progressive multiple sclerosis (PPMS) via CD20-targeted depletion implicates B cells as causal agents in the pathogenesis of PPMS. This review explores the possible mechanisms by which B cells contribute to disease progression in PPMS, specifically exploring cytokine production, antigen presentation, and antibody synthesis. B cells may contribute to disease progression in PPMS through cytokine production, specifically GM-CSF and IL-6, which can drive naïve T-cell differentiation into pro-inflammatory Th1/Th17 cells. B cell production of the cytokine LT-α may induce follicular dendritic cell production of CXCL13 and lead indirectly to T and B cell infiltration into the CNS. In contrast, production of IL-10 by B cells likely induces an anti-inflammatory effect that may play a role in reducing neuroinflammation in PPMS. Therefore, reduced production of IL-10 may contribute to disease worsening. B cells are also capable of potent antigen presentation and may induce pro-inflammatory T-cell differentiation via cognate interactions. B cells may also contribute to disease activity via antibody synthesis, although it's unlikely the benefit of ocrelizumab in PPMS occurs via antibody decrement. Finally, various B cell subsets likely promulgate pro- or anti-inflammatory effects in MS.
Highlights
Multiple Sclerosis (MS) is the most prevalent chronic demyelinating disorder of the central nervous system (CNS) affecting more than 2 million people worldwide and over 700,000 people in the United States [1]
The characteristics of patients treated in ORATORIO indicate that ocrelizumab likely exerts an anti-inflammatory effect with the most pronounced benefit occurring in younger primary progressive MS (PPMS) patients with a high propensity for disease activity [114]
This idea is supported in the rituximab clinical trial in PPMS that showed benefit to a subgroup of younger patients with gadolinium enhancing lesions on MRI [35]
Summary
Multiple Sclerosis (MS) is the most prevalent chronic demyelinating disorder of the central nervous system (CNS) affecting more than 2 million people worldwide and over 700,000 people in the United States [1]. In PPMS, the success of ocrelizumab in reducing disability progression is likely a result of selective depletion of pro-inflammatory B cell subsets in PPMS patients with MRI evidence of clinically significant ongoing inflammation. Teriflunomide [41], natalizumab [42], alemtuzumab [43], mitoxantrone [44], and hematopoietic bone marrow transplantation [45, 46] have been found to alter B cells in MS patients but have not been tested in large scale clinical trials for PPMS It is not currently known whether PPMS is pathogenetically distinct from RRMS and SPMS but the clinical success of Ocrelizumab in PPMS, viewed in the context of the failure of other disease-modifying therapies, implies a difference in the disease mechanism of PPMS. These findings indicate a potential pathogenic role for intrathecal immunoglobulins in MS
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