MS and the B cell controversy

Abstract

The contribution of B cells and their products to the pathogenesis of MS has long been debated. The presence of B cells, plasma cells and excess immunoglobulins in MS lesions and in the cerebrospinal fluid of MS patients implicate the humoral immune system in the disease. Correlations of higher levels of CSF B cells and immunoglobulins found in some studies with a more aggressive clinical course of MS have bolstered the notion that the humoral immune system is involved in MS pathogenesis. However, until the advent of rituximab, a monoclonal antibody therapy that specifically lyses B cells, confirmation of the key role of B cells and their products in MS had been lacking. Development of this therapeutic monoclonal antibody to CD20, a cell surface molecule confined to B cells, allowed determination of the effects of B cell depletion. Perhaps somewhat unexpectedly, depletion of circulating B cells led to rapid and profound reduction in gadolinium enhancing lesions on brain MRI in three separate studies in relapsing MS subjects. When examined, depletion of B cells in the blood was accompanied by depletion of B cells in CSF. Notably, reduction of enhancing brain lesions was not accompanied by reduction in CSF immunoglobulins. Whether the critical role of B cells occurs in the periphery, in the CNS, or in both locations has not yet been determined.

Modelling MS: Chronic-Relapsing EAE in the NOD/Lt Mouse Strain

“…On the other hand, demonstration of the relevance of anti-MOG antibodies to MS pathogenesis has proven more challenging. Studies have provided variable results regarding the frequency of anti-MOG antibodies in MS patients relative to controls (Cross and Waubant 2011;Haase et al 2001;Iglesias et al 2001;Reindl et al 2013), as well as a correlation between anti-MOG antibody status in serum after a first demyelinating event [or clinically isolated syndrome (CIS)] and risk for conversion to definite MS (Berger et al 2003;Kuhle et al 2007). More recent evidence suggests that (a) quantitative evaluation of serum antibodies against MOG is dependent on the selected detection method, (b) MOG antibodies are associated with a broad spectrum of acquired human CNS demyelinating diseases and (c) high titre of MOG antibodies is associated with paediatric rather than adult MS, suggesting a B-cell-dominated pathogenesis in the paediatric MS sub-type (Iglesias et al 2001;Lee and Linker 2010;Reindl et al 2013).…”

T cell mediated pathogenesis in EAE: Molecular mechanisms

“…[105,[107][108][109] Here, B cells probably act rather as efficient APCs and cytokine producers for pathogenic T cell development, reminiscent of the situation in MS where depletion of B cells by Rituximab (an anti-CD20 monoclonal antibody) also shows a beneficial effect independent of the plasma antibody levels found. [110] Molecular interactions in these B cell-antibody dependent models probably occur via TCR/MHCII and CD40L-CD40, as well as by the cytokines produced from T cells. In the RR model, intra-CNS antibody secretion, presumably by plasma cells, can be observed.…”

High-Density Peptide Microarray Analysis of IgG Autoantibody Reactivities in Serum and Cerebrospinal Fluid of Multiple Sclerosis Patients

“…Episodes of inflammatory activity are mainly characteristic for RRMS patients, whereas PPMS patients present less prominent inflammation and more neurodegenerative pathology. T cells are assumed to be critical drivers of the disease, but B-cells and other immune cells play significant roles as well (5,6). Autoreactive T-and B cells may be activated in the periphery and then reactivated after entering the CNS.…”

“…Within the last years, it became evident that the B-cell response is not restricted to myelin but is much more widespread. Antibodies against several other CNS components (proteins, lipids, and glycans) have been described (reviewed in (6,18)). Additionally, apparently nonspecific immune responses in the serum and CSF of MS patients involve nonbrain targets and common infectious agents.…”