Evidence for the role of B cells and immunoglobulins in the pathogenesis of multiple sclerosis

Abstract

The pathogenesis of multiple sclerosis (MS) remains elusive. Recent reports advocate greater involvement of B cells and immunoglobulins in the initiation and propagation of MS lesions at different stages of their ontogeny. The key role of B cells and immunoglobulins in pathogenesis was initially identified by studies in which patients whose fulminant attacks of demyelination did not respond to steroids experienced remarkable functional improvement following plasma exchange. The positive response to Rituximab in Phase II clinical trials of relapsing-remitting MS confirms the role of B cells. The critical question is how B cells contribute to MS. In this paper, we discuss both the deleterious and the beneficial roles of B cells and immunoglobulins in MS lesions. We provide alternative hypotheses to explain both damaging and protective antibody responses.

Figure 1

The in vitro effects of 1,25(OH)₂D on the immune system. The effects of 1,25(OH)₂D either directly or indirectly are depicted by arrows. While a green arrow represents positive influence, a red arrow represents the negative influence. The negative influence on inflammation indicates dampening of the inflammatory response. DC: dendritic cell, Th1: T helper type 1 lymphocyte, Th2: T helper type 2 lymphocyte, Tr: regulatory T lymphocyte [17].

Figure 2

The role of B cells in MS pathogenesis. Antigens (viral, processed, novel, or auto) are internalized and presented via antigen presenting cells (APC's, such as dendritic cells, microglia and other mononuclear phagocyte system cells) to antigen-specific naïve T cells and/or B cells. B cells can sometimes act as APC's. Activated B cells undergo clonal expansion and mature into either antigen-specific memory B cells or into plasma cells that secrete antigen-specific antibodies that may have a detrimental (further damage to myelin sheaths of axons) or a beneficial effect (remyelination, clearing the metabolic wastes away, and neurite extension), depending on the microenvironment. The oligoclonal immune response observed in patients with MS thus represents an ambivalent role. It is of priority to determine clinical assays to delineate patients who would respond to B cell depletion therapies, or to remyelination promoting antibody therapy. This approach supports the concept of “individualized medicine”, where deleterious antibodies would be removed from circulation or in other cases endogenous remyelination would be promoted.