B cells and autoantibodies in the pathogenesis of multiple sclerosis and related inflammatory demyelinating diseases

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The mainstream view is that MS is caused by an autoimmune attack of the CNS myelin by myelin-specific CD4 T cells, and this perspective is supported by extensive work in the experimental autoimmune encephalomyelitis (EAE) model of MS as well as immunological and genetic studies in humans. However, it is important to keep in mind that other cell populations of the immune system are also essential in the complex series of events leading to MS, as exemplified by the profound clinical efficacy of B cell depletion with Rituximab. This review discusses the mechanisms by which B cells contribute to the pathogenesis of MS and dissects their role as antigen-presenting cells (APCs) to T cells with matching antigen specificity, the production of proinflammatory cytokines and chemokines, as well as the secretion of autoantibodies that target structures on the myelin sheath and the axon. Mechanistic dissection of the interplay between T cells and B cells in MS may permit the development of B cell based therapies that do not require depletion of this important cell population.

FIGURE 4.1

Antigen presentation by B cells to T cells with matching specificity. Crosslinking of the BCR by antigen induces signaling events leading to B cell activation and receptor endocytosis (1). MHC class II molecules assemble in the ER with the invariant chain (2). The internalized antigen is targeted to an intracellular compartment enriched in MHC (3), where proteases break down the antigen into peptides. In this compartment, the invariant is proteolytically cleaved such that only the CLIP peptide remains bound. DM facilitates the exchange of the MHC-associated CLIP for other peptides, including those derived from the endocytosed antigen. MHC molecules bearing high affinity peptides leave the loading compartment and are exported to the cell surface with co-stimulatory molecules (4). Antigen-derived peptide-MHC complexes can then activate specific CD4 T cells. Initial T cell activation leads to expression of CD40 ligand, which provides signals required for B cell survival and differentiation into memory cells through CD40 on the B cell surface.

FIGURE 4.2

B cell-derived cytokines direct the ensuing immune response. Antigen-specific immune responses are perpetuated by collaboration of T and B cells in germinal centers, the formation of which is dependent on production of lymphotoxin α and TNF by activated B cells. The cytokines present during antigen presentation to T cells determine their effector phenotype. In the presence of IL-4, T cells follow the Th2 maturation pathway, which is involved in allergic responses and protective in MS. Expression of IL-12 or TGFβ and IL-6 by APCs lead to differentiation of proinflammatory Th1 and Th17 cells, respectively, which are pathogenic in animal models of MS. These proinflammatory cells can be inhibited by IL-10, produced by APCs and a subset of regulatory T cells.

FIGURE 4.3

Locations of autoantibody targets in the CNS. Oligodendrocytes (blue) ensheath axons with the spiral myelin membrane, a specialized extension of the plasma membrane. Each oligodendrocyte produces a segmental myelin structure for several surrounding axons. MBP and PLP are the primary protein components of myelin, but are located within the many layers and therefore unavailable to antibody binding in noninjured myelin. Although less abundant, MOG is specifically expressed on the outer surface of myelin, making it a target for demyelinating antibodies. Antibodies to neurofascin, found at the myelin-axon junction and exposed on axons at the nodes of Ranvier, can contribute to both demyelination and axonal damage. Specific lipids and glycolipids can be released from the membranes of damaged oligodendrocytes, and are also recognized by antibodies in MS. The foot processes of astrocytes (green) form the blood-brain barrier which restricts access of molecules from the circulatory system to the CNS. Aquaporin-4, a water channel, is enriched in these structures, and is the target of autoantibodies specifically found in NMO.