CD19 as a molecular target in CNS autoimmunity

Abstract

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the most prevalent neuroinflammatory diseases of the central nervous system (CNS). The immunological cascade of these disorders is complex, and the exact spatial and temporal role of different immune cells is not fully understood. Although MS has been considered for many years to be primarily T cell driven, it is well established that B cells and the humoral immune response play an important role in its pathogenesis. This has long been evident from laboratory findings that include the presence of oligoclonal bands in the CSF. In NMO, the importance of the humoral immune system appears even more obvious as evidenced by pathogenic antibodies against aquaporin 4 (AQP4). Besides their capacity to mature into antibody-producing plasma cells, B cells are potent antigen-presenting cells to T lymphocytes and they can provide soluble factors for cell activation and differentiation to other immune-competent cells. In MS and NMO, there are substantial data from clinical trials that B cell depletion with CD20-directed agents is effective and relatively safe. Plasma cells, which produce antibodies against molecular targets expressed by the host, but which also provide humoral immune responses against pathogens, are not targeted by anti-CD20 therapies. Therefore, the depletion of CD19-expressing cells would offer potential advantages with regard to efficacy, but potentially higher risks with regard to infectious complications. This review will outline the rationale for CD19 as a molecular target in CNS autoimmunity. The current stage of drug development is illustrated. Potential safety concerns will be discussed.

Figure 1. The triple role of B lymphocytes – Antigen presentation, cytokine expression, and antibody secretion

B lymphocytes are capable of presenting antigen to T cells. They recognize pathogens via the B cell receptor (BCR), and then endocytose the antibody-fixed antigen. Like dendritic cells, B cells constitutively express MHC class II molecules. Upon antigen engagement via the BCR, B cells initiate the expression of various cytokines, including interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNFα). These cytokines affect CD4⁺ T cell activation and differentiation. CD4⁺ T cells, once activated and differentiated into a specific T helper (Th) cell phenotype, cross-activate B cells via cytokines and co-stimulatory molecules, including cluster of differentiation (CD)40-CD40 ligand and CD80/CD86-CD28. In addition, the class switch from immunoglobulin (Ig) M to IgG requires CD4⁺ T cell help via cytokines and co-stimulation.

Figure 2. B lymphocyte compartmentalization, development, and differentiation

In adult mammals, B lymphocytes common lymphocytes progenitors (CLP) originate in the bone marrow, where they develop into Pro-B cells, Pre-B cells, and immature B cells. As part of their life cycle, immature B cells that possess a mature B cell receptor (BCR) and chemokine receptors, egress from the bone marrow into lymphatic vessels. Once within the afferent lymphatics, these cells by definition are considered mature naïve B cells. In the lymph node, there a very heterogeneous groups of B lymphocytes, including marginal zone B cells, B1 cells, B regulatory cells, transitional B cells, mature B cells, memory B cells, as well as short-lived plasma cells, and plasmablasts. The CD19 antigen is a type I transmembrane glycoprotein that belongs to the immunoglobulin Ig superfamily. It is expressed throughout B-cell development, including early pro-B cells and late pro-B cells, as well as in memory B cells, plasmablasts, and a proportion of plasma cells. The overall expression increases approximately threefold as B cells mature. In terminally differentiated plasma cells, which are highly prevalent in the bone marrow, CD19 can no longer be detected.