B Cells As Therapeutic Targets In Autoimmune Neurological Disorders

Marinos C Dalakas


Nat Clin Pract Neurol. 2008;4(10):557-567. 

In This Article

B-cell Maturation and Homeostasis

B lymphocytes arise from hematopoietic stem cells in the bone marrow. These cells mature independently of an antigen first into pro-B cells, then into pre-B cells and immature B cells (Figure 2).[4,5] They subsequently enter the antigen-dependent phase in the peripheral lymphoid tissues, where mature-but-naive B cells, after encountering their antigen in the extrafollicular regions of the lymphoid organs, become activated B cells and migrate to the follicular regions. From here, they exit to differentiate into memory B cells, late plasmablasts and plasma cells (Figure 2).[1,2,3,4,5,6] Specific markers, such as CD20, CD27, BAFF-R (B-cell-activating factor receptor), CD38 and CD138, identify the transitional phases of B cells from stem cells to plasma cells (Figure 2).

Figure 2.

Maturation of B cells. The B-cell maturation process involves two phases of differentiation-an antigen-independent process in the bone marrow, and an antigen-dependent process that occurs not only in the lymphoid tissue but also in the brain. Specific CD (cluster of differentiation) markers such as CD20, CD27, BAFF-R, CD38 and CD138 are helpful for distinguishing the transitional phases, including stem cells, memory B cells and plasma cells, through which B cells pass during maturation. Abbreviation: BAFF-R = B-cell-activating factor receptor.

The memory B cells, late plasmablasts and long-lived plasma cells migrate not only to the bone marrow, spleen and lymphoid tissues, but also to the brain, where they transform into antibody-secreting cells after encountering their antigen (Figure 3).[12] Interactions between the homeostatic chemokines CXC-chemokine ligand (CXCL) 13, CXCL10 and CXCL12 secreted from the endothelial cell wall and their respective receptors on B cells[3,13] are fundamental for B-cell homeostasis not only within the lymphoid follicles but also within the brain. These molecules are upregulated in the brains of patients with MS, allowing the recruitment and transmigration of antibody-producing B cells into the brain.[14,15] B-cell transmigration into the brain is also facilitated by the adhesion molecules very late antigen-4 (VLA-4; also known as integrin α-4 or ITA4) and lymphocyte function-associated antigen-1 (LFA-1; also known as integrin α-L or ITAL) and their counter-receptors vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1) on the endothelial cells.[13] In secondary progressive MS, activated B cells form germinal centers not only in the lymphoid tissues but also within the intermeningeal spaces, where they undergo the same stages of differentiation as in the periphery (Figure 3).[16,17] Within these structures, which are observed in 41.4% of patients with secondary progressive MS,[17] B cells generate inflammatory mediators that can stimulate plasma cells for in situ production of immunoglobulins. The production of intrathecal immunoglobulins (i.e. the life-long persistent oligoclonal bands) in all forms of MS indicates a central role for activated B cells and plasma cells in this disease.

Figure 3.

Activated B cells in the circulation and brain. Activated B cells-including memory B cells and plasmablasts-from the circulation migrate, after encountering their antigen, to the bone marrow and lymphoid tissue, where they are transformed into ASCs. These cells can also enter the CNS compartment and transform into ASCs within the brain. B-cell recruitment and transmigration depends on interactions between molecules such as CXCR5 and VLA-4 expressed on B cells and molecules such as CXCL13 and VCAM1, respectively, which are expressed by the endothelial cell walls of both the lymphoid tissue and the meningeal spaces, where germinal centers are formed. The upregulation of BAFF and APRIL and the secretion of these molecules by astrocytes within the brain promote the in situ clonal expansion of B cells. Abbreviations: APRIL = a proliferation-inducing ligand; ASC = antibody-secreting cell; B = B cell; BAFF = B-cell-activating factor; BAFF-R = B-cell-activating factor receptor; BCMA = B-cell-maturation antigen; CXCL = CXC-chemokine ligand; CXCR = CXC-chemokine receptor; ICAM1 = intercellular adhesion molecule 1; LFA-1 = lymphocyte function-associated antigen-1; TACI = transmembrane activator and calcium modulator and cyclophilin ligand interactor; VCAM1 = vascular cell adhesion molecule 1; VLA-4 = very late antigen-4.

Two members of the TNF family, BAFF (B-cell-activating factor) and APRIL (a proliferation-inducing ligand), have emerged as crucial factors for B-cell survival, differentiation, germinal center formation and immunoglobulin production.[3,18,19] BAFF and APRIL are produced by monocytes, macrophages and dendritic cells, and they circulate in trimeric forms. They bind to B cells through three different receptors ( Table 1 ): BAFF-R, BCMA (B-cell-maturation antigen) and TACI (transmembrane activator and calcium modulator and cytophilin ligand interactor). Levels of BAFF-R and APRIL mRNA are increased in the monocytes and B cells of patients with MS[20] and in the muscles of patients with inflammatory myopathies (Raju R and Dalakas MC, unpublished data). In MS lesions, BAFF and APRIL are produced by astrocytes, and they promote the in situ survival and clonal expansion of B cells (Figure 3).[21,22] Agents that target BAFF or APRIL might, therefore, exert therapeutic effects in various neurological disorders by suppressing B-cell proliferation.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.