B cells in the pathophysiology of myasthenia gravis

Abstract

Myasthenia gravis (MG) is an archetypal autoimmune disease. The pathology is characterized by autoantibodies to the acetylcholine receptor (AChR) in most patients or to muscle-specific tyrosine kinase (MuSK) in others and to a growing number of other postsynaptic proteins in smaller subsets. A decrease in the number of functional AChRs or functional interruption of the AChR within the muscle end plate of the neuromuscular junction is caused by pathogenic autoantibodies. Although the molecular immunology underpinning the pathology is well understood, much remains to be learned about the cellular immunology contributing to the production of autoantibodies. This Review documents research concerning the immunopathology of MG, bringing together evidence principally from human studies with an emphasis on the role of adaptive immunity and B cells in particular. Proposed mechanisms for autoimmunity, which take into account that different types of MG may incorporate divergent immunopathology, are offered. Muscle Nerve 57: 172-184, 2018.

Keywords: AChR; B cells; B lymphocytes; MuSK; autoantibodies; autoimmunity; immunopathology; myasthenia gravis.

Figure 1

Schematic diagram outlining the mechanistic hypothesis for the production of AChR or MuSK MG autoantibodies. The proposed mechanistic path to autoantibody production in MG begins with naïve B cells (Steps 1 and 2), which likely encounter antigen(s) and receive T cell help in the lymph node (3). They then differentiate into memory B cells (4), antibody-secreting plasmablasts (5), and antibody-secreting long-lived plasma cells, which reside in the bone marrow (6A) and may also be present in the thymus (6B) of some patients with AChR MG. Plasmablasts and plasma cells may contribute to MG autoantibody production. B cell depletion therapy eliminates CD20+ memory and naïve B cells but does not directly eliminate plasmablasts or plasma cells, which are CD20-negative. After CD20-targeted depletion, MG serum autoantibody titers markedly diminish (especially in MuSK MG), suggesting that plasma cells are unlikely candidates for autoantibody production. Rather, short-lived plasmablasts are more viable candidates. As only a small fraction of these cells express CD20, the effectiveness of B cell depletion therapy may depend upon depletion of a pool of plasmablast-progenitor CD20+ memory B cells. Conversely, autoantibody titers that remain elevated following CD20-targeted depletion may be the product of long-lived plasma cells.