B cell depletion therapies in autoimmune disease: advances and mechanistic insights

Abstract

In the past 15 years, B cells have been rediscovered to be not merely bystanders but rather active participants in autoimmune aetiology. This has been fuelled in part by the clinical success of B cell depletion therapies (BCDTs). Originally conceived as a method of eliminating cancerous B cells, BCDTs such as those targeting CD20, CD19 and BAFF are now used to treat autoimmune diseases, including systemic lupus erythematosus and multiple sclerosis. The use of BCDTs in autoimmune disease has led to some surprises. For example, although antibody-secreting plasma cells are thought to have a negative pathogenic role in autoimmune disease, BCDT, even when it controls the disease, has limited impact on these cells and on antibody levels. In this Review, we update our understanding of B cell biology, review the results of clinical trials using BCDT in autoimmune indications, discuss hypotheses for the mechanism of action of BCDT and speculate on evolving strategies for targeting B cells beyond depletion.

Fig. 1. B cell biology.

Following their development in the bone marrow, immature B cells enter the circulation and complete their development in the spleen. In the spleen, they first become naive B cells (NBCs). If activated by an antigen (Ag), NBCs may then enter an emerging germinal centre (GC), where affinity maturation occurs. The highest-affinity B cells emerge from the GC as memory B cells or plasma cells. Some NBCs can also be activated in extrafollicular environments, for example in the T cell area or in the medullary cords. NBCs activated in extrafollicular environments quickly become plasma cells. In the presence of IFNγ, B cells also can also acquire the expression of T-bet, and some T-bet⁺ cells will remain in the spleen as memory B cells. Some T-bet⁺ cells can adopt a double-negative 1 (DN1) or DN2 phenotype, with the latter being influenced by cytokines such as IL-21. CXCR, CXC-chemokine receptor; Ig, immunoglobulin; T_FH cell, T follicular helper cell.

Fig. 2. Roles of B cell lineage cells in autoimmune disorders.

B cells and their effectors such as antibodies and cytokines differ in their contributions to pathobiology depending on the disease. Seven autoimmune disorders (multiple sclerosis, N-methyl-d-aspartate receptor (NMDAR) encephalitis, myasthenia gravis, systemic lupus erythematosus (SLE), rheumatoid arthritis, myelin–oligodendrocyte glycoprotein (MOG) spectrum disorder (MOGSD) and neuromyelitis optica spectrum disorder (NMOSD)), their targets, and the implicated B cell subtype or pathogenic autoantibodies are shown. Based on the vast options for how B cells can influence pathobiology, patients must be carefully assessed to ensure that B cell depletion therapy reduces pathogenic but not beneficial B cell subsets. ACh, acetylcholine; AChR, nicotinic acetylcholine receptor; ACP, anti-citrullinated protein; AQP4, aquaporin 4; dsDNA, double-stranded DNA; GM-CSF, granulocyte–macrophage colony-stimulating factor; MuSK, muscle-specific tyrosine kinase; RF, rheumatoid factor; TLT, tertiary lymphoid tissue; TNF, tumour necrosis factor.

Fig. 3. Effects of BCDT on B cell populations.

Most of our knowledge of how B cell populations change after B cell depletion therapy (BCDT) is derived from treatment with anti-CD20 agents and is depicted here. We hypothesize that the efficacy of BCDT in some autoimmune diseases begins with a reset of the B cell pool in the periphery. By elimination of CD20⁺ memory B cells, some of which may be producing proinflammatory cytokines such as granulocyte–macrophage colony-stimulating factor (GM-CSF), the periphery is enriched with naive B cells and IL-10-producing regulatory B cells. Moreover, short-lived plasmablasts that are potentially autoreactive are not replenished by autoreactive memory B cells after BCDT. Long-lived plasma cells (LLPCs), however, which are present in the bone marrow (BM) and gut, are not eliminated. Surges in BAFF levels that occur after BCDT may promote the accumulation of immunoregulatory LLPCs, which could have a beneficial effect in some diseases, such as multiple sclerosis. In target tissues, B cells in tertiary lymphoid tissues (TLTs) may not be replaced. Consequently, the ability for other pathogenic immune cells to take up residence in the inflamed tissue may be compromised, and other immunoregulatory cells, such as T follicular helper cells (T_FH cells), may take up residence, resulting in reduced disease. LTα₃, lymphotoxin-α₃; PC, plasma cell; TNF, tumour necrosis factor.

Fig. 4. Future approaches using B cell-targeted therapies in autoimmune disease.

The next generation of B cell-targeted therapies, rather than B cell depletion therapies, will need to target specific proinflammatory and anti-inflammatory B cell functions. BAFF homotrimers versus higher-order aggregates (60-mers) of BAFF or APRIL impact different B cell subsets differently. Inhibiting BAFF homotrimers could have a beneficial effect because it may remove T-bet⁺ B cells and/or B cells that participate in the extrafollicular response. Because a subtype of T-bet⁺ B cells (double-negative 2 (DN2) cells, which are considered to be non-circulating memory B cells) gives rise to antibody-producing plasmablasts and plasma cells in an IL-21-dependent manner, IL-21 blockade may ameliorate disease by inhibiting these non-circulating memory B cells. However, supplementation with BAFF 60-mers or APRIL may promote the accumulation of IgA⁺ immunoregulatory plasma cells, which could be beneficial in multiple sclerosis (MS). Likewise, the levels of immunoregulatory plasma cells may be increased by manipulating the microbiota. The germinal centre (GC) itself is the source of somatically hypermutated B cells that play an important role in diseases such as systemic lupus erythematosus. Interrupting the entanglement between B cells and T follicular helper cells T (T_FH cells) by blocking CD40 (or other candidates such as inducible T cell costimulator (ICOS)) could provide a means for staving off this source of potentially bad B cells. In tertiary lymphoid tissues (TLTs), removal of B cells may change the cellular environment of TLT, reducing its ability to foster autoimmune reactions.