Table 1.

Strategies for therapeutic targeting of B cells and plasma cells in SLE^*

Molecular target	Effect on cellular target		Drug
	B cells	Plasma cells
Depletion
CD205	Killing	Depletes precursors; kills some PBs	Rituximab, others
CD1986	Killing	Depletes precursors; kills PBs and some PCs	Antibodies
Proteasome72	Kills activated B cells or GC cells	Kill PCs	Bortezomib, car3lzomib
Depletion and inhibition
CD22,49 CD79α/β58	Depletes and inhibits proliferation	Depletes precursors, inhibits differentiation	Epratuzumab, other antibodies
B-cell receptor inhibition
Syk, PI3K53–55	↓ Activation and survival	↓ Generation	Inhibitors
Survival and/or differentiation
BAFF37	↓ Naive-cell and transitional-cell survival; promotes tolerance; ↓ GC survival43	Depletes some precursors	Belimumab
BAFF + APRIL37	↓ Naive-cell and transitional-cell survival; promotes tolerance; ↓ GC survival	Depletes SLPC, spleen LLPC; ↓ BM PCs	Atacicept
Type I IFN66	↓ Naive-cell activation; ↓ memory-cell differentiation	↓ Generation	Antibodies to IFN, IFN receptor
IL-2187–89	↓ Naive-cell differentiation; inhibits CC and memory-cell differentiation, survival	↓ Generation	Antibodies‡
IL-690	↓ Memory-cell differentiation	↓ Generation	Tocilizumab
TNF91	↓ Memory-cell formation; ↓ GC reactions	↓ Survival	Anti-TNF agents
IL-1792,93	Prolongs GC reactions	↑ Generation	Antibodies‡
IFN-γ69	↓ TH1 cell-dependent autoantibodies	↓ Generation?	Antibodies§
Co-stimulation
CD40 ligand94,95	Inhibits early-B-cell activation, GC formation	↓ Generation?	Antibodies||
TLR65	Inhibits B-cell activation	↓ Differentiation	Inhibitors
ICOS96	↓ CC differentiation, B-cell activation	↓ Generation?	Antibodies¶
BAFF or APRIL or IFN	As above	As above	As above
CD30–CD30 ligand97	Inhibits B-cell activation, GC reactions	Unknown	Antibodies‡
Homing and positioning
CXCR4–CXCL1210,98,99	Inhibits GC reactions	↓ BM homing, survival	Antagonists, antibodies
CXCR5–CXCL13100,101	Inhibits GC, ectopic lymphogenesis	↓ Generation	Antagonists,‡ antibodies§
CXCR3–CXCL9–11102	Inhibits/kills CXCR3+ effector B cells	Inhibits migration to target organs	Antagonists,‡ antibodies‡
LTβR103	Disrupts GC, ectopic lymphogenesis	↓ Generation	Baminercept
Induction of BREG cells#
CD40	Expands IL-10-producing T2 B cells	Unknown	Agonistic CD40 antibody13
IL-15 receptor	Expands IL-10-producing B cells	Unknown	GM-CSF–IL-15 fusokine14

^*Mechanisms range from preclinical studies to phase III clinical studies, and the main known biologic effects are derived on the basis of primarily animal experiments but also human data when available. In many instances, the impact on PCs was deduced from the effect of the intervention on antibody levels and not necessarily from direct cellular evidence.

^‡Preclinical studies.

^§Antibodies or small molecules under development.

^||Study interrupted owing to thromboembolic complications.

^¶In phase I trial.

^#Induction of B_REG cells could also be accomplished through B-cell depletion¹⁰⁴ or infusion of B_REG cells expanded in vitro.

Abbreviations: APRIL, a proliferation-inducing agent; BAFF, B-cell activating factor; BM, bone marrow; B_REG cell, regulatory B cell; CC, centrocyte; CXCL, CXC-chemokine ligand; CXCR, CXC-chemokine receptor; ICOS, inducible T-cell co-stimulator; IFN, interferon; IL, interleukin; GC, germinal center; GM-CSF, granulocyte-macrophage colony stimulating factor; LLPC, long-lived plasma cell; LTβR, lymphotoxin β receptor; PB, plasmablast; PC, plasma cell; PI3K, phosphoinositide 3-kinase; SLPC, short-lived plasma cell; T_H1 cell, type 1 T-helper cell; TLR, Toll-like receptor; TNF, tumor necosis factor.