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B cells move to centre stage: novel opportunities for autoimmune disease treatment

Key Points

  • In recent years, a popular view of the pathogenesis of autoimmune disorders has been that B-cell derived events are ancillary to a basic breakdown in T-cell tolerance, and that although autoantibodies are present, the effector function of T cells is the fundamental pathological component.

  • However, the B-cell-depleting antibody rituximab — originally developed as a lymphoma therapy — has recently been shown to be effective in the treatment of rheumatoid arthritis, and has received regulatory approval for this indication.

  • This success, as well as indicating that removal of the B-cell component is beneficial in rheumatoid arthritis, has ushered in a new era of exploration of the contribution of B cells to a range of immune disorders in general.

  • This review discusses the role of B cells in autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus and Sjogrens syndrome, and considers various therapeutic strategies involving modulation of B-cell function, including B-cell depletion, manipulation of B-cell survival, and targeting T-cell help, Toll-like receptors and Fc receptors.

Abstract

The B-cell arm of the immune system has long been appreciated for its crucial role in pathogen resistance, but in the study of many autoimmune diseases, T cells have dominated the limelight for decades. However, the development of the B-cell-depleting antibody rituximab as a lymphoma therapy has provided a tool to probe the contribution made by B cells in several immune disorders. Recently, the success of B-cell depletion with rituximab in the treatment of rheumatoid arthritis has stimulated investigation of its effects in several other immune disorders, and considerable interest in the potential of drugs that can modulate B-cell function for the treatment of such diseases in general. This article discusses the role of B cells in a range of autoimmune disorders, including rheumatoid arthritis and systemic lupus erythematosus, and analyses approaches to therapeutic B-cell manipulation.

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Figure 1: B-cell lineages.
Figure 2: How B cells can be bad.
Figure 3: Mechanism of action of anti-CD20 antibodies.
Figure 4: Manipulation of B-cell survival.

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Acknowledgements

The author would like to thank M. Kehry, E. Notidis, A. Ranger, E. Beckman, S. Kalled and L. Burkly for helpful discussions and critical reading.

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Competing interests

J.B. is employed at Biogen Idec, which, along with Genentech and Roche are developing and selling Rituximab for the treatment of autoimmune disease. Likewise, Biogen Idec and Genentech are jointly developing BAFF receptor blockers for similar indications. A favourable article could be seen as advertising.

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DATABASES

OMIM

Crohn's disease

Grave's disease

Multiple sclerosis

Myasthenia gravis

Pemphigus vulgaris

Rheumatoid arthritis

Sjögren's syndrome

Systemic lupus erythematosus

Waldenstrom's macroglobulinaemia

Glossary

Rheumatoid factors (Rf)

Antibodies capable of recognizing soluble immunoglobulins. These antibodies represent a form of autoreactivity and are prevalent in rheumatoid arthritis and SLE.

Natural antibodies

Typically IgM antibodies formed early in development. These antibodies are produced by B1 cells (in mice) and do not display extensive hypermutation. They often have a low affinity for structures on the surfaces of bacteria and often can recognize multiple antigens — that is, they are polyreactive.

Plasma cells

Terminally differentiated B cells essentially dedicated to massive secretion of immunoglobulins. Short (2–3 days) and long-lived (0.5–1 year) versions exist; long-lived cells reside in the bone marrow and the short-lived cells remain in the splenic red pulp and the medullary cords of the lymph nodes. The gut compartment also has large numbers of plasma cells.

Extrafollicular response

For 2–6 days following B-cell activation in the presence of T-cell help, B cells undergo rapid proliferation and differentiation, leading to a burst of plasmablasts. Foci containing these cells remain in the T-cell region of the secondary lymphoid tissues. The resultant plasmablasts reside in the red pulp or medullary cords of the lymph nodes and survive for about 2–3 days.

Germinal-centre reaction

A collection of rapidly dividing B cells assembled on a scaffold of reticular cells. Within this nucleus, affinity maturation and class-switching events are optimized, and memory B cells and plasmablasts are generated.

Fc receptors

A family of generally low-affinity receptors that bind the immunoglobulin Fc domain. Oligomerized immunoglobulin is required for effective binding, and so these receptors serve a pivotal role as one of the primary sensors of immune complex formation. The receptors come in activating and inhibitory versions, and the balance between these two functions determines whether there is a response to immune complexes.

Complement

An enzyme cascade triggered by IgG immune complexes, bound IgM, some mannose-containing substances or certain bacterial surfaces. Activation deposits covalently the protein C3b on the antigen or pathogen, thereby marking it for binding by the various complement receptors. In the case of a cell surface, complement activation triggers the assembly of the membrane attack complex that kills the cell by forming pores in membrane.

Co-stimulatory molecules

A central dogma of immunology states that activation of T- or B-cell receptors alone is insufficient to initiate an immune response. Only when activation is accompanied by a second or third signal does cell activation ensue. The membrane receptors and ligands that provide the second and third signals are collectively referred to as co-stimulatory molecules.

Lymphotoxin system

Within the TNF family, the lymphotoxin-α/βligand binds to the lymphotoxin-β receptor on a subset of specialized stromal or endothelial cells to maintain their differentiation status. Constitutive lymphotoxin-β receptor signalling is required to maintain various micro-environments such as the polarized B-cell follicles, follicular dendritic cells and high endothelial venules.

Non-obese diabetic mice

(NOD mouse). A strain of autoimmune-prone mice that spontaneously develops diabetes due to an autoimmune attack on the pancreatic islet cells. This mouse serves as a common model for autoimmune disease and specifically human type I diabetes.

Lymphoid neogenesis

Within chronically inflamed tissues, leukocytic infiltrates can organize into an ectopic structure that resembles a lymph node. Aggregates of T and B cells, macrophages and dendritic cells assemble and specialized 'high endothelial venules' develop, allowing for additional trafficking opportunities. In the most organized cases, T cells segregate spatially from B cells, and germinal-centre reactions form within the B-cell follicle.

Antibody-dependent cellular cytotoxicity

(ADCC). Antibody-coated cells can be recognized by Fc receptors on natural killer cells and macrophages. Receptor engagement leads to direct killing of the coated cell by release of various agents.

Complement-dependent cytotoxicity

(CDC). Complement components assemble on complexes between antibodies and antigen (immune complexes). The assembly culminates with formation of the membrane attack complex, which directly creates pores in the membrane surface and kills the cell.

Affinity maturation

Somatic hypermutation results in altered antibodies and occurs efficiently in the germinal centre. Antibodies with higher affinity for the antigen are selected for as the response progresses.

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Browning, J. B cells move to centre stage: novel opportunities for autoimmune disease treatment. Nat Rev Drug Discov 5, 564–576 (2006). https://doi.org/10.1038/nrd2085

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