Bcells Gone Wrong

B lymphocytes normally respond only to foreign substances, or antigens, such as bacteria. But in people with lupus the cells react to the body's own molecules, generating antibodies that bind to those "self-antigens" and then accumulate in tissues. There the antibody-antigen complexes lead to tissue damage. Several therapies under study for lupus aim to delete B cells or to block one or another of the molecular interactions that lead to antibody production and tissue injury. Red arrows in the diagram point to molecules targeted by the drugs listed in the table below.


B cell


Cytokine receptor

The stage for antibody production is set when antigen-presenting cells take up and degrade potential antigens (a). They fit selected fragments into MHC molecules and display the resulting complexes on the cell surface for perusal by helper T cells ( b ).

Activated T cells

Microbe or cellular debris

Activated T cells

Antigen complex

Activation signal

T cell receptor MHC II

Cytokine receptor

I CD40 CD1S4


B cell receptor

Antigen complex

Activation signal

T cell receptor MHC II


If a T cell binds to such a complex and also links to a B7 molecule on the antigen-presenting cell, the signals generated by the binding will activate the T cell, causing it to proliferate (c) and undergo changes that enable it to stimulate B cells (d). In particular, the T cells begin to secrete stimulatory cytokines, or signaling molecules, and to display a molecule called CD154 that can lock onto CD40 on B cells.

B cell activation also depends on several other signaling events (e), including attachment of the T cell receptor to the same antigen-MHC complex it saw on the antigen-presenting cell, stimulation of the B cell by a molecule called BAFF, and binding of antigen by B cell receptors. A receptor known as CD20 may also participate in B cell activation, although its exact function is still unclear.

Fragments of ingested matter

Antigen-presenting cell

Some Treatment Strategies under Study


Blocker of B7's interaction with CD28, to impede activation of helper T cells

Blocker of BAFF's interaction with its receptor, to keep BAFF (also called BLyS) from promoting B cell survival and antibody production

Blocker of B cell receptors and of antibodies that recognize the body's own DNA, to inhibit the production and activity of antibodies that target such DNA

Antibody to CD20, to deplete B cells

Complement inhibitor, to prevent complement-mediated tissue damage


Immune Tolerance Network, a research consortium, and the National Institutes of Health are undertaking a small human trial of a blocker called RG2077

Human Genome Sciences (Rockville, Md.) is evaluating one such drug, LymphoStat-B, in a multicenter trial; ZymoGenetics (Seattle) and Serono S.A. (Geneva, Switzerland) are conducting an early human trial of an agent named TACI-Ig

La Jolla Pharmaceuticals (San Diego) is conducting a multicenter trial of abetimus sodium (Riquent) against lupus-related kidney disease

Genentech (South San Francisco, Calif.) and Biogen Idec (Cambridge, Mass.) are conducting a multicenter lupus trial of rituximab (Rituxan), a drug already approved for B cell cancer

Alexion Pharmaceuticals (Cheshire, Conn.) found evidence of disease amelioration in mice given an inhibitor of complement C5

Having received the needed stimulation, a B cell matures into an antibody-secreting plasma cell (f), and the antibodies go off to attack or mark for destruction any cells or tissues possessing the antigen recognized by the antibodies (g). For instance, antibodies attract complement molecules and inflammatory cells, both of which can be destructive (inset).

Having received the needed stimulation, a B cell matures into an antibody-secreting plasma cell (f), and the antibodies go off to attack or mark for destruction any cells or tissues possessing the antigen recognized by the antibodies (g). For instance, antibodies attract complement molecules and inflammatory cells, both of which can be destructive (inset).

administration of large quantities of irradiated apoptotic cells is able to induce autoantibody synthesis in normal mice.

Hence, part of the underlying process leading to the formation of destructive immune complexes may involve the body's production of foreign-seeming antigens, which cause the body to behave as if tissues bearing those antigens were alien and threatening. But other work indicates that, in addition, the B lymphocytes of lupus patients are inherently deranged; they are predisposed to generate autoantibodies even when the self-molecules they encounter are perfectly normal. In other words, the mechanisms that should ensure self-tolerance go awry.

Deranged Cells the problem mostly seems to stem from signaling imbalances within B cells. In the healthy body, a B cell matures into an antibody-secreting machine—known as a plasma cell—only after antibodylike projections on the B cell's surface (B cell receptors) bind to a foreign antigen. If a B cell instead attaches to a self-component, this binding normally induces the cell to kill itself, to retreat into a nonresponsive (anergic) state or to "edit" its receptors until they can no longer recognize the self-antigen.

Whether the cell responds appropriately depends in large measure on the proper activity of the internal signaling pathways that react to external inputs. Mouse studies show that even subtle signaling imbalances can predispose animals to produce antibodies against the self. And various lines of evidence indicate that certain signaling molecules (going by such names as Lyn, CD45 and SHP-1) on and in B cells of patients with lupus are present in abnormal amounts.

Other work suggests that it is not only the B cells that are deranged. For a B cell to become an antibody maker, it must do more than bind to an antigen. It must also receive certain stimulatory signals from immune system cells known as helper T lymphocytes. Helper cells of lupus patients are afflicted by signaling abnormalities reminiscent of those in the B cells. The T cell aberrations, though, may lead to autoantibody production indirectly—by causing the T cells to inappropriately stimulate self-reactive B cells.

All theorizing about the causes of lupus must account not only for the vast assortment of autoantibodies produced by patients but also for another striking aspect of the disease: the disorder is 10 times as common in women than in men. It also tends to develop earlier in women (during childbearing years). This female susceptibility—a pattern also seen in some other autoimmune diseases—may stem in part from greater immune reactivity in women. They tend to produce more antibodies and lymphocytes than males and, probably as a result, to be more resistant to infections. Among mice, moreover, females reject foreign grafts more rapidly than the males do. Perhaps not surprisingly, sex hormones seem to play a role in this increased reactivity, which could explain why, in laboratory animals, estrogens exacerbate lupus and androgens ameliorate it.

Estrogens could pump up immune reactivity in a few ways. They augment the secretion of prolactin and growth hormone, substances that contribute to the proliferation of lymphocytes, which bear receptor molecules sensitive to estrogens. Acting through such receptors, estrogens may modulate the body's immune responses and may even regulate lymphocyte development, perhaps in ways that impair tolerance of the self.

Toward New Therapies those of us who study the causes of lupus are still pondering how the genetic, environmental and immunological features that have been uncovered so far collaborate to cause the disease. Which events come first, which are most important, and how much do the underlying processes differ from one person to another? Nevertheless, the available clues suggest at least a partial scenario for how the disease could typically develop.

The basic idea is that genetic susceptibilities and environmental influences may share responsibility for an impairment of immune system function—more specifically an impairment of the signaling within lymphocytes and possibly within other cells of the immune system, such as those charged with removing dead cells and debris. Faulty signaling, in turn, results in impaired self-tolerance, accelerated lymphocyte death, and defective disposal of apoptotic cells and

MONCEFZOUALI, an immunologist and molecular biologist, is a director of research at INSERM, the French national institute for medical research. He focuses on conducting basic research into the molecular causes of systemic autoimmune diseases and on translating scientific insights into useful approaches to disease management. Zouali has edited several books on autoimmunity and won research awards.

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