Editors' ChoiceSystemic Lupus Erythematosus

Antibodies Stop Secretion of Antibodies in Lupus

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Science Translational Medicine  04 Jul 2012:
Vol. 4, Issue 141, pp. 141ec115
DOI: 10.1126/scitranslmed.3004529

People with the autoimmune disease systemic lupus erythematosus (SLE) endure chronic inflammation of the skin, kidneys, joints, nervous system, and other organs. Current therapies include steroids in combination with cytotoxic compounds (for example, cyclophosphamide), but not all patients respond to this treatment. A growing body of evidence suggests that autoantibodies secreted by B lymphocytes contribute to pathogenesis. This link between disease severity and antibody-secreting B cells has pointed to new, more specific treatment options. These include antibody therapy against two members of the tumor necrosis factor superfamily that activates B cells: B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL).

Joo and colleagues now have investigated the mechanism by which APRIL and BAFF induce B cell activation and autoantibody secretion in lupus patients: Their results show that serum from SLE patients, in concert with interferon α, induces differentiation of naïve monocytes into a specific type of dendritic cell (SLE-DC). These specialized dendritic cells coax naïve B cells to differentiate into the immunoglobulin G (IgG)– and IgA-secreting plasmablasts characteristic of SLE patients.

Using antibody co-cultures, the authors show that an antibody to BAFF reduces the amount of IgG secreted by B cells, and an antibody to both BAFF and APRIL reduces IgM and IgA secretion. Neither antibody could reduce immunoglobulin secretion when added to co-cultures of classically induced dendritic cells and naïve B cells. Joo et al. also demonstrate that a considerable amount of APRIL is bound to the surface of SLE-DC via CD138. In vitro, presentation of CD138-bound APRIL to B cells by SLE-DC leads to the induction of IgA switching and plasmablast differentiation. In humans, they show that the percentage of circulating, APRIL-expressing monocytes correlates with SLE disease activity.

The work by Joo et al. shows how B cells are stimulated to secrete a pathogenic autoantibody by a specific subset of dendritic cells found only in SLE patients, illuminating the mechanism of recently introduced treatments for the disease.

H. Joo et al., Serum from patients with SLE instructs monocytes to promote IgG and IgA plasmablast differentiation. J. Exp. Med., 11 June 2012 (10.1084/jem.20111644). [Abstract]

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