TNF Homologue Implicated in Systemic Lupus Erythematosus (SLE)

Figure 1. Panels A and B represent kidney sections from age-matched control (A) and zTNF4-TG (B) mice. Note the amyloid deposition and thickened mesangium of the glomeruli in panel B (arrows). Adapted from Gross, J.A. et al. (2000) Nature 404:995.

B cells play a key role in the development of autoimmune disease. B cell activation, production of pathogenic antibodies and co-stimulation of autoreactive T cells can promote autoimmunity. Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with polyclonal B-cell secretion of pathogenic autoantibodies and formation of immune complexes, which deposit in sites such as the kidney. Unregulated expression of the TNF homologue zTNF4 (BlyS, BAFF, TALL-1, THANK)1-5 can lead to the development of SLE-like symptoms.6

zTNF4 can stimulate proliferation of human B cells, augment immunoglobulin (Ig) production and upregulate cell surface expression of molecules involved in B cell effector function.1,2 Transgenic mice overexpressing zTNF4 (zTNF4-TG) demonstrate an expansion of splenic B-1a lymphocytes. This particular B-cell lineage is rare (0.5% of normal mice splenocytes) and produces primarily self-reactive IgM antibodies.7 IgM, IgG and IgE levels are increased in the serum of zTNF4-TG mice vs. control mice. Figure 1 represents an example of the appearance of kidney glomeruli within age-matched zTNF4-TG and control mice. Circulating levels of zTNF4 are also increased during the onset and progression of SLE in two mouse strains that develop chronic, spontaneous autoimmune disease.6,8

Two TNF receptor family members that bind zTNF4 include TACI9 and BCMA.10,11 A TACI-Ig fusion protein can prevent zTNF4 from binding to B cells and subsequently inhibit zTNF4 stimulatory activity in vitro.6 TACI-Ig treatment can also prolong survival in an animal model of SLE. Suppression of disease appears to result from a decrease in peripheral B cell populations within TACI-Ig treated animals.6 Interaction between zTNF4 and its receptors may thus regulate levels of peripheral B cells that are involved in the development of SLE.


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