Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren’s syndrome
Joanna Groom, … , Charles R. Mackay, Fabienne Mackay
Joanna Groom, … , Charles R. Mackay, Fabienne Mackay
Published January 1, 2002
Citation Information: J Clin Invest. 2002;109(1):59-68. https://doi.org/10.1172/JCI14121.
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Article

Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren’s syndrome

Abstract

BAFF (BLyS, TALL-1, THANK, zTNF4) is a member of the TNF superfamily that specifically regulates B lymphocyte proliferation and survival. Mice transgenic (Tg) for BAFF develop an autoimmune condition similar to systemic lupus erythematosus. We now demonstrate that BAFF Tg mice, as they age, develop a secondary pathology reminiscent of Sjögren’s syndrome (SS), which is manifested by severe sialadenitis, decreased saliva production, and destruction of submaxillary glands. In humans, SS also correlates with elevated levels of circulating BAFF, as well as a dramatic upregulation of BAFF expression in inflamed salivary glands. A likely explanation for disease in BAFF Tg mice is excessive survival signals to autoreactive B cells, possibly as they pass through a critical tolerance checkpoint while maturing in the spleen. The marginal zone (MZ) B cell compartment, one of the enlarged B cell subsets in the spleen of BAFF Tg mice, is a potential reservoir of autoreactive B cells. Interestingly, B cells with an MZ-like phenotype infiltrate the salivary glands of BAFF Tg mice, suggesting that cells of this compartment potentially participate in tissue damage in SS and possibly other autoimmune diseases. We conclude that altered B cell differentiation and tolerance induced by excess BAFF may be central to SS pathogenesis.

Authors

Joanna Groom, Susan L. Kalled, Anne H. Cutler, Carl Olson, Stephen A. Woodcock, Pascal Schneider, Jurg Tschopp, Teresa G. Cachero, Marcel Batten, Julie Wheway, Davide Mauri, Dana Cavill, Tom P. Gordon, Charles R. Mackay, Fabienne Mackay

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Figure 4

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Elevated levels of BAFF in sera and salivary gland tissues from patients...
Elevated levels of BAFF in sera and salivary gland tissues from patients suffering from primary SS; no correlation with levels of total IgG, RF, and presence of anti-Ro/La autoantibodies. (a) Individual serum BAFF levels in 39 healthy controls (squares), 41 patients with primary SS (diamonds), 53 patients with SLE (circles), and 53 patients with RA (triangles) were measured by ELISA. The horizontal black bars indicate the mean for each group: normal 10.4 ± 13 (ng/ml); SS 53 ± 67 (ng/ml); SLE 12.7 ± 24.4 (ng/ml); and RA 23 ± 47 (ng/ml). Sera of 16 normal individuals, 6 SS, 20 SLE, and 10 RA patients had no detectable levels of BAFF. The dotted line delineates the range of normal BAFF levels. *P < 0.04, as determined by ANOVA. (b and c) Correlation of serum BAFF levels in patients with SS with the levels of IgG (b) and RF (c) in each serum sample. R and P values were calculated by ANOVA. (d) Levels of BAFF in patients with anti-Ro plus anti-La or anti-Ro only, and in patients with no precipitin detected (Neg). (e) Paraffin sections of a human labial gland biopsy from a patient with SS were stained with anti-human BAFF antibody or an isotype-matched control antibody. Magnification: ×200. Staining of normal human labial gland with anti-human BAFF antibody is also shown (magnification: ×100). These pictures are representative of four patients with primary SS and three control tissues analyzed. RF, rheumatoid factors.