The Fms-like Tyrosine Kinase 3 Ligand, a Mediator of B Cell Survival, Is Also a Marker of Lymphoma in Primary Sjogren's Syndrome

Objective. To determine if the Fms-like tyrosine kinase 3 ligand (Flt-3L), a cytokine implicated in B cell ontogenesis and proliferation in hematologic malignancies, might be responsible for the increased numbers of circulating Bm2 and Bm2' B cell subsets in patients with primary Sjogren's syndrome (SS). Methods. Serum levels of Flt-3L were measured in 64 patients with primary SS and in 20 healthy controls matched for age and sex. Flt-3L and its receptor Flt-3 were quantified in circulating B cells and in salivary gland (SG) biopsy tissues by immunofluorescence analysis. The effect of Flt-3L on circulating B lymphocytes was then determined by coculture with cells of a human SG (HSG) epithelial cell line. Results. Serum levels of Flt-3L were increased in patients with primary SS as compared with controls (mean +/- SD 135.8 +/- 5.5 versus 64.4 +/- 4.5 pg/ml; P < 0.001). Serum levels of Flt-3L in primary SS patients correlated with the numbers of Bm2 and Bm2' cells (r = 0.46, P < 0.0006), and Flt-3 was selectively expressed in Bm2 and Bm2' cells. B cell culture experiments showed that Flt-3L potentiated the proliferative effect of anti-IgM stimulation. In SGs, we found that infiltrating B cells expressed Flt-3 and epithelial cells produced Flt-3L. Finally, Flt-3L levels were associated with high disease activity scores and increased risk of developing lymphoma. Conclusion. Serum levels of Flt-3L are elevated in patients with primary SS and correlate with abnormal B cell distribution. Flt-3 is mainly expressed by Bm2 and Bm2' cells. Serum levels of Flt-3L might explain the clinical evolution of primary SS to B cell lymphoma that is observed in some patients, thus opening the possibility of new avenues for therapy.