The Fms-like tyrosine kinase 3 ligand, a mediator of B cell survival, is also a marker of lymphoma in primary Sjögren'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 Sjögren'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.


CONCLUSIONS
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.
Tobón
Gabriel J
GJ
EA 2216 Immunology and Pathology and IFR 148 ScInBioS, Université de Brest, and Université Européenne de Bretagne, Brest, France.
Renaudineau
Yves
Y
Hillion
Sophie
S
Cornec
Divi
D
Devauchelle-Pensec
Valérie
V
Youinou
Pierre
P
Pers
Jacques-Olivier
JO
D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002470:Cell Survival; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008223:Lymphoma / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D012859:Sjogren's Syndrome / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D018709:Statistics, Nonparametric; D051941:fms-Like Tyrosine Kinase 3 / Q000276:immunology / Q000378:metabolism*
D015415:Biomarkers; D008565:Membrane Proteins; D012333:RNA, Messenger; C084881:flt3 ligand protein; D051941:fms-Like Tyrosine Kinase 3