Direct B cell stimulation by dendritic cells in a mouse model of lupus.
OBJECTIVE
Dendritic cells (DCs) play a major role in regulating lymphocytes, including B cells, and defective DC functions have been implicated in lupus. The purpose of this study was to assess the contribution of DCs to B cell hyperactivity in the B6.Sle1.Sle2.Sle3 (B6.TC) murine lupus model.


METHODS
We compared the effects of B6 and B6.TC bone marrow-derived DCs on naive B cells cocultured in the presence of lipopolysaccharide (LPS), anti-CD40, or anti-IgM. We measured the proliferation, antibody production, and expression of activation markers and chemokine receptors for the B cells, as well as DC cytokine production. B cell proliferation was also assessed in Transwell experiments and in response to activated DC supernatants or exosomes. The role of DC-produced cytokines was evaluated with blocking antibodies and transgenic mice.


RESULTS
LPS-stimulated or anti-CD40-stimulated DCs from B6.TC mice increased B cell proliferation, antibody production, and chemokine receptor expression as compared with DCs from B6 mice. Cell-to-cell contact was not necessary for the augmented effect of the lupus-prone DCs. Anti-CD40 treatment induced a higher production of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), IL-10, and tumor necrosis factor alpha in B6.TC DCs. Blocking these individual cytokines, however, did not abrogate the effects of B6.TC DCs. Additional experiments also ruled out involvement of BAFF, IL-12, and interferon-alpha.


CONCLUSIONS
Activated DCs from B6.TC mice directly increase B cell effector functions. This effect depends on soluble factors released by activated DCs, but none of the single major DC-produced cytokines known to affect B cells are necessary. Increased sIL-6R production suggests that increased sensitivity to IL-6 may be involved.
University of Florida, Gainesville, FL 32610-0275, USA.
Suigui
S
Wan
Zhenhai
Z
Zhou
Biyan
B
Duan
Laurence
L
Morel
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology*; D049109:Cell Proliferation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D019707:Receptors, Chemokine / Q000378:metabolism
D000906:Antibodies; D019707:Receptors, Chemokine