Prevention of murine antiphospholipid syndrome by BAFF blockade.
OBJECTIVE
This study was undertaken to determine whether BAFF blockade can be used to prevent or treat antiphospholipid syndrome in a mouse model.


METHODS
Eight- and 12-week-old (NZW x BXSB)F(1) mice were treated with BAFF-R-Ig or TACI-Ig alone or in addition to a short course of CTLA-4Ig. Mice were monitored for thrombocytopenia and proteinuria. Sera were tested for anticardiolipin antibodies (aCL), BAFF levels, and levels of soluble vascular cell adhesion molecule and E-selectin. Mice were killed at 17, 22, or 32 weeks of age, and kidneys and hearts were subjected to histologic examination. Spleen cells were phenotyped and enzyme-linked immunospot assays for autoantibody-producing B cells were performed.


RESULTS
Both BAFF-R-Ig and TACI-Ig prevented disease onset and significantly prolonged survival. Treated mice had significantly smaller spleens than controls, with fewer B cells and fewer activated and memory T cells. BAFF blockade did not prevent the development of aCL, and there was only a modest delay in the development of thrombocytopenia. However, treated mice had significantly less nephritis and myocardial infarcts than did controls.


CONCLUSIONS
Our findings suggest that aCL are generated in the germinal center, which is relatively independent of BAFF. Effector function of antiplatelet antibodies was only modestly affected by BAFF blockade. In contrast, myocardial infarctions were prevented, suggesting that triggering of thromboses requires both autoantibodies and mediators of inflammation. Similarly, renal damage requires both immune complexes and effector cells. The dissociation between autoantibody production and inflammation that may occur with B cell-depleting therapies underscores the role of B cells as effector cells in the autoimmune response.
Kahn
Philip
P
Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
Ramanujam
Meera
M
Bethunaickan
Ramalingam
R
Huang
Weiqing
W
Tao
Haiou
H
Madaio
Michael P
MP
Factor
Stephen M
SM
Davidson
Anne
A