Abstracts (complete list) - Wissenschaft Online

Kirsten Neubert, Silke Meister, Damian Maseda, Kerstin Amann, Reinhard Voll
Proteasome inhibition ameliorates lupus symptomes in NZB/
W mice
Systemic lupus erythematosus (SLE) is an autoimmune disease which is characterized
by circulating IgG autoantibodies predominantly directed towards nuclear antigens. The
proteasome inhibitor bortezomib (Bz) is used for the treatment of multiple myeloma, a
malignant plasma cell neoplasia. One mechanism of Bz might be the blockade of the key
transcription factor NF-κB, which is also important for survival of B lymphocytes
especially mature B cells. Therefore, we investigated the effects of NF-κB inhibiting
agents such as Bz in a mouse model for SLE.
To address this question, we treated NZB/W mice with Bz twice weekly over 10 months.
Bz-treated mice have significantly prolonged survival time and decreased proteinuria
compared to the control mice. Histologically, there were no or only minor signs of
glomerulonephritis in Bz-treated mice. The IgG anti-dsDNA and anti-Histone antibodies
were strongly reduced during the whole treatment. The IgG concentrations in sera were
significantly decreased during the first months of treatment, respectively. After the first
month of treatment the IgG serum concentrations increased again and reached the
levels of control mice.
Flow cytometric analyses of the splenic lymphocyte compartment from NZB/W mice,
which were Bz-treated over 8 weeks, revealed a strong reduction of T and B cell
numbers. Interestingly, Bz had no significant effect on the B cell numbers in the bone
marrow.
These data indicate that Bz prolongs the survival and ameliorates the clinical
parameters of lupus-like disease in NZB/W mice. We suggest that both T and B
lymphocyte subsets are affected by Bz, potentially due to inhibition of NF-κB activation
along with induction of terminal endoplasmic reticulum stress leading to apoptotic cell
death of lymphocytes.