- Paper Report
- Open Access
Autoimmunity in BAFF transgenic mice
- Chaim Putterman1
© Current Science Ltd 2000
- Published: 24 March 2000
- BAFF (B cell activating factor)
- transgenic mice
Apoptosis of autoreactive T cells and B cells is an important mechanism by which self-tolerance is normally maintained. A striking example of this is the Fas/Fas ligand pathway, as the presence of defective Fas or Fas ligand molecules leads to lupus-like systemic autoimmunity in the mouse. The authors of this paper have recently identified another TNF-like ligand, which they called BAFF. This molecule has also been independently discovered by other groups and named TALL-1, THANK, and BlyS. BAFF has been shown to be expressed by dendritic cells, and binds to B cells. To further characterize and understand the physiological role of BAFF by generating mice transgenic for BAFF.
Mackay et al found an expanded B lymphocyte population in spleens and lymph nodes of BAFF-transgenic mice. B cells were also in a state of activation, as shown by increased expression of MHC class II. bcl2 expression was also upregulated. In the T cell compartment, about 50% of cells expressed the activated CD44hi, L-selectinlophenotype. Mature B cell numbers were increased in lymph nodes and spleen, while no change in mature or immature B cells was observed in the bone marrow, suggesting that it is mostly the peripheral mature B cells that are being affected. Histological and immunohistochemical studies confirmed the FACS findings.
BAFF-transgenic mice had significantly higher IgG and IgM levels. Most of the mice were positive for rheumatoid factor in the serum, mainly of the IgM, IgA, and IgG2a isotypes. Increased levels of circulating immune complexes and antibodies to single stranded DNA were also found in about 25% of the 21 animals examined. Anti-double-stranded-DNA activity was present in three of five mice in which this specificity was looked for. Kidney immunoglobulin deposition was present in six of six mice, and proteinuria (>+3) was found in nine of ten transgenic mice.
Transgenic mice overexpressing BAFF were generated under the control of the liver-specific promoter a-1 antitrypsin. Full-length BAFF was expressed with this promoter in order to study the systemic effects if BAFF were cleaved, or local liver changes if the molecule remains membrane-bound. Overexpression of BAFF was confirmed by northern blot. While an ELISA for BAFF was not available, the presence of soluble BAFF in the serum of the transgenic mice was supported by functional assays: serum from BAFF-transgenic mice inhibited the binding of soluble BAFF to BJAB cells, and increased human B cell proliferation with anti-IgM stimulation. B- and T cell compartments were analyzed by fluorescence-activated cell sorter (FACS) analysis. B cell subsets were analyzed in the bone marrow, spleen and mesenteric lymph nodes, to determine if BAFF was acting centrally on B cells, or in the periphery. In addition, histological, immunohistochemical, and serological analyses were carried out to elucidate the phenotype of BAFF overexpression.