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TALL-1 and autoimmunity
Arthritis Research & Therapyvolume 3, Article number: 66802 (2000)
The TNF- and ApoL-related leukocyte-expressed ligand (TALL-1), known also as BAFF (B cell activating factor), THANK and BLYS (B lymphocyte stimulator), is a type II membrane protein of the TNF ligand superfamily which is involved in the modulation of B cell proliferation. In vitro recombinant TALL-1 induces B cell proliferation in a dose-dependent manner. In vivo administration intraperitoneally of recombinant TALL-1 into BALB/c mice causes disordered splenic architecture, B cell expansion and increased levels of IgM and IgA, but not IgG. To investigate the biological function of TALL-1 in vivo.
Necropsy of 8-week-old transgenic mice showed enlarged spleens (45% increase), lymph nodes and Peyer's patches. Immunohistologic staining with T- and B-cell- specific markers and flow cytometry analysis demonstrated that the B cell numbers were significantly increased, while the T cells numbers were reduced. All the other organs, including the thymus, were comparable between the transgenic mice and the littermate controls. No differences in B cell developmental stages were found. In addition to having B cell hyperplasia the TALL-1 trasgenic mice also had severe hypergammaglobulinemia. This was accompanied by the presence of elevated level of autoantibodies (ANA, anti-dsDNA and antihistone antibodies). Kidney lesions, compatible with immune complex deposits in the glomeruli, were detected in 8-month-old mice. Renal function was also impaired. In vitro transgenic expression of TALL-1 was shown to prolong B cell survival. In addition TALL-1 was demonstrated to be a weak stimulant and a powerful co-stimulant of B cell growth in vitro.
This interesting paper suggests a physiological role for TALL-1 (TNF- [tumour necrosis factor] and ApoL-related leukocyte-expressed ligand) in the regulation of B cell proliferation and activation. Transgenic TALL-1 mice developed an autoimmune phenotype, supporting the hypothesis that abnormalities in the regulation and thresholds of B and T cell activation may drive an autoimmune response. To understand the biological significance of these findings, however, it would have been useful to know the amount of transgenic TALL-1 present in circulation. It will be also of interest to determine if overexpression of this gene can be demonstrated in human autoimmune disorders.
TALL-1 transgenic mice were developed using standard techniques. Transgene expression was identified by RT-PCR of splenic total RNA. Histological analysis at various ages was performed. Expression of T and B lymphocyte activation markers from spleen, thymus and mesenteric lymph nodes was analysed by flow cytometry. Serum immunoglobulin levels, antinuclear antibody (ANA), anti-dsDNA and antihistone antibodies were quantitated by ELISA. B cell survival was investigated using B cells purified by negative selection from spleens of mice that were 2 to 4 months old. FACS analysis was used to confirm the purity of the B population. B cells were cultured in medium and the percentage of dead cells, identified by propidium iodide staining, was calculated daily. B cell proliferation was measured by the uptake of tritiated thymidine after stimulation with anti-mouse IgM and/or TALL-1 for 4 days.
Khare SD, Sarosi I, Xia XZ, McCabe S, Miner K, Solovyev I, Hawkins N, Kelley M, Chang D, Van G, Ross L, Delaney J, Wang L, Lacey D, Boyle WJ, Hsu H: Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci USA. 2000, 97: 3370-3375.