Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice

Abstract

TALL-1/Blys/BAFF is a member of the tumor necrosis factor (TNF) ligand superfamily that is functionally involved in B cell proliferation. Here, we describe B cell hyperplasia and autoimmune lupus-like changes in transgenic mice expressing TALL-1 under the control of a beta-actin promoter. The TALL-1 transgenic mice showed severe enlargement of spleen, lymph nodes, and Peyer's patches because of an increased number of B220+ cells. The transgenic mice also had hypergammaglobulinemia contributed by elevations of serum IgM, IgG, IgA, and IgE. In addition, a phenotype similar to autoimmune lupus-like disease was also seen in TALL-1 transgenic mice, characterized by the presence of autoantibodies to nuclear antigens and immune complex deposits in the kidney. Prolonged survival and hyperactivity of transgenic B cells may contribute to the autoimmune lupus-like phenotype in these animals. Our studies further confirm TALL-1 as a stimulator of B cells that affect Ig production. Thus, TALL-1 may be a primary mediator in B cell-associated autoimmune diseases.

Figure 1

Histology analysis of TALL-1 transgenic mice. Sections of spleen (A–C), lymph node (D–F), and Peyer's patches (G–I) from control mice (Left) and TALL-1 transgenic mice (Right) were stained with hematoxylin and eosin (A, D, and G), anti-mouse B220 antibody (B, E, and H), or anti-mouse CD3 antibody (C, F, and I). Stained sections were analyzed under microscope at ×10.

Figure 2

FACS analysis splenocytes, lymph node cells, and thymocytes of TALL-1 transgenic mice. Single-cell suspensions were prepared from spleen, lymph nodes, and thymus from 10 TALL-1 transgenic mice and 5 control littermates. Cells were stained with FITC- or PE-conjugated monoclonal antibodies against Thy-1.2, B220, CD11b, Gr-1, CD4, or CD8.

Figure 3

Kidney Ig deposits in TALL-1 transgenic mice. Kidney sections of 5-mo-old control littermate (A–C), 5-mo-old TALL-1 mice (D–F), and 8-mo-old TALL-1 mice (G–I) were stained with hematoxylin and exosin (A, D, and G), anti-mouse IgM (B, E, and H), anti-mouse IgG (C, F, and I), and Trichrome (G, Inset). Stained sections were analyzed under microscope at ×60.

Figure 4

TALL-1 stimulates B cell survival and proliferation. (A) Increased B cell viability in TALL-1 transgenic mice. B cells were isolated from spleens of 3-mo-old TALL-1 transgenic mice (n = 3) and control littermates (n = 3). A total of 2.5 × 10⁵ B cells was aliquoted per well in a 96-well round-bottom plate and incubated for 9 days. At the indicated days, cells were incubated with 5 μg/ml propidium iodide and subjected to FACS analysis for positive staining cells. Values are expressed as mean ± SEM. (B) TALL-1 stimulates B cell proliferation. Purified B cells (10⁵) from B6 mice were cultured in triplicates in 96-well plate with indicated amount of TALL-1 at the absence (Upper) or presence of 2 μg/ml anti-IgM antibody (Lower) for a period of 4 days. Proliferation was measured by radioactive [³H]thymidine uptake in the last 18 h of pulse. Data shown represent mean ± SD of triplicate wells.