Anatomy of autoantibody production: Dominant localization of antibody-producing cells to T cell zones in fas-deficient mice

Abstract

The goal of this study was to examine the in vivo site of autoantibody production in normal and autoimmune-prone mice. B cells were identified in tissue sections with IgM- and IgG2a-specific riboprobes that readily distinguished resting cells from antibody-forming cells (AFC). In normal mice, the few identifiable IgG2a-secreting cells were found in the red pulp. By contrast, in Ipr mice exceedingly high numbers of IgG2a and autoantibody-producing cells were found deep within the T cell-rich periarteriolar lymphoid sheaths (PALS). This unusual anatomic location of autoantibody-secreting B cells is unique to Fas dysregulated strains, since IgG2-producing cells in MRL/+ and (SWR x NZB)F1 mice were found predominantly in the red pulp or outer PALS, similar to normal mice. Furthermore, analysis of spleens from Ipr and non-Ipr anti-DNA immunoglobulin transgenic mice revealed dramatic accumulation of Tg+ cells in the inner PALS only in Ipr mice. These data suggest that in the absence of Fas, autoreactive B cells accumulate in T cell-rich zones, and this anatomic feature may contribute to autoantibody production.

Chronic Graft-Versus-Host in Ig Knockin Transgenic Mice Abrogates B Cell Tolerance in Anti-Double-Stranded DNA B Cells

“…This occurred not just in the bridging channels, as would be expected (53,54), but also in high concentration in the T cell area. The same pattern of AFC cell distribution has been observed previously by Marshak-Rothstein and colleagues (72) in another cGVH model, as well as in the conventional anti-DNA 3H9 transgenics on an autoimmune background (12,55). Further investigation should help determine what causes these AFC to congregate in the T cell area.…”

“…Additionally, a high concentration of darkly stained ϩ cells was present in the PALS, as well as in the bridging channels of the red pulp. This pattern of darkly staining cells, which presumably reflects intracytoplasmic Ig, has been correlated with AFC in several models (12,(52)(53)(54)(55). Curiously, the same pattern was also observed in bm1233H9(Ϫ) mice.…”

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

“…The major observation is that TLR2-and 4-deficient B6 lpr/lpr mice exhibit a lower proportion of MZ B cells than B6 lpr/lpr mice that could constitute another factor contributing to the decreased production of autoantibodies directed against TI Ags. Indeed, several works have shown that the autoantibody response, notably in MRL-Fas lpr/lpr mice, does not occur in the germinal centers but takes place at extrafollicular sites similar to those involving TI responses (44). This is particularly demonstrated for RF-secreting B cells and highly suspected for DNA-specific B cells (45,46).…”

Unusual expression of LINE-1 transposable element in the MRL autoimmune lymphoproliferative syndrome-prone strain

“…Germinal centres in the spleen and LN are areas of intense proliferation of antigen-specific B cells. Such localization was not possible in the MRL/ lpr strain because the anatomic organization of the spleen is disrupted due to the accumulation of T lymphocytes expressing the CD4 7 CD8 7 B220 + phenotype (Jacobson et al, 1995). Regardless of the strain, the striking feature of splenic ISH was the ringlabelling pattern encircling a weakly labelled nucleus ( Figure 2C,a), which shows the presence of LINE-1 sense-strand transcripts in the cytoplasm.…”