Spontaneous development of plasmacytoid tumors in mice with defective Fas-Fas ligand interactions.

The recessive mutant genes, lpr and gld, map to the Fas and Fasl (ligand) loci, respectively (1, 2). In normal mice, Fas encodes a 45-kD cell surface receptor (Fas/ CD95/APO-1) belonging to the TNF/NGF receptor family and Fasl encodes a 40-kD type II membrane protein, FasL, homologous to members of the TNF family (1–5). In receptive cells, the aggregation of Fas receptors by FasL or anti-Fas mAb leads to the induction of cell death by apoptosis (6–8). Mice bearing the lpr mutation have a defect in the expression of Fas caused by the insertion of a retroviral transposon into the second intron of Fas that prevents normal transcription of the gene (1, 3). In gld mice, a point mutation in the COOH-terminal region of Fasl results in the expression of a non-functional form of FasL on the cell surface (2, 4). Defective interactions between Fas and FasL in mice homozygous for lpr or gld lead to indistinguishable, progressive diseases typified by profound lymphadenopathy, splenomegaly, high titers of circulating autoantibodies, hypergammaglobulinemia, strain-dependent systemic autoimmune disease and premature death (reviewed in reference 9). Recently, there have been several reports of pediatric patients with a variety of genetic mutations at the FAS locus and a spectrum of immune abnormalities closely resembling those of lpr and gld mice (10–14). The consistency of the immunologic defects associated with Fas mutations suggests a universal role for the Fas-associated cell deletion pathway in regulating lymphocyte survival and in preventing the accumulation of autoreactive B cells. Between 1 and 6 mo of age, the spleens and lymph nodes of lpr and gld mice undergo progressive enlargement associated with the accumulation of two functionally unresponsive B220+ T cell subsets not detected in normal mice. Lymphadenopathy results predominantly from the selective amassing of non-transformed B220+CD4−CD8− double negative (B220+DN)1 T cells (9, 15). The majority of these cells are derived from CD8+ precursors selected in the thymus on MHC class I Ag (16–19). The other B220+ T cell subset is a minor one that expresses low levels of CD4 and arises independently of MHC class I expression (16–20). As the B220+ T cells accumulate, they dilute conventional CD4+ and CD8+ T cells and B cells and disrupt the normal architecture of the spleen and LN. Although normal T and B lymphocytes are reduced by proportion, their total numbers in LN are increased approximately 10-fold (21, 22). The expanded CD4+ and CD8+ T cell populations in 4–6-mo-old lpr and gld mice are greatly enriched for memory-like cells (9, 20–23). Similarly, the B cell population is enriched for cells with the phenotype of chronically activated B cells and for Ig-secreting cells (9, 24). The skewing of the T and B cell populations towards primed and activated cells is consistent with the demonstrated role of Fas-mediated apoptosis in regulating the survival of Ag-activated T cells and autoreactive B cells (25–29). For C3H-gld, C3H-lpr and BALB-gld mice whose median lifespans are ∼12 mo, lymphoproliferative disease persists until death but the cellular composition of the lymphoid tissues in aging mice has not been extensively studied. Although defective Fas–FasL interactions in lpr and gld mice lead to the accumulation of massive numbers of lymphocytes, there have been no reports of malignant T or B lineage tumors arising in these mice. In unpublished studies involving the transfer of spleen cells from BALB-gld mice with advanced disease into immunodeficient CB.17-scid mice, we observed that a significant number of recipients developed malignant B cell lymphomas of donor origin. To further investigate the possibility that gld mice spontaneously develop lymphomas that are masked by the preexisting lymphoproliferative disease, we surveyed groups of C3H-gld and BALB-gld mice of various ages for evidence of clonal, transformed lymphoid populations. These studies revealed that by 1 yr of age, 28% of C3H-gld mice and 57% of BALB-gld mice had monoclonal outgrowths of B cells in spleen and LN. After transfer into scid recipients, the majority of these clonal B cell populations gave rise to metastatic plasmacytoid tumors. These findings provide evidence that in addition to limiting the accumulation of polyclonally activated and autoreactive lymphocytes, normal Fas–FasL interactions also prevent the development of B cell neoplasms.