Differences Defined by Bone Marrow Transplantation

Homozygosity for either of the lymphoproliferation (lpr) or generalized lymphoproliferative disease (g1d) mutations o£ mice causes the development of systemic lupus erythematosus-like autoimmune syndromes that are characterized by severe lymphadenopathy and highly elevated serum immunoglobulin levels. Although the mutations are nonallelic, analysis of homozygous lpr/lpr and gidlgld mice on the same strain background has indicated that the pathology and severity of the autoimmune syndromes induced by these mutations are indistinguishable. To explain this, it has previously been suggested that lpr and gld may represent mutations in molecules involved in sequential steps of an intracellular metabolic pathway of T cells . We have now investigated the behavior ofboth lpr andgldin a variety ofbone marrow chimeras and have found that functional differences between lpr and gld become apparent after bone marrow transfer. Transfer of lprllpr bone marrow to irradiated congenic + /+ recipients caused the development of a graft-vs.-host-like lymphoid wasting syndrome, whereas transfer ofgld/gld bone marrow to + /+ recipients resulted in development ofagld-like autoimmune syndrome. Additionally, gld/gld hosts behaved like + /+ hosts irrespective of the genotype of the donor bone marrow, whereas lpr/lpr hosts behaved unlike + /+ hosts when reconstituted with either lpr/lpr, gld/gld, or + /+ bone marrow. These are the first clear differences between these two mutations yet described . Our studies indicate that the molecule altered by theg1dmutation is expressed only by bone marrow-derived cells, whereas the molecule altered by the lpr mutation is expressed by both bone marrow-derived cells and by one or more peripheral radioresistant cell populations. To reconcile these differences with the fact that homozygous lpr/lpr andgld/gld mice are indistinguishable, we suggest an alternative model for the relationship between the lpr and gld mutations in which the two molecules affected represent an interacting ligand-receptor pair expressed by different cells .