Autoimmunity in Mice Bearing lpr^cs: A Novel Mutant Gene

Abstract

A novel mutation at the lpr (lymphoproliferation) (Fas) locus, lpr^cg, that can complement gld (generalized lymphoproliferative disease) in induction of lymphadenopathy was discovered in CBA/K1Jms mice. The lpr and lpr^cg mutations are a defective allele of the Fas locus that encodes an apoptosis-mediating receptor. The former does not express the receptor and the latter expresses the point-mutated nonfunctional receptor. The gld locus is hypothesized to encode a ligand for the receptor and the gld mutation to have a defect that leads to incompetent expression of the ligand. The absence and non-functioning of the receptor in lpr/lpr and lpr^cg/lpr^cg mice, respectively, and the lack of the ligand in gld/gld mice may arrest apoptosis of lymphoid cells in the thymus, resulting in the same type of lymphadenopathy characterized by expansion of unusual CD4⁻CD8⁻DN) T cells. Less severe lymphadenopathy induced by complementarity between lpr^cg and gld may be explained by less efficient apoptosis resulting from competition for the ligand between the functional and nonfunctional receptors. Phenotypically, lpr and lpr^cg are different from gld in the function at bone marrow (BM) and lymph node (LN) levels: lpr/lpr and lpr^cg/lpr^cg BM cause atrophy but gld/gld BM hyperplasia of wild-type (+/+) LNs, and lpr/lpr and lpr^cg/lpr^cg LNs but not gld/gld LNs allow the homing of lpr- and lpr^cg-induced DN T cells. Lymphadenopathy is equally prominent in CBA-lpr^cg/lpr^cg and MRL-lpr^cg/lpr^cg mice. Hypergammaglobulinemia, autoantibodies and circulating immune complexes are detectable at significant levels in both lpr^cg/lpr^cg mice but at higher levels on the MRL background. Pathological signs like glomerulonephritis and vasculitis are clinically unimportant in CBA-lpr^cg/lpr^cg but strikingly severe in MRL-lpr^cg/lpr^cg mice. Noticeably, clinically significant glomerulonephritis and vasculitis also develop with slight but significant serological aberrations in MRL-lpr^cg/+ hetero-zygotes. Graft-vs.-host disease-like syndrome in the lpr^cg/lpr^cg BM→+/+ chimera is minimal on the CBA but as severe as life-threatening on the MRL background as in the MRL-lpr/lpr BM→MRL-+/+ chimera. Thus, autoimmune diseases induced by the lpr, lpr^cg and gld genes are actually indistinguishable in the clinical, serological and pathological aspects on the same strain background and the disease caused by the interaction between lpr^cg and gld is less severe in all the aspects, consistent with the receptor-ligand theory. The lpr^cg/lpr^cg mice with different strain backgrounds together with lpr/lpr and gld/gld mice will serve as a powerful tool for elucidation of the mechanism of development of single-gene autoimmune diseases at a molecular biological level.

Key Words:

• lymphoproliferation
• lpr^cg