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Int Rev Immunol. 1994;11(3):193-210.

Autoimmunity in mice bearing lprcg: a novel mutant gene.

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Department of Infectious Diseases and Applied Immunology, University of Tokyo, Japan.


A novel mutation at the lpr (lymphoproliferation)(Fas) locus, lprcg, that can complement gld (generalized lymphoproliferative disease) in induction of lymphadenopathy was discovered in CBA/K1Jms mice. The lpr and lprcg 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 lprcg/lprcg 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 lprcg and gld may be explained by less efficient apoptosis resulting from competition for the ligand between the functional and nonfunctional receptors. Phenotypically, lpr and lprcg are different from gld in the function at bone marrow (BM) and lymph node (LN) levels: lpr/lpr and lprcg/lprcg BM cause atrophy but gld/gld BM hyperplasia of wild-type (+/+) LNs, and lpr/lpr and lprcg/lprcg LNs but not gld/gld LNs allow the homing of lpr- and lprcg-induced DN T cells. Lymphadenopathy is equally prominent in CBA-lprcg/lprcg and MRL-lprcg/lprcg mice. Hypergammaglobulinemia, autoantibodies and circulating immune complexes are detectable at significant levels in both lprcg/lprcg mice but at higher levels on the MRL background. Pathological signs like glomerulonephritis and vasculitis are clinically unimportant in CBA-lprcg/lprcg but strikingly severe in MRL-lprcg/lprcg mice. Noticeably, clinically significant glomerulonephritis and vasculitis also develop with slight but significant serological aberrations in MRL-lprcg/+ heterozygotes. Graft-vs.-host disease-like syndrome in the lprcg/lprcg 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, lprcg 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 lprcg and gld is less severe in all the aspects, consistent with the receptor-ligand theory. The lprcg/lprcg 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.

[Indexed for MEDLINE]

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