Systemic Lupus Erythematosus Animal Models

Argyrios N Theofilopoulos, Immunology Department, Research Institute of Scrlpps Clinic, La Jolla, California, USA

Copyright © 1998 Elsevier Ltd. All Rights Reserved.

As in any disease entity, animal models with spontaneous incidence of systemic autoimmunity have been sought, and a few have been identified. Of these models, the inbred murine strains of lupus are the best suited for study because their serologic, cellular and histopathologic characteristics closely match the corresponding human disorder.

There are three main types of mice with lupus predisposition (Table 1). The New Zealand (NZ) mice (NZB, NZW and their F1 hybrid), the BXSB mouse and the MRL mouse. Crosses of SWR with NZB also develop a lupus-like disease, as do certain F1 mice undergoing a graft-versus-host reaction upon injection of parental lymphoid cells, and mice with the motheaten (me) mutation. The NZB (H-2d) and the NZW (H-2'-) mice are of unknown background, the BXSB mouse (H-2b) was derived from crosses of C57BL/6 females with SB/Le males, and the MRL mouse has a complex genome composed of LG/J (75%), AKR (12.6%), C3H (12.1%) and C57BL/6 (0.3%). For (NZB X W)F1 mice, the females develop disease earlier than males, but, in contrast, BXSB males are much more severely affected. During inbreeding, some of the MRL offspring developed massive lymph node enlargement, splenomegaly and early-life severe lupus, while others remained free of this lymphoid cell accumulation and developed a mild, late-life, lupus disease, thereby creating the MRL-lpr/lpr (lymphoproliferation) and the MRL-+/+ sublines, respectively. The incidence and severity of disease is almost equal for both MRL-/pr sexes. The Ipr mutation is inherited as a single autosomal recessive gene. Since its original description, the Ipr mutation has been transferred to a number of other standard inbred strains. These normal background Ipr homozygous mice similarly develop various grades of lymphadenopathy and autoantibodies but, in contrast to lupus-background Ipr homozygous mice, exhibit minimal histopathologic manifestations, thereby indicating the requirement of additional genes for lupus pathology.

Two additional single autosomal recessive mutations, termed gld (generalized lymphoprolifer-ative disease) and lprCf- (/pr-complementing gene) have been described. Normal background mice with these mutations also develop early-onset humoral autoimmune responses and lymphoid hyperplasia, but histopathologic manifestations such as nephritis and vasculitis are minimal. The Ipr mutation (mapped on chromosome 19) and the gld mutation (mapped on chromosome 1) are nonallelic and non-complementary, while the Ipr■L'B mutation is complementary to both the Ipr and the gld mutation.

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