Studies on the Mechanism of Induction of Autoimmune Disease by the Novel Lymphoproliferation gene, lpr^<cg>

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Several mice with generalized lymphadenopathy were found in the CBA/KlJms (CBA) colony maintained at the Laboratory Animal Research Center. A new mutant strain of mice that develop massive lymphoid hyperplasia at 100% incidence within 5 months of age was established by crossing these diseased mice. Genetic analyses revealed that lymphadenopathy is controlled by a single autosomal recessive gene which is allelic with lpr but can complement qld on chromosome 1 in the induction of swelling of lymph nodes (LN). Thus, the new mutant gene was named lpr^<cg> and the mutant strain was designa Led CBA-lpr^<cg>/lpr^<cg> (CBA-lpr^<cg>). Mutant mice developed hypergammaglobulinemia and various autoantibodies, and their swelled LN were composed of Thy-l^+CD4^-CD8^-B220^+ lymphoid cells or "double-negatice (DN)" T cells. Bone marrow (BM) transfer from CBA-lpr^<cg> to CBA-+/+ (CBA-+) mice caused autoantibody formation but not lymphadenopathy. We developed a simple technique for whole LN transplantati … More on to, demonstrate that lpr^<cg> DN T cells could home into lpr^<cg> and lpr LN but not into gld and + LN. Therefore, the lpr and gld genes are different from each other in the phenotype expression at the LN site. LN from mice heterozygous for both lpr^<cg> and gld (1pr^<cg>-gld mice) allowed homing of 1pr^<cg> DN T cells in support of the cooperativity between lpr^<cg> and gld. Despite milder lymphadenopathy in lpr^<cg>-gld mice, the expanding LN cells showed the same pattern of surface markers as that in lpr^<cg> and gld mice. Serum immunoglobulin and autoantibody levels of IgM class but not those of IgG class were elevated in lpr^<cg> and gld mice. Serum IgG from ILRO and lpr^<cg>-gld mice induced interleukin 3 in an interleukin 3-dependent cell line in relation to the severity. of lymphadenopathy. Athymic lpr^<cg> mice were constructed to investigate the role of the thymus in induction of lymphadenopathy by lpr^<cg>. LN swelling occurred with thymus grafts regardless of their genetic backgrounds but not without them, indicating that the thymus is essential for abnormal differentiation of BM cells into DN T cells. The lpr^<cg> gene is being mapped on chromosome 19. Less