Susceptibility to autoimmunity in B6.Sle1b mice is associated with extensive polymorphisms between two divergent haplotypes of the SLAM/CD2 family of genes. The B6.Sle1b-derived SLAM/CD2 family haplotype is found in many other laboratory mouse strains but only causes autoimmunity in the context of the C57Bl/6 (B6) genome. Phenotypic analyses have revealed variations in the structure and expression of several members of the SLAM/CD2 family in T and B lymphocytes from B6.Sle1b mice. T lymphocytes from B6.Sle1b mice have modified signaling responses to stimulation at 4-6 weeks of age. While autoimmunity may be mediated by a combination of genes in the SLAM/CD2 family cluster, the strongest candidate is Ly108, a specific isoform of which is constitutively upregulated in B6.Sle1b lymphocytes.

The susceptibility locus for the autoimmune disease lupus on murine chromosome 1, Sle1z/Sle1bz, and the orthologous human locus are associated with production of autoantibody to chromatin. We report that the presence of Sle1z/Sle1bz impairs B cell anergy, receptor revision, and deletion. Members of the SLAM costimulatory molecule family constitute prime candidates for Sle1bz, among which the Ly108.1 isoform of the Ly108 gene was most highly expressed in immature B cells from lupus-prone B6.Sle1z mice. The normal Ly108.2 allele, but not the lupus-associated Ly108.1 allele, was found to sensitize immature B cells to deletion and RAG reexpression. As a potential regulator of tolerance checkpoints, Ly108 may censor self-reactive B cells, hence safeguarding against autoimmunity.

Chapter summarySystemic lupus erythematosus (SLE) is the paradigm of a multisystem autoimmune disease in which genetic factors strongly influence susceptibility. Through genome scans and congenic dissection, numerous loci associated with lupus susceptibility have been defined and the complexity of the inheritance of this disease has been revealed. In this review, we provide a brief description of animal models of SLE, both spontaneous models and synthetic models, with an emphasis on the B6 congenic model derived from analyses of the NZM2410 strain. A hypothetical model of disease progression that organizes many of the identified SLE susceptibility loci in three distinct biological pathways that interact to mediate disease pathogenesis is also described. We finally discuss our recent fine mapping analysis, which revealed a cluster of loci that actually comprise the Sle1 locus.

MA104 cells (a monkey kidney cell line) can internalize 5-methyltetrahydrofolate via a receptor mediated process termed potocytosis. Uptake is initiated by binding to an external folate receptor which cycles to an internal, but membrane bound compartment. These two pools can be measured by determining the amount of [3H]ligand removed by an acid-saline wash, i.e. acid labile and acid resistant pools. When assayed in confluent nonmitotic cells, 2/3 of the folate receptor pool is located in an internal (acid resistant) compartment, but phorbol 12-myristate 13-acetate (PMA) causes a shift such that 65-75% of the receptor pool resides on the surface of the plasma membrane. This new steady state is likely the result of an increased rate of receptor movement. In addition, PMA increases the rate of 5-methyl[3H]tetrahydrofolate delivery to the cytoplasm 1.8 fold. Using known inhibitors of potocytosis, we were able to show that the increased rate of delivery is receptor mediated. Comparison of the time courses of the PMA effects on folate receptor redistribution assessed by membrane binding of [3H]folic acid and 5-methyl[3H]tetrahydrofolate delivery to the cytoplasm suggests that PMA may be activating more than one protein kinase C independent signal transduction pathway. PMA is the first reported positive modulator of receptor mediated folate uptake.

Motivated by the fundamental model of a collisionless plasma, the Vlasov-Maxwell (VM) system, we consider a related, nonlinear system of partial differential equations in one space and one momentum dimension. As little is known regarding the regularity properties of solutions to the nonrelativistic version of the (VM) equations, we study a simplified system which also lacks relativistic velocity corrections and prove local-in-time existence and uniqueness of classical solutions to the Cauchy problem. For special choices of initial data, global-in-time existence of these solutions is also shown. Finally, we provide an estimate which, independent of the initial data, yields additional global-in-time regularity of the associated field.