L Gabriel

A Defect in Marco Expression Contributes to Systemic Lupus Erythematosus Development via Failure to Clear Apoptotic Cells

Systemic lupus erythematosus is a multisystem autoimmune disease characterized by the production of numerous antinuclear autoantibodies and inflammatory mediators. The BXSB mouse strain is an excellent model of the disease. Previous work has determined a number of important disease susceptibility intervals that have been isolated in separate congenic strains. Here, we have combined expression data from those strains with functional analyses to demonstrate that reduced expression of the innate scavenger receptor Marco (macrophage receptor with collagenous structure) is a primary event in BXSB mice, that reduced mRNA expression is mirrored at the protein level, and that this results in a significant alteration in function. We have confirmed a role for Marco in the clearance of apoptotic cells and a generalized defect in both endocytosis and phagocytosis. The failure to clear apoptotic cells has previously been linked to the development of systemic lupus erythematosus. However, the use of congenic mice with limited phenotypes in this study has enabled us to propose that in the case of Marco at least, disease results from the production of anti-dsDNA Abs.

The Bxs6 Locus of BXSB Mice Is Sufficient for High-Level Expression of gp70 and the Production of gp70 Immune Complexes

High levels of the retroviral envelope protein gp70 and gp70 immune complexes have been linked to a single locus on chromosome 13 (Bxs6) in the BXSB model, to which linkage of nephritis was also seen. Congenic lines containing the BXSB Bxs6 interval on a non-autoimmune C57BL/10 background were bred in the presence or absence of the BXSB Y chromosome autoimmune accelerator gene (Yaa), which accelerates disease in male mice. In these mice, we have shown that Bxs6 is sufficient to cause high-level expression of gp70 and the production of gp70 autoantibodies, independently of Yaa, with gp70 immune complex levels enhanced by Yaa. In the presence of Yaa, Bxs6 also causes mild nephritis, and interestingly the sporadic production of high levels of anti-DNA Abs in some mice. Fine mapping using rare recombinant mice suggested that Bxs6 lies between 59.7 and 74.8 megabases (Mb), although the interval of 0.6 Mb between 73.6 and 78.6 Mb on chromosome 13 cannot be excluded in this study.

The Role of iNKT Cells in the Immunopathology of Systemic Lupus Erythematosus

An increasing body of evidence suggests that CD1d‐restricted invariant natural killer T (iNKT) cells play an important immunoregulatory role in a variety of autoimmune diseases in both humans and mouse models. Their role in systemic lupus erythematosus (SLE), however, is not fully determined, as SLE mouse models have yielded conflicting results demonstrating both a protective function and a pathogenic role. The reduced frequency of iNKT cells in peripheral blood of lupus patients supports the idea of a protective role for these cells in the immunopathology of SLE. Therapeutic approaches using glycolipids provide a promising tool to correct numerical iNKT cell deficiencies and to modulate their function. This review highlights the potential role of iNKT cells in lupus immunopathology and summarizes recent studies concerning iNKT cells in SLE patients, lupus‐prone murine models and glycolipid therapy.

Monocytosis in BXSB mice is due to epistasis between Yaa and the telomeric region of chromosome 1 but does not drive the disease process.

The BXSB murine model of systemic lupus erythematosus is differentiated from other murine models of lupus by a severe monocytosis. The recently identified Y-linked autoimmune accelerator locus, Yaa, which is fundamental to accelerated disease in male BXSB mice, is required for the monocytic phenotype in BXSB. It has also recently been shown to induce monocytosis in combination with the Nba2 locus from NZB. To dissect the genetic basis and associated pathogenicity of BXSB-related monocytosis, a panel of existing congenic mice were studied and a novel sub-congenic mouse B10.YBXSB.BXSB-Bxs3 was generated. Monocytosis was found to be caused by an epistatic interaction between Yaa and the telomeric region of chromosome 1, an area of approximately 30 cM. Bxs3 and Yaa together were sufficient to generate monocytosis equivalent to that of BXSB. In contrast to the NZB model, however, where monocytosis tightly correlated with autoantibody production and lethal lupus nephritis, this was not the case in BXSB. While Yaa+ mice bearing the Bxs3 locus drive monocytosis, glomerulonephritis and autoantibody production, both autoantibody production and nephritis are discreet events that occur in the absence of the Bxs3 locus. Yaa is a pre-requisite for monocytosis, demonstrating a novel synergistic interaction between Yaa and Bxs3.

BXSB/long-lived Is a Recombinant Inbred Strain Containing Powerful Disease Suppressor Loci

The BXSB strain of recombinant inbred mice develops a spontaneous pathology that closely resembles the human disease systemic lupus erythematosus. Six non-MHC loci, Yaa, Bxs1–4, and Bxs6, have been linked to the development of aspects of the disease while a further locus, Bxs5, may be a BXSB-derived disease suppressor. Disease development is delayed in a substrain of BXSB, BXSB/MpJScr-long-lived (BXSB/ll). We compared the genetic derivation of BXSB/ll mice to the original strain, BXSB/MpJ, using microsatellite markers and single nucleotide polymorphisms across the genome. These differences were clustered and included two regions known to be important in the disease-susceptibility of these mice, Bxs5 and 6, as well as regions on chromosomes 5, 6, 9, 11, 12, and 13. We compared BXSB/ll to >20 strains including the BXSB parental SB/Le and C57BL/6 strains. This revealed that BXSB/ll is a separate recombinant inbred line derived from SB/Le and C57BL/6, but distinctly different from BXSB, that most likely arose due to residual heterozygosity in the BXSB stock. Despite the continued presence of the powerful disease-susceptibility locus Bxs3, BXSB/ll mice do not develop disease. We propose that the disappearance of the disease phenotype in the BXSB/ll mice is due to the inheritance of one or more suppressor loci in the differentially inherited intervals between the BXSB/ll and BXSB strains.