Spontaneous Autoimmune Skin Lesions of MRL/n Mice: Autoimmune Disease-Prone Genetic Background in Relation to Fas-Defect MRL/1pr Mice

When mutations that inactivate molecules that function in the immune system have been crossed to murine lupus strains, the result has generally been a uniform up-regulation or down-regulation of autoimmune disease in the end organs. In the current work we report an interesting dissociation of target organ disease in β2-microglobulin (β2m)-deficient MRL-Faslpr (MRL/lpr) mice: lupus skin lesions are accelerated, whereas nephritis is ameliorated. β2m deficiency affects the expression of classical and nonclassical MHC molecules and thus prevents the normal development of CD8- as well as CD1-dependent NK1+ T cells. To further define the mechanism by which β2m deficiency accelerates skin disease, we studied CD1-deficient MRL/lpr mice. These mice do not have accelerated skin disease, excluding a CD1 or NK1+ T cell-dependent mechanism of β2m deficiency. The data indicate that the regulation of systemic disease is not solely governed by regulation of initial activation of autoreactive lymphocytes in secondary lymphoid tissue, as this is equally relevant to renal and skin diseases. Rather, regulation of autoimmunity can also occur at the target organ level, explaining the divergence of disease in skin and kidney in β2m-deficient mice.

Section: ␤ 2 M Deficiency In Mrl/lpr Mice Accelerates Spontaneous Lupmentioning

confidence: 53%

Deficiency in β2-Microglobulin, But Not CD1, Accelerates Spontaneous Lupus Skin Disease While Inhibiting Nephritis in MRL-FaslprMice: An Example of Disease Regulation at the Organ Level

Chan¹,

Paliwal²,

McNiff

et al. 2001

“…The impact of autoantibodies on disease was demonstrated by infusing monoclonal autoantibody-secreting hybridoma cells into normal mice which resulted in the development of glomerular immune deposits, renal lesions, proteinuria, and skin vasculitis (39 -41). In MRL-Fas lpr mice, IgG deposits are prevalent in the kidney, but their presence is also closely associated with skin lesions, as they are detected in the dermoepidermal junction in the skin of older MRL-Fas lpr mice and thought to be directed against desmoglein 3 in the skin (42). B cell-deficient MRL-Fas lpr mice have abrogated skin lesions, although this is likely due to the B cell-mediated activation of T cells and not Ig production (18).…”

Section: Discussionmentioning

confidence: 99%

IL-21 Has a Pathogenic Role in a Lupus-Prone Mouse Model and Its Blockade with IL-21R.Fc Reduces Disease Progression

Herber

Brown²,

Liang

et al. 2007

272

235

Systemic lupus erythematosus is a complex autoimmune disease characterized by dysregulated interactions between autoreactive T and B lymphocytes and the development of anti-nuclear Abs. The recently described pleiotropic cytokine IL-21 has been shown to regulate B cell differentiation and function. IL-21 is produced by activated T lymphocytes and its interactions with IL-21R are required for isotype switching and differentiation of B cells into Ab-secreting cells. In this report, we studied the impact of blocking IL-21 on disease in the lupus-prone MRL-Faslpr mouse model. Mice treated for 10 wk with IL-21R.Fc fusion protein had reduced proteinuria, fewer IgG glomerular deposits, no glomerular basement membrane thickening, reduced levels of circulating dsDNA autoantibodies and total sera IgG1 and IgG2a, and reduced skin lesions and lymphadenopathy, compared with control mice. Also, treatment with IL-21R.Fc resulted in a reduced number of splenic T lymphocytes and altered splenic B lymphocyte ex vivo function. Our data show for the first time that IL-21 has a pathogenic role in the MRL-Faslpr lupus model by impacting B cell function and regulating the production of pathogenic autoantibodies. From a clinical standpoint, these results suggest that blocking IL-21 in systemic lupus erythematosus patients may represent a promising novel therapeutic approach.

“…3A-C). Spontaneous skin manifestations of alopecia and erythematosus lesions have been reported in the B6-MRL Fas lpr/j MRL lpr mice (21). They are usually located in the upper dorsal region of the mice and around the ears.…”

Section: Measurement Of Anti-dsdna Ab Titers and Total Iggmentioning

confidence: 99%

Deletion of Receptor for Advanced Glycation End Products Exacerbates Lymphoproliferative Syndrome and Lupus Nephritis in B6-MRL Fas lpr/j Mice

Goury

Meghraoui-Kheddar

Belmokhtar

et al. 2015

The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that interacts with advanced glycation end products, but also with C3a, CpG DNA oligonucleotides, and alarmin molecules such as HMGB1 to initiate a proinflammatory reaction. Systemic lupus erythematosus is an autoimmune disorder associated with the accumulation of RAGE ligands. We generated mice invalidated for RAGE in the lupus-prone B6-MRL Fas lpr/j background to determine the role of RAGE in the pathogenesis of systemic lupus erythematosus. We compared the phenotype of these mice with that of their wild-type and B6-MRL Fas lpr/j littermates. Lymphoproliferative syndrome, production of anti-dsDNA Abs, lupus nephritis, and accumulation of CD3+B220+CD4−CD8− autoreactive T cells (in the peripheral blood and the spleen) were significantly increased in B6-MRL Fas lpr/j RAGE−/− mice compared with B6-MRL Fas lpr/j mice (respectively p < 0.005, p < 0.05, p < 0.001, and p < 0.001). A large proportion of autoreactive T cells from B6-MRL Fas lpr/j mice expressed RAGE at their surface. Time course studies of annexin V expression revealed that autoreactive T cells in the spleen of B6-MRL Fas lpr/j-RAGE−/− mice exhibited a delay in apoptosis and expressed significantly less activated caspase 3 (39.5 ± 4.3%) than T cells in B6-MRL Fas lpr/j mice (65.5 ± 5.2%) or wild-type mice (75.3 ± 2.64%) (p = 0.02). We conclude that the deletion of RAGE in B6-MRL Fas lpr/j mice promotes the accumulation of autoreactive CD3+B220+CD4−CD8− T cells, therefore exacerbating lymphoproliferative syndrome, autoimmunity, and organ injury. This suggests that RAGE rescues the apoptosis of T lymphocytes when the death receptor Fas/CD95 is dysfunctional.