Systemic lupus erythematosus (SLE) is regarded as a failure of adaptive immunity due to a loss of tolerance to nuclear self-antigens. In human SLE patients and mouse models, the presence of anti-nuclear antibodies is a diagnostic criterion for the disease. Despite significant advances in our understanding of the progression of SLE, including the critical role of type I interferons, less is known of the mechanisms that mediate the development of autoimmunity. Defects in the initiation, execution or resolution of apoptosis can induce the development of anti-nuclear antibodies. This suggests that proper handling of the nucleus during apoptosis is essential to avoid induction of an aberrant immune response. Nuclear fragmentation involves cleavage of both genomic DNA and structural components of the nuclear envelope. A nuclear envelope protein cleaved during apoptosis is the Lamin B Receptor (LBR). The LBR stabilizes nuclear structure by binding both chromatin and the nuclear lamina. LBR located within the SLEB1 lupus susceptibility interval on 1q42 in humans, and in the syntenic regions Sle1, Nba-2, Swrl-1 in mice. This proposal tests the role of disruption of LBR in the development of lupus autoimmunity by introducing a defective Lbr gene into established models of lupus, and by analyzing the expression of LBR in lupus-prone mouse strains.
Patients with systemic lupus erythematosus (SLE) have alterations in the function of the immune system. A hallmark feature of SLE is the development of abnormal antibodies that recognize the cell nucleus. While the influence of alterations in immune system function in SLE autoimmunity are widely studied, the contributions of nuclear structure itself in promoting autoimmunity have not been established. This project tests the hypothesis that disruption of the nuclear membrane structure can induce lupus autoimmunity in model systems.
|Singh, Namrata; Johnstone, Duncan B; Martin, Kayla A et al. (2016) Alterations in nuclear structure promote lupus autoimmunity in a mouse model. Dis Model Mech 9:885-97|