An analysis of apoptosis in lymphoid organs and lupus disease in murine systemic lupus erythematosus (SLE)

Abstract

SUMMARYApoptosis is a programmed cell death process that helps to regulate both T cell and B cell development. In this study, we have investigated the levels of apoptotic death in cells of the thymuses and spleens (white matter) of autoimmune MRL-lpr/lpr mice with progressive lymphadenopathy and SLE disease activity; we also examined the renal pathology in these animals. Fas is a cell surface receptor, which when activated initiates the sequence of events that lead to apoptosis. In MRL-lpr/lpr mice Fas is defective, so the competency for apoptosis may be reduced. In young animals of advancing age the thymuses enlarged until in 5-month-old females the average weight was three times that at 1 month, and spleen and kidney weights also increased in size disproportionately. At light microscope level apoptotic cells in tissue sections were counted using both routine eosin and haematoxylin staining (to identify them by their morphology) and in situ end-labelling of cells with DNA strand breaks; their presence was further confirmed by electron microscopy. As the mice aged, the numbers of apoptotic cells in thymic cortex, thymic medulla and spleen white pulp areas reduced significantly (P < 0 . 01-0 . 001), whereas in BALB/c normal controls they increased significantly (P < 0 . 05). These changes were coincident with the development of severe lupus, whose activity was assessed by measuring serum anti-ssDNA and antidsDNA antibody titres and urinary protein (albumin) level which were elevated significantly by 5 months of age (P < 0 . 001 for both ssDNA and dsDNA and P < 0 . 01 for urine albumin) compared with their younger counterparts. Thus, lymphoid organ enlargement, decrease in apoptotic indices, elevated serum anti-ssDNA and anti-dsDNA antibody levels, and impaired renal function coincided with the onset and severity of lupus disease in lpr mice. It seems likely that there is a causal relationship between defective deletion of autoreactive lymphoid cells, imperfect Fas-mediated apoptosis and development of murine SLE.

Relation of impaired energy metabolism to apoptosis and necrosis following transient cerebral hypoxia-ischaemia

“…A few necrotic cells were also labelled using this method. Other studies have found similar inconsistencies with end-labelling methods (Ravirajan et al, 1996). The results of the present study confirmed that ISEL detected fewer cells as apoptotic than morphological analysis, but also showed that there was a significant relation between the fraction of ISEL positive cells and the severity of cerebral injury measured by MRS.…”

Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Faslpr mice

“…The MRL/ MpJ-Fas lpr (MRL/lpr) mouse is a prototypical model for human SLE in which the presence of a single gene mutation on the Fas (CD95) gene leads to reduced signaling for apoptosis (10). Actually, the impaired clearance of apoptotic cells favors the self-antigen presentation and the production of multiple autoantibodies, which represents the central immunological disturbance in murine SLE (11). Indeed anti-double-stranded DNA (anti-dsDNA) and antitissue transglutaminase (anti-tTG) IgGs (12), splenomegaly, and deregulated production of Th1 and Th2 cytokines (13) have been used as markers to monitor murine SLE disease progression.…”

Autoimmune Renal Injury in C3- and C4-Deficient Mice: A Histological and Functional Study

“…C4-deficient mice show a significant delay in the phagocytosis of apoptotic cells, but to a lesser degree than C1q-deficient mice [20]. C3 activation via both the classical and alternative pathways also promotes uptake of apoptotic cells by human macrophages [27]. Complement deficiency may increase autoantibody production by other mechanisms, for example, loss of C4-mediated negative selection of auto-reactive B lymphocytes [28].…”