Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by polysystemic inflammation as a result of auto-reactive T and B cells. In mammals, the immune system can sustain prolonged adaptive immune responses to nearly any foreign antigen by generating, through genetic recombination, lymphocytes with highly diverse receptors. Due to the randomness of this process, a proportion of T and B cells inevitably have receptors that are directed against self-antigen; however, these lymphocytes are typically eliminated, reprogrammed, or inactivated in the lymphoid organs. In SLE patients, regulatory T cells that clear out autoantibody-antigen complexes may be reduced or lacking, and the continued presence of these complexes activate an autoimmune positive feedback loop that allows the disease to progress beyond the inciting autoantigen through “epitope spreading”1.
SLE has been recognized in a variety of species including humans, mice, rats, and other domesticated animals. SLE in mice closely resembles SLE in humans, including autoantibody production and renal disease. Mouse models of SLE fall under two main categories—spontaneous and induced—and each model presents its own iterations of lupus-like disease with a subset of symptoms similar to those seen in human SLE2.The most commonly used mouse models are the NZBWF1 and MRL/lpr strains, which develop spontaneous disease characterized by hyperactive B and T cells, high titers of several autoantibodies directed against nuclear antigens, defective clearance of immune complexes, and fatal immune glomerulonephritis1.
Various factors from genetic defects to infectious agents and drug exposure contribute to the pathogenesis of SLE. Patients with SLE have been shown to have defective B- and T-cell tolerance to nuclear antigens, hypomethylated DNA, an increased rate of apoptosis, and defective clearance of apoptotic debris; it has been hypothesized that, in SLE patients, apoptotic debris becomes immunogenic through abnormal processing. Plasmacytoid and myeloid dendritic cells and B-cell activating factor (BAFF) have been implicated in the disease’s feedback loop.
Clinical symptoms of SLE differ depending upon the underlying genetic abnormalities and the anatomic location of the cellular responses against self-antigen. Autoantibody-antigen immune complexes contribute to the clinical manifestation of the disease by causing lesions in blood vessels and tissues where they accumulate. In the case of lupus nephritis, circulating immune complexes deposit in the glomerular subendothelial space and in the mesangium, leading to deterioration of the glomerulus and eventual end-stage renal disease3. In addition to renal disease (glomerulonephritis, interstitial nephritis, vasculitis, and proteinuria), SLE patiens may present with swollen joints, skin rash, hematologic disorders, and respiratory and neurologic dysfunction1. Although mouse models are primarily characterized by the development of nephritis, some other lupus-like symptoms may develop in certain strains2.
Over the years, a variety of therapeutic approaches for disease intervention have been taken. Treatments have included generalized immunosuppressants (e.g. methotrexate), specific cytokine blocking (e.g. INFa), innate immune inhibitors (e.g. chloroquine), adaptive immune inhibitors (e.g. monoclonal antibodies against BAFF), and costimulation inhibitors (e.g. abatacept). Generalized immunosuppressants are considered undesirable because they increase a patient’s susceptibility to bacterial or fungal infections, so recent research has focused on the more specific approaches with a monoclonal antibody against BAFF (anti-BLys; belimumab) showing promising results1.
- Perry D, Sang A, Yin Y, et al. Murine models of systemic lupus erythematosus. J Biomed Biotechnol, 2011. doi:10.1155/2011/271694.
- Rottman JB, and Willis CR. Mouse models of systemic lupus erythematosus reveal a complex pathogenesis. Vet Pathol, 2010;41:664. doi:10.1177/0300985810370005.
- Mohan C, Datta SK. Key pathogenic mechanisms and contributing factors. Clin Immunol Immunopathol, 1995;77:209–220.
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