Lupus Disease Mechanisms
Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of self tolerance, production of antinuclear autoantibodies, immune complex deposition, and multiorgan inflammation. Mouse models provide essential tools for understanding these complex pathogenic mechanisms.
Autoantibody Production
Lupus is characterized by autoantibodies against nuclear antigens including dsDNA, histones, and ribonucleoproteins. Understanding the B cell and T cell dysregulation that enables autoantibody production is central to developing effective therapies.
Immune Complex Disease
Autoantibodies form immune complexes that deposit in kidneys, skin, and other tissues, triggering complement activation and inflammatory damage. Models that recapitulate immune complex mediated pathology enable study of tissue injury mechanisms.
Lupus Nephritis
Kidney involvement is a major cause of morbidity in lupus patients. Mouse models that develop glomerulonephritis enable study of renal immunopathology and testing of nephroprotective therapeutic strategies.
Custom Model Approaches for Lupus Research
Susceptibility Gene Knockouts
Knockout models enable study of genes implicated in lupus susceptibility through human genetic studies. Loss of function models can reveal how deficiency in specific genes contributes to breakdown of immune tolerance and development of autoimmunity.
Common targets include complement components, Fc receptors, B cell signaling molecules, and DNA sensing pathway components.
Conditional Knockouts for Cell Type Specificity
Lupus involves multiple immune cell populations including B cells, T cells, dendritic cells, and macrophages. Conditional knockout approaches enable study of gene function in specific cell types to identify which populations are responsible for disease phenotypes.
Cell type specific Cre lines crossed with floxed alleles enable deletion in B cells (CD19 Cre), T cells (CD4 Cre, Lck Cre), dendritic cells (CD11c Cre), or myeloid cells (LysM Cre).
Knockin Models
Knockin approaches enable study of specific genetic variants associated with lupus in humans. Point mutation knockins reproduce human disease associated mutations in the mouse genome.
Reporter knockins enable tracking of specific cell populations or visualization of gene expression patterns relevant to lupus pathogenesis.
Humanized Models
When therapeutic antibodies are specific for human targets, humanization of the target gene enables preclinical efficacy testing. This is particularly relevant for biologics targeting B cell surface molecules or cytokine receptors.
Strain Background Considerations
Lupus Prone Backgrounds
Some mouse strain backgrounds are inherently predisposed to autoimmunity. NZB, NZW, BXSB, and MRL strains carry genetic variants that promote lupus like disease. Introducing additional genetic modifications on these backgrounds can accelerate or modify disease phenotypes.
C57BL/6 Background
C57BL/6 is resistant to spontaneous autoimmunity but provides a well characterized genetic background for studying effects of single gene modifications. Lupus phenotypes on C57BL/6 typically require multiple genetic hits or immune challenge.
Mixed Background Considerations
Backcrossing onto defined genetic backgrounds ensures reproducible phenotypes and enables comparison across studies. ingenious targeting laboratory provides backcrossing services to establish your model on the optimal strain background.
Lupus Model Types
| Model Type | Description |
|---|---|
| NZB/W F1 | Combines NZB and NZW backgrounds, develops lupus nephritis |
| MRL/lpr | Fas deficient, accelerated autoimmunity and lymphoproliferation |
| BXSB | Y chromosome accelerated autoimmunity |
| Gene Targeted | Knockout or knockin of lupus susceptibility genes |
| Conditional | Tissue-specific deletion of genes involved in SLE |
Applications in Lupus Research
Disease Mechanism Studies
Custom models enable investigation of specific genes and pathways in lupus pathogenesis, from initial tolerance breakdown through autoantibody production to organ damage.
Therapeutic Target Validation
Knockout and knockin models can validate potential therapeutic targets by demonstrating that target modulation affects disease phenotypes.
Drug Efficacy Testing
Models that develop measurable lupus phenotypes such as autoantibodies, proteinuria, or renal pathology enable preclinical testing of therapeutic interventions.
Biomarker Discovery
Reporter knockins and tissue specific models support identification of biomarkers for disease activity and treatment response.
Phenotyping Lupus Models
Disease typically develops over months, with female mice showing earlier and more severe disease in many models. Key endpoints include:
What Researchers Say
“I've been working with iTL over the past 5 years in the production of 3 different genetically altered mice. Not only did iTL help in the design of the mice, but the entire process was transparent with the opportunity at any time along the way to discuss my questions or concerns with scientists who had significant insight into the process. The mice were delivered on time, as billed!”
— Raghu Mirmira, MD, PhD
University of Chicago
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