Animal models of neuropsychiatric systemic lupus erythematosus: deciphering the complexity and guiding therapeutic development

Figures & data

Figure 1. Progression and key manifestations of animal lupus models: a timeline overview.

Table 1. Behavioral phenotypes in key spontaneous and pristane-induced mouse SLE models.

	NZB	NZM	NZB/WF1	MRL/lpr	BXSB/Yaa	CReCOM	PIM
CNS-related morphological differences
Neuronal and synaptic loss				− [50]		+ [93]
				+ [67,75,93,180,181]
Ectopias	+ [182]				+ [89,182]
Spine loss				+ [75,183]
Learning and memory deficits
Conditioned avoidance	+ [184]
Morris Water Maze	+ [185]	+ [62]		+ [65,67,186]	+ [88,89]	+ [93]
Barnes maze							+ [104,187]
Contextual fear conditioning				+ [67]		+ [93]
Y-maze			+ [48]	− [93]		− [93]
				+ [188]
Novel object location, recognition			+ [35,47]	− [69,72]			− [103]
				+ [70,188,189]
Social interaction deficits
Social preference test			+ [35,48]	− [68,70]			− [103]
				+ [69]
Anxiety and depression
Open field			+ [47,48]	+ [69,75]		− [93]	+ [103]
				− [70,93]
Forced swim test				+ [68-73,190]			+ [103]
Sucrose preference test			+ [35]	+ [70,77,78,190]
Elevated plus maze, zero maze			+ [35,47,48]	− [68,69,76,93]		− [93]	+ [103]
				+ [74,75]
Tail suspension test			+ [35]	+ [75,188,190]
Neurological signs
Abnormal postural response	+ [186]	+ [61]	+ [49,186]	+ [186]
Placing reflex			+ [49]
Tremor on rod test	+ [186]		+ [186]	+ [186]
Cranial nerve deficits	+ [186]		+ [186]	+ [186]
Rotarod	+ [184]		+ [35]			+ [93]

NZB: New Zealand black; NZM: New Zealand mixed; MRL: Murphy Roths large; PIM: pristane-induced model; (+) presence of phenotype; (-) absence of phenotype and/or equal to control.

Table 2. Validating criteria and evaluating challenges in animal models of NPSLE.

Type of validity	Limiting factors in achieving
Construct validity The fidelity of animal models to human disease etiology. Construct validity reflects alignment of causes and pathophysiology, including early developmental similarities, and mechanistic analogy between biology and behavior. Triggering validity (especially in induced models).	Disparities in both the structure and functions of animal brains relative to their human counterparts, and the complexity of human pathophysiology. Genetic diversity within the human population, contrasting with inbred genetically homogeneous animals. Characteristic mutations observed in current murine SLE models do not usually align with genetic susceptibility loci present in patients. Pharmacologically induced models fail to replicate natural triggers.
Face validity The fidelity of a model in replicating the human phenotype, encompassing analogous signs, symptoms, and biomarkers.	Fundamental challenges in comparing animal and human phenotypes.
Predictive validity The performance of the animal model in reaction to a defined experimental manipulation, as well as responses to treatment. The utility of a model in predicting currently unknown aspects of the human disease.	Simplicity of behavioral paradigms vs human behavior. Discordance of human and animal disease biomarkers. Diverse serological profiles of murine SLE models. Certain experiments lie outside an animal’s natural repertoire. Ethologically valid behavior is characterized by stimuli and responses within the typical scope encountered in nature. Difficulty in replicating the intricate array of stressful factors triggering the onset of SLE.

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