## 3 Conclusions  
This review has focused on the potential pathogenic factors involved in cognitive dysfunction including anti-NR2A/B antibodies, MMP-9, NETs and pro-inflammatory mediators, based on the recent advances in cognitive dysfunction research from murine models and human SLE. Cognitive dysfunction in SLE sits at the interface of two of the most complicated organ systems in the human body, namely, the nervous system and the immune system. Obtaining clear and simple answers about disease causality is not easy, as evident from this review. In 1890, the great microbiologist [PERSON] established a set of postulates that have guided investigation into the pathogenesis of infectious diseases for over a century [102]. [PERSON]'s postulates, which theorized that one microbe would cause one disease, cannot be applied for autoimmunity as the pathogenic mechanisms leading to disease are multi-etiological in nature [102]. Based on the current information as discussed in this review, a hypothesis for the pathogenesis of cognitive dysfunction in SLE can be put forth as outlined in Figure 1. Anti-NR2A/B antibodies are produced extrathecally and must cross the BBB into the CSF to influence brain function. MMP-9 is released by prestimulated LDGs, leading to the degradation of basal lamina and compromise of the BBB integrity. Anti-NR2A/B antibodies activate the BBB with increased expression of endothelial cell adhesion molecules, facilitating the recruitment, rolling, adhesion and transmigration of neutrophils, leading to further NETosis intrathecally. Lastly, the intrathecal release of NETs contributes to neurotoxicity by inducing neuronal cell death, which subsequent leads to neuropsychiatric manifestations of SLE. Neuropathology in this disease model requires two hits: (i) presence of neurotoxic anti-NR2A/B antibodies and (ii) a breach in the integrity of the BBB [37, 103]. Thus, measurement of serum titers of anti-NR2A/B antibodies solely cannot be expected to correlate with antibody-mediated damage. The measurement of serum anti-NR2A/B antibodies, without CSF anti-NR2A/B antibodies levels or other biomarkers of BBB function, is therefore not ideal and likely the reason for the controversial results of the aforementioned 8 studies on anti-NR2A/B antibodies and cognitive dysfunction [9, 19, 31, 43, 44, 45, 46, 47]. However, since obtaining CSF from SLE patients without overt neuropsychiatric manifestations is hindered by practical and ethical issues, non-invasive assessment of the integrity of the BBB opens an  
Figure 1: Proposed model of cognitive dysfunction in SLE. Abbreviations: NMDA, \(N\)-methyl-d-aspartate; MMP-9, matrix metalloproteinase-9; NET, neutrophil extracellular trap. attractive research direction to study anti-NR2A/B antibody mediated cognitive dysfunction in SLE patients. Evident from this review, the process leading to cognitive dysfunction in SLE probably involves abnormal endothelial cell-immune cell interactions that permit access of immune cells (e.g., neutrophils) and therefore, immune mediators (e.g., NETs) into the CNS [16]. In mice models, the BBB has been compromised by simulating infection (e.g., lipopolysaccharideacharide) and stress (e.g., epinephrine) [103,104]. However, such _in vivo_ results cannot explain the spontaneous development of BBB disruption and neuropsychiatric manifestations observed in anti-NR2A/B antibody positive MRL/Mpl-_fa\({}^{\text{spr}}\)_ mice [97,105]. MMP-9 on NETs, released spontaneously by LDGs, might fulfill a critical role for the abrogation of BBB integrity in SLE. This is line with the recent findings of [PERSON] who screened biomarkers for the identification of cognitive dysfunction in childhood-onset SLE: (i) anti-NR2A/B antibodies; (ii) S100B (a biomarker of decreased BBB integrity); and (iii) neutrophil gelatinase associated lipocalin, S100A8 and S100A9 (all NET-reported proteomes) were included in the final predictive model with a sensitivity of 100%, specificity of 76% and area under ROC curve of 83.4% [31].