Systemic lupus erythematosus (SLE; lupus) primarily affects women of reproductive age [1]. Unpredictable flares of inflammatory activity followed by relative quiescence complicate monitoring and managing lupus [2]. A physician's ability to accurately track individual organ pathology continues to be limited by the heterogeneity of clinical presentations [3] and conflicting evidence regarding the utility of current biomarkers [4]. While elevated serum anti-nuclear antibodies are required for diagnosis, they are not lupus specific [5] and do not consistently correlate with disease activity [4,6]. Lupus implicated cytokines such as B-cell activating factor and interleukin 6 (IL-6) show promising flare prediction and can be targeted therapeutically [7]; however, their serum levels appear too variable or do not reliably correspond to specific manifestations [8,9]. SLE can affect nearly all organ systems, including the skin, joints, heart, and brain [10]. However, among those lupus-attributable complications, severe kidney inflammation, a.k.a lupus nephritis, poses the greatest risk of patient mortality [11].

Biomarkers corresponding to components of systemic disease, active kidney pathology, or both would enable clinicians to tailor therapy to each patient and intervene early to prevent loss of organ function [6]. The list of putative biomarkers in SLE is quite long. One way to categorize the mediators of lupus would be to consider the cellular location of each protein. Extracellular signals and plasma membrane receptors, such as cytokines and their receptors, can drive inflammatory signaling [8]. Alternatively, cytoplasmic and nuclear proteins, such as second messengers and transcription factors, mediate cellular changes that facilitate long-lasting impacts of autoimmunity [12]. Many prior biomarker studies focused primarily on those extracellular markers [4,7], but few have looked at the potential of intracellular markers.

The present study applied high-throughput array analysis of lupus mouse serum to detect novel protein biomarker candidates relevant to pathogenic mechanisms in SLE. Performing these exploratory analyses in an animal model that replicates many lupus features provides unrivaled access to the tissues needed for analysis. Simultaneously, animal studies limit treatment confounders and environmental variations which often complicate the interpretation of clinical exploratory studies [4]. Moreover, to our knowledge, no prior studies have simultaneously assessed the expression of hundreds of proteins, ranging from inflammatory cytokines to homeostatic nuclear signals, in the serum of lupus mice.

These analyses utilize the MRL/lpr mouse, a widely studied lupus model exhibiting female-dominance, lymphoproliferation, humoral immunity, kidney pathology, and many other features of SLE [13]. Decades of MRL/lpr research have not yet generated a comprehensive serum proteome of this strain (or, for that matter, any other lupus mouse model). The degree to which the MRL/lpr proteome overlaps with the human serum inflammatory profile remains unknown. Moreover, no prior investigations in any lupus mouse model have combined high-throughput and unbiased serum microarray analysis with measurements of disease features. This knowledge gap could be obscuring potential targets for future inhibition or knockout studies. By validating a novel array-based screening approach in lupus mice, generating an MRL/lpr serum proteome, and identifying new biomarker candidates, the present study illuminates many avenues for future basic and clinical research which could eventually improve care for SLE patients.