A discovery from a single protein in urine is shining new light on the management of a complex autoimmune disease.
Systemic lupus erythematosus (SLE) is a complex autoimmune condition that affects millions worldwide, with a particular preference for women during their reproductive years. One of its most severe complications is lupus nephritis - kidney inflammation that occurs in up to 60% of SLE patients and significantly increases mortality risk.
Lupus nephritis affects up to 60% of SLE patients and is a leading cause of mortality in this population.
For decades, physicians have relied on traditional biomarkers like proteinuria, urinary sediment, and serum complement levels to monitor LN activity. While these tools are valuable, they have limitations. They cannot always distinguish between active inflammation and chronic damage, nor do they reliably predict impending flares. The search for better biomarkers has led researchers to an unexpected place: our urine, and a protein called Interleukin-22 Binding Protein (IL-22BP).
To understand why IL-22BP matters in lupus nephritis, we must first meet its counterpart: Interleukin-22 (IL-22). This cytokine, primarily produced by immune cells, plays a dual role in our bodies. It can promote tissue repair and antimicrobial defense, but when unregulated, it drives inflammation and autoimmunity.
Promotes inflammation when unregulated
Acts as natural brake on inflammation
IL-22 primarily targets epithelial cells in various tissues, including the kidneys. It exerts its effects by binding to a receptor complex on cell surfaces, triggering inflammatory pathways including the JAK-STAT signaling cascade.
Enter IL-22BP, the natural brake on this system. This soluble receptor acts as a decoy molecule, binding to IL-22 and preventing it from interacting with cell surface receptors. The balance between IL-22 and IL-22BP thus becomes crucial in determining whether tissue protection or inflammation prevails 1 2 9 .
In lupus nephritis, this balance appears to be disrupted. Research indicates that IL-22 levels increase in the renal tissue of LN patients, contributing to kidney damage through multiple mechanisms, including recruitment of inflammatory cells to the kidneys 2 .
In 2014, a team of researchers from Zhejiang University made a crucial discovery that would advance our understanding of LN monitoring. Their study, published in The Journal of Rheumatology, revealed that urinary IL-22BP levels correlate strongly with lupus nephritis activity 1 4 .
The researchers designed a comprehensive study involving 112 SLE patients and healthy controls. Patients were carefully categorized based on:
They employed enzyme-linked immunosorbent assays (ELISA) to measure IL-22BP concentrations in both serum and urine samples, recognizing that urine tests offer non-invasive advantages for kidney disease monitoring. Additionally, they used immunohistochemistry to examine IL-22BP expression directly in renal tissue obtained from biopsies 1 .
The results were striking in their consistency:
Patients with active renal disease showed significantly higher urinary IL-22BP levels compared to those with active SLE but no kidney involvement, patients with a history of LN currently in remission, and healthy controls 1 .
| Patient Group | Urinary IL-22BP Levels | Significance |
|---|---|---|
| Active lupus nephritis | Significantly elevated | Higher than all other groups |
| Active SLE without renal involvement | Moderate | Lower than active LN patients |
| LN patients in remission | Low | Similar to healthy controls |
| Healthy controls | Low | Baseline reference level |
Perhaps even more revealing was what the researchers didn't find: there was no significant difference in serum IL-22BP levels among the groups. This crucial observation highlighted that urinary IL-22BP wasn't simply leaking from the blood but was likely being produced directly in the kidneys during active inflammation 1 .
The correlations didn't stop there. Urinary IL-22BP levels positively correlated with established disease activity indices:
Most compellingly, when the researchers followed patients over time, they observed that urinary IL-22BP levels decreased significantly in patients who achieved complete response to treatment, but remained elevated in those with only partial or no response 1 . This suggested urinary IL-22BP could potentially serve not just as a diagnostic marker but as a tool for monitoring treatment effectiveness.
Interactive Chart: Urinary IL-22BP levels across patient groups and treatment response
While the 2014 study established a strong clinical correlation between urinary IL-22BP and LN activity, subsequent research has helped explain the underlying mechanisms.
A 2021 study published in Frontiers in Immunology demonstrated that IL-22 produced by type 3 innate lymphoid cells (ILC3) in the kidneys of lupus-prone mice directly contributed to renal damage. When researchers knocked out either IL-22 or its receptor in these mice, they observed significant improvement in both systemic illness and local kidney lesions 2 .
The mechanism appears to involve kidney epithelial cells. When stimulated by IL-22, these cells produce chemokines CCL2 and CXCL10, which recruit inflammatory macrophages to the kidneys. This process depends on STAT3 phosphorylation - when this pathway was inhibited, the production of these chemokines decreased significantly 2 .
| Research Tool | Application in LN Research | Function/ Significance |
|---|---|---|
| Recombinant IL-22 (rIL-22) | In vitro stimulation of kidney cells | Demonstrates direct effects of IL-22 on kidney epithelium |
| ELISA kits | Measuring IL-22BP concentrations | Quantifies biomarker levels in clinical samples |
| Anti-IL-22 monoclonal antibodies | Therapeutic intervention in mouse models | Blocks IL-22 activity to assess therapeutic potential |
| STAT3 pathway inhibitors (e.g., C188-9) | Mechanism investigation | Determines role of STAT3 signaling in IL-22 effects |
| Flow cytometry antibodies | Immune cell characterization | Identifies IL-22 producing cells in tissues |
The quest for better LN biomarkers has intensified in recent years. While traditional markers like proteinuria, anti-dsDNA antibodies, and complement levels remain fundamental to clinical practice, their limitations have driven research into more specific alternatives 3 .
Among promising novel biomarkers, urinary monocyte chemoattractant protein-1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), and vascular cell adhesion molecule-1 (VCAM-1) have shown potential. Interestingly, some of these molecules may be part of the same inflammatory pathways as IL-22BP 3 5 .
A 2024 study in Scientific Reports highlighted that urinary IL-17, IL-6, and IL-23 could predict treatment response in LN patients, with combined models showing improved predictive capability 5 . This underscores a growing recognition that biomarker panels rather than single markers may offer the best approach for monitoring complex diseases like LN.
While the evidence supporting urinary IL-22BP as a LN biomarker is compelling, several steps remain before it can enter routine clinical practice. As noted in a 2025 comprehensive review of LN biomarkers, "Novel biomarkers should be validated in multiple longitudinal independent cohorts, compared with conventional biomarkers, and integrated with renal histology information" 3 .
Potential to detect renal flares before traditional markers become abnormal
Identifying patients who need more aggressive therapy
Determining whether current therapies are working effectively
Providing non-invasive insights into renal inflammation
Beyond diagnostics, the IL-22/IL-22BP axis represents a potential therapeutic target. If excess IL-22 drives kidney inflammation in LN, strategies to enhance IL-22BP activity or directly inhibit IL-22 might offer new treatment avenues 2 .
The discovery of urinary IL-22BP's correlation with lupus nephritis activity represents more than just another potential biomarker—it offers a window into the fundamental processes driving kidney inflammation in SLE. This protein provides a crucial link between immune system dysregulation and end-organ damage, helping explain why the kidneys so frequently become battlegrounds in lupus.
Urinary IL-22BP provides a crucial link between immune system dysregulation and end-organ damage in lupus nephritis.
As research progresses, the integration of IL-22BP measurement with other novel biomarkers and traditional clinical parameters may finally deliver the precision medicine approach that lupus patients deserve—one where treatment decisions are guided by real-time insights into kidney inflammation, potentially preventing damage before it becomes irreversible.
While more validation is needed before urinary IL-22BP measurement becomes standard practice, it stands as a promising example of how basic scientific investigation can reveal simple yet powerful solutions to complex clinical challenges. In the ongoing fight against lupus nephritis, our urine may contain messages we're only now learning to read.
References will be listed here in the final version.