Granzyme K—A new frontier in systemic lupus erythematosus pathogenesis and therapy

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with significant morbidity, yet the mechanisms driving organ damage remain incompletely understood. In a new review published in Rheumatology & Autoimmunity, researchers from Kunming Medical University synthesize single-cell transcriptomic and mechanistic evidence to propose Granzyme K (GZMK) as a critical pathogenic node in SLE, particularly in lupus nephritis (LN). The review challenges the traditional view of granzymes as purely intracellular cytotoxic molecules and presents GZMK as a multifaceted extracellular mediator that activates complement, drives inflammation, and disrupts vascular integrity.

"GZMK breaks the traditional paradigm of purely intracellular cytotoxicity, serving as a critical novel mechanism driving tissue damage in SLE target organs by directly activating noncanonical complement pathways and mediating pro-inflammatory cell-cell crosstalk," said Dr. Deng, corresponding author.

The Challenge: A Local Mediator with Systemic Implications

While serum GZMK levels in SLE patients show no correlation with overall disease activity, GZMK+CD8+ T cells are highly enriched and functionally activated in target organs, particularly in LN kidneys and cutaneous lupus lesions. Single-cell transcriptomics reveal that infiltrating GZMK+CD8+ T cells display marked activation and inflammatory pathway upregulation, coupled with expansion of atypical B cells and plasma cells. Spatial analyses demonstrate co-localization in tertiary lymphoid structures, and chromatin accessibility indicates higher accessibility at IFNG and IL-21 loci, supporting their potential to drive local B-cell responses via IFN-γ/IL-21 signaling. Furthermore, IL-7RlowCD8+ effector memory T cells expressing GZMK have been linked to clinical treatment outcomes.

Mechanistic Roles in SLE Pathology

The review identifies several interconnected mechanisms. First, GZMK can initiate a noncanonical complement activation pathway by cleaving C4 and C2 on cell membranes, independent of classical initiators—though this awaits validation in SLE models. Second, GZMK cleaves PAR-1 and PAR-2 on fibroblasts, epithelial cells, and endothelial cells, inducing pro-inflammatory cytokine secretion. Third, GZMK induces endothelial microvascular damage by cleaving syndecan-1 and promotes sVEGFR1 release, suppressing angiogenesis. Fourth, GZMK+CD8+ T cells interact with CXCL12-secreting fibroblasts and co-localize with atypical B cells, driving local antibody production through IFN-γ/IL-21 signaling.

A distinctive regulatory feature is that cytokines (IL-2, IL-12, IL-15) upregulate GZMK, whereas strong TCR stimulation downregulates it while upregulating GZMB. In the interferon-rich SLE microenvironment, these cells are likely maintained by local cytokines, contributing to chronic inflammation rather than acute cytotoxicity.

Clinical Implications and Future Directions

Peripheral serum GZMK appears limited as a systemic biomarker. However, urinary GZMK or GZMK+ T cells in urinary sediment may better reflect renal disease burden, particularly in patients with active nephritis despite low anti-dsDNA and complement levels. Therapeutic targeting faces challenges: high structural homology with GZMA complicates selective inhibitor design; GZMK plays a dual role in antiviral defense and inflammation; and local tissue effects may require targeted delivery.

Critical future needs include: establishing GZMK-knockout lupus models to confirm causality; validating GZMK-mediated complement activation in SLE; investigating whether GZMK cleaves SLE-related autoantigens or impacts autoantigen immunogenicity; and clarifying its role in tissue remodeling and fibrosis.

"GZMK appears to serve as a key 'nexus' molecule in the SLE immunopathological network, tightly linking dysfunction of specific T-cell subsets with core SLE pathogenic pathways," the authors conclude. Future research should focus on defining precise substrates and regulatory networks across different disease stages, laying the foundation for translation into diagnostic tools or therapeutic targets—particularly for refractory patients who fail to respond to standard care.