3D Epitope Mapping of Autoantigens in SLE

 

3D Epitope Mapping of Autoantigens in SLE

 

Lead: Shalaka Dhavalikar

Project Summary

Systemic lupus erythematosus (SLE) is driven by a broad autoantibody response targeting nuclear, cytoplasmic, and ribonucleoprotein autoantigens. Although key autoantigens are well known, the three-dimensional (3D) arrangement and accessibility of their immunodominant epitopes remain poorly understood. This project combines structural modeling with peptide-level reactivity data to create 3D maps of major SLE autoantigens, with the goal of identifying structurally exposed, disease-relevant epitope hotspots and understanding how they relate to disease activity, particularly in lupus nephritis (LN).

What is already known in the field?

  • Many SLE autoantigens exist as multi-protein complexes, yet most epitope analyses rely on linear peptides lacking structural context.
  • Epitope position, accessibility, and conformation strongly influence autoantibody binding and pathogenicity.

What is new?

  • Integrating computational protein models, peptide-level reactivity datasets, and quantitative 3D structural metrics to map how conformational epitopes cluster across chains and complexes.

Why is this important / Potential Clinical Relevance?

  • Insight into disease mechanism: Identifying structurally exposed, highly targeted epitopes may reveal how autoantibodies initiate tissue injury, especially in renal pathogenesis.
  • Therapeutic targeting: Understanding which epitopes drive the immune response can guide the design of targeted tolerizing peptides or epitope-blocking therapies.
  • Peptidomic biomarkers: Spatially defined epitope hotspots serve as peptide-level signatures for stratifying patients and predicting renal involvement.

Ongoing/Future Steps:

  • Comparing epitope patterns between active LN, inactive SLE, and healthy controls to identify structural regions associated with renal flare and disease progression.
  • Correlating autoantigen hits to gene expression in SLE to track pathogenesis.
  • Validating structural epitope hotspots using protein-fragment ELISAs and longitudinal patient samples.