Drs. Egle Kvedaraite (Karolinska Institutet, Solna, Sweden)
Year Awarded: 2012
Amount: 50,000 USD
Dr. Egle Kvedaraite is a Postdoctoral Fellow with the Department of Pathology and Cancer Diagnostics at the Karolinska University Hospital – Unit of Molecular Neurobiology in Stockholm, Sweden. Dr. Kvedaraite was awarded the Early Career Investigator Award for $50,000 to conduct the study Spatial understanding of Erdheim-Chester Disease origin and lesional microenvironment.
Final Report (December 2025)
The overarching objective of this project was to gain a deeper understanding of the cellular and molecular heterogeneity of Erdheim-Chester disease (ECD) and its relationship to the lesional microenvironment across affected tissues. A particular focus was placed on central nervous system (CNS) involvement and the mechanisms contributing to histiocytosis-associated neurodegeneration, a major clinical complication for which knowledge and therapeutic options remain limited. Through integrative spatial transcriptomics, single-cell genomics, and targeted proteomics, we have generated new insights into the immunopathology of ECD, including processes occurring within the brain, and identified promising biomarker candidates that may enable earlier detection of neurodegenerative disease in clinical practice.
Achieved and achievements
Patient Material, Sample Selection, and Cohort Establishment: In collaboration with Prof. Haroche, Prof. Emile, Dr. Charlotte, and neuropathologist Dr. Plu, we assembled a unique cohort of CNS and peripheral tissue samples from patients with ECD and related histiocytic disorders. In total: 48 frozen CNS samples were selected from five ECD patients and two controls, representing a broad anatomical distribution including hippocampus, amygdala, cerebellum, pons, caudate nucleus, thalamus, and multiple cortical lesions; Six additional frozen samples were obtained from three ECD patients, two Langerhans cell histiocytosis (LCH) patients, and one Rosai-Dorfman-Destombes disease (RDD) patient, providing valuable reference material.
Peripheral biopsies included bone, skin, lymph node, and peri-renal tissue-covering the most common accessible sites of ECD disease activity. Importantly, two patients had matched CNS and peripheral biopsies, enabling direct comparison across tissue microenvironments.
All samples were reviewed for clinical, radiological, and histopathological characteristics, including macrophage marker expression, immune infiltrates, and mutational status. Joint microscopy sessions were conducted at Hôpital Pitié–Salpêtrière and Hôpital Ambroise-Paré (travel supported by external funding, not the ECD Global Alliance). Final selected specimens were shipped to Stockholm for advanced molecular profiling.
Specific accomplishments
Our work has uncovered previously unrecognized immunopathological pathways involved in histiocytosis-associated neurodegeneration, highlighting pronounced macrophage activation, dysregulation of decoy receptor systems, and contributions from both the innate and adaptive immune compartments. Together, these findings outline a mechanistic roadmap for future investigations aimed at clarifying the immunobiology of histiocytic disorders. In parallel, we identified several promising biomarker candidates that are consistently elevated in patients with neurodegenerative manifestations of histiocytosis. Notably, we observed increased concentrations of neurofilament light chain (NFL) in patients with ECD and other histiocytoses who developed neurodegenerative disease, including individuals receiving BRAF/MEK inhibitor therapy. These results indicate that ongoing neuroaxonal injury may persist despite targeted MAPK-pathway inhibition. A comprehensive report of these findings will be presented in our manuscript, “Targeted Proteomics Reveals Histiocytosis-Associated Neurodegeneration Signatures” (Kvedaraite et al., in preparation).
Significance and future perspective
Collectively, our findings open new translational avenues for scientists working in the field of histiocytosis, demonstrating that current treatments, although life-saving, may be insufficient to prevent or reverse CNS complications such as neurodegenerative disease. The identification of robust biomarker candidates provides an opportunity for clinicians to detect neurological involvement earlier and to monitor disease progression with greater precision. Moreover, the immunopathological insights generated by this work highlight specific macrophage signaling pathways and immune circuits that could be targeted by next-generation therapeutic strategies. These discoveries may ultimately support the development of novel immunomodulatory or pathway-specific interventions designed to mitigate neuroinflammation and neurodegeneration in ECD and related histiocytic disorders.