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3920 The Role of CABIN1 in the Pathogenesis of Idiopathic Multicentric Castleman DiseaseClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 203. Lymphocytes and Acquired or Congenital Immunodeficiency Disorders: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Diseases, Immune Disorders, immunology, Biological Processes, pathogenesis
Monday, December 11, 2023, 6:00 PM-8:00 PM

Dorottya Laczko, MD, PhD1*, David C. Fajgenbaum, MD, MBA, MSc2 and Taku Kambayashi, MD, PhD1*

1Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
2Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Introduction: Idiopathic Multicentric Castleman Disease (iMCD) is a rare disease characterized by flares of hypercytokinemia, leading to life threatening complications. Although several hypotheses have emerged including autoimmune, immune dysregulation, and/or infectious etiology, to date the exact pathogenesis of iMCD is unknown. IL-6 is thought to be the key cytokine that drives symptoms in a proportion of patients and current standard of care targets IL-6; however, it is only successful in one third of patients. Therefore, there is a dire need to identify additional driver cytokines/pathways to address treatment-refractory cases. Lately, the pathogenic role of CXCL13 in iMCD has emerged, as proteomic studies have shown that serum CXCL13 is elevated in iMCD and a biomarker of response to therapy. Given the heterogeneity of the disease, research into iMCD has been limited by the lack of an animal model. Through whole exome sequencing of an iMCD patient, we recently discovered a potential disease-causing mutation in a protein known as CABIN1. CABIN1 in known to play a role in T cell activation as a negative regulator of calcineurin and MEF2. Using Crispr/Cas9 technology, we generated a mouse model that harbors this gene mutation (CABIN1V2185M).

Methods: Following LCMV infection or ovalbumin (OVA)-mRNA-LNP immunization serum cytokine levels were measured using Luminex assay or CXCL13 specific ELISA kit. Different immune cell populations and Nur77 levels were assessed by flow cytometry. MEF2D protein levels were determined by Western blot analysis.

Results: Although CABIN1V2185M mice do not demonstrate spontaneous pathology at baseline, we found that upon LCMV CL13 infection, mice harboring the CABIN1V2185M mutation displayed significantly higher morbidity and mortality compared to control mice. LCMV-infected CABIN1V2185M mice displayed elevated serum levels of cytokines/chemokines including IL-6 and CXCL13, which are associated with human iMCD flares. Concurrently, we also measured a robust increase in the frequency of CD4+ T cells expressing CXCR5, which is the receptor for CXCL13. Similar to LCMV CL13, infection with LCMV Armstrong or immunization with OVA-mRNA-LNP also led to an increase in serum CXCL13 levels and CXCR5+CD4+ T cells in the associated secondary lymphoid organ in CABIN1V2185M compared to control mice. In terms of the underlying mechanism, we found that T cells of CABIN1V2185M mice exhibit increased MEF2D protein and expression of a MEF2D-regulated gene, Nur77 following CD3/CD28 stimulation, suggesting that CABIN1V2185M mutation acts through MEF2 dysregulation in T cells.

Conclusion: Our preliminary data shows that LCMV-infected CABIN1 mutant mice recapitulate the cytokine milieu of human iMCD. Therefore, CABIN1 could be the first ever described mutation that could drive iMCD disease. Furthermore, this mouse model could serve as a model platform to study the underlying pathogenic pathway(s) in iMCD.

Disclosures: Fajgenbaum: EUSA Pharma/Recordati Rare Disease: Consultancy, Research Funding; Medidata, a Dassault Systemes company: Consultancy.

*signifies non-member of ASH