Investigating Hedgehog Signaling and TH17-Mediated Inflammation in Blau Syndrome: Insights into Chronic Inflammation

Author

Benjamin Volinski, Portland State UniversityFollow

First Advisor

Dr. Ruth Napier

Date of Award

Spring 6-13-2025

Document Type

Thesis

Degree Name

Bachelor of Arts (B.A.) in Biology and University Honors

Department

Biology

Language

English

Subjects

Blau syndrome, NOD2 Mutation, TH17 Differentiation, IL-17A, Hedgehog Signaling, Gli2

Abstract

Blau syndrome is a rare, monogenic inflammatory disorder caused by autosomal dominant mutations in NOD2, a cytosolic pattern recognition receptor that regulates immune signaling. Although traditionally considered an autoinflammatory disease driven by innate immune dysfunction, emerging evidence implicates T cells in Blau pathogenesis. Recent studies show that Nod2-deficient mice exhibit elevated IL-17A production despite normal TH17 differentiation, suggesting Nod2 regulates cytokine output independently of canonical lineage commitment. This study investigates how Nod2 mutations influence TH17-mediated inflammation and explores the role of Hedgehog (Hh) signaling, particularly the transcription factor Gli2, in this process.

Using the Nod2^R314Q/R314Q mouse model, we evaluated IL-17A production under TH17-differentiation conditions and performed Western blot analysis to assess Gli2 expression in spleen and brain tissue. Additionally, phosphoproteomic profiling of CD3/CD28-stimulated T cells was used to identify signaling pathway alterations. Results revealed no significant increase in IL-17A production in Nod2^R314Q/R314Q cells under baseline stimulation, but proteomic data indicated elevated Gli2 expression and other phospho-targets linked to Hh signaling.

These findings suggest that while baseline IL-17A output may not fully capture inflammatory dysregulation, Hedgehog pathway activity is altered in Nod2-mutant T cells. Ongoing studies will explore cytokine regulation under varied stimulation conditions and assess the functional significance of Gli2 isoforms. Together, this work offers new insight into T cell-mediated inflammation in Blau syndrome and identifies signaling axes that may underlie its chronic immune activation.

Recommended Citation

Volinski, Benjamin, "Investigating Hedgehog Signaling and TH17-Mediated Inflammation in Blau Syndrome: Insights into Chronic Inflammation" (2025). University Honors Theses. Paper 1642.