# Immune Privilege, CNS Autoimmunity, and Clostridium perfringens Epsilon Toxin

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $662,275

## Abstract

Why some people develop Multiple Sclerosis and others do not, despite similar genetic risk and quantities of
circulating autoreactive lymphocytes, is not known. Our long-term goal is to identify environmental triggers of
MS, define the molecular and cellular basis of their action, and in doing so, propose new diagnostic tools and
therapeutic targets. The objectives of this proposal are to determine mechanistically how Clostridium
perfringens epsilon toxin (ETX) and Bordetella pertussis toxin (PTX) overcome CNS immune privilege to trigger
autoimmunity in the context of myelin autoreactive lymphocytes and to understand why ETX causes lesions to
develop in the forebrain, cerebellum, brainstem, and spinal cord in contrast to PTX where lesions are more
commonly localized to the spinal cord. The central hypothesis of this project is that ETX and PTX trigger CNS
autoimmunity by inducing critical dysfunction at CNS barriers necessary for entry of pathogenic lymphocytes.
The central hypothesis will be tested by pursuing two aims: 1) Determining the effect of cell specific deletion or
introduction of the ETX receptor MAL (Myelin and Lymphocyte Protein) in active immunization models of
experimental autoimmune encephalomyelitis (EAE), compare the neuroanatomical location, phenotype, and
activation state of immune infiltrates between PTX- and ETX-induced EAE, and explore the effect of ETX on
human lymphocytes, and 2) Determine the genes induced and suppressed in CNS-endothelial cells by ETX and
PTX and define their function in overcoming CNS immune privilege through loss-of-function strategies. We will
pursue these aims using an innovative combination of targeted genetic mutations to isolate cellular and
molecular targets of ETX required to induce disease. We will use confocal microscopy, immunohistochemistry,
high dimensional flow cytometry, and unbiased sampling of the entire CNS to compare the effects of ETX with
PTX on immune phenotype, demyelination, and neuroanatomic localization of lesions. To determine toxin
induced genes functioning to overcome CNS immune privilege, we will apply a combination of unbiased mRNA
profiling techniques to CNS endothelial cells isolated from different neuroanatomic regions, advanced
bioinformatics to define relevant gene modules, immunohistochemistry to validate localization of these induced
proteins within individual post-capillary venules, and conditional loss-of-function mutations in endothelial cells
to determine function. The rationale underlying this proposal is that completion will define the role by which a
toxin, clinically associated with MS, functions in the multi-step process of autoimmunity, and will identify key
molecular targets that can be tested therapeutically. This work will also help establish an experimental model
that has greater clinical relevance to MS and more closely resembles MS neuropathology than experimental
autoimmune encephalomyelitis models reliant on pertussis toxin.

## Key facts

- **NIH application ID:** 10850801
- **Project number:** 5R01AI174064-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** TIMOTHY VARTANIAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $662,275
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850801

## Citation

> US National Institutes of Health, RePORTER application 10850801, Immune Privilege, CNS Autoimmunity, and Clostridium perfringens Epsilon Toxin (5R01AI174064-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10850801. Licensed CC0.

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