Neuromyelitis optica (NMO) is a rare, disabling and sometimes fatal, central nervous system (CNS) autoimmune inflammatory demyelinating disease. Aquaporin-4 (AQP4), a water channel that is expressed abundantly on astrocytes, is the primary target in NMO. A majority of NMOSD patients have AQP4-specific Abs, which are IgG1, a T cell-dependent subclass, indicating that AQP4-specific T cells have a key role in this humoral autoimmune disease. Certain clinical and pathologic findings suggest that Th17 cells participate in NMO pathogenesis. Our group first identified AQP4-specific T cells, an observation that was confirmed by other groups. We observed that T cells specific for dominant AQP4 epitopes exhibited Th17 polarization, providing further support that Th17 cells participate in NMO pathogenesis. Further, the dominant AQP4 T cell epitope identified in NMO contains a ten amino acid (aa) sequence that shares 90% homology to an aa sequence within an ABC-TP in Clostridium perfringens, a ubiquitous anaerobic gram-positive bacterium found in human commensal gut flora. This discovery, along with the demonstration that certain Clostridia species in the gut of humans can regulate the balance between regulatory T cells (Treg) and Th17 cells, suggest that gut microbiota, and possibly C. perfringens itself, could participate in NMO pathogenesis. Recently, we evaluated the gut microbiome in NMO, multiple sclerosis (MS) and healthy controls (HC). Remarkably, C. perfringens was the second most significantly enriched taxon in NMO, and among bacteria identified at the species level, C. perfringens was the one most highly associated with NMO. Thus, we have hypothesized that C. perfringens may have dual functions in NMO pathogenesis: it may (1) serve as its own proinflammatory adjuvant, promoting Th17 polarization, and (2) expose a determinant of a Clostridium ABC-TP that cross-reacts with AQP4, leading to expansion of AQP4-reactive T cells. Here, we propose to colonize germ-free mice with gut microbiota from NMO patients or by mono-colonization with C. perfringens, in order to directly examine the potential role of gut microbiota in NMO and C. perfringens, respectively, in proinflammatory T cell differentiation. In the process of examining our hypothesis regarding C. perfringens, our study should provide important information regarding the potential role of gut microbiota in NMO and CNS autoimmunity in general.

Public Health Relevance

T cell-dependent antibodies that target the water channel protein aquaporin-4 (AQP4) are considered to be the principal cause of neuromyelitis optica (NMO), a rare, sometimes fatal central nervous system autoimmune disease. Results from recent studies indicate that proinflammatory AQP4-specific T cells in NMO also recognize a protein in Clostridium perfringens, a common bacteria in the human gastrointestinal tract, and that C. perfringens is overabundant in the gastrointestinal tract of NMO patients, findings that support a potential role of C. perfringens in NMO. Here, we propose to colonize germ-free mice with fecal material from NMO patients or C. perfringens alone to determine how gut microbiota in NMO may contribute to development of proinflammatory AQP4-specific cells, which may direct cellular and humoral responses that are characteristic of NMO.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS108159-02
Application #
9766417
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2018-09-01
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
University-Wide
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Ryu, Jae Kyu; Rafalski, Victoria A; Meyer-Franke, Anke et al. (2018) Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol 19:1212-1223