Current and Recent Research

Neuromyelitis optica (NMO)

Our group is currently studying T cell reactivity to AQP4, the primary autoantigen in NMO.  We provided the first evidence that AQP4-specific T cells exist in NMO patients and that there is a higher frequency of AQP4-reactivity T cells in NMO patients than controls.  In NMO, T cells specific for the immunodominant AQP4 determinant exhibit a Th17 bias, providing support for a Th17-mediated pathogenesis, and cross-react with a homologous amino acid sequence in a Clostridium perfringens ABC transporter, suggesting molecular mimicry.  Recently, we discovered there is an overabundance of C. perfringens in the gut microbiome of NMO patients, further supporting the potential role of C. perfringens in NMO pathogenesis.  We are currently investigating out the gut microbiome in NMO influences T cell activation. We have identified the pathogenic T cell epitopes of AQP4 in mice and demonstrated that T cells targeting them can cause paralysis and opticospinal inflammation. Our findings indicate that the T cell repertoire to AQP4 is regulated strongly by negative selection, a possibilty that we are investigating currently. 


B cells in CNS autoimmunity

My laboratory has investigated the role of B cells in Ag presentation in CNS autoimmunity. We engineered chimeric mice that selectively express MHC II on B cells, and created transgenic mice containing B cells expressing a rearranged MOG-specific Ig heavy chain, but are incapable of secreting antibodies. Studies with those mice provided definitive evidence for B cell APC function in T cell mediated CNS autoimmunity and provide insight regarding the mechanism of action of anti-CD20 B cell depletion in MS therapy. In recent studies we have demonstrated that meningeal B cell follicles in spontaneous EAE are sites of B cell repertoire expansion.  


Previous Immunology Research

Antigen-specific T cells in CNS autoimmunity 

Dr. Zamvil's early publications focused on identification of CNS autoantigen-specific T cells and characterization of their specificity and MHC restriction. It was then that they demonstrated for the first time that T cell clones specific for a self-antigen can cause autoimmune disease.  Those clones, which recognized the autoantigen, myelin basic protein (MBP), permitted identification of pathogenic MBP epitopes, MHC II restriction and T cell receptor (TCR) gene usage. This work provided a foundation for many other investigators who also made seminal observations in autoimmunity. TCR genes from our MBP-reactive T cell clones were used for generation of the first CNS autoantigen-specific TCR transgenic mice, and led to the observation that environmental factors participate in susceptibility to spontaneous CNS autoimmunity. One of my T cell clones was used to elucidate the first crystal structure of an autoantigen-specific TCR. Epitope spreading was first described through analysis of the MBP determinants that we discovered.


Antigen processing and presentation 

Our group has studied CNS autoantigen presentation by various APC subsets and demonstrated that endocytic processing is required for presentation of T cell epitopes located within native forms of those Ags. Our work revealed that astrocytes were capable of Ag processing and presentation in vitro.  Subsequently, we targeted transgenic expression of the MHC class II transactivator (CIITA) to astrocytes in order to express MHC II and MHC II-related gene products and study Ag presentation by astrocytes in vivo.  



My laboratory evaluates mechanisms of immune modulation by novel and established MS therapeutics.  We demonstrated for the first time that cholesterol-reducing statins can induce T cell immune modulation and are capable of reversing autoimmune disease in vivo. We demonstrated that atorvastatin inhibits expression of genes involved in Ag presentation as well as genes and proteins involved in T cell immune modulation, effects that occur through inhibition of isoprenoid metabolism, but is independent of cholesterol reduction.  This work led us to conduct the first placebo-controlled trial of a statin in MS, an NIH-sponsored multicenter trial that demonstrated oral atorvastatin reduced the risk of developing new brain demyelinating lesions. In our investigation evaluating the mechanism of action of glatiramer acetate (GA, Copolymer-1, Copaxone®), a medication used in MS therapy, my laboratory demonstrated for the first time that type II (M2) myeloid cells could prevent or reverse CNS autoimmune disease and induce T cell immune modulation in vivo. These studies demonstrated that APC are the initial target of GA, and are responsible for inducing T cell immune modulation.