Other articles by Collin M. Spencer on PubMed

• Aquaporin 4-specific T Cells in Neuromyelitis Optica Exhibit a Th17 Bias and Recognize Clostridium ABC Transporter Annals of Neurology. Jul, 2012  |   Pubmed ID: 22807325 Aquaporin 4 (AQP4)-specific autoantibodies in neuromyelitis optica (NMO) are immunoglobulin (Ig)G1, a T cell-dependent Ig subclass, indicating that AQP4-specific T cells participate in NMO pathogenesis. Our goal was to identify and characterize AQP4-specific T cells in NMO patients and healthy controls (HC).
• Therapeutic Decisions in Multiple Sclerosis: Moving Beyond Efficacy JAMA Neurology. Oct, 2013  |   Pubmed ID: 23921521 Several innovative disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis have been licensed recently or are in late-stage development. The molecular targets of several of these DMTs are well defined. All affect at least 1 of 4 properties, namely (1) trafficking, (2) survival, (3) function, or (4) proliferation. In contrast to β-interferons and glatiramer acetate, the first-generation DMTs, several newer therapies are imbued with safety issues, which may be attributed to their structure or metabolism. In addition to efficacy, understanding the relationship between the mechanism of action of the DMTs and their safety profile is pertinent for decision making and patient care. In this article, we focus primarily on the safety of DMTs in the context of understanding their pharmacological characteristics, including molecular targets, mechanism of action, chemical structure, and metabolism. While understanding mechanisms underlying DMT toxicities is incomplete, it is important to further develop this knowledge to minimize risk to patients and to ensure future therapies have the most advantageous benefit-risk profiles. Recognizing the individual classes of DMTs described here may be valuable when considering use of such agents sequentially or possibly in combination.
• MOG Transmembrane and Cytoplasmic Domains Contain Highly Stimulatory T-cell Epitopes in MS Neurology(R) Neuroimmunology & Neuroinflammation. Aug, 2014  |   Pubmed ID: 25340072 Recently, we reported that the 218 amino acid murine full-length myelin oligodendrocyte glycoprotein (MOG) contains novel T-cell epitopes p119-132, p181-195, and p186-200, located within its transmembrane and cytoplasmic domains, and that p119-132 is its immunodominant encephalitogenic T-cell epitope in mice. Here, we investigated whether the corresponding human MOG sequences contain T-cell epitopes in patients with multiple sclerosis (MS) and healthy controls (HC).
• Reduction of CD8(+) T Lymphocytes in Multiple Sclerosis Patients Treated with Dimethyl Fumarate Neurology(R) Neuroimmunology & Neuroinflammation. Jun, 2015  |   Pubmed ID: 25738172 To evaluate the influence of dimethyl fumarate (DMF, Tecfidera) treatment of multiple sclerosis (MS) on leukocyte and lymphocyte subsets.
• Glatiramer Acetate Treatment Negatively Regulates Type I Interferon Signaling Neurology(R) Neuroimmunology & Neuroinflammation. Dec, 2015  |   Pubmed ID: 26601118 Glatiramer acetate (GA; Copaxone), a disease-modifying therapy for multiple sclerosis (MS), promotes development of anti-inflammatory (M2, type II) monocytes that can direct differentiation of regulatory T cells. We investigated the innate immune signaling pathways that participate in GA-mediated M2 monocyte polarization.
• CNS Accumulation of Regulatory B Cells is VLA-4-dependent Neurology(R) Neuroimmunology & Neuroinflammation. Apr, 2016  |   Pubmed ID: 27027096 To investigate the role of very late antigen-4 (VLA-4) on regulatory B cells (Breg) in CNS autoimmune disease.
• Dimethyl Fumarate Treatment Induces Adaptive and Innate Immune Modulation Independent of Nrf2 Proceedings of the National Academy of Sciences of the United States of America. Apr, 2016  |   Pubmed ID: 27078105 Dimethyl fumarate (DMF) (BG-12, Tecfidera) is a fumaric acid ester (FAE) that was advanced as a multiple sclerosis (MS) therapy largely for potential neuroprotection as it was recognized that FAEs are capable of activating the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, DMF treatment in randomized controlled MS trials was associated with marked reductions in relapse rate and development of active brain MRI lesions, measures considered to reflect CNS inflammation. Here, we investigated the antiinflammatory contribution of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE). C57BL/6 wild-type (WT) and Nrf2-deficient (Nrf2(-/-)) mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (p35-55) for EAE induction and treated with oral DMF or vehicle daily. DMF protected WT and Nrf2(-/-) mice equally well from development of clinical and histologic EAE. The beneficial effect of DMF treatment in Nrf2(-/-) and WT mice was accompanied by reduced frequencies of IFN-γ and IL-17-producing CD4(+) cells and induction of antiinflammatory M2 (type II) monocytes. DMF also modulated B-cell MHC II expression and reduced the incidence of clinical disease in a B-cell-dependent model of spontaneous CNS autoimmunity. Our observations that oral DMF treatment promoted immune modulation and provided equal clinical benefit in acute EAE in Nrf2(-/-) and WT mice, suggest that the antiinflammatory activity of DMF in treatment of MS patients may occur through alternative pathways, independent of Nrf2.
• Gut Microbiome Analysis in Neuromyelitis Optica Reveals Overabundance of Clostridium Perfringens Annals of Neurology. Sep, 2016  |   Pubmed ID: 27398819 T cells from neuromyelitis optica (NMO) patients, which recognize the immunodominant epitope of aquaporin-4, exhibit Th17 polarization and cross-react with a homologous sequence of a Clostridium perfringens adenosine triphosphate-binding cassette transporter. Therefore, this commensal microbe might participate in NMO pathogenesis. We examined the gut microbiome by PhyloChip G3 from 16 NMO patients, 16 healthy controls (HC), and 16 multiple sclerosis patients. A significant difference in the abundance of several microbial communities was observed between NMO and HC (Adonis test, p = 0.001). Strikingly, C. perfringens was overrepresented in NMO (p = 5.24 × 10(-8) ). These observations support a potential role for C. perfringens in NMO pathogenesis. Ann Neurol 2016;80:443-447.
• Associations Between the Gut Microbiota and Host Immune Markers in Pediatric Multiple Sclerosis and Controls BMC Neurology. Sep, 2016  |   Pubmed ID: 27652609 As little is known of association(s) between gut microbiota profiles and host immunological markers, we explored these in children with and without multiple sclerosis (MS).
• Treatment of Spontaneous EAE by Laquinimod Reduces Tfh, B Cell Aggregates, and Disease Progression Neurology(R) Neuroimmunology & Neuroinflammation. Oct, 2016  |   Pubmed ID: 27704036 To evaluate the influence of oral laquinimod, a candidate multiple sclerosis (MS) treatment, on induction of T follicular helper cells, development of meningeal B cell aggregates, and clinical disease in a spontaneous B cell-dependent MS model.
• Tolerance Checkpoint Bypass Permits Emergence of Pathogenic T Cells to Neuromyelitis Optica Autoantigen Aquaporin-4 Proceedings of the National Academy of Sciences of the United States of America. Dec, 2016  |   Pubmed ID: 27940915 Aquaporin-4 (AQP4)-specific T cells are expanded in neuromyelitis optica (NMO) patients and exhibit Th17 polarization. However, their pathogenic role in CNS autoimmune inflammatory disease is unclear. Although multiple AQP4 T-cell epitopes have been identified in WT C57BL/6 mice, we observed that neither immunization with those determinants nor transfer of donor T cells targeting them caused CNS autoimmune disease in recipient mice. In contrast, robust proliferation was observed following immunization of AQP4-deficient (AQP4(-/-)) mice with AQP4 peptide (p) 135-153 or p201-220, peptides predicted to contain I-A(b)-restricted T-cell epitopes but not identified in WT mice. In comparison with WT mice, AQP4(-/-) mice used unique T-cell receptor repertoires for recognition of these two AQP4 epitopes. Donor T cells specific for either determinant from AQP4(-/-), but not WT, mice induced paralysis in recipient WT and B-cell-deficient mice. AQP4-specific Th17-polarized cells induced more severe disease than Th1-polarized cells. Clinical signs were associated with opticospinal infiltrates of T cells and monocytes. Fluorescent-labeled donor T cells were detected in CNS lesions. Visual system involvement was evident by changes in optical coherence tomography. Fine mapping of AQP4 p201-220 and p135-153 epitopes identified peptides within p201-220 but not p135-153, which induced clinical disease in 40% of WT mice by direct immunization. Our results provide a foundation to evaluate how AQP4-specific T cells contribute to AQP4-targeted CNS autoimmunity (ATCA) and suggest that pathogenic AQP4-specific T-cell responses are normally restrained by central tolerance, which may be relevant to understanding development of AQP4-reactive T cells in NMO.