P. Calabresi
Johns Hopkins University Neurology and NeurosciencePeter A. Calabresi, MD is a Professor of Neurology and Neuroscience at the Johns Hopkins School of Medicine and Director of the Johns Hopkins Multiple Sclerosis (MS) Center. Dr. Calabresi is also Director of the Richard T. Johnson Division of Neuroimmunology and Neuroinfectious Diseases. He earned his undergraduate degree from Yale College and medical degree from Brown University. Dr. Calabresi completed residency training at Strong Memorial Hospital in Rochester, NY, and completed a research fellowship at the National Institutes of Health, Neuroimmunology Branch. Dr. Calabresi serves on the Editorial Boards of the Journal of Clinical Investigation and the Multiple Sclerosis Journal. He served as Chair of a grant review committee of the National Multiple Sclerosis Society and was a standing member of the NIH Clinical Neuroimmunology and Brain Tumors Study Section. As co-director of the Johns Hopkins Precision Medicine MS Center of Excellence, Dr. Calabresi has been the principal investigator on several clinical trials and also oversees translational laboratory research projects. His specific laboratory research interest lies in understanding the mechanisms of T lymphocyte differentiation into effector memory T cells and how these T cells interface with glial cells in the brain to modulate remyelination. Dr. Calabresi has published over 300 research papers including numerous articles on imaging and the immunopathogenesis of MS. He was the recipient of a five-year NMSS Collaborative Center grant from the National MS Society to study endogenous remyelination in MS, and the Jacob Javits Neuroscience Investigator award from the National Institutes of Health. Dr. Calabresi was co-awarded the Barancik prize for innovation in MS research in 2015, and was elected to the American Association of Physicians in 2017.
Author Of 3 Presentations
PS15.04 - The presence of epiretinal membranes in multiple sclerosis may be associated with increased disability
Abstract
Background
Neuroglial cells are implicated in the pathobiology of Multiple sclerosis (MS). Müller glia, specialized radial glial cells of the retina responsible for helping maintain retinal neuronal integrity, are postulated to be activated in MS. Müller glia activation is also implicated in epiretinal membrane (ERM) formation, an aberrant healing response to retinal damage.
Objectives
To examine ERM prevalence in MS, and differences in expanded disability status scale (EDSS) and optical coherence tomography (OCT) measured retinal layer thicknesses, between MS patients with (ERM-MS) and without ERMs (non-ERM-MS).
Methods
In this cross-sectional study, 1463 MS patients (2926 eyes) underwent Cirrus spectral-domain OCT (with automated macular layer segmentation). All scans underwent qualitative and quantitative quality control (QC), and ERM presence was recorded. Excluding patients with optic neuritis history, ERM-MS (n=48) were matched 1:1 to non-ERM-MS based on age, body mass index (BMI) and sex. Fellow eye layer thicknesses of ERM-MS were compared to the average binocular layer thicknesses of non-ERM-MS patients, to investigate the possibility of a phenotype effect. Mixed effects linear regression models were used in analyses.
Results
ERM prevalence in this MS cohort was 4.9%. Post-matching mean age and BMI were respectively 60.7 years (SD 6.3) and 28.2 kg/m2 (SD 9.6) in ERM-MS, and 60.4 years (SD 5.7) and 27.5 kg/m2 (SD 8.9) in non-ERM-MS (p=0.7 for both). Both groups had 77.1% females. Median EDSS was 4 (IQR 2.5-6.5) in ERM-MS and 3 (IQR 1.5-6) in non-ERM-MS (difference: 1.1, CI: 0.2 – 1.9, p=0.021). Mean ganglion cell-inner plexiform layer (GCIPL) thickness was 67.1 um (SD 6.5) in ERM-MS and 70.2 um (SD 6.2) in non-ERM-MS (difference: -3.1, CI: -6.3 – -0.1, p=0.049). Moreover, mean retinal pigment epithelium (RPE) thickness was 31.6 um (SD 1.3) in ERM-MS and 32.4 um (SD 0.9) in non-ERM-MS (difference: -0.7 um, CI: -1.3 - -0.1, p=0.017).
Conclusions
Our findings suggest ERM-MS patients phenotypically have higher EDSS scores, and lower GCIPL and RPE thicknesses, as compared to non-ERM-MS patients. Blood-retinal barrier disruption due to retinal inflammation, among other reasons, may activate Müller glia in MS. This may help explain our finding that ERM presence in MS may be associated with disability. Moreover, RPE cells may be recruited in the ERM formation process, similarly explaining our finding of reduced RPE thickness among ERM-MS patients.
YI01.04 - Generation of MHC class I and MHC class II reporter mice for investigation of antigen presentation by oligodendroglia
Abstract
Background
Emerging evidence from both human multiple sclerosis (MS) tissue and rodent experimental autoimmune encephalomyelitis (EAE) models has demonstrated that subsets of oligodendrocyte lineage cells are capable of expressing antigen presenting and processing molecules, including MHC class I and MHC class II molecules, in an inflammatory environment. Antigen presentation by inflammatory oligodendroglia (iOPCs/iOLs) to CD4 and CD8 T cells may result in cytotoxic death of oligodendroglia and perpetuation of the inflammatory response. However, the dynamics of MHC class I and MHC class II expression by oligodendrocyte lineage cells in an inflammatory environment are unknown.
Objectives
To better define these dynamic changes in phenotype, we developed two new mouse reporter lines by targeting Beta-2-microglobulin (B2m) and CD74 invariant chain (Ii) genes, which are upregulated by oligodendroglia in human MS and mouse EAE. Beta-2-microglobulin (B2m) is a component of both classical and non-classical MHC class I molecules and CD74 invariant chain (Ii) is involved in occupancy of the peptide binding groove of MHC class II molecules in the endoplasmic reticulum and formation of stable MHC class II-antigen complexes.
Methods
We generated reporter lines by Crispr/Cas9-mediated insertion of a P2A-TdTomato-WPRE-pA sequence, replacing the stop codon of B2m (for class I reporter) and CD74 (for class II reporter).
Results
Both B2m-TdT and CD74-TdT mice demonstrate robust reporter expression in cultured OPCs upon exposure to interferon gamma. In naïve CD74-TdT reporter mice, TdT reporter expression was not detected in the brain or spinal cord parenchyma, but strong expression was observed in peripheral immune cells in the meninges and choroid plexus. B2m-TdT reporter mice exhibited TdT reporter expression in microglia throughout the brain and spinal cord, and some expression in spinal cord white matter oligodendroglia near the meningeal surface. No TdT reporter expression was detected in brain oligodendroglia at baseline. Cortical stab injury in B2m-TdT reporter mice resulted in TdT reporter co-localization with Iba1+ microglia and Mac2+ macrophages within the lesion core and Olig2+CC1+ oligodendrocytes in the corpus callosum ipsilateral and contralateral to the stab injury.
Conclusions
Further investigation of MHC class I and MHC class II expression in oligodendroglia in the setting of inflammatory demyelinating models will help reveal the spatial and temporal dynamics of this phenotypic change in oligodendroglia.
YI02.01 - Optic Neuritis-Independent Retinal Atrophy In Neuromyelitis Optica Spectrum Disorders
Abstract
Background
Prior studies have suggested that retinal neuro-axonal loss may occur in aquaporin-4 (AQP4)-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) in the absence of optic neuritis (ON), but data are conflicting.
Objectives
To examine whether patients with AQP4-IgG seropositive NMOSD exhibit progressive retinal neuro-axonal loss, independently of optic neuritis (ON) attacks.
Methods
In this single-center, longitudinal study, 32 AQP4-IgG+ NMOSD patients and 48 healthy controls (HC) were followed with serial spectral-domain optical coherence tomography (OCT). NMOSD patients with ON less than 6 months prior to baseline were excluded, while data from patients with ON during follow-up were censored at the last visit prior to ON. Rates of peri-papillary retinal nerve fiber layer (pRNFL) and macular ganglion cell+inner plexiform layer (GCIPL) thinning were compared between groups utilizing mixed-effects linear regression models adjusted for age, race and sex.
Results
Median follow-up duration was 4.3 years (IQR: 2.6 -7.5) for the NMOSD cohort and 4.0 years (IQR: 1.8 – 7.5) for the HC. We observed faster pRNFL (β=-0.25µm/year, 95%CI: -0.45 to -0.05, p=0.014) and GCIPL thinning (β=-0.09µm/year, 95%CI: -0.17 to 0, p=0.05) in NMOSD compared to HC eyes. This difference appeared to be driven by faster pRNFL and GCIPL thinning in NMOSD eyes without a history of ON compared to HC (GCIPL: β=-0.15µm/year, 95%CI: -0.25 to -0.05, p=0.005; pRNFL: β=-0.43µm/year, 95%CI: -0.67 to -0.19, p<0.001), while rates of pRNFL (β=-0.07µm/year , 95%CI: -0.31 to 0.16, p=0.53) and GCIPL (β=-0.01µm/year, 95%CI: -0.11 to 0.10, p=0.90) thinning did not differ between NMOSD-ON and HC eyes .
Furthermore, we explored the effects of non-ON relapses during follow-up on rates of pRNFL and GCIPL thinning. Ten patients had relapses during follow-up (9 transverse myelitis, 1 area postrema syndrome). Patients with relapses did not exhibit differences in rates of GCIPL (β=0.05µm/year, 95%CI:-0.10 to 0.20, p=0.51) or pRNFL thinning (pRNFL: β=0.08µm/year, 95%CI: -0.28 to 0.43, p=0.67), compared to those who were clinically stable.
Conclusions
In this longitudinal study, we observed progressive pRNFL and GCIPL atrophy in AQP4-IgG+ NMOSD eyes unaffected by ON. These results support that subclinical involvement of the anterior visual pathway may occur in AQP4-IgG+ NMOSD.