Müller cell activation, proliferation and migration following laser injury.

PurposeMüller cells are well known for their critical role in normal retinal structure and function, but their reaction to retinal injury and subsequent role in retinal remodeling is less well characterized. In this study we used a mouse model of retinal laser photocoagulation to examine injury-induced Müller glial reaction, and determine how this reaction was related to injury-induced retinal regeneration and cellular repopulation.MethodsExperiments were performed on 3-4-week-old C57BL/6 mice. Retinal laser photocoagulation was used to induce small, circumscribed injuries; these were principally confined to the outer nuclear layer, and surrounded by apparently healthy retinal tissue. Western blotting and immunohistochemical analyses were used to determine the level and location of protein expression. Live cell imaging of green fluorescent protein (GFP)-infected Müller cells (AAV-GFAP-GFP) were used to identify the rate and location of retinal Müller cell nuclear migration.ResultsUpon injury, Müller cells directly at the burn site become reactive, as evidenced by increased expression of the intermediate filament proteins glial fibrillary acidic protein (GFAP) and nestin. These reactive cells re-enter the cell cycle as shown by expression of the markers Cyclin D1 and D3, and their nuclei begin to migrate toward the injury site at a rate of approximately 12 microm/hr. However, unlike other reports, evidence for Müller cell transdifferentiation was not identified in this model.ConclusionsRetinal laser photocoagulation is capable of stimulating a significant glial reaction, marked by activation of cell cycle progression and retinal reorganization, but is not capable of stimulating cellular transdifferentiation or neurogenesis

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (n(NationMS) = 946, n(BIONAT) = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis

Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology

Association of Intrathecal Immunoglobulin G Synthesis With Disability Worsening in Multiple Sclerosis

IMPORTANCE Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed. OBJECTIVE To determine a possible association of intrathecal IgG synthesis and early disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing-remitting MS or clinically isolated syndrome. DESIGN, SETTING, AND PARTICIPANTS Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018. EXPOSURE Patients were offered standard immunotherapies per national treatment guidelines. MAIN OUTCOMES AND MEASURES A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated. RESULTS Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 [95% CI, 1.15-3.58]; P=.01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found. CONCLUSIONS AND RELEVANCE Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS

Erratum: Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk (Cell (2019) 178(1) (262), (S0092867419306798), (10.1016/j.cell.2019.06.016))

(Cell 175, 1679–1687.e1–e7; November 29, 2018) It has come to our attention that in preparing the final version of this article, the authors inadvertently misspelled the last name of author Charlotte E. Teunissen as “Charlotte E. Theunissen.” This error has been corrected in the article online. In the Editorial Note (Cell 178, 262, June 27, 2019), the editors refer to the original version of the published manuscript. That version contained a misspelled name, and as that has now been corrected, we are updating the Editorial Note as well