Roisin Lonergan

CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis.

Despite the fact that CD4+CD25+Foxp3+ regulatory T cells (Treg cells) play a central role in maintaining self-tolerance and that IL-17-producing CD4+ T cells (Th17 cells) are pathogenic in many autoimmune diseases, evidence to date has indicated that Th17 cells are resistant to suppression by human Foxp3+ Treg cells. It was recently demonstrated that CD39, an ectonucleotidase which hydrolyzes ATP, is expressed on a subset of human natural Treg cells. We found that although both CD4+CD25highCD39+ and CD4+CD25highCD39− T cells suppressed proliferation and IFN-γ production by responder T cells, only the CD4+CD25highCD39+, which were predominantly FoxP3+, suppressed IL-17 production, whereas CD4+CD25highCD39− T cells produced IL-17. An examination of T cells from multiple sclerosis patients revealed a normal frequency of CD4+CD25+CD127lowFoxP3+, but interestingly a deficit in the relative frequency and the suppressive function of CD4+CD25+CD127lowFoxP3+CD39+ Treg cells. The mechanism of suppression by CD39+ Treg cells appears to require cell contact and can be duplicated by adenosine, which is produced from ATP by the ectonucleotidases CD39 and CD73. Our findings suggest that CD4+CD25+Foxp3+CD39+ Treg cells play an important role in constraining pathogenic Th17 cells and their reduction in multiple sclerosis patients might lead to an inability to control IL-17 mediated autoimmune inflammation.

IL-27 mediates the response to IFN-β therapy in multiple sclerosis patients by inhibiting Th17 cells

Interferon (IFN)-β is a commonly used therapy for relapsing remitting multiple sclerosis (RRMS). However its protective mechanism is still unclear and the failure of many patients to respond has not been explained. We have found that IFN-β suppressed IL-23 and IL-1β production and increased IL-10 production by human dendritic cells (DC) activated with the TLR2 and dectin-1 agonist zymosan. Furthermore, IFN-β impaired the ability of DC to promote IL-17 production by CD4(+) T cells, but did not affect IFN-γ production. IFN-β induced IL-27 expression by DC, and neutralisation of IL-27 abrogated the suppressive effects of IFN-β on zymosan-induced IL-1 and IL-23 production and the generation of Th17 cells in vitro. Complementary in vivo studies in a mouse model showed that treatment with IFN-β enhanced expression of IL-27, and reduced IL-17 in the CNS and periphery and attenuated the clinical signs of experimental autoimmune encephalomyelitis (EAE). In addition, the significant suppressive effect of IFN-β on the ability of DC to promote Th17 cells was lost in cells from IL-27 receptor deficient mice. Finally, we showed that PBMC from non-responder RRMS patients produced significantly less IL-27 in response to IFN-β than patients who responded to IFN-β therapy. Our findings suggest that IFN-β mediates its therapeutic effects in MS at least in part via the induction of IL-27, and that IL-27 may represent an alternative therapy for MS patients that do not respond to IFN-β.

Sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) in a sibling pair with a homozygous p.A467T POLG mutation.

Two siblings who developed fifth‐decade‐onset, concurrent progressive sensory ataxia, dysarthria, and ophthalmoparesis were found to be homozygous for the p.A467T mutation of the polymerase gamma (POLG) gene. The clinical course in both subjects was progression to severe disability. The enlarging spectrum of sensory ataxic neuropathies associated with mitochondrial DNA (mtDNA) instability and POLG mutations should be recognized and considered in the differential diagnosis of this unusual presentation. Muscle Nerve, 2010

Discontinuing disease-modifying therapy in progressive multiple sclerosis: can we stop what we have started?

Disease-modifying therapy is ineffective in disabled patients (Expanded Disability Status Scale [EDSS] > 6.5) with secondary progressive multiple sclerosis (MS) without relapses, or in primary progressive MS. Many patients with secondary progressive MS who initially had relapsing MS continue to use disease-modifying therapies. The enormous associated costs are a burden to health services. Regular assessment is recommended to guide discontinuation of disease-modifying therapies when no longer beneficial, but this is unavailable to many patients, particularly in rural areas. The objectives of this study are as follows: 1. To observe use of disease-modifying therapies in patients with progressive multiple sclerosis and EDSS > 6.5. 2. To examine approaches used by a group of international MS experts to stopping-disease modifying therapies in patients with secondary progressive MS without relapses. During an epidemiological study in three regions of Ireland (southeast Dublin city, and Wexford and Donegal Counties), we recorded details of disease-modifying therapies in patients with progressive MS and EDSS > 6.5. An e-questionnaire was sent to 26 neurologists with expert knowledge of MS, asking them to share their approach to stopping disease-modifying therapies in patients with secondary progressive MS. Three hundred and thirty-six patients were studied: 88 from southeast Dublin, 99 from Wexford and 149 from Donegal. Forty-four had EDSS > 6.5: 12 were still using disease-modifying therapies. Of the surveyed neurologists, 15 made efforts to stop disease-modifying therapies in progressive multiple sclerosis, but most did not insist. A significant proportion (12 of 44 patients with progressive MS and EDSS > 6.5) was considered to be receiving therapy without benefit. Eleven of the 12 were from rural counties, reflecting poorer access to neurology services. The costs of disease-modifying therapies in this group (>170,000 yearly) could be re-directed towards development of neurology services to optimize their management.

Reactivation of BK polyomavirus in patients with multiple sclerosis receiving natalizumab therapy.

Natalizumab therapy in multiple sclerosis has been associated with JC polyomavirus—induced progressive multifocal leucoencephalopathy. We hypothesized that natalizumab may also lead to reactivation of BK, a related human polyomavirus capable of causing morbidity in immunosuppressed groups. Patients with relapsing remitting multiple sclerosis treated with natalizumab were prospectively monitored for reactivation of BK virus in blood and urine samples, and for evidence of associated renal dysfunction. In this cohort, JC and BK DNA in blood and urine; cytomegalovirus (CMV) DNA in blood and urine; CD4 and CD8 T-lymphocyte counts and ratios in peripheral blood; and renal function were monitored at regular intervals. BK subtyping and noncoding control region sequencing was performed on samples demonstrating reactivation. Prior to commencement of natalizumab therapy, 3 of 36 patients with multiple sclerosis (8.3%) had BK viruria and BK reactivation occurred in 12 of 54 patients (22.2%). BK viruria was transient in 7, continuous in 2 patients, and persistent viruria was associated with transient viremia. Concomitant JC and CMV viral loads were undetectable. CD4:CD8 ratios fluctuated, but absolute CD4 counts did not fall below normal limits. In four of seven patients with BK virus reactivation, transient reductions in CD4 counts were observed at onset of BK viruria: these resolved in three of four patients on resuppression of BK replication. No renal dysfunction was observed in the cohort. BK virus reactivation can occur during natalizumab therapy; however, the significance in the absence of renal dysfunction is unclear. We propose regular monitoring for BK reactivation or at least for evidence of renal dysfunction in patients receiving natalizumab.

Preliminary evidence for correlation between PASAT performance and P3a and P3b amplitudes in progressive multiple sclerosis.

Background:  The no‐go P3a event‐related potential (ERP) is a measure of attentional engagement and the P3b is a measure of context updating. The aim of this study was to compare ERP topographies: (i) to Paced Auditory Serial Addition Test (PASAT) results, (ii) of visual and auditory P3a and P3b of patients with primary progressive multiple sclerosis (PPMS) versus patients with secondary‐progressive multiple sclerosis (SPMS) and (iii) of both progressive subtypes to healthy controls.

Change in PASAT performance correlates with change in P3 ERP amplitude over a 12-month period in multiple sclerosis patients.

OBJECTIVE To examine the correlation between the change in PASAT and the change in P3 event-related potentials (ERPs) over a 12-month period in multiple sclerosis (MS) patients, and to compare the 12-month change in the P3 ERP between MS patients and controls. METHODS Forty-four subjects (27 MS patients, 17 controls) completed visual and auditory two-stimulus oddball and three-stimulus oddball tasks at Month 0 and Month 12. Data were recorded from a 128-scalp channel electroencephalography array. Data from scalp channels were converted into continuous interpolated images (incorporating the entire scalp and time). Amplitude, topographical differences and correlations were then tested using statistical parametric mapping. RESULTS The change in visual and auditory P3a correlated significantly with the change in PASAT score (r=0.56, p<0.001 and r=0.48, p=0.003, respectively). Visual P3b and P3a showed greater decrease in 12 months in MS patients relative to controls. Visual P3b, auditory P3b and auditory P3a amplitudes had significantly decreased in MS patients after 12-month period. CONCLUSIONS Change in visual and auditory P3a ERP amplitudes correlate with change in PASAT scores in MS patients. Visual modality is more sensitive to changes in P3 ERP amplitudes over 12-month period. SIGNIFICANCE P3 ERPs may have utility in monitoring the change in cognitive functioning in MS.

OAS1 A multiple sclerosis susceptibility gene that influences disease severity

Background:Type 1 interferons upregulate oligoadenylate synthetase 1 (OAS1). A single nucleotide polymorphism (SNP) in exon 7 of OAS1 results in differential RNAseL enzyme activity, the A allele coding for a truncated form with low activity and the G conferring high activity. We hypothesized that OAS1 genotypes would influence both susceptibility to multiple sclerosis (MS) and disease activity with the AA genotype being overrepresented and the GG genotype underrepresented in relapsing-remitting MS (RRMS) with increased disease activity. Methods:We examined OAS1 genotype distribution in 401 patients with MS, 394 healthy controls, and 178 patients with RRMS receiving interferon-&bgr; (IFN&bgr;) assessed as 1) having no or minimal disease activity on IFN&bgr;, 2) having disease activity despite IFN&bgr;, and 3) 65 patients with RRMS with highly active disease. Results:The OAS1 genotype distribution differed between patients with MS and controls (p = 0.000003), with lower frequency of GG homozygotes in patients with MS (6%) compared with controls (17%). In relation to disease severity, 34 (32%) patients with no or minimal disease activity on IFN&bgr; had the AA and 8 (8%) the GG genotype; of patients with disease activity despite IFN&bgr;, 27 (51%) were AA, while only 1 (2%) was GG (p = 0.03). Median time to first relapse on IFN&bgr; was 24 months in patients with RRMS with AA genotype and 33 months with AG or GG genotype (p = 0.04). The GG genotype was absent in 65 patients with highly active RRMS (p = 0.03). Conclusions:A functional OAS1 SNP, AA genotype, confers susceptibility to MS and the GG genotype may protect against increased disease activity. GLOSSARYEDSS = Expanded Disability Status Scale; HCV = hepatitis C virus; HW = Hardy-Weinberg; IFN = interferon; IFN&bgr; = interferon-&bgr;; MS = multiple sclerosis; MxA = myxovirus A; NAb = neutralizing antibody; OAS1 = oligoadenylate synthetase 1; RRMS = relapsing-remitting multiple sclerosis; SNP = single nucleotide polymorphism; TRU = 10-fold reduction units; TTFR = time to first relapse.

Genetics of Frontotemporal Dementia

Frontotemporal dementia (FTD) is the second most common cause of dementia following Alzheimer’s disease (AD). Between 20 and 50% of cases are familial. Mutations in MAPT, GRN and C9orf72 are found in 60% of familial FTD cases. C9orf72 mutations are the most common and account for 25%. Rarer mutations (<5%) occur in other genes such as VPC, CHMP2B, TARDP, FUS, ITM2B, TBK1 and TBP. The diagnosis is often challenging due to symptom overlap with AD and other conditions. We review the genetics, clinical presentations, neuroimaging, neuropathology, animal studies and therapeutic trials in FTD. We describe clinical scenarios including the original family with the tau stem loop mutation (+14) and also the recently discovered ‘missing tau’ mutation +15 that ‘closed the loop’ in 2015.

Symptom overlap in anxiety and multiple sclerosis

Background: The validity of self-rated anxiety inventories in people with multiple sclerosis (pwMS) is unclear. However, the appropriateness of self-reported depression scales has been widely examined. Given somatic symptom overlap between depression and MS, research emphasises caution when using such scales. Objective: This study evaluates symptom overlap between anxiety and MS in a group of 33 individuals with MS, using the Beck Anxiety Inventory (BAI). Methods: Participants underwent a neurological examination and completed the BAI. Results: A novel procedure using hierarchical cluster analysis revealed three distinct symptom clusters. Cluster one (‘wobbliness’ and ‘unsteady’) grouped separately from all other BAI items. These symptoms are well-recognised MS-related symptoms and we question whether their endorsement in pwMS can be considered to reflect anxiety. A modified 19-item BAI (mBAI) was created which excludes cluster one items. This removal reduced the number of MS participants considered ‘anxious’ by 21.21% (low threshold) and altered the level of anxiety severity for a further 27.27%. Conclusion: Based on these data, it is suggested that, as with depression measures, researchers and clinicians should exercise caution when using brief screening measures for anxiety in pwMS.