Thomas Masterman

Multiple Sclerosis Severity Score Using disability and disease duration to rate disease severity

Background: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. Methods: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. Results: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. Conclusion: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.

CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms.

CTLA-4, expressed mainly on activated T cells, helps maintain, through its inhibitory function, immune-system homeostasis. Polymorphisms in the CTLA-4 gene (CTLA4) are known to be important in several autoimmune diseases, including multiple sclerosis (MS). Here, we have performed genotyping for CTLA4 polymorphisms, and investigated expression by peripheral blood mononuclear cells of CTLA-4 mRNA and protein, in patients with MS and myasthenia gravis and in healthy controls. Expression levels for mRNA and protein were similar in the patient and control groups; however, there was a clear relationship between genotype and CTLA-4 expression. Specifically, individuals carrying thymine at position −318 of the CTLA4 promoter (T−318) and homozygous for adenine at position 49 in exon 1 showed significantly increased expression both of cell-surface CTLA-4 after cellular stimulation and of CTLA-4 mRNA in non-stimulated cells. The association was seen most clearly for unsorted CD3+ cells and was absent in the CD8+ subset. The T−318 allele has been shown to be negatively associated with susceptibility to MS in an earlier study by our group. Thus, we propose that the susceptibility-influencing role of CTLA4 in MS may be related to genotypically conditioned promoter function, whereby high gene expression may decrease the risk of disease.

Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis.

Multiple sclerosis (MS) is a T-cell-mediated disease of the central nervous system, characterized by damage to myelin and axons, resulting in progressive neurological disability. Genes may influence susceptibility to MS, but results of association studies are inconsistent, aside from the identification of HLA class II haplotypes. Whole-genome linkage screens in MS have both confirmed the importance of the HLA region and uncovered non-HLA loci that may harbor susceptibility genes. In this two-stage analysis, we determined genotypes, in up to 672 MS patients and 672 controls, for 123 single-nucleotide polymorphisms (SNPs) in 66 genes. Genes were chosen based on their chromosomal positions or biological functions. In stage one, 22 genes contained at least one SNP for which the carriage rate for one allele differed significantly (P<0.08) between patients and controls. After additional genotyping in stage two, two genes—each containing at least three significantly (P<0.05) associated SNPs—conferred susceptibility to MS: LAG3 on chromosome 12p13, and IL7R on 5p13. LAG3 inhibits activated T cells, while IL7R is necessary for the maturation of T and B cells. These results imply that germline allelic variation in genes involved in immune homeostasis—and, by extension, derangement of immune homeostasis—influence the risk of MS.

A Proliferation-inducing Ligand (APRIL) is Expressed by Astrocytes and is Increased in Multiple Sclerosis

A proliferation‐inducing ligand (APRIL) is a newly described member of the tumour necrosis factor (TNF) superfamily that was first identified as a factor favouring tumorigenesis. APRIL is also important for several immune functions, including B‐cell survival. Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that is commonly diagnosed in early adulthood. Several TNF superfamily members have been identified in brains of patients with MS, although their exact function within the CNS is presently unknown. To investigate whether APRIL is expressed in the CNS, we studied APRIL protein expression by immunohistochemistry in MS patients and controls. Morphologically, APRIL‐positive cells appeared to be astrocytes. A two‐colour immunohistochemistry revealed that APRIL expression was cytoplasmic, granular and restricted to GFAP‐positive cells. Conversely, HLA class II‐positive microglial cells were negative for APRIL expression. APRIL‐positive cells were fewer in brains of controls compared with those with MS. We further corroborated our findings by studying APRIL protein expression in several glioblastoma cell lines, and found APRIL to be expressed by most cell lines analysed. APRILs binding partner syndecan‐1 (CD138) was detected in brains of neither MS nor control patients. Furthermore, B cells were detectable in the brain of one of five patients with MS. We conclude that APRIL is expressed by reactive astrocytes in MS and may be of relevance in gliotic scar formation.

Lipid-specific immunoglobulin M in CSF predicts adverse long-term outcome in multiple sclerosis.

Background and Objective The presence of lipid-specific immunoglobulin M bands in the cerebrospinal fluid (CSF) predicts an aggressive course in patients with relapsing–remitting multiple sclerosis (MS) during early stages of the disease. This study examined whether it is also a predictor of long-term prognosis in MS. Methods Eighty-one patients with MS and 22 headache controls were analyzed for anti-lipid IgM reactivity in CSF samples. The correlation between the presence of lipid-specific immunoglobulin M bands in CSF and disease progression was assessed in patients with MS who had been followed longitudinally for, on average, more than 11 years. Results Lipid-specific immunoglobulin M bands were detected in the CSF of 24 of 81 patients with MS and were absent in the CSF of all headache controls. Median time to conversion to a secondary progressive course was 11 years in patients with bands and 22 years in patients without bands. Median time to an Expanded Disability Status Scale score of 4 was 14 years in patients with bands and 24 years in patients without bands. Conclusion The presence of lipid-specific immunoglobulin M bands in CSF predicts a more adverse long-term outcome in patients with MS; it may thus define a subset of patients who might benefit from aggressive treatment during the early phase of the disease.

The thymus is a source of B-cell-survival factors–APRIL and BAFF–in myasthenia gravis

The accumulation of B cells in the thymus is a common feature of myasthenia gravis (MG). To understand whether factors enhancing B-cell survival are increased in MG, we studied the expression of APRIL, BAFF and three of their receptors in the thymus. In hyperplastic thymi, macrophages expressed APRIL and BAFF, and germinal-center B cells, BAFF-R. CD138-positive plasma cells were abundant in MG thymi. By contrast, BCMA-positive plasma cells were scarce. The expression of APRIL and BAFF in MG thymi may reflect the establishment of an environment favorable to B-cell survival.

Lipid‐specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab

Progressive multifocal leukoencephalopathy (PML) is a serious side effect associated with natalizumab treatment in multiple sclerosis (MS). PML risk increases in individuals seropositive for anti–John Cunningham virus (JC) antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immunosuppressants. We explored whether the presence of lipid‐specific immunoglobulin M oligoclonal bands in cerebrospinal fluid (CSF; IgM bands), a recognized marker of highly inflammatory MS, may identify individuals better able to counteract the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk of developing PML.

Plasma cerebrosterol and magnetic resonance imaging measures in multiple sclerosis

OBJECTIVES The concentration in plasma of the brain-specific cholesterol metabolite cerebrosterol has been proposed as a biomarker of neurodegeneration in multiple sclerosis (MS) and other neurological diseases. It is unknown, however, which pathophysiological process in MS best accounts for variations in plasma cerebrosterol. PATIENTS AND METHODS In this study, we related plasma cerebrosterol concentrations in 46 MS patients - 27 with a relapsing-remitting (RR) disease course and 19 with a primary progressive (PP) course - to three conventional magnetic resonance imaging measures: on T(1)-weighted brain scans, volume of gadolinium-enhanced lesions (a marker of active inflammation) and hypointense lesions (a marker of edema or axonal loss) and on T(2)-weighted scans, volume of hyperintense lesions (a marker of disease extent). RESULTS By multiple-regression analysis, we uncovered negative correlations between the cerebrosterol-cholesterol ratio in plasma and both age at sampling (beta=-0.35 and p=0.079 in RRMS; beta=-0.76 and p=0.006 in PPMS) and volume of T(2)-weighted lesions (beta=-0.52 and p=0.078 in RRMS; beta=-0.50 and p=0.247 in PPMS). CONCLUSION We hypothesize that decreases in plasma cerebrosterol may reflect the total spatiotemporal burden of MS-the cumulative effects of its dissemination in space and its duration in time.

HLA-DRB1⁎15 and cerebrospinal-fluid-specific oligoclonal immunoglobulin G bands lower age at attainment of important disease milestones in multiple sclerosis

Carriage of HLA-DRB1*15 is the most important genetic risk factor in multiple sclerosis (MS), while CSF-specific oligoclonal immunoglobulin G bands (OCB) constitute the most sensitive biochemical marker for diagnosing MS. We demonstrated in an earlier study the interdependence of HLA-DRB1 genotype and OCB status; the effect of these phenotypic features on MS prognosis remains controversial, however. We investigated by survival analysis the impact of each variable on age at two important MS milestones: onset of clinical symptoms and an Expanded Disability Status Scale (EDSS) score of 6.0. Both carriage of HLA-DRB1*15 and the presence of OCB hastened attainment of EDSS 6.0.

CSF oligoclonal band patterns reveal disease heterogeneity in multiple sclerosis

Oligoclonal IgG bands (OCGB) are characteristic of multiple sclerosis (MS). Most patients show OCGB exclusively in cerebrospinal fluid (CSF). Others have serum bands with additional ones in CSF. Moreover, IgM bands against myelin lipids (LS-OCMB) associate with aggressive relapsing-remitting MS (RRMS). We studied oligoclonal bands in 424 MS patients. Most primary progressive (PPMS) patients showed serum OCGB with additional bands in CSF. Conversely, most RRMS and secondary progressive (SPMS) patients showed OCGB exclusively in CSF (p<0.0001). Moreover, no PPMS patient presented LS-OCMB, while 31% of RRMS and 60% of SPMS groups showed these antibodies (p<0.0001). This suggests heterogeneous autoimmune mechanisms in MS.