Characterizing the Mechanisms of Progression in Multiple Sclerosis

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies

“…T cell differentiation and activation was thought to be at the heart of MS pathogenesis [33], however recent evidence has expanded this view, suggesting that a complex network of immune mechanisms involving both innate and adaptive immunity is likely to be involved [34]. MS GWAS [2] identified risk genes are predominantly expressed in other immune cell subsets [10]; and the success of B cell specific therapies [35], and master-regulation of other immune cell types by myeloid cells [36] support their fundamental roles in MS. Eomes and Tbet are most highly expressed by NK cells, which have already been implicated as pathogenically significant, in that their numbers are reduced in MS [37] and their killing of activated T cells and macrophages [38] is important in therapy.…”

“…It is also striking that that a significant proportion of these genes are classified as being involved in regulation of cell migration. Trafficking of immune cells across the blood brain barrier is likely fundamental to MS pathology [33] and these chemokines have been identified as contributing to MS pathogenesis in previous studies looking for biomarkers [42]. It remains to be determined if the ETlow phenotype in blood represents increased trafficking of EThigh cells to tissues, so leaving their proportions and median expression low in blood, or whether they are simply low in blood due to an intrinsic regulatory mechanism associated with production and differentiation of ET expressing cells.…”

Haplotypes of the interleukin 7 receptor alpha gene are correlated with altered expression in whole blood cells in multiple sclerosis

“…Further support comes from the success of drugs which reduce or modulate T cell activation and movement, such as anti-VLA4 antibody, FTY720, interferon beta and glatiramer acetate. 20 We hypothesized that the CD127 genotypic association we detected in PPMS was due to its effect on mRNA and protein expression. Differences in transcription and cell surface protein levels due to haplotype in healthy controls and MS were sought by measuring in vivo expression in whole blood.…”

MR Imaging Intensity Modeling of Damage and Repair In Multiple Sclerosis: Relationship of Short-Term Lesion Recovery to Progression and Disability

“…2 Although the cause of the progression is not known, a commonly offered theory is an exhaustion of both structural and functional redundancies that increasingly prevents repair and recovery. 3,4 Such a model would explain the disassociation between relapses and progression, 5 as well as the eventual conversion to a progressive phase, with a steady accrual of disability in the absence of relapses. 6 This paper presents a study of new lesion formation in the context of such a model, expressing progression of disease as the balance between injury and repair, with the rationale that the above-mentioned global shift in reparative capacity might also be expressed in the individual behavior of the lesion.…”