Regulation of proteins mediating neurodegeneration in experimental autoimmune encephalomyelitis and multiple sclerosis

Multiple sclerosis is characterized by inflammatory demyelination and axonal loss as pathophysiological correlates of relapsing activity and progressive development of clinical disability. The molecular processes involved in this pathogenesis are still unclear as they are quite complex and heterogeneous. In this article we present protein expression analysis of brain and spinal cord tissues from different models of murine experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model for multiple sclerosis. We observed a number of EAE-specific protein expression and PTM differences. Proteome analysis was extended to multiple sclerosis specimens in order to validate the EAE findings. Our findings suggest the regulation of a number of proteins that shed light on the molecular mechanisms of the disease processes taking place in EAE and multiple sclerosis. We found consistent modulation of proteins including serum amyloid P component, sirtuin 2, dihydropyrimidinase-related protein family proteins, stathmin 1, creatine kinase B and chloride intracellular channel protein 1. Functional classification of the proteins by database and the literature mining reveals their association with neuronal development and myelinogenesis, suggesting possible disease processes that mediate neurodegeneration.     

Acute Effects of Ocrelizumab Infusion in Multiple Sclerosis Patients

B cell-depleting therapies such as ocrelizumab (OCR) are highly effective in people with multiple sclerosis (MS). Especially at treatment start and initial infusion, infusion-related reactions (IRR) are a common adverse event. The relevance of acute changes of cell-depleting therapies on peripheral immune compartments and routine lab testing is important for clinical practice. We systematically analyzed routine blood parameters, detailed blood immunophenotyping and serum cytokine profiles in 45 MS patients starting on OCR. Blood samples were collected before and after corticosteroid premedication and directly after each OCR infusion of the first three ocrelizumab infusions. Blood B cells were rapidly depleted and accompanied only by a mild cytokine release at the first OCR infusion. Cytokine release was not significantly detectable from a third application in line with decreasing IRRs. B cell depletion was accompanied by short-lived changes in other immune cell populations in number, activation and cytokine secretion after each OCR infusion. Standard lab parameters did not show any clinically relevant changes. Our data demonstrate only mild changes during the first OCR infusion, which are not present any more during long-term treatment.     

Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs

Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.     

Ella versus Simoa Serum Neurofilament Assessment to Monitor Treatment Response in Highly Active Multiple Sclerosis Patients

The measurement of serum neurofilament light chain (sNfL) is of growing importance in the field of neurology. In the management of multiple sclerosis, it can serve as a useful marker to assess disease activity and treatment response. This paper compares two available methods, namely the Single Molecule Array (Simoa) and the Ella microfluid platform, to measure longitudinal sNfL levels of 42 highly active multiple sclerosis patients treated with alemtuzumab over a period of 36 months. In order to assess the methods agreement, Bland–Altman plots and Passing–Bablok regression were analyzed. Here, we show that despite the fact that Ella measures around 24% higher values than Simoa, both are equally suitable for longitudinal sNfL monitoring.