Identification of naturally processed peptides bound to the class I MHC molecule H-2Kd of normal and TAP-deficient cells

This report details the biochemical features of natural peptides selected by the H-2Kd class I MHC molecule. In normal cell lines, the length of the naturally processed peptides ranged from 8 to 18 amino acids, although the majority were 9-mers (16% were longer than nine residues). The binding motif for the 9-mer peptides was dominated by the presence of a tyrosine at P2 and an isoleucine/leucine at the P9 position. The P2 residue contributed most towards binding; and the short peptides bound better and formed longer-lived cell surface complexes than the long peptides, which bound poorly and dissociated rapidly. The longer peptides did not exhibit this strictly defined motif. Trimming the long peptides to their shorter forms did not enhance binding and conversely, extending the 9-mer peptides did not decrease binding. The long peptides were present on the cell-surface bound to H-2Kd (Kd) and were not intermediate products of the class I MHC processing pathway. Finally, in two different TAP-deficient cells the long peptides were the dominant species, which suggested that TAP-independent pathways selected for long peptides by class I MHC molecules.     

St john's wort (Hypericum perforatum) counteracts deleterious effects of the chronic restraint stress on recall in rats

This study aimed at verifying a hypothesis that St. John's wort (Hypericum perforatum) alleviates stress-induced memory impairments. Administration of Hypericum perforatum (350 mg kg(-1) daily for 21 days) significantly enhanced recall of passive avoidance behavior (PAB), but had no effect on the acquisition of conditioned avoidance responses (CARs). Rats stressed chronically (2 h daily for 21 days) displayed diminished recall of the PAB and this effect was abolished by St John's wort. Chronic administration of the "equivalent" to the stress dose of exogenous corticosterone (5 mg kg(-1) daily for 21 days) also impaired recall of PAB, and this effect was also reversed by Hypericum perforatum. None of our treatments produced significant motor coordination impairments as tested in a 'chimney' test. It appears that H. perforatum prevents stress-induced deterioration of memory in rats.     

The long-term impact of early treatment of multiple sclerosis on the risk of disability pension

Journal of Neurology - The objective of this retrospective, observational study was to estimate the long-term impact of early treatment of multiple sclerosis (MS) on the risk of disability pension....     

Screening for Fabry disease and Hereditary ATTR amyloidosis in idiopathic small-fiber and mixed neuropathy

Introduction: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small-fiber neuropathy (SFN) or mixed neuropathy in a clinical setting. Methods: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed. Results: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD. Discussion: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting. Muscle Nerve 59 :354–357, 2019     

Microglia damage precedes major myelin breakdown in X-linked adrenoleukodystrophy and metachromatic leukodystrophy

X-linked adrenoleukodystrophy (X-ALD) and metachromatic leukodystrophy (MLD) are two relatively common examples of hereditary demyelinating diseases caused by a dysfunction of peroxisomal or lysosomal lipid degradation. In both conditions, accumulation of nondegraded lipids leads to the destruction of cerebral white matter. Because of their high lipid content, oligodendrocytes are considered key to the pathophysiology of these leukodystrophies. However, the response to allogeneic stem cell transplantation points to the relevance of cells related to the hematopoietic lineage. In the present study, we aimed to better characterize the pathogenetic role of microglia in the above-mentioned diseases. Applying recently established microglia markers to human autopsy cases of X-ALD and MLD we were able to delineate distinct lesion stages in evolving demyelinating lesions. The immune-phenotype of microglia was altered already early in lesion evolution, and microglia loss preceded full-blown myelin degeneration both in X-ALD and MLD. DNA fragmentation indicating phagocyte death was observed in areas showing microglia loss. The morphology and dynamics of phagocyte decay differed between the diseases and between lesion stages, hinting at distinct pathways of programmed cell death. In summary, the present study shows an early and severe damage to microglia in the pathogenesis of X-ALD and MLD. This hints at a central pathophysiologic role of these cells in the diseases and provides evidence for an ongoing transfer of toxic substrates primarily enriched in myelinating cells to microglia.