The dysregulation of the immune system in Chronic Lymphocytic Leukemia (CLL) often allows for the development of immune-mediated diseases. Among them, autoimmune cytopenias are the most common, but ...cases of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been reported. We herein report on a patient who developed a CIDP while undergoing ibrutinib treatment for CLL, prompting drug discontinuation. Steroid treatment and a rituximab course proved to be ineffective at obtaining long-term control of CIDP, but therapy with venetoclax and rituximab, which was started due to CLL progression, led to the progressive amelioration of the symptoms up to complete remission of the neurological disease.
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•Also intracerebral tumors may be a trigger for anti-NMDAR antibodies.•Dysregulated lymphoma cells might produce anti-NMDAR antibodies.•Neuronal damage induced by neoplastic cells ...could lead to antibody synthesis.
Physiological (
spontaneous) and reactive (
reparative) regenerative processes are fundamental part of life and greatly differ among the different animals and tissues. While spontaneous regeneration ...naturally occurs upon cell attrition, reparative regeneration occurs as a consequence of tissue damage. Both spontaneous and reparative regeneration play an important role in maintaining the normal equilibrium of the central nervous system (CNS) as well as in promoting its repair upon injury. Cells play a critical role in reparative regeneration as regenerating structures (cells or tissues) depend on the proliferation without (de)differentiation of parenchymal cells surviving to the injury, proliferation of stem (progenitor) cells resident in the injured tissue, dedifferentiation of mature cells in the remaining tissue, or by the influx of stem cells originating outside the damaged tissue. Considering the central role of stem and progenitor cells in regeneration, a spur of experimental stem cell-based transplantation approaches for tissue (e.g. CNS) repair has been recently generated. This review will focus on the therapeutic efficacy of different sources of somatic stem cells – and in particular on those of neural origin – in promoting CNS repair in a chronic (auto)immune-mediated inflammatory disorder such as multiple sclerosis.
A human bone marrow-derived mesenchymal stromal cell (MSCs) and cord blood-derived CD34+ stem cell co-culture system was set up in order to evaluate the proliferative and differentiative effects ...induced by MSCs on CD34+ stem cells, and the reciprocal influences on gene expression profiles. After 10 days of co-culture, non-adherent (SN-fraction) and adherent (AD-fraction) CD34+ stem cells were collected and analysed separately. In the presence of MSCs, a significant increase in CD34+ cell number was observed (fold increase = 14.68), mostly in the SN-fraction (fold increase = 13.20). This was combined with a significant increase in CD34+ cell differentiation towards the BFU-E colonies and with a decrease in the CFU-GM. These observations were confirmed by microarray analysis. Through gene set enrichment analysis (GSEA), we noted a significant enrichment in genes involved in heme metabolism (e.g. LAMP2, CLCN3, BMP2K), mitotic spindle formation and proliferation (e.g. PALLD, SOS1, CCNA1) and TGF-beta signalling (e.g. ID1) and a down-modulation of genes participating in myeloid and lymphoid differentiation (e.g. PCGF2) in the co-cultured CD34+ stem cells. On the other hand, a significant enrichment in genes involved in oxygen-level response (e.g. TNFAIP3, SLC2A3, KLF6) and angiogenesis (e.g. VEGFA, IGF1, ID1) was found in the co-cultured MSCs. Taken together, our results suggest that MSCs can exert a priming effect on CD34+ stem cells, regulating their proliferation and erythroid differentiation. In turn, CD34+ stem cells seem to be able to polarise the BM-niche towards the vascular compartment by modulating molecular pathways related to hypoxia and angiogenesis.
Peripheral neuropathy with antibodies to myelin-associated glycoprotein (MAG) is an autoimmune demyelinating disorder of the peripheral nervous system caused by pathogenic IgM recognizing the human ...natural killer-1 glycoepitope expressed on MAG. This study aimed to analyze the performance of a new indirect immunofluorescence cell-based assay (CBA, EUROIMMUN) for the detection of anti-MAG IgM. Antibody reactivity was determined in sera from 95 patients with clinical and neurophysiological evidence of anti-MAG-associated neuropathy and in control samples from 55 patients with other forms of peripheral neuropathy. Compared to the results of the gold standard method (ELISA, Bühlmann) and using samples at a dilution of 1:100, the CBA had a sensitivity of 98.9% and a specificity of 100% (PPV 100%, NPV 98.2%). In conclusion, the CBA allows the detection of antibodies to MAG using an easy and standardized technique, and it presents a sensitive and specific alternative to the more time-consuming ELISA. Larger studies are needed to address anti-MAG titer monitoring in parallel with clinical activity.
The metallic impregnation invented by Camillo Golgi in 1873 has allowed the visualization of individual neurons in their entirety, leading to a breakthrough in the knowledge on the structure of the ...nervous system. Professor of Histology and of General Pathology, Golgi worked for decades at the University of Pavia, leading a very active laboratory. Unfortunately, most of Golgi's histological preparations are lost. The present contribution provides an account of the original slides on the nervous system from Golgi's laboratory available nowadays at the Golgi Museum and Historical Museum of the University of Pavia. Knowledge on the organization of the nervous tissue at the time of Golgi's observations is recalled. Notes on the equipment of Golgi's laboratory and the methodology Golgi used for his preparations are presented. Images of neurons from his slides (mostly from hippocampus, neocortex and cerebellum) are here shown for the first time together with some of Golgi's drawings. The sections are stained with the Golgi impregnation and Cajal stain. Golgi-impregnated sections are very thick (some more than 150 μm) and require continuous focusing during the microscopic observation. Heterogeneity of neuronal size and shape, free endings of distal dendritic arborizations, axonal branching stand out at the microscopic observation of Golgi-impregnated sections and in Golgi's drawings, and were novel findings at his time. Golgi also pointed out that the axon only originates from cell bodies, representing a constant and distinctive feature of nerve cells which distinguishes them from glia, and subserving transmission at a distance. Dendritic spines can be seen in some cortical neurons, although Golgi, possibly worried about artifacts, did not identify them. The puzzling intricacy of fully impregnated nervous tissue components offered to the first microscopic observations still elicit nowadays the emotion Golgi must have felt looking at his slides.
The presence of circulating anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) has been described in sera of patients with different inflammatory conditions of the central nervous system. ...In adults the core clinical feature is usually characterised by acute myelitis and/or optic neuritis. We here report an atypical case with serum and cerebrospinal fluid MOG-Abs and a clinical picture suggestive for acute encephalitis.
A 31-year-old Indian man presented with altered mental status, slight fever, and ataxia. Brain magnetic resonance imaging noted a widespread involvement of the white matter associated with slight cortical and subcortical damage in absence of contrast enhancement. An extensive infectious screening resulted negative while autoimmune analysis revealed the presence of MOG-Abs, detected with live cell-based assay. After treatment with intravenous immunoglobulins a marked and prompt clinical and radiological improvement was observed.
To date, several areas of uncertainty still remain regarding clinical features and prognosis of subjects with MOG-Abs. The description of atypical cases is crucial, since recognition of this condition leads to prompt treatment and better prognosis, as in the case here reported.
Determine global gene dysregulation affecting 4q-linked (FSHD-1) and non 4q-linked (FSHD-2) cells during early stages of myogenic differentiation. This approach has been never applied to FSHD ...pathogenesis.
By in vitro differentiation of FSHD-1 and FSHD-2 myoblasts and gene chip analysis we derived that gene expression profile is altered only in FSHD-1 myoblasts and FSHD-2 myotubes. The changes seen in FSHD-1 regarded a general defect in cell cycle progression, probably due to the upregulation of myogenic markers PAX3 and MYOD1, and a deficit of factors (SUV39H1 and HMGB2) involved in D4Z4 chromatin conformation. On the other hand, FSHD-2 mytubes were characterized by a general defect in RNA metabolism, protein synthesis and degradation and, to a lesser extent, in cell cycle. Common dysregulations regarded genes involved in response to oxidative stress and in sterol biosynthetic process. Interestingly, our results also suggest that miRNAs might be implied in both FSHD-1 and FSHD-2 gene dysregulation. Finally, in both cell differentiation systems, we did not observe a gradient of altered gene expression throughout the 4q35 chromosome.
FSHD-1 and FSHD-2 cells showed, in different steps of myogenic differentiation, a global deregulation of gene expression rather than an alteration of expression of 4q35 specific genes. In general, FSHD-1 and FSHD-2 global gene deregulation interested common and distinctive biological processes. In this regard, defects of cell cycle progression (FSHD-1 and to a lesser extent FSHD-2), protein synthesis and degradation (FSHD-2), response to oxidative stress (FSHD-1 and FSHD-2), and cholesterol homeostasis (FSHD-1 and FSHD-2) may in general impair a correct myogenesis. Taken together our results recapitulate previously reported defects of FSHD-1, and add new insights into the gene deregulation characterizing both FSHD-1 and FSHD-2, in which miRNAs may play a role.
Neurofilaments are the major structural proteins of the neuronal cytoskeleton and are classified according to molecular weight into heavy, intermediate, and light chains. They are released into the ...interstitial fluid and cerebrospinal fluid (CSF) as a consequence of axonal damage. In particular, the light chain (NfL) represents the most abundant and soluble subunit and has been demonstrated to be increased in the CSF of patients with inflammatory, degenerative, vascular, or traumatic injuries in correlation with clinical and radiological activity. Similar results have been obtained measuring serum NfL with high-sensitivity single-molecule array, which enables reliable and repeatable measurement of the low NfL concentrations in serum. In particular, CSF and serum NfL values are strongly correlated in patients with multiple sclerosis (MS) and have been demonstrated to be increased in patients with MS and clinically isolated syndromes (CIS) in accordance with clinical and radiological activity. NfL levels increase in patients with a recent relapse and seem to predict cognitive impairment, long-term outcome, and conversion of CIS to MS. The few available data on patients with other demyelinating diseases suggest that NfL levels are also increased in neuromyelitis optica spectrum disorders and related conditions in correlation with attack severity, suggesting that axonal damage may occur in these disorders. We herein report and discuss published data on the role of NfL as a possible predictor of disease activity, clinical outcome and treatment response in patients with demyelinating conditions of the central nervous system.
•NfL levels are increased in patients with MOGAD at onset•NfL levels decrease over time in most patients with MOGAD•NfL levels do not increase significantly during relapses in patients with ...MOGAD•Axonal damage predominantly occurs at onset in patients with MOGAD
The unpredictable course and uncertain impact of relapses make treatment strategies of anti-myelin oligodendrocyte glycoprotein antibodies associated disorders (MOGAD) challenging. We analysed neurofilament light chain levels (NfL) in onset and follow-up sera of 18 patients with MOGAD to clarify the timing of axonal damage. In comparison with disease onset values (median 8.9 pg/mL, range 1.8-97), NfL levels remained stable or decreased in most follow-up measurements (n=52, median 6.7 pg/mL, range 0.2-207), including those measured on relapses. The predominant axonal damage occurs during onset, which could be the main driving factor of final disability, with subsequent relevant clinical and therapeutic implications.
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