Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system

Oligodendrocytes have been considered as a functionally homogeneous population in the central nervous system (CNS). We performed single-cell RNA sequencing on 5072 cells of the oligodendrocyte lineage from 10 regions of the mouse juvenile and adult CNS. Thirteen distinct populations were identified, 12 of which represent a continuum from Pdgfra(+) oligodendrocyte precursor cells (OPCs) to distinct mature oligodendrocytes. Initial stages of differentiation were similar across the juvenile CNS, whereas subsets of mature oligodendrocytes were enriched in specific regions in the adult brain. Newly formed oligodendrocytes were detected in the adult CNS and were responsive to complex motor learning. A second Pdgfra(+) population, distinct from OPCs, was found along vessels. Our study reveals the dynamics of oligodendrocyte differentiation and maturation, uncoupling them at a transcriptional level and highlighting oligodendrocyte heterogeneity in the CNS

Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis

Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS

Novel CTSC mutations in a patient with Papillon-Lefevre syndrome with recurrent pyoderma and minimal oral and palmoplantar involvement

SIR, Papillon–Lefe`vre syndrome (PLS) is an autosomal recessivegenodermatosis mainly characterized by early-onset periodontitisand palmoplantar keratoderma. Recurrent pyogenic skininfections, usually of mild degree and self-healing, are relativelycommon additional features.1,2 PLS is caused by lossof-function mutations in the CTSC gene, which encodes forcathepsin C, a lysosomal cysteine protease required forthe activation of granule-associated serine proteases inimmune ⁄inflammatory cells

Dystrophic epidermolysis bullosa pruriginosa in Italy: clinical and molecular characterization

Dystrophic epidermolysis bullosa (DEB) pruriginosa (DEB-Pr) is a rare variant of DEB due to COL7A1 dominant and recessive mutations, which is characterized by severe itching and lichenoid or nodular prurigo-like lesions, mainly involving the extremities. Less than 30 patients have been described showing variable disease expression, and frequently, delayed age of onset. We report the clinical and molecular characterization of seven Italian DEB patients, three affected with recessive DEB-Pr and four with dominant DEB-Pr. In all the patients, the signs were typical of a mild DEB phenotype, until the onset of pruritus, which was followed by worsening of the clinical picture, with appearance of the distinctive lichenified lesions of DEB-Pr. Nine mutations were found in the COL7A1 gene, three of which were novel and one was de novo. DEB-Pr patients with either dominant or recessive mutations were shown to synthesize a normal or variably reduced amount of type VII collagen, which was correctly deposited at the dermal-epidermal junction. Since six of these mutations have been reported in DEB patients in the absence of intense pruritus, these data implicate a role of yet unidentified phenotype-modifying factors in the pathogenesis of DEB-Pr

Retrospective comparison of qualitative and quantitative reverse transcriptase polymerase chain reaction in diagnosing and monitoring the ALL1-AF4 fusion transcript in patients with acute lymphoblastic leukaemia

We compared quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR) to qualitative RT-PCR in determining response to therapy and predicting clinical outcome in 18 retrospectively selected patients with ALL positive for the ALL1-AF4 fusion and with frozen RNA samples collected at diagnosis and during follow-up ( 96 samples analysed). The ALL1-AF4 junction was detected by qualitative RT-PCR in 18 patients and by Q-RT-PCR in 17 patients ( one patient harboured the rare e10-e6 ALL1-AF4 junction, which falls outside of the primer and probe location designed for the Q-RT-PCR). In three of the 12 patients negative to qualitative RT-PCR after induction therapy, a small number of ALL1-AF4 copies was detected by Q-RT-PCR. Thus nine patients were negative and eight positive. Seven of the eight positive patients suffered a relapse, including two of the three patients positive to Q-RT-PCR yet negative to qualitative RT-PCR. Moreover, we found two (5%) discordant results among the 39 follow-up tests of the nine patients who converted to a negative qualitative-quantitative PCR status. The results suggest that qualitative RT-PCR is more appropriate for the routine diagnosis of this genetic alteration. However, Q-RT-PCR is more accurate in assessing the molecular response after induction treatment and could be more useful in clinical decision-making in ALL1-AF4-positive ALL patients

Retrospective comparison of qualitative and quantitative reverse transcriptase polymerase chain reaction in diagnosing and monitoring the ALL1-AF4 fusion transcript in patients with acute lymphoblastic leukaemia

We compared quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR) to qualitative RT-PCR in determining response to therapy and predicting clinical outcome in 18 retrospectively selected patients with ALL positive for the ALL1-AF4 fusion and with frozen RNA samples collected at diagnosis and during follow-up (96 samples analysed). The ALL1-AF4 junction was detected by qualitative RT-PCR in 18 patients and by Q-RT-PCR in 17 patients (one patient harboured the rare e10-e6 ALL1-AF4 junction, which falls outside of the primer and probe location designed for the Q-RT-PCR). In three of the 12 patients negative to qualitative RT-PCR after induction therapy, a small number of ALL1-AF4 copies was detected by Q-RT-PCR. Thus nine patients were negative and eight positive. Seven of the eight positive patients suffered a relapse, including two of the three patients positive to Q-RT-PCR yet negative to qualitative RT-PCR. Moreover, we found two (5%) discordant results among the 39 follow-up tests of the nine patients who converted to a negative qualitative-quantitative PCR status. The results suggest that qualitative RT-PCR is more appropriate for the routine diagnosis of this genetic alteration. However, Q-RT-PCR is more accurate in assessing the molecular response after induction treatment and could be more useful in clinical decision-making in ALL1-AF4-positive ALL patients. © 2004 Nature Publishing Group All rights reserved