Showing papers by "Herbert Budka published in 2018"
TL;DR: It is found that CD4+, CD8+, and also γδ T cells infiltrate the brain tissue in RE and suggest a specific role for CD4+ T cells in orchestrating the CD8+ T-cell effector immune response.
Abstract: Objective: To characterize the brain-infiltrating immune cell repertoire in Rasmussen encephalitis (RE) with special focus on the subsets, clonality, and their cytokine profile. Methods: The immune cell infiltrate of freshly isolated brain tissue from RE was phenotypically and functionally characterized using immunohistology, flow cytometry, and T-cell receptor (TCR) deep sequencing. Identification of clonally expanded T-cell clones (TCCs) was achieved by combining flow cytometry sorting of CD4 + and CD8 + T cells and high-throughput TCR Vβ-chain sequencing. The most abundant brain-infiltrating TCCs were isolated and functionally characterized. Results: We found that CD4 + , CD8 + , and also γδ T cells infiltrate the brain tissue in RE. Further analysis surprisingly revealed that not only brain-infiltrating CD8 + but also CD4 + T cells are clonally expanded in RE. All 3 subsets exhibited a Tc1/Th1 phenotype characterized by the production of interferon (IFN)-γ and TNF. Broad cytokine profiling at the clonal level showed strong production of IFN-γ and TNF and also secretion of interleukin (IL)-5, IL-13, and granzyme B, both in CD4 + and CD8 + T cells. Conclusions: CD8 + T cells were until now considered the central players in the immunopathogenesis of RE. Our study adds to previous findings and highlights that CD4 + TCCs and γδ T cells that secrete IFN-γ and TNF are also involved. These findings underline the complexity of T-cell immunity in RE and suggest a specific role for CD4 + T cells in orchestrating the CD8 + T-cell effector immune response.
21 citations
TL;DR: A discrepancy of the described mutation site and the DNA-based mutation within the mutant-protein is observed, and it is observed that alterations in the histone protein typically do not follow the “standard mutation nomenclature in molecular diagnostics (2007)”.
Abstract: The discovery of H3F3A mutations in pediatric gliomas [11] marked a milestone in understanding the pathogenesis of these tumors. Schwartzentruber et al. demonstrated that so-called H3.3K27M and H3.3G34R/V alterations serve as driver mutations in pediatric glioblastomas. Further investigations revealed that G34R/V mutations are seen mainly in hemispheric glioblastomas. In contrast, neoplasms with histone H3K27M mutations are often located in midline structures. An important example is the diffuse intrinsic pontine glioma (DIPG), with a median overall survival of less than 12 months [5]. The discovery of the above as well as H3.3K27I, H3.1K27M and H3.2K27M [2] mutations proved not only to be of major diagnostic and prognostic relevance [1] but also as a potential therapeutic target [9]. In fact, the correlation of H3K27M mutations with poor overall survival has led to the introduction of a new entity, the “diffuse midline glioma H3K27M-mutant”, in the updated “WHO Classification of Tumours of the Central Nervous System” (2016) [8]. In our analyses, we have observed a discrepancy of the described mutation site and the DNA-based mutation within the mutant-protein. Figure 1 (a) depicts the first 15 amino acids of the coding H3F3A sequence. Molecular genetic analysis of a representative diffuse midline glioma (WHO grade IV) H3K27M-mutant is shown in (b), indicating that the amino acid 28 rather than 27 shows a conversion from lysine (K) into methionine (M). Furthermore, the amino acid sequence of a tumor from another patient (c) demonstrates that the discrepancy also applies to the H3.3G34Rmutation, which involves amino acid G35 rather than G34. One explanation for this discrepancy is that alterations in the histone protein typically do not follow the “standard mutation nomenclature in molecular diagnostics (2007)” [10], which states that the first nucleotide of a coding DNA sequence is the A of ATG and that the first amino acid of a protein is labeled with 1. Instead, the numeration of histone amino acids is based on initial papers that disregarded the first methionine, as it is cleaved in an early posttranslational state, and was, therefore, initially not detected. [4]. Maintaining separate nomenclatures for cancer-related mutations will certainly be a hopeless endeavor in times of whole-genome sequencing, which follow the standard nomenclature from 2007 [10]. In addition, standard references such as the “Catalogue of Somatic Mutations in Cancer” (COSMIC) or the NCBI database, as well as single publications follow this nomenclature and describe such alterations as K28M or G35 mutations [6, 7]. Exactness is particularly important in G34-related mutations, as the DNA-based 34th amino acid of H3F3A is also a glycine that could be converted into arginine. Therefore, it needs to be discussed, how the histone nomenclature by convention should be adapted. A precedent for a successful nomenclature change is the BRAFV600E mutation, which was formerly reported as BRAFV599E mutation [3]. We believe that this lack of clarity is prone to erroneous interpretation of the reported mutations and to diagnostic inaccuracy. * Henning Leske Henning.Leske@medisin.uio.no
11 citations
TL;DR: The syndrome of sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO), defined genetically by mutations of the gene for the mitochondrial DNA polymerase-γ, POLG, was first described in 1997 and several case reports with various POLG mutations have been published.
Abstract: The syndrome of sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO), defined genetically by mutations of the gene for the mitochondrial DNA polymerase-γ, POLG, was first described in 1997 (1). Since then, several case reports with various POLG, or more rarely PEO1, mutations have been published (2-4), some specifically addressing muscle and nerve pathology (1, 3), nerve electrophysiology (5), or radiological aspects (4, 6, 7).
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3 citations