Anna Brunn

Bio: Anna Brunn is an academic researcher from University of Cologne. The author has contributed to research in topics: Cytotoxic T cell & Primary central nervous system lymphoma. The author has an hindex of 24, co-authored 70 publications receiving 1826 citations.

Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma

Abstract: Primary central nervous system lymphoma (PCNSL) is a special lymphoma entity. Although being a rare disease, the incidence of PCNSL has significantly raised in the last decades [3, 4], however, a specific standard therapeutic regimen is still a matter of debate [2]. Despite the fact that PCNSL histopathologically resemble diffuse large B cell lymphoma (DLBCL) [3, 4], they are characterized by unique clinical and molecular features [6], including their exclusive manifestation in the unique microenvironment of the immunologically privileged CNS. Activation of the nuclear factor jB (NF-jB) pathway is a hallmark of PCNSL [1, 5]. Various mechanisms of NF-jB activation have been identified in PCNSL. These include gains in chromosome 18q21 being present in 37% of PCNSL and activating mutations of the CARD11 gene being present in 16% of PCNSL [5, 6]. Moreover, NF-jB activation might be triggered by stimulation of either the B cell receptor pathway, the tumor necrosis factor or the toll-like receptor (TLR) pathway. Here, we provide evidence for deregulation of the TLR pathway in the pathogenesis of PCNSL through mutation of the myeloid differentiation primary response gene 88 (MYD88). Analysis of the MYD88 gene, the central integrator of the TLR pathway, in a series of 14 PCNSL by a biphased PCR approach followed by sequencing of all the exons revealed mutations in seven (50%) of the tumors (for details see supplementary information). Interestingly, in five of these seven (71%) PCNSL, i.e. 36% of all tumors analyzed, mutations were identified as a leucine to proline exchange at position 265 (L265P), which is an oncogenically activating mutation and has recently been shown to be of somatic origin [7]. In the remaining two PCNSL, MYD88 mutations resided at positions 103 and 143, respectively. In one tumor a nucleotide exchange corresponded to a silent mutation (L103L). In the other PCNSL the mutation resulted in an amino acid exchange (Q143E), which has not been reported before and the functional impact of which remains to be elucidated. Till date, MYD88 mutations have been described only in 9% of gastric mucosa-associated lymphoid tissue lymphoma, in 3% of chronic lymphocytic leukemia, in 5% of Burkitt’s lymphoma, and in systemic DLBCL, affecting 39% of the activated B cell like (ABC)-DLBCL subtype and 6% of the germinal center B cell like subgroup, respectively [7, 8]. Interestingly, 29% of systemic ABCDLBCL harbored the MYD88 L265P mutation [7]. Two of the five PCNSL (40%) with the recurrent MYD88 L265P mutation concomitantly harbored a CARD11 mutation, which results in the constitutive activation of the CARD11 protein [5]. While either the MYD88 L265P or the CARD11 mutation activates the NF-jB pathway, the combined presence of these mutations may act synergistically; thus, further enhancing NFjB activation [1, 5]. In addition to a direct effect on the NF-jB pathway, MYD88 mutations may alter the Electronic supplementary material The online version of this article (doi:10.1007/s00401-011-0891-2) contains supplementary material, which is available to authorized users.

Gene expression profiling suggests primary central nervous system lymphomas to be derived from a late germinal center B cell

Abstract: To characterize the molecular origin of primary lymphomas of the central nervous system (PCNSL), 21 PCNSLs of immunocompetent patients were investigated by microarray-based gene expression profiling. Comparison of the transcriptional profile of PCNSL with various normal and neoplastic B-cell subsets demonstrated PCNSL (i) to display gene expression patterns most closely related to late germinal center B cells, (ii) to display a gene expression profile similar to systemic diffuse large B-cell lymphomas (DLBCLs) and (iii) to be in part assigned to the activated B-cell-like (ABC) or the germinal center B-cell-like (GCB) subtype of DLBCL.

Astrocyte gp130 Expression Is Critical for the Control of Toxoplasma Encephalitis

Abstract: Toxoplasma gondii infects astrocytes, neurons and microglia cells in the CNS and, after acute encephalitis, persists within neurons. Robust astrocyte activation is a hallmark of Toxoplasma encephalitis (TE); however, the in vivo function of astrocytes is largely unknown. To study their role in TE we generated C57BL/6 GFAP-Cre gp130 fl/fl mice (where GFAP is glial fibrillary acid protein), which lack gp130, the signal-transducing receptor for IL-6 family cytokines, in their astrocytes. In the TE of wild-type mice, the gp130 ligands IL-6, IL-11, IL-27, LIF, oncostatin M, ciliary neurotrophic factor, B cell stimulating factor, and cardiotrophin-1 were up-regulated. In addition, GFAP + astrocytes of gp130 fl/fl control mice were activated, increased in number, and efficiently restricted inflammatory lesions and parasites, thereby contributing to survival from TE. In contrast, T. gondii - infected GFAP-Cre gp130 fl/fl mice lost GFAP + astrocytes in inflammatory lesions resulting in an inefficient containment of inflammatory lesions, impaired parasite control, and, ultimately, a lethal necrotizing TE. Production of IFN-γ and the IFN-γ-induced GTPase (IGTP), which mediate parasite control in astrocytes, was even increased in GFAP-Cre gp130 fl/fl mice, indicating that instead of the direct antiparasitic effect the immunoregulatory function of GFAP-Cre gp130 fl/fl astrocytes was disturbed. Correspondingly, in vitro infected GFAP-Cre gp130 fl/fl astrocytes inhibited the growth of T. gondii efficiently after stimulation with IFN-γ, whereas neighboring noninfected and TNF-stimulated GFAP-Cre gp130 fl/fl astrocytes became apoptotic. Collectively, these are the first experiments demonstrating a crucial function of astrocytes in CNS infection.

Gp130-Dependent Astrocytic Survival Is Critical for the Control of Autoimmune Central Nervous System Inflammation

Abstract: Astrocytes are activated in experimental autoimmune encephalomyelitis (EAE) and have been suggested to either aggravate or ameliorate EAE. However, the mechanisms leading to an adverse or protective effect of astrocytes on the course of EAE are incompletely understood. To gain insight into the astrocyte-specific function of gp130 in EAE, we immunized mice lacking cell surface expression of gp130, the signal-transducing receptor for cytokines of the IL-6 family, with myelin oligodendrocyte glycoprotein(35-55) peptide. These glial fibrillary acid protein (GFAP)-Cre gp130(fl/fl) mice developed clinically a significantly more severe EAE than control mice and succumbed to chronic EAE. Loss of astrocytic gp130 expression resulted in apoptosis of astrocytes in inflammatory lesions of GFAP-Cre gp130(fl/fl) mice, whereas gp130(fl/fl) control mice developed astrogliosis. Astrocyte loss of GFAP-Cre gp130(fl/fl) mice was paralleled by significantly larger areas of demyelination and significantly increased numbers of CD4 T cells in the CNS. Additionally, loss of astrocytes in GFAP-Cre gp130(fl/fl) mice resulted in a reduction of CNS regulatory Foxp3(+) CD4 T cells and an increase of IL-17-, IFN-γ-, and TNF-producing CD4 as well as IFN-γ- and TNF-producing CD8 T cells, illustrating that astrocytes regulate the phenotypic composition of T cells. An analysis of mice deficient in either astrocytic gp130- Src homology region 2 domain-containing phosphatase 2/Ras/ERK or gp130-STAT1/3 signaling revealed that prevention of astrocyte apoptosis, restriction of demyelination, and T cell infiltration were dependent on the astrocytic gp130-Src homology region 2 domain-containing phosphatase 2/Ras/ERK, but not on the gp130-STAT1/3 pathway, further demonstrating that gp130-dependent astrocyte activation is crucial to ameliorate EAE.

Immunohistochemical profile and chromosomal imbalances in papillary tumours of the pineal region.

Abstract: The histopathology of papillary tumours of the pineal region (PTPR) closely resembles that of ependymomas and choroid plexus tumours. Therefore, immunohistochemical staining profiles were investigated in a series of 15 PTPR. In addition to cytokeratin, synaptophysin and glial fibrillary acidic protein expression, PTPR were examined for the presence of dot- or ring-like epithelial membrane antigen (EMA) immunoreactivity typically encountered in ependymoma, staining for inwardly rectifying potassium channel Kir7.1 and stanniocalcin-1 (specifically expressed in choroid plexus tumours) as well as microtubule-associated protein-2 (MAP-2). Furthermore, comparative genomic hybridization was performed in five PTPR. Cytokeratin was expressed in all PTPR examined, whereas glial fibrillary acidic protein and synaptophysin staining were absent. Dot- or ring-like EMA immunoreactivity was only observed in 1 out of 15 PTPR. Membranous Kir7.1 and cytoplasmic stanniocalcin-1 staining were present in the minority of PTPR (3/15 and 4/15, respectively). In contrast, MAP-2 immunoreactivity was encountered in 13 out of 15 PTPR, but was significantly less frequently observed in a series of choroid plexus tumours (7/37). PTPR mainly presented with chromosomal losses affecting chromosomes 10 (4/5 cases) and 22q (3/5 cases) as well as gains on chromosomes 4 (4/5 cases), 8 (3/5 cases), 9 (3/5 cases) and 12 (3/5 cases). To conclude, the majority of PTPR can be distinguished from ependymomas and choroid plexus tumours by absent staining for epithelial membrane antigen, Kir7.1 and staniocalcin-1 as well as the presence of distinct MAP-2 immunoreactivity. Antibodies directed against these antigens are thus expected to be valuable markers in the diagnosis of papillary tumours located in the vicinity of the third ventricle.

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

Abstract: WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , کتابخانه مرکزی دانشگاه علوم پزشکی تهران

Astrocytes: biology and pathology

Abstract: Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

Integrative Genomics Viewer

Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.