ORCID Profile
0000-0002-5639-8690
Current Organisations
Bond University
,
Hospital for Children and Adolescents, University of Leipizig
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Publications
Expression and activation of mitogen-activated protein kinases in the optic nerve head in a rat model of ocular hypertension
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.MCN.2018.01.002
Abstract: Glaucoma is a leading cause of irreversible blindness manifesting as an age-related, progressive optic neuropathy with associated retinal ganglion cell (RGC) loss. Mitogen-activated protein kinases (MAPKs: p42/44 MAPK, SAPK/JNK, p38 MAPK) are activated in various retinal disease models and likely contribute to the mechanisms of RGC death. Although MAPKs play roles in the development of retinal pathology, their action in the optic nerve head (ONH), where the initial insult to RGC axons likely resides in glaucoma, remains unexplored. An experimental paradigm representing glaucoma was established by induction of chronic ocular hypertension (OHT) via laser-induced coagulation of the trabecular meshwork in Sprague-Dawley rats. MAPKs were subsequently investigated over the following days for expression and activity alterations, using RT-PCR, immunohistochemistry and Western immunoblot. p42/44 MAPK expression was unaltered after intraocular pressure (IOP) elevation, but there was a significant activation of this enzyme in ONH astrocytes after 6-24 h. Activated SAPK/JNK isoforms were present throughout healthy RGC axons but after IOP elevation or optic nerve crush, they both accumulated at the ONH, likely due to RGC axon transport disruption, and were subject to additional activation. p38 MAPK was expressed by a population of microglia which were significantly more populous following IOP elevation. However it was only significantly activated in microglia after 3 days, and then only in the ONH and optic nerve in the retina it was solely activated in RGC perikarya. In conclusion, each of the MAPKs showed a specific spatio-temporal expression and activation pattern in the retina, ONH and optic nerve as a result of IOP elevation. These findings likely reflect the roles of the in idual enzymes, and the cells in which they reside, in the developing pathology following IOP elevation. These data have implications for understanding the mechanisms of ocular pathology in diseases such as glaucoma.
The transcription factor Bcl11b promotes both canonical and adaptive NK cell differentiation
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-03-2021
DOI: 10.1126/SCIIMMUNOL.ABC9801
Abstract: Epigenetic and functional analyses of human NK cells identify a role for Bcl11b in canonical and adaptive NK cell differentiation.
Improved immunohistochemical detection of phosphorylated mitogen-activated protein kinases in the injured rat optic nerve head
Publisher: Springer Science and Business Media LLC
Date: 11-03-2019
DOI: 10.1007/S00418-019-01771-X
Abstract: The activity of mitogen-activated protein kinases (MAPKs) is largely controlled by addition or removal of phosphate groups, which are carried out by kinase or phosphatase enzymes, respectively. Determining the phosphorylation status of MAPK isoenzymes, therefore, aids elucidation of the physiological and pathological roles of this enzyme. In practical terms, however, end-point procurement of appropriate experimental tissues produces conditions where MAPK phosphorylation status can rapidly alter, thus giving rise to aberrant data. We therefore attempted to instigate a means of stabilising end-point MAPK phosphorylation levels when procuring tissues for analysis. We employed a well-described rat model of ocular hypertension in which MAPK isoenzyme activation occurs in the optic nerve head (ONH), but can vary according to the level of resultant tissue pathology. Animals were appropriately treated and after 3 days were perfused in the presence or absence of a cocktail of phosphatase inhibitors (PIs), immediately prior to tissue fixation, in order to prevent dephosphorylation of phosphorylated MAPKs. Immunohistochemical labelling for phosphorylated MAPKs in untreated ONH sections was unaffected by the presence of PIs in the perfusate. MAPK activation was detected by immunohistochemistry in the treated ONH, but findings varied considerably, particularly in animals with less extensive tissue damage. The presence of PIs in the perfusate, however, significantly reduced this variation and enabled consistent changes to be detected, particularly in the animals with less extensive tissue damage. Thus, the addition of PIs to the perfusate is suggested when studying MAPK activation by immunohistochemistry, especially in the ONH.
Mechanisms of Neuroprotection by Glucose in Rat Retinal Cell Cultures Subjected to Respiratory Inhibition
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 15-11-2013
Abstract: Previous experiments have demonstrated that short-term hyperglycemia in rats renders the retina resistant to subsequent metabolic insults. The present study aimed to elucidate putative mechanisms involved in this protective response. Retinal cultures comprising neurons and glia were treated with the mitochondrial complex I inhibitor, rotenone, at a range of concentrations, for up to 24 hours. In some cases, glucose or the alternative energy substrates, pyruvate or lactate, and/or inhibitors of glycolysis or the pentose phosphate pathway (PPP) were also applied. Cell viability was assessed using complementary techniques: immunocytochemistry, immunoblotting, cytotoxicity assay, and TUNEL. Cellular levels of ATP, reactive oxygen species (ROS), and nicotinamide adenine dinucleotide phosphate (NAD[P]H) were also assessed. Rotenone caused the preferential loss of neurons from retinal cultures in a concentration-dependent manner glial cells were also affected, but only at a higher concentrations (10 μM). Cell loss was by apoptosis, and was preceded by a reduction of both cellular ATP and NAD(P)H levels and an increase in the production of ROS. Glucose counteracted the detrimental effects of rotenone. This involved a reduction in ROS levels and an increase in the cellular ATP/NAD(P)H ratio. The protective effect of glucose was partially reversed by either PPP or glycolysis inhibition. Glucose rescued cultured rat retinal cells from rotenone-induced toxicity. Glucose acted via both the PPP and the glycolytic pathway, maintaining cellular ATP and NAD(P)H levels and reducing ROS production. These data have implications for treatment of retinal diseases that involve metabolic compromise to neurons.
Mitochondrial Inhibition in Rat Retinal Cell Cultures as a Model of Metabolic Compromise: Mechanisms of Injury and Neuroprotection
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 26-07-2012
DOI: 10.1167/IOVS.11-9171
Abstract: Our study aimed to establish a model of energetic and metabolic dysfunction to cultured retinal cells by chemically inhibiting the mitochondrial electron transport chain with sodium azide (NaN(3)), and subsequently investigating toxic mechanisms and potential neuroprotective strategies. Methods. Mixed rat retinal cultures comprising neurons and glia were treated with a range of NaN(3) concentrations for up to 24 hours and toxicity levels were determined by immunologic Detailed pathologic mechanisms were investigated by assessing apoptosis (TUNEL assay), mitochondrial membrane potential, reactive oxygen species (ROS), and levels of adenosine triphosphate (ATP). Finally, a number of pharmacologic agents were tested to determine whether they could abrogate the effects of NaN(3) to retinal cells. Neurons and glia were killed by NaN(3) in a concentration- and time-dependent manner, with neurons being relatively more susceptible. Cell loss was via apoptosis for glia but not for neurons. Cell death generally involved a loss of mitochondrial membrane potential, a reduction in cellular ATP, and an increase in intracellular ROS levels. Glucose was partially able to prevent neuron death, as were the antioxidants trolox and pyruvate, calpain inhibitor III, the ryanodine receptor blocker dantrolene, and the nitric oxide synthase inhibitor L-NAME. Mitochondrial respiratory inhibition via NaN(3) treatment, with delineated mechanisms of toxicity and neuroprotection, represents a valid and reproducible metabolic challenge to cultured retinal cells.
Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome
Publisher: Elsevier BV
Date: 04-2023
DOI: 10.1016/J.JACI.2022.09.002
Abstract: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%) increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.
Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency
Publisher: Elsevier BV
Date: 08-2021
Related Organisations
Primary Industries And Regions Of South Australia
Location: Australia
Center For Chronic Immunodeficiency, Medical Center - University Of Freiburg, Faculty Of Medicine, University Of Freiburg, Freiburg, Germany.
Location: Germany
Center For Pediatrics, Medical Center - University Of Freiburg, Faculty Of Medicine, University Of Freiburg, Freiburg, Germany
Location: Germany
Hospital For Children And Adolescents, University Of Leipizig
Location: Germany
Related Funding Activities
No related grants have been discovered for Christian Klemann.