@article{BrechtWeissbrichBraunetal.2012, author = {Brecht, Isabel and Weissbrich, Benedikt and Braun, Julia and Toyka, Klaus Viktor and Weishaupt, Andreas and Buttmann, Mathias}, title = {Intrathecal, Polyspecific Antiviral Immune Response in Oligoclonal Band Negative Multiple Sclerosis}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {7}, doi = {10.1371/journal.pone.0040431}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134426}, pages = {e40431}, year = {2012}, abstract = {Background: Oligoclonal bands (OCB) are detected in the cerebrospinal fluid (CSF) in more than 95\% of patients with multiple sclerosis (MS) in the Western hemisphere. Here we evaluated the intrathecal, polyspecific antiviral immune response as a potential diagnostic CSF marker for OCB-negative MS patients. Methodology/Principal Findings: We tested 46 OCB-negative German patients with paraclinically well defined, definite MS. Sixteen OCB-negative patients with a clear diagnosis of other autoimmune CNS disorders and 37 neurological patients without evidence for autoimmune CNS inflammation served as control groups. Antibodies against measles, rubella, varicella zoster and herpes simplex virus in paired serum and CSF samples were determined by ELISA, and virus-specific immunoglobulin G antibody indices were calculated. An intrathecal antibody synthesis against at least one neurotropic virus was detected in 8 of 26 (31\%) patients with relapsing-remitting MS, 8 of 12 (67\%) with secondary progressive MS and 5 of 8 (63\%) with primary progressive MS, in 3 of 16 (19\%) CNS autoimmune and 3 of 37 (8\%) non-autoimmune control patients. Antibody synthesis against two or more viruses was found in 11 of 46 (24\%) MS patients but in neither of the two control groups. On average, MS patients with a positive antiviral immune response were older and had a longer disease duration than those without. Conclusion: Determination of the intrathecal, polyspecific antiviral immune response may allow to establish a CSF-supported diagnosis of MS in OCB-negative patients when two or more of the four virus antibody indices are elevated.}, language = {en} } @article{BadrMcFlederWuetal.2022, author = {Badr, Mohammad and McFleder, Rhonda L. and Wu, Jingjing and Knorr, Susanne and Koprich, James B. and H{\"u}nig, Thomas and Brotchie, Jonathan M. and Volkmann, Jens and Lutz, Manfred B. and Ip, Chi Wang}, title = {Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson's disease mice}, series = {Journal of Neuroinflammation}, volume = {19}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-022-02685-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300580}, year = {2022}, abstract = {Background Regulatory CD4\(^+\)CD25\(^+\)FoxP3\(^+\) T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson's disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create an anti-inflammatory environment. Methods Using the AAV1/2-A53T-α-synuclein Parkinson's disease mouse model that overexpresses the pathogenic human A53T-α-synuclein (hαSyn) variant in dopaminergic neurons of the substantia nigra, we assessed the neuroprotective and disease-modifying efficacy of a single intraperitoneal dose of CD28SA given at an early disease stage. Results CD28SA led to Treg expansion 3 days after delivery in hαSyn Parkinson's disease mice. At this timepoint, an early pro-inflammation was observed in vehicle-treated hαSyn Parkinson's disease mice with elevated percentages of CD8\(^+\)CD69\(^+\) T cells in brain and increased levels of interleukin-2 (IL-2) in the cervical lymph nodes and spleen. These immune responses were suppressed in CD28SA-treated hαSyn Parkinson's disease mice. Early treatment with CD28SA attenuated dopaminergic neurodegeneration in the SN of hαSyn Parkinson's disease mice accompanied with reduced brain numbers of activated CD4\(^+\), CD8\(^+\) T cells and CD11b\(^+\) microglia observed at the late disease-stage 10 weeks after AAV injection. In contrast, a later treatment 4 weeks after AAV delivery failed to reduce dopaminergic neurodegeneration. Conclusions Our data indicate that immune modulation by Treg expansion at a timepoint of overt inflammation is effective for treatment of hαSyn Parkinson's disease mice and suggest that the concept of early immune therapy could pose a disease-modifying option for Parkinson's disease patients.}, language = {en} } @article{WieseDennstaedtHollmannetal.2021, author = {Wiese, Teresa and Dennst{\"a}dt, Fabio and Hollmann, Claudia and Stonawski, Saskia and Wurst, Catherina and Fink, Julian and Gorte, Erika and Mandasari, Putri and Domschke, Katharina and Hommers, Leif and Vanhove, Bernard and Schumacher, Fabian and Kleuser, Burkard and Seibel, J{\"u}rgen and Rohr, Jan and Buttmann, Mathias and Menke, Andreas and Schneider-Schaulies, J{\"u}rgen and Beyersdorf, Niklas}, title = {Inhibition of acid sphingomyelinase increases regulatory T cells in humans}, series = {Brain Communications}, volume = {3}, journal = {Brain Communications}, number = {2}, doi = {10.1093/braincomms/fcab020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259868}, year = {2021}, abstract = {Genetic deficiency for acid sphingomyelinase or its pharmacological inhibition has been shown to increase Foxp3\(^+\) regulatory T-cell frequencies among CD4\(^+\) T cells in mice. We now investigated whether pharmacological targeting of the acid sphingomyelinase, which catalyzes the cleavage of sphingomyelin to ceramide and phosphorylcholine, also allows to manipulate relative CD4\(^+\) Foxp3\(^+\) regulatory T-cell frequencies in humans. Pharmacological acid sphingomyelinase inhibition with antidepressants like sertraline, but not those without an inhibitory effect on acid sphingomyelinase activity like citalopram, increased the frequency of Foxp3\(^+\) regulatory T cell among human CD4\(^+\) T cells in vitro. In an observational prospective clinical study with patients suffering from major depression, we observed that acid sphingomyelinase-inhibiting antidepressants induced a stronger relative increase in the frequency of CD4\(^+\) Foxp3\(^+\) regulatory T cells in peripheral blood than acid sphingomyelinase-non- or weakly inhibiting antidepressants. This was particularly true for CD45RA\(^-\) CD25\(^{high}\) effector CD4\(^+\) Foxp3\(^+\) regulatory T cells. Mechanistically, our data indicate that the positive effect of acid sphingomyelinase inhibition on CD4\(^+\) Foxp3\(^+\) regulatory T cells required CD28 co-stimulation, suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Foxp3+ regulatory T cells among human CD4\(^+\) T cells. In summary, the widely induced pharmacological inhibition of acid sphingomyelinase activity in patients leads to an increase in Foxp3+ regulatory T-cell frequencies among CD4\(^+\) T cells in humans both in vivo and in vitro.}, language = {en} } @article{KarikariMcFlederRibechinietal.2022, author = {Karikari, Akua A. and McFleder, Rhonda L. and Ribechini, Eliana and Blum, Robert and Bruttel, Valentin and Knorr, Susanne and Gehmeyr, Mona and Volkmann, Jens and Brotchie, Jonathan M. and Ahsan, Fadhil and Haack, Beatrice and Monoranu, Camelia-Maria and Keber, Ursula and Yeghiazaryan, Rima and Pagenstecher, Axel and Heckel, Tobias and Bischler, Thorsten and Wischhusen, J{\"o}rg and Koprich, James B. and Lutz, Manfred B. and Ip, Chi Wang}, title = {Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson's disease mice}, series = {Brain, Behavior, and Immunity}, volume = {101}, journal = {Brain, Behavior, and Immunity}, doi = {10.1016/j.bbi.2022.01.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300600}, pages = {194 -- 210}, year = {2022}, abstract = {Background Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson's disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model. Methods We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1)\(^{-/-}\) mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4\(^{+}\)/CD8\(^{-}\), CD4\(^{-}\)/CD8\(^{+}\), or CD4\(^{+}\)/CD8\(^{+}\) (JHD\(^{-/-}\)) mice into the RAG-1\(^{-/-}\) mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized. Results AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68-78) and surrounding the pathogenically relevant S129 (120-134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration. Conclusions Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology.}, language = {en} } @article{SteinhardtWiercinskaPhametal.2020, author = {Steinhardt, M. J. and Wiercinska, E. and Pham, M. and Grigoleit, G. U. and Mazzoni, A. and Da-Via, M. and Zhou, X. and Meckel, K. and Nickel, K. and Duell, J. and Krummenast, F. C. and Kraus, S. and Hopkinson, C. and Weissbrich, B. and M{\"u}llges, W. and Stoll, G. and Kort{\"u}m, K. M. and Einsele, H. and Bonig, H. and Rasche, L.}, title = {Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes}, series = {Journal of Translational Medicine}, volume = {18}, journal = {Journal of Translational Medicine}, doi = {10.1186/s12967-020-02337-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229307}, year = {2020}, abstract = {Background Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT. Methods To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion. Results Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion. Conclusion We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy.}, language = {en} } @article{TraubGrondeyGassenmaieretal.2022, author = {Traub, Jan and Grondey, Katja and Gassenmaier, Tobias and Schmitt, Dominik and Fette, Georg and Frantz, Stefan and Boivin-Jahns, Val{\´e}rie and Jahns, Roland and St{\"o}rk, Stefan and Stoll, Guido and Reiter, Theresa and Hofmann, Ulrich and Weber, Martin S. and Frey, Anna}, title = {Sustained increase in serum glial fibrillary acidic protein after first ST-elevation myocardial infarction}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms231810304}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288261}, year = {2022}, abstract = {Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11\% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0-4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway.}, language = {en} } @article{GschmackMonoranuMaroufetal.2022, author = {Gschmack, Eva and Monoranu, Camelia-Maria and Marouf, Hecham and Meyer, Sarah and Lessel, Lena and Idris, Raja and Berg, Daniela and Maetzler, Walter and Steigerwald, Frank and Volkmann, Jens and Gerlach, Manfred and Riederer, Peter and Koutsilieri, Eleni and Scheller, Carsten}, title = {Plasma autoantibodies to glial fibrillary acidic protein (GFAP) react with brain areas according to Braak staging of Parkinson's disease}, series = {Journal of Neural Transmission}, volume = {129}, journal = {Journal of Neural Transmission}, number = {5-6}, doi = {10.1007/s00702-022-02495-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325161}, pages = {545-555}, year = {2022}, abstract = {Idiopathic Parkinson's disease (PD) is characterized by a progredient degeneration of the brain, starting at deep subcortical areas such as the dorsal motor nucleus of the glossopharyngeal and vagal nerves (DM) (stage 1), followed by the coeruleus-subcoeruleus complex; (stage 2), the substantia nigra (SN) (stage 3), the anteromedial temporal mesocortex (MC) (stage 4), high-order sensory association areas and prefrontal fields (HC) (stage 5) and finally first-order sensory association areas, premotor areas, as well as primary sensory and motor field (FC) (stage 6). Autoimmunity might play a role in PD pathogenesis. Here we analyzed whether anti-brain autoantibodies differentially recognize different human brain areas and identified autoantigens that correlate with the above-described dissemination of PD pathology in the brain. Brain tissue was obtained from deceased individuals with no history of neurological or psychiatric disease and no neuropathological abnormalities. Tissue homogenates from different brain regions (DM, SN, MC, HC, FC) were subjected to SDS-PAGE and Western blot. Blots were incubated with plasma samples from 30 PD patients and 30 control subjects and stained with anti-IgG antibodies to detect anti-brain autoantibodies. Signals were quantified. Prominent autoantigens were identified by 2D-gel-coupled mass spectrometry sequencing. Anti-brain autoantibodies are frequent and occur both in healthy controls and individuals with PD. Glial fibrillary acidic protein (GFAP) was identified as a prominent autoantigen recognized in all plasma samples. GFAP immunoreactivity was highest in DM areas and lowest in FC areas with no significant differences in anti-GFAP autoantibody titers between healthy controls and individuals with PD. The anti-GFAP autoimmunoreactivity of different brain areas correlates with the dissemination of histopathological neurodegeneration in PD. We hypothesize that GFAP autoantibodies are physiological but might be involved as a cofactor in PD pathogenesis secondary to a leakage of the blood-brain barrier.}, language = {en} }