Tuftsin Promotes an Anti-Inflammatory Switch and Attenuates Symptoms in Experimental Autoimmune Encephalomyelitis

Multiple sclerosis (MS) is a demyelinating autoimmune disease mediated by infiltration of T cells into the central nervous system after compromise of the blood-brain barrier. We have previously shown that administration of tuftsin, a macrophage/microglial activator, dramatically improves the clinical course of experimental autoimmune encephalomyelitis (EAE), a well-established animal model for MS. Tuftsin administration correlates with upregulation of the immunosuppressive Helper-2 Tcell (Th2) cytokine transcription factor GATA-3. We now show that tuftsin-mediated microglial activation results in shifting microglia to an anti-inflammatory phenotype. Moreover, the T cell phenotype is shifted towards immunoprotection after exposure to tuftsin-treated activated microglia; specifically, downregulation of pro-inflammatory Th1 responses is triggered in conjunction with upregulation of Th2-specific responses and expansion of immunosuppressive regulatory T cells (Tregs). Finally, tuftsin-shifted T cells, delivered into animals via adoptive transfer, reverse the pathology observed in mice with established EAE. Taken together, our findings demonstrate that tuftsin decreases the proinflammatory environment of EAE and may represent a therapeutic opportunity for treatment of MS

Oligodendrocytes: biology and pathology

Oligodendrocytes are the myelinating cells of the central nervous system (CNS). They are the end product of a cell lineage which has to undergo a complex and precisely timed program of proliferation, migration, differentiation, and myelination to finally produce the insulating sheath of axons. Due to this complex differentiation program, and due to their unique metabolism/physiology, oligodendrocytes count among the most vulnerable cells of the CNS. In this review, we first describe the different steps eventually culminating in the formation of mature oligodendrocytes and myelin sheaths, as they were revealed by studies in rodents. We will then show differences and similarities of human oligodendrocyte development. Finally, we will lay out the different pathways leading to oligodendrocyte and myelin loss in human CNS diseases, and we will reveal the different principles leading to the restoration of myelin sheaths or to a failure to do so

M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination

The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia/macrophages, which can be polarized to distinct functional phenotypes: proinflammatory (M1) or anti-inflammatory/immunoregulatory (M2). Here we show that a switch from an M1- to M2-dominant response occurred within microglia and peripherally-derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 conditioned media, and impaired in vivo following intra-lesional M2 depletion. M2 densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger animal, and in MS lesions that normally show remyelination. Blocking M2-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Our results therefore show that M2 polarization is essential for efficient remyelination and identify activin-A as a novel therapeutic target for CNS regeneration

Kasuistik und Review einer seltenen Erkrankung

Pyothorax-associated lymphoma (PAL) is a rare haematological malignancy often associated with artificial pneumothorax due to the treatment of pulmonary tuberculosis. A 76 year old man with chronic tube-drained pyothorax and a history of artificial pneumothorax for pulmonary tuberculosis was admitted to our hospital because of progressive right thoracic pain, weight loss, and pyrexia. After clinical examination and imaging processes a chest wall tumour anterior on the right side was diagnosed as well as a persisting pyothorax. Surgery was performed to resect the tumour and drain the pleural cavity. A diagnosis of a high grade B-cell lymphoma was established after histological examination of the surgical biopsy. Epstein-Barr virus (EBV) was identified in the tumour by immunocytochemical and molecular methods. Additional gastric involvement of B-cell lymphoma could be diagnosed by gastroscopy because of postoperative gastrointestinal bleeding. The patient received chemotherapy with 2 courses of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP). The response was favourable initially, but 2 months later the patient died because of lymphoma progression.Most cases of PAL have been described by Japanese investigators and only a few cases are reported in Western countries. To the best of our knowledge this case of PAL is the first to be documented in Germany.Awareness of this rare entity, together with diligent histological examination, in patients with chronic pyothorax are essential for a correct diagnosis and correct early treatment.Das Pyothorax-assoziierte Lymphom (PAL) stellt eine seltene maligne Erkrankung dar, die sich häufig auf der Basis einer Pneumothoraxbehandlung nach Tuberkulose entwickelt. Ein 76 jähriger Mann mit einem chronischen Pleuraempyem auf der Basis einer artifiziellen Pneumothoraxtherapie nach stattgehabter Tuberkulose wurde mit zunehmenden rechts-thorakalen Schmerzen, Gewichtsabnahme und Fieber stationär aufgenommen. Nach klinischer Untersuchung und bildgebenden Verfahren wurde die Diagnose eines Tumors der rechten Thoraxwand bei weiterhin bestehendem Pyothorax gestellt. Nach chirurgischer Resektion des Tumors und Debridement des Pyothorax ergab sich die Diagnose eines hoch malignen Epstein-Barr-Virus (EBV) positiven B-Zell-Lymphoms. Zusätzlich gelang der gastroskopische Nachweis des B-Zell-Lymphoms im Magen bei postoperativ aufgetretener oberer gastrointestinaler Blutung. Der Patient erhielt postoperativ 2 Zyklen Chemotherapie nach dem CHOP-Schema (Cyclophosphamid, Doxorubicin, Vincristin und Prednisolon). Nach primärem Erfolg der Chemotherapie starb der Patient 2 Monate später an einer Progression des Tumorleidens.PAL stellt eine vor allem von japanischen Autoren berichtete Entität dar. Nur wenige europäische Fälle sind bisher beschrieben worden. Nach unserem Kenntnisstand ist dies der erste in Deutschland dokumentierte Fall. Die Differentialdiagnose des PAL verbunden mit einer genauen histologischen Untersuchung sollte bei Patienten mit chronischem Pyothorax immer in Erwägung gezogen werden, um durch eine frühzeitige Diagnosestellung die Patienten der adäquaten Therapie zuführen zu können

Detection of fetal chromosomal anomalies : Does nuchal translucency measurement have added value in the era of non-invasive prenatal testing?

OBJECTIVES: The objective of this study is to determine what percentage of fetal chromosomal anomalies remains undetected when first trimester combined testing is replaced by non-invasive prenatal testing for trisomies 13, 18, and 21. We focused on the added clinical value of nuchal translucency (NT) measurement. METHODS: Data on fetal karyotype, ultrasound findings, and pregnancy outcome of all pregnancies with an NT measurement ≥3.5 mm were retrospectively collected from a cohort of 25,057 singleton pregnancies in which first trimester combined testing was performed. RESULTS: Two hundred twenty-five fetuses (0.9 %) had an NT ≥3.5 mm. In 24 of these pregnancies, a chromosomal anomaly other than trisomy 13, 18, or 21 was detected. Eleven resulted in fetal demise, and ten showed fetal ultrasound anomalies. In three fetuses with normal ultrasound findings, a chromosomal anomaly was detected, of which one was a triple X. CONCLUSIONS: In three out of 25,057 pregnancies (0.01%), non-invasive prenatal testing and fetal ultrasound would have missed a chromosomal anomaly that would have been identified by NT measurement