| 1. |
- Bejerot, Susanne, 1955-, et al.
(författare)
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Neuromyelitis optica spectrum disorder with increased aquaporin-4 microparticles prior to autoantibodies in cerebrospinal fluid : a case report
- 2019
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Ingår i: Journal of Medical Case Reports. - : BioMed Central (BMC). - 1752-1947. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neuromyelitis optica spectrum disorders are severe autoimmune inflammatory diseases of the central nervous system associated with the presence of immunoglobulin G antibodies against the water channel protein aquaporin-4. During exacerbation, specific aquaporin-4 immunoglobulin G may be produced intrathecally. We measured extracellular aquaporin-4 microparticles in the cerebrospinal fluid of a patient who later developed the typical symptoms and signs of a neuromyelitis optica spectrum disorder.CASE PRESENTATION: A 17-year-old South American girl developed acute severe motor and vocal tics and difficulties in walking, peripheral numbness, muscle pain, and bilateral headache. At age 22, she had a multitude of motor and psychiatric symptoms. Over the years, she fulfilled the diagnostic criteria for anorexia nervosa, depression, sleep disorder, obsessive-compulsive disorder, generalized anxiety disorder, panic disorder, agoraphobia, social anxiety disorder, development coordination disorder, attention-deficit/hyperactivity disorder, hypomania, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, conversion disorder, psychosis, and schizotypal personality syndrome. At age 24, she was found to have elevated titers of aquaporin-4 antibodies in serum, suggestive of probable neuromyelitis optica. She subsequently developed visual impairment, and swollen optic nerves were verified by magnetic resonance imaging. She was thus treated with a chimeric monoclonal antibody targeted against the pan-B-cell marker CD20 (rituximab), and almost all symptoms, including the psychiatric symptoms, rapidly decreased. We found a significant increase of extracellular microparticles of aquaporin-4 in cerebrospinal fluid sampled from our patient when she was 22 years old, 2 years before the full clinical development of neuromyelitis optica.CONCLUSIONS: Microparticles of aquaporin-4 represent subcellular arrangements that may influence the pathogenesis of neuromyelitis optica spectrum disorders and may serve as biomarkers for the underlying cellular disturbances. The increase of aquaporin-4 microparticles in cerebrospinal fluid may be used for early diagnostic purposes; for prevention; and for evaluation of effective treatment, long-term follow-up studies, and elucidating the pathophysiology in neuromyelitis optica spectrum disorders. Further studies of aquaporin-4 microparticles in cerebrospinal fluid of patients with neuromyelitis optica and similar neuropsychiatric disorders are thus called for.
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| 2. |
- Bejerot, Susanne, 1955-, et al.
(författare)
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Study protocol for a randomized controlled trial with rituximab for psychotic disorder in adults (RCT-Rits)
- 2023
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Ingår i: BMC Psychiatry. - : BioMed Central (BMC). - 1471-244X. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The role of inflammation in the aetiology of schizophrenia has gained wide attention and research on the association shows an exponential growth in the last 15 years. Autoimmune diseases and severe infections are risk factors for the later development of schizophrenia, elevated inflammatory markers in childhood or adolescence are associated with a greater risk of schizophrenia in adulthood, individuals with schizophrenia have increased levels of pro-inflammatory cytokines compared to healthy controls, and autoimmune diseases are overrepresented in schizophrenia. However, treatments with anti-inflammatory agents are so far of doubtful clinical relevance. The primary objective of this study is to test whether the monoclonal antibody rituximab, directed against the B-cell antigen CD20 ameliorates psychotic symptoms in adults with schizophrenia or schizoaffective disorder and to examine potential mechanisms. A secondary objective is to examine characteristics of inflammation-associated psychosis and to identify pre-treatment biochemical characteristics of rituximab responders. A third objective is to interview a subset of patients and informants on their experiences of the trial to obtain insights that rating scales may not capture.METHODS: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of B-cell depletion in patients with psychosis. 120 participants with a diagnosis of schizophrenia spectrum disorders (SSD) (ICD-10 codes F20, F25) will receive either one intravenous infusion of rituximab (1000 mg) or saline. Psychiatric measures and blood samples will be collected at baseline, week 12, and week 24 post-infusion. Brief assessments will also be made in weeks 2 and 7. Neuroimaging and lumbar puncture, both optional, will be performed at baseline and endpoints. Approximately 40 of the patients and their informants will be interviewed for qualitative analyses on the perceived changes in well-being and emotional qualities, in addition to their views on the research.DISCUSSION: This is the first RCT investigating add-on treatment with rituximab in unselected SSD patients. If the treatment is helpful, it may transform the treatment of patients with psychotic disorders. It may also heighten the awareness of immune-psychiatric disorders and reduce stigma.TRIAL REGISTRATION: NCT05622201, EudraCT-nr 2022-000220-37 version 2.1. registered 14th of October 2022.
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| 3. |
- Hietala, Max Albert, 1969, et al.
(författare)
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Complement activation by both classical and alternative pathways is critical for the effector phase of arthritis.
- 2004
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Ingår i: European journal of immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 34:4, s. 1208-16
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Tidskriftsartikel (refereegranskat)abstract
- To analyze the role of the classical and alternative pathways of complement activation in the effector phase of arthritis, we have induced arthritis in C3- and factor B (FB)-deficient (C3(-/-) and FB(-/-)) DBA/1J mice using well-defined monoclonal IgG2b and IgG2a antibodies to type II collagen. In control DBA/1J mice, severe swelling of the joints, destruction of cartilage and erosion of bone developed very rapidly with a 100% incidence and a peak on days 7-10. Although 75% of C3(-/-) mice developed arthritis, the clinical severity was very mild and the onset was delayed. Severity of arthritis in FB(-/-) mice ranked intermediate in comparison with C3(-/-) and control mice with an incidence of 100%. Immunohistochemical analysis of the inflamed joints demonstrated substantial reduction in macrophage and neutrophilic leukocyte infiltration in both C3(-/-) and FB(-/-) mice, thereby confirming the clinical findings. We conclude that both the classical and the alternative pathways of complement activation are involved in the effector phase of arthritis.
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| 4. |
- Hietala, Max Albert, 1969
(författare)
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The role of the complement system in arthritis and stroke
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Complement is part of the innate immune system and functions primarily as a first line of defense against invading microorganisms. It is a complex cascade, which can be activated via three pathways: the classical, alternative and mannan-binding lectin pathway. To study the role of the complement system in disease pathogenesis, we have generated mice deficient in C3, which is the central protein in all three pathways, and mice deficient in factor B, which is critical for the activation of the alternative pathway. Using these complement deficient mice, we have found that complement activation by both the classical and the alternative pathways plays a critical role in two models of rheumatoid arthritis, namely collagen-induced arthritis and arthritis induced by arthritogenic monoclonal antibodies. Our findings indicate that antibody binding to collagen triggers the activation of the classical pathway, which is then amplified by the alternative pathway.When subjected to permanent focal brain ischemia by middle cerebral artery occlusion, the infarction volume in the C3 deficient mice was significantly larger than that in control mice. These results, together with the finding of reduced number of presumed neural progenitor cells in the penumbra and infarction area of C3 deficient mice, implicate the complement system as a positive regulator of neurogenesis in brain ischemia. Thus, besides its well-established role in host defense against pathogens, the complement system may have additional roles in disease pathogenesis: its activation appears to augment tissue damage in autoantibody-associated diseases such as arthritis, but may contribute to tissue repair after cerebral ischemia.Designing drugs targeting complement activation may be a rational therapeutic strategy. However, great care will have to be executed in defining and reaching the proper balance between the two contradictory effects of the complement system.
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| 5. |
- Kalm, Marie, 1981, et al.
(författare)
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Neurochemical Evidence of Potential Neurotoxicity After Prophylactic Cranial Irradiation.
- 2014
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Ingår i: International journal of radiation oncology, biology, physics. - : Elsevier BV. - 1879-355X .- 0360-3016. ; 89:3, s. 607-614
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Tidskriftsartikel (refereegranskat)abstract
- Toexamine whether cerebrospinal fluid biomarkers for neuroaxonal damage, neuroglial activation, and amyloid β-related processes could characterize the neurochemical response to cranial radiation.
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| 6. |
- Nyberg, Jenny, 1976, et al.
(författare)
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Glucose-dependent insulinotropic polypeptide is expressed in adult hippocampus and induces progenitor cell proliferation.
- 2005
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - : Society for Neuroscience. - 1529-2401. ; 25:7, s. 1816-25
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal dentate gyrus (DG) is an area of active proliferation and neurogenesis within the adult brain. The molecular events controlling adult cell genesis in the hippocampus essentially remain unknown. It has been reported previously that adult male and female rats from the strains Sprague Dawley (SD) and spontaneously hypertensive (SHR) have a marked difference in proliferation rates of cells in the hippocampal DG. To exploit this natural variability and identify potential regulators of cell genesis in the hippocampus, hippocampal gene expression from male SHR as well as male and female SD rats was analyzed using a cDNA array strategy. Hippocampal expression of the gene-encoding glucose-dependent insulinotropic polypeptide (GIP) varied strongly in parallel with cell-proliferation rates in the adult rat DG. Moreover, robust GIP immunoreactivity could be detected in the DG. The GIP receptor is expressed by cultured adult hippocampal progenitors and throughout the granule cell layer of the DG, including progenitor cells. Thus, these cells have the ability to respond to GIP. Indeed, exogenously delivered GIP induced proliferation of adult-derived hippocampal progenitors in vivo as well as in vitro, and adult GIP receptor knock-out mice exhibit a significantly lower number of newborn cells in the hippocampal DG compared with wild-type mice. This investigation demonstrates the presence of GIP in the brain for the first time and provides evidence for a regulatory function for GIP in progenitor cell proliferation.
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| 7. |
- Ragnarsson, Oskar, 1971, et al.
(författare)
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Neurodegenerative and inflammatory biomarkers in cerebrospinal fluid in patients with Cushing's syndrome in remission.
- 2013
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Ingår i: European journal of endocrinology / European Federation of Endocrine Societies. - 1479-683X. ; 169:2, s. 211-5
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Tidskriftsartikel (refereegranskat)abstract
- Patients with Cushing's syndrome (CS) in long-term remission have impaired cognitive function. Cerebrospinal fluid (CSF) biomarkers are important diagnostic tools in the work-up of patients with cognitive impairment. The aim of this study was to analyze neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission.
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| 8. |
- Rahpeymai, Yalda, 1977, et al.
(författare)
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Complement: a novel factor in basal and ischemia-induced neurogenesis.
- 2006
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Ingår i: The EMBO journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 25:6, s. 1364-74
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Tidskriftsartikel (refereegranskat)abstract
- Through its involvement in inflammation, opsonization, and cytolysis, the complement protects against infectious agents. Although most of the complement proteins are synthesized in the central nervous system (CNS), the role of the complement system in the normal or ischemic CNS remains unclear. Here we demonstrate for the first time that neural progenitor cells and immature neurons express receptors for complement fragments C3a and C5a (C3a receptor (C3aR) and C5a receptor). Mice that are deficient in complement factor C3 (C3(-/-)) lack C3a and are unable to generate C5a through proteolytic cleavage of C5 by C5-convertase. Intriguingly, basal neurogenesis is decreased both in C3(-/-) mice and in mice lacking C3aR or mice treated with a C3aR antagonist. The C3(-/-) mice had impaired ischemia-induced neurogenesis both in the subventricular zone, the main source of neural progenitor cells in adult brain, and in the ischemic region, despite normal proliferative response and larger infarct volumes. Thus, in the adult mammalian CNS, complement activation products promote both basal and ischemia-induced neurogenesis.
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