Pemphigus vulgaris (PV) is a severe autoimmune blistering disease affecting the skin and mucous membranes. Autoreactive CD4(+) T helper (Th) lymphocytes are crucial for the autoantibody response against the desmosomal adhesion molecules, desmoglein (dsg)-3 and dsg1. Eleven patients with extensive PV were treated with the anti-CD20 antibody, rituximab (375 mg per m(2) body surface area once weekly for 4 weeks). Frequencies of autoreactive CD4(+) Th cells in the peripheral blood of the PV patients were determined 0, 1, 3, 6, and 12 months after rituximab treatment. Additionally, the clinical response was evaluated and serum autoantibody titers were quantified by ELISA. Rituximab induced peripheral B-cell depletion for 6-12 months, leading to a dramatic decline of serum autoantibodies and significant clinical improvement in all PV patients. The frequencies of dsg3-specific CD4(+) Th1 and Th2 cells decreased significantly for 6 and 12 months, respectively, while the overall count of CD3(+)CD4(+) T lymphocytes and the frequency of tetanus toxoid-reactive CD4(+) Th cells remained unaffected. Our findings indicate that the response to rituximab in PV involves two mechanisms: (1) the depletion of autoreactive B cells and (2) the herein demonstrated, presumably specific downregulation of dsg3-specific CD4(+) Th cells.
Background and Purpose— We studied the dynamics of extracellular brain tissue concentrations of glucose, lactate, pyruvate, and glutamate during the occurrence of spreading depolarizations (SDs) in patients with aneurysmal subarachnoid hemorrhage. Methods— In this prospective observational study, patients with aneurysmal subarachnoid hemorrhage received multimodal cerebral monitoring, including intracranial pressure, cerebral microdialysis, and subdural electrocorticography. Results— Seven of the 17 recruited patients had intracerebral hemorrhage, acute ischemia and severe brain oedema leading to acute ischemic neurological deficits associated with early disturbance of metabolism at the recording site. They displayed a total of 130 SDs. The remaining 10 patients without acute ischemic neurological deficits exhibited 138 single SDs and 68 SDs in clusters. In patients without acute ischemic neurological deficits, clustered SDs were associated with a significant transient decrease in glucose and increase in lactate compared with baseline during the first 140 minutes after SDs. Moreover, the number of clustered SDs correlated with the outcome ( R =−0.659; P <0.01). Conclusion— SDs can propagate in nonischemic human brain tissue. Clusters of SDs are related to metabolic changes suggestive of ongoing secondary damage in primarily nonischemic brain tissue.
Introduction Hyperglycaemia following aneurysmal subarachnoid hemorrhage (SAH) is associated with complications and impaired neurological recovery. The aim of this study was to determine the effect of insulin treatment for glucose control on cerebral metabolism in SAH patients. Methods This prospective, nonrandomized study was conducted in 31 SAH patients in an intensive care unit (age 52 ± 10 years, World Federation of Neurological Surgeons grade 2.9 ± 1.6). A microdialysis catheter was inserted into the vascular territory of the aneurysm after clipping. Blood glucose levels above 140 mg/dl were treated with intravenous insulin and the microdialysates were analyzed hourly for the first 12 hours of infusion. Results No hypoglycaemia occurred. Twenty-four patients were treated with insulin for glucose control. Higher age and World Federation of Neurological Surgeons score were risk factors for need for insulin treatment ( P < 0.05). Although blood glucose remained stable after initiation of insulin infusion, insulin induced a significant decrease in cerebral glucose at 3 hours after onset of the infusion until the end of the observation period ( P < 0.05), reflecting high glucose utilization. The lactate:pyruvate ratio and glutamate did not increase, excluding ischaemia as possible cause of the decrease in glucose. Glycerol tended toward higher values at the end of the observation period (9 to 12 hours), reflecting either tissue damage after SAH or the beginning of cellular distress after insulin infusion. Conclusion Higher SAH grade was among the risk factors for need for insulin. Intensive glycaemic control using insulin induced a decrease of cerebral glucose and a slight increase in glycerol, though blood glucose remained normal. Future studies might detect relevant metabolic derangements when insulin treatment starts at low cerebral glucose levels, and may allow us to design a strategy for avoidance of insulin-induced metabolic crisis in SAH patients.
Although hyperglycemia was more frequent in symptomatic patients and associated with high glycerol levels, hyperglycemia was not related to cerebral high glucose. It appears that the association of adverse outcome with acute-phase hyperglycemia is not mediated by cerebral glucose metabolism. Cerebral low glucose was associated with severe metabolic distress and may present a target for therapy to improve clinical outcome.
Intracranial hypertension is associated with a strong activation of the inflammatory cascade in the brain and systemic circulation, and might be underestimated as proinflammmatory trigger in the pathogenesis of complications after SAH. Future therapies targeting anti-inflammatory response in plasma may help to reduce the inflammatory cascade responsible for development of intracranial hypertension.
The basic understanding of inflammatory dermatoses and autoimmune-mediated skin disorders has greatly advanced and broadened our understanding of underlying immune mechanisms that shape the complex network of chronic inflammation and autoimmunity. The new treatment options for psoriasis exemplify how new insights into (auto)immune responses, especially the role and function of various immune cells and proinflammatory cytokines, may lead to new therapeutic strategies. The concept of targeting B cells in autoimmune-mediated disorders is closely related to the discovery of autoantibodies and their cellular origin. However, the appreciation of B cells in autoimmunity has significantly changed and is not limited to their role as progenitors of autoantibody secreting plasma cells. Recent investigations of various inflammatory skin diseases, that is, autoimmune blistering disorders, collagen vascular diseases, and atopic dermatitis, actually support the concept that B cells might be as important as T cells in the etiopathogenesis of these disorders. The striking clinical improvement seen in patients with rheumatoid arthritis following B-cell depletion with the anti-CD20 mAb rituximab has tremendously catalyzed the interest in B-cell-targeted therapies in different autoimmune diseases. Future translational and clinical investigations are mandatory to precisely define the role and the contribution of impaired B-cell function in (auto)immune-mediated skin diseases.
Pemphigus vulgaris (PV) is a severe autoimmune disease affecting the skin and mucous membranes, characterized by autoantibodies mainly against desmoglein 3 (dsg3). This study investigated the effects of different treatment options on two B-cell mediators, B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL), in 19 PV patients on immunosuppressive drugs alone or in combination with immunoadsorption and anti-CD20 antibody, respectively. Serum BAFF and APRIL levels, circulating desmoglein-reactive autoantibodies, and serum IgG specific for varicella-zoster virus (VZV) and Epstein-Barr virus (EBV) were determined by ELISA before and at different time points after initiation of the respective therapy. In contrast to immunosuppressive therapy alone and in combination with adjuvant immunoadsorption, respectively, rituximab treatment led to a strong and significant elevation of BAFF, but not of APRIL levels, which normalized upon recovery of peripheral CD19(+) B cells. Moreover, rituximab treatment led to a statistically significant increase of anti-VZV-IgG and anti-EBV-IgG titers, whereas anti-dsg1 and -3 specific autoantibody titers decreased significantly. Our results suggest that elevated BAFF levels might exert a differential effect on the induction of autoreactive versus pathogen-specific IgG antibody production in PV patients, possibly due to promotion of antibody release of pathogen-specific long-lived plasma cells.
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