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Objective: Bridging the gap between experimental stroke and patients by ischemic blood probing during the hyperacute stage of vascular occlusion is crucial to assess the role of inflammation in human stroke and for the development of adjunct treatments beyond recanalization., Methods: We prospectively observed 151 consecutive ischemic stroke patients with embolic large vessel occlusion of the anterior circulation who underwent mechanical thrombectomy. In all these patients, we attempted microcatheter aspiration of 3 different arterial blood samples: (1) within the core of the occluded vascular compartment and controlled by (2) carotid and (3) femoral samples obtained under physiological flow conditions. Subsequent laboratory analyses comprised leukocyte counting and differentiation, platelet counting, and the quantification of 13 proinflammatory human chemokines/cytokines., Results: Forty patients meeting all clinical, imaging, interventional, and laboratory inclusion criteria could be analyzed, showing that the total number of leukocytes significantly increased under the occlusion condition. This increase was predominantly driven by neutrophils. Significant increases were also apparent for lymphocytes and monocytes, accompanied by locally elevated plasma levels of the T-cell chemoattractant CXCL-11. Finally, we found evidence that short-term clinical outcome (National Institute of Health Stroke Scale at 72 hours) was negatively associated with neutrophil accumulation., Interpretation: We provide the first direct human evidence that neutrophils, lymphocytes, and monocytes, accompanied by specific chemokine upregulation, accumulate in the ischemic vasculature during hyperacute stroke and may affect outcome. These findings strongly support experimental evidence that immune cells contribute to acute ischemic brain damage and indicate that ischemic inflammation initiates already during vascular occlusion. Ann Neurol 2020;87:466-479., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Objective: Recent evidence suggests that ischemic stroke is a thromboinflammatory disease. Plasma kallikrein (PK) cleaves high-molecular-weight kininogen to release bradykinin (BK) and is a key constituent of the proinflammatory contact-kinin system. In addition, PK can activate coagulation factor XII, the origin of the intrinsic coagulation cascade. Thus, PK triggers 2 important pathological pathways of stroke formation, thrombosis and inflammation., Methods: We investigated the consequences of PK inhibition in transient and permanent models of ischemic stroke., Results: PK-deficient mice of either sex challenged with transient middle cerebral artery occlusion developed significantly smaller brain infarctions and less severe neurological deficits compared with controls without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarctions as well as after permanent stroke. Reduced intracerebral thrombosis and improved cerebral blood flow could be identified as underlying mechanisms. Moreover, blood-brain barrier function was maintained in mice lacking PK, and the local inflammatory response was reduced. PK-deficient mice reconstituted with PK or BK again developed brain infarctions similar to wild-type mice. Important from a translational perspective, inhibition of PK in wild-type mice using a PK-specific antibody was likewise effective even when performed in a therapeutic setting up to 3 hours poststroke., Interpretation: PK drives thrombus formation and inflammation via activation of the intrinsic coagulation cascade and the release of BK but appears to be dispensable for hemostasis. Hence, PK inhibition may offer a safe strategy to combat thromboembolic disorders including ischemic stroke., (© 2015 American Neurological Association.)

In this study, the terminal complement complex C5b-9 (TCC) was localized by immunocytochemistry at different clinical stages of experimental autoimmune neuritis. Deposits of TCC were found on the surface of Schwann cells and their myelin sheaths, and to some extent in the extracellular space at predilective sites of impending demyelination before onset of clinical signs and for a short period thereafter. Additionally, TCC was deposited on the surface of W3/13 positive leukocytes. No TCC immunoreactivity was seen in the distal stump of transected sciatic nerves 1 to 15 days after axotomy. The early and transient deposition of TCC on Schwann cells and myelin sheaths in experimental autoimmune neuritis before overt demyelination suggests that complement activation plays a pathogenic role in the initiation of immune-mediated myelin damage. The lack of TCC immunoreactivity after nerve transection excludes a nonspecific activation process. The signals involved in local TCC formation in demyelinating peripheral nervous system disorders have yet to be explored.

Serum concentrations of the cytokine interleukin-2 (IL-2) were quantitated by enzyme-linked immunosorbent assay in 42 patients with Guillain-Barré syndrome, 15 patients with chronic idiopathic demyelinating polyradiculoneuropathy, 37 patients with other neuropathies, 54 patients with other noninflammatory, nondemyelinating neurological disorders, and 26 healthy control subjects. We found markedly increased serum levels of IL-2 in patients with Guillain-Barré syndrome and to a much lesser extent, in patients with chronic idiopathic demyelinating polyradiculoneuropathy. Increased serum concentrations of IL-2 in patients with Guillain-Barré syndrome returned to normal in parallel with recovery from the disease. These findings suggest ongoing T-cell proliferation in patients with Guillain-Barré syndrome and some patients with chronic idiopathic demyelinating polyradiculoneuropathy. IL-2 levels were also raised in patients with active multiple sclerosis, myasthenia gravis, and herpes simplex encephalitis, and some patients with polymyositis, invoking T cells in the pathogenesis of these diseases.

This study was designed to identify which cells express major histocompatibility complex class II (Ia) antigen in experimental autoimmune neuritis and may therefore be antigen presenters. Serial 1-micron-thick cryosections of ventral roots of animals with experimental autoimmune neuritis were labeled with Ox6 antibody against rat Ia, the ED1 antibody to identify monocytes/macrophages and an antiserum against S100, a marker for Schwann cells. Ia-positive cells were predominantly present before overt clinical signs and demyelination (day 12). At later stages when many axons were demyelinated, their number was markedly reduced. Few Ia-positive cells that had extending long processes, which over some distance were in immediate contact with several myelin sheaths, were scattered in normal-appearing nerve roots at these later time points. Most of the Ia-positive cells could be identified as ED1-positive lean monocytes/macrophages, but in contrast most phagocytic macrophages in advanced stages of myelin degradation no longer expressed Ia. Ia-positive structures were invariably negative for S100 at early and late stages of experimental autoimmune neuritis, indicating that Schwann cells did not express identifiable Ia antigen. These findings contrast with reports of expression of major histocompatibility complex class II antigens by Schwann cells in human neuropathies. Furthermore they do not support the notion that aberrant Ia expression by Schwann cells plays a major pathogenic role in experimental autoimmune disease of the peripheral nervous system.

Macrophages are prominent participants in inflammatory demyelinating neuropathies. To provide a different means of evaluating macrophage behavior, we used immunostaining of teased nerve fibers and endoneurial blood vessels. We assessed the frequency with which macrophages were seen in inflammatory demyelinating neuropathies, their relationship to normal and demyelinating fibers, and their expression of major histocompatibility Class II markers (Ia antigen). In 6 patients with chronic inflammatory neuropathy and 1 with Guillain-Barré syndrome, we found regularly that macrophages were adherent to teased blood vessels. Cells presumed to be entering the nerve were elongated, often with a polarized appearance suggesting motility, and were Ia-positive. After entry into nerve, the Ia-positive macrophages were adherent to both normal and demyelinating fibers. They often retained their Ia positivity after penetrating into the nerve fiber and removing myelin. Foamy macrophages, judged to be postphagocytic, were Ia-negative. The foamy macrophages found adhering to blood vessels were presumed to be leaving the nerve. This pattern of entry as Ia-positive prephagocytic cells and evolution to Ia-negative foamy macrophages was compared with other experimental and human neuropathies.

Rabbits were immunized with galactocerebroside and a crush lesion was created in the tibial nerve before the onset of experimental allergic neuritis. Normal regeneration and myelination of distal peripheral nerve sprouts occurred and was identical to that of controls, although circulating antigalactocerebroside antibodies were present and nerve roots showed typical signs of beginning experimental allergic neuritis.

P2-specific T cells (LiP2/A) mediate experimental allergic neuritis (EAN) in the Lewis rat after adoptive transfer to naive recipients. After a latent period of 4 days, injection of 2 X 10(6) line cells induced fulminant paraplegia and complete conduction failure in the peripheral nerves and roots, resembling acute axonal breakdown. Injection with 10(6) cells caused milder clinical signs, nerve conduction failure, and conduction slowing. Clinical and electrophysiological recovery from adoptively transferred EAN was nearly complete and its time course was inversely correlated to the initial severity of EAN. These findings suggest that EAN induced by the P2-specific T-cell line can lead to a profound and rapidly evolving nerve dysfunction in a dose-dependent fashion.