C1q-targeted inhibition of the classical complement pathway prevents injury in a novel mouse model of acute motor axonal neuropathy

Introduction Guillain-Barré syndrome (GBS) is an autoimmune disease that results in acute paralysis through inflammatory attack on peripheral nerves, and currently has limited, non-specific treatment options. The pathogenesis of the acute motor axonal neuropathy (AMAN) variant is mediated by complement-fixing anti-ganglioside antibodies that directly bind and injure the axon at sites of vulnerability such as nodes of Ranvier and nerve terminals. Consequently, the complement cascade is an attractive target to reduce disease severity. Recently, C5 complement component inhibitors that block the formation of the membrane attack complex and subsequent downstream injury have been shown to be efficacious in an in vivo anti-GQ1b antibody-mediated mouse model of the GBS variant Miller Fisher syndrome (MFS). However, since gangliosides are widely expressed in neurons and glial cells, injury in this model was not targeted exclusively to the axon and there are currently no pure mouse models for AMAN. Additionally, C5 inhibition does not prevent the production of early complement fragments such as C3a and C3b that can be deleterious via their known role in immune cell and macrophage recruitment to sites of neuronal damage. Results and Conclusions In this study, we first developed a new in vivo transgenic mouse model of AMAN using mice that express complex gangliosides exclusively in neurons, thereby enabling specific targeting of axons with anti-ganglioside antibodies. Secondly, we have evaluated the efficacy of a novel anti-C1q antibody (M1) that blocks initiation of the classical complement cascade, in both the newly developed anti-GM1 antibody-mediated AMAN model and our established MFS model in vivo. Anti-C1q monoclonal antibody treatment attenuated complement cascade activation and deposition, reduced immune cell recruitment and axonal injury, in both mouse models of GBS, along with improvement in respiratory function. These results demonstrate that neutralising C1q function attenuates injury with a consequent neuroprotective effect in acute GBS models and promises to be a useful new target for human therapy

Candida meningitis in an immunocompetent patient detected through (1→3)-beta-d-glucan

SummaryA 44-year-old female presented with a 3-month history of headache, dizziness, nausea, and vomiting. Her past medical history was significant for long-standing intravenous drug abuse. Shortly after admission, the patient became hypertensive and febrile, with fever as high as 38.8°C. The lumbar puncture profile supported an infectious process; however multiple cultures of blood and cerebrospinal fluid (CSF) did not initially show growth of organisms. Finally after 9 days of incubation, a CSF culture showed evidence of a few colonies of Candida albicans. To confirm the diagnosis, preserved CSF from that sample was tested for (1→3)-β-d-glucan, showing levels >500pg/ml. This report illustrates a rare complication of intravenous drug use in an immunocompetent patient and demonstrates the utility of (1→3)-β-d-glucan testing in possible Candida meningitis

Status of the European Green Crab, Carcinus maenas, in Oregon and Washington coastal Estuaries in 2018

The European green crab (Carcinus maenas) has persisted in Oregon and Washington coastal estuaries since the late 1990s. After the arrival of a strong year class in 1998, significant recruitment to the populations occurred only in 2003, 2005, 2006, 2010, 2015, 2016, 2017 and 2018. Warm winter water temperatures, high Pacific Decadal Oscillation (PDO) and Multivariate ENSO (El Niño Southern Oscillation) Indices, and a high abundance of southern copepods are all correlated with strong year classes and vice versa (Behrens Yamada Peterson and Kosro 2015). Prior to 2015, green crabs were too rare to exert measurable effects on the native benthic community and on shellfish culture in Oregon and Washington. Following the recent strong El Niño, however, we documented the arrival of four strong year classes in 2015, 2016, 2017 and 2018. Average catch rates over the last four years steadily increased from 0.5 to 0.8 to 2.2 and to 3.2 crabs per trap. The catches in the last 2 years are much higher than in any of the previous years, including 1998. Since green crabs live for 6 years, these four consecutive year classes will produce larvae until 2024. A switch to cooler ocean conditions in the coming years will result in poor recruitment, but a return to high PDO and strong El Niño patterns would signal good recruitment and higher green crab densities. For example, green crabs were first documented in New England in 1817, but it took warm ocean conditions during the 1950’s for their numbers to build to a level at which they decimated the soft-shelled clam industry in Maine. With the recent warm trend on the East Coast, green crabs are again abundant. Not only are they preying on shellfish, they are also damaging valuable eelgrass habitat by ripping up the plants in search of food (Neckles 2015). Even though green crab abundance in Oregon and Washington is still low when compared to Europe, eastern North America, Tasmania, California and the west coast of Vancouver Island, it is imperative to continue monitoring efforts for two reasons:1) to elucidate the process of range expansion and population persistence of this model non-indigenous marine species with planktonic larvae, and 2) to predict the arrival of strong year classes from ocean conditions and alert managers and shellfish growers of possible increases in predation pressure from this invader

Adhesion molecules controlling lymphocyte migration

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28009/1/0000445.pd

Increased serum levels of MRP-8/14 in type 1 diabetes induce an increased expression of CD11b and an enhanced adhesion of circulating monocytes to fibronectin

The recruitment of monocytes from the bloodstream is crucial in the accumulation of macrophages and dendritic cells in type 1 diabetic pancreases. Adhesion via integrins to endothelium and extracellular matrix proteins, such as fibronectin (FN), and the production of myeloid-related protein (MRP)-8, -14, and -8/14 by recently transmigrated monocytes are thought to be instrumental in such recruitment. We determined the FN-adhesive capacity and integrin expression of monocytes of type 1 and type 2 diabetic patients and related them to the subjects' serum levels of MRP-8, -14 and -8/14. Monocytes of type 1 diabetic patients displayed an increased adhesion to fibronectin in comparison with type 2 patients and healthy control subjects but had a normal expression of the FN binding integrins CD29, CD49a, CD49d, and CD49e (although CD11b and CD18 expression was increased). MRP-8/14, which was increased in the sera of type 1 diabetic patients, induced healthy donor monocytes to adhere to FN and upregulate CD11b expression in a dosage-dependent manner. The observed MRP-induced increased adhesion of monocytes to FN and upregulation of CD11b most likely contributed to a facilitated accumulation of monocytes and monocyte-derived cells at the site of inflammation, in this case the pancreatic islets