Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity

Abstract

COVID-19 has been associated with many neurological complications including stroke, delirium and encephalitis. Furthermore, many individuals experience a protracted post-viral syndrome which is dominated by neuropsychiatric symptoms, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of severe COVID-19 more broadly.We sought to investigate the dynamics of, and relationship between, serum markers of brain injury (neurofilament light [NfL], Glial Fibrillary Acidic Protein [GFAP] and total Tau) and markers of dysregulated host response including measures of autoinflammation (proinflammatory cytokines) and autoimmunity. Brain injury biomarkers were measured using the Quanterix Simoa HDx platform, cytokine profiling by Luminex (R&D) and autoantibodies by a custom protein microarray.During hospitalisation, patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependant manner, and there was evidence of ongoing active brain injury at follow-up 4 months later. Raised NfL and GFAP were associated with both elevations of pro-inflammatory cytokines and the presence of autoantibodies; autoantibodies were commonly seen against lung surfactant proteins as well as brain proteins such as myelin associated glycoprotein, but reactivity was seen to a large number of different antigens.Furthermore, a distinct process characterised by elevation of serum total Tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses in the same manner as NfL and GFAP.

Acute Neurologic Complications of COVID-19 and Postacute Sequelae of COVID-19

“…Serum markers of brain injury including neurofilament light (NFL), glial fibrillary acidic protein (GFAP), and total Tau have been found to be increased in a severity-dependent manner in hospitalized patients, with elevations persisting at 4-month follow-up. 29 In these patients, elevations in NFL and GFAP were associated with elevations of proinflammatory cytokines, as well as autoantibodies. Another case-control study that included plasma samples from n 5 57 patients at less than 48 hours of COVID-19 hospitalization, and 20 matched controls investigated levels of 6 brain injury molecules (BIMs), 2 endothelial injury molecules (EIMs), and chemokines/cytokines.…”

“…27 In patients with COVID-19 with neurologic manifestations, CSF pleocytosis was found to be associated with parainfectious or postinfectious encephalitis and polyradiculitis. Elevations in anti-GD1b and anti-Caspr2 autoantibodies 28 and myelin-associated glycoprotein 29 may be seen raising the possibility of SARS-CoV-2-induced secondary autoimmunity.…”

Autoimmunity and SARS‐CoV‐2 infection: Unraveling the link in neurological disorders

“…Interestingly, while serum Nfl levels were elevated across hospitalized Neuro‐COVID patients regardless of neurological manifestations, Nfl concentrations in the CSF increased exclusively in patients with CNS inflammatory diseases, namely, ADEM and encephalitis [ 26 ]. The levels of Nfl and glial fibrillary acidic protein (GFAP), which is a specific indicator of astrocyte injury, were shown to rise during acute SARS‐CoV‐2 infection and to remain elevated up to 4 months after infection in a severity‐dependent manner [ 28 ]. All these observations point to the presence of compartmentalized biomarkers reflecting the existence of neuronal pathology in Neuro‐COVID patients, which may represent a potential useful diagnostic tool for accurate clinical classification of neurological disease subtype and severity.…”

“…Many autoantibodies targeting intracellular and extracellular CNS antigens have also been detected in the serum of COVID‐19 patients [ 28 , 54 , 72 , 85 , 86 ]. Interestingly, antibodies against hypocretin receptor 2 (HCRTR2), which is selectively enriched in the hypothalamus and controls the sleep‐wake circuit through HCRT signaling, have been identified and shown to be functional in in vitro assays [ 72 ].…”

“…Interestingly, antibodies against hypocretin receptor 2 (HCRTR2), which is selectively enriched in the hypothalamus and controls the sleep‐wake circuit through HCRT signaling, have been identified and shown to be functional in in vitro assays [ 72 ]. In addition, anti‐myelin‐associated glycoprotein (MAG) antibodies, which are frequently associated with peripheral neuropathies, were recently described in 9.6% of Neuro‐COVID‐19 patients but were absent in healthy controls [ 28 ]. Another recent study detected serum anti‐myelin antibodies in a fraction of Neuro‐COVID‐19 patients (6 out of 40) by indirect immunofluorescence of peripheral nerve tissue sections [ 54 ].…”