An Autoantigen Atlas From Human Lung HFL1 Cells Offers Clues to Neurological and Diverse Autoimmune Manifestations of COVID-19

Abstract

COVID-19 is accompanied by a myriad of both transient and long-lasting autoimmune responses. Dermatan sulfate (DS), a glycosaminoglycan crucial for wound healing, has unique affinity for autoantigens (autoAgs) from apoptotic cells. DS-autoAg complexes are capable of stimulating autoreactive B cells and autoantibody production. We used DS-affinity proteomics to define the autoantigen-ome of lung fibroblasts and bioinformatics analyses to study the relationship between autoantigenic proteins and COVID-induced alterations. Using DS-affinity, we identified an autoantigen-ome of 408 proteins from human HFL1 cells, at least 231 of which are known autoAgs. Comparing with available COVID data, 352 proteins of the autoantigen-ome have thus far been found to be altered at protein or RNA levels in SARS-CoV-2 infection, 210 of which are known autoAgs. The COVID-altered proteins are significantly associated with RNA metabolism, translation, vesicles and vesicle transport, cell death, supramolecular fibrils, cytoskeleton, extracellular matrix, and interleukin signaling. They offer clues to neurological problems, fibrosis, smooth muscle dysfunction, and thrombosis. In particular, 150 altered proteins are related to the nervous system, including axon, myelin sheath, neuron projection, neuronal cell body, and olfactory bulb. An association with the melanosome is also identified. The findings from our study illustrate a connection between COVID infection and autoimmunity. The vast number of COVID-altered proteins with high intrinsic propensity to become autoAgs offers an explanation for the diverse autoimmune complications in COVID patients. The variety of autoAgs related to mRNA metabolism, translation, and vesicles suggests a need for long-term monitoring of autoimmunity in COVID. The COVID autoantigen atlas we are establishing provides a detailed molecular map for further investigation of autoimmune sequelae of the pandemic, such as “long COVID” syndrome.Summary SentenceAn autoantigen-ome by dermatan sulfate affinity from human lung HFL1 cells may explain neurological and autoimmune manifestations of COVID-19.

The 2022 Report on the Human Proteome from the HUPO Human Proteome Project

“…Several papers show a striking relationship to human autoimmunity; 100−103 an analysis of human lung cells showed that a large number of COVID-dysregulated proteins during acute infection are known human autoantigens. 104 Finally, the HPP Pathology mission is to enhance education and outreach for physicians and healthcare providers worldwide, raise awareness about proteomics, provide education through meetings and tutorials, and increasingly bring international…”

The relationship between chronic immune response and neurodegenerative damage in long COVID-19

“…consequent generation of autoantibodies (169,170). The analysis of the "autoantigenicoma" in patients who suffered from COVID-19 through the detection of autoantigens bound to determatan sulfate (autoantigen-DS complex) seems to be helpful to predict the appearance of autoimmune diseases and neurological damage (171,172). Using this strategy, 751 autoantigen candidates were found, of which 657 are directly altered by infection with SARS-CoV-2.…”

“…Regarding the nervous system, 150 autoantigens of proteins are related to axon guidance, neuron projection, myelin sheath, axon growth cone, neuronal cell body, cerebellar Purkinje cell layer, peripheral nervous system axon regeneration, radial glial scaffolds and proteins related to the olfactory bulb. There were also 193 autoantigens of proteins related to neurological diseases such as neuronal infection with Japanese encephalitis virus, neuroblastoma, glioblastoma, neurodegeneration in Down syndrome, AD, schizophrenia, cerebral ischemia induced neurodegenerative diseases, PD, and neurodegeneration (Supplementary Table 2) (172). The mechanism by which coronaviruses could resemble conditions of early events of neurodegeneration should be explored considering the participation of the immune system and the uncontrolled generation of autoantibodies that deteriorate neuronal circuits.…”

SARS-CoV-2 infection is associated with anti-desmoglein 2 autoantibody detection

“…COVID-19 is no exception with clinical syndromes such as autoimmune cytopenia, Guillain-Barre syndrome, autoimmune encephalitis, lupus and acquired haemophilia being reported (12). COVID-19 infection results in the post-translational modification of a vast number of proteins with high intrinsic propensity to become autoantigens, offering an explanation for the diverse autoimmune complications observed (13).…”