Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent for coronavirus disease 2019 (COVID-19), is associated with several clinical features common in autoimmune diseases as myalgias, arthralgias, fatigue, and rashes. COVID-19 patients also exhibit less common autoimmunity manifestations such as myositis, thrombosis, myocarditis, encephalitis, vasculitis, and arthritis.
These observations, coupled with the increasing number of "recovered" long-COVID patients with post-COVID-19 symptoms, indicate that SARS-CoV-2-related inflammation promotes tissue damage. Prior research has shown that about 50% of hospitalized COVID-19 patients at an academic hospital in Greece had high serum levels of autoantibodies, often associated with thrombosis, rashes, and vasculitis. Also, serum anti-nuclear antibodies (ANAs) were detected in about one-third of the patients. Reports have also shown that autoantibodies can help the formation of clots in mouse models.
The apparent connection between clinical manifestations seen in patients with autoimmune diseases and those in COVID-19 patients has prompted quests for target autoantigen candidates to better understand COVID-19 pathogenesis.
Quantifying the impact of SARS-CoV-2 on autoimmunity and associated anti-viral responses
The molecular targets of autoantibodies in COVID-19 patients and their associations with SARS-CoV-2 immune responses and their timing are still mostly unknown. However, a team of researchers from Germany and the USA recently hypothesized that SARS-CoV-2 induces antibody production against autoantigens and cytokines/chemokines de novo, which correlates with anti-viral responses.
They assembled three different bead-based protein arrays to quantify IgG antibodies associated with connective tissue diseases (CTDs), anti-cytokine antibodies (ACA), and anti-viral responses in 197 COVID-19 samples obtained from 147 hospitalized COVID-19 patients. Some of the samples were collected longitudinally, in 3 different geographical locations. The research is published on the preprint server medRxiv*.
"One of the most important unanswered questions raised by our studies is why specific molecules are targeted in hospitalized COVID-19 patients."
Antibodies target several autoantigens in most COVID-19 patients, but <15% of healthy controls
The study results demonstrate that circulating antibodies target a large set of autoantigens in a significant number of hospitalized COVID-19 patients, which happens only in <15% of healthy controls not infected by SARS-CoV-2. When present, autoantibodies mostly targeted autoantigens linked to rare disorders, including systemic sclerosis, myositis, and CTD overlap syndromes. ANAs were observed in about 25% of the patients. Patients with autoantibodies demonstrated one or more specificities, and they often had antibodies to multiple cytokines.
Rarely, some patients had IgG antibodies against angiotensin-converting enzyme 2 (ACE 2). A subset of autoantibodies and ACA developed de novo post-infection with SARS-CoV-2 while others were transient. COVID-19 patients who had one or more autoantibodies were found to have greater levels of antibodies against SARS-CoV-2 methyltransferase (ME) and non-structural protein 1 (NSP1).
"We hypothesize that prolonged inability to eradicate and clear virus expands the adaptive immune response to target non-structural viral proteins, some of which might physically interact or cross-react with autoantigens in the context of an intense local or systemic inflammatory environment, exceeding a threshold for breaking tolerance to self."
Findings confirm emerging reports of IgG autoantibodies in hospitalized COVID-19 patients
The researchers concluded that SARS-CoV-2 triggers the development of new-onset IgG autoantibodies in a considerable percentage of hospitalized COVID-19 patients and positively correlated with immune responses against SARS-CoV-2 proteins. The study's findings confirm emerging reports of the presence of IgG autoantibodies in hospitalized COVID-19 patients and show that a substantial subset of patients develops autoantibodies that could increase their risk for symptomatic classifiable autoimmunity in the future.
According to the authors, these studies offer a starting point for large-scale epidemiology studies to estimate the extent of autoimmunity resulting from SARS-CoV-2 infection and its long-term impacts on the health care system well as the economy.
"While the COVID-19 pandemic is leaving a wake of destruction as it progresses, it also provides an unprecedented opportunity to understand how exposure to a new virus could potentially break tolerance to self, potentially giving rise to autoimmunity and other chronic, immune-mediated, diseases."
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- New-Onset IgG Autoantibodies in Hospitalized Patients with COVID-19, Sarah Esther Chang, Allan Feng, Wenzhao Meng, Sokratis A. Apostolidis, Elisabeth Mack, Maja Artandi, Linda Barman, Kate Bennett, Saborni Chakraborty, Iris Chang, Peggie Cheung, Sharon Chinthrajah, Shaurya Dhingra, Evan Do, Amanda Finck, Andrew Gaano, Reinhard Geßner, Heather M. Giannini, Joyce Gonzalez, Sarah Greib, Margrit Gündisch, Alex Ren Hsu, Alex Kuo, Monali Manohar, Rong Mao, Indira Neeli, Andreas Neubauer, Oluwatosin Oniyide, Abigail Elizabeth Powell, Rajan Puri, Harald Renz, Jeffrey M. Schapiro, Payton A Weidenbacher, Rich Wittman, Neera Ahuja, Ho-Ryun Chung, Pras Jagannathan, Judith James, Peter S. Kim, Nuala J. Meyer, Kari Nadeau, Marko Radic, William H. Robinson, Upinder Singh, Taia T. Wang, E. John Wherry, Chrysanthi Skevaki, Eline T. Luning Prak, PJ Utz, medRxiv, 2021.01.27.21250559; doi: https://doi.org/10.1101/2021.01.27.21250559, https://www.medrxiv.org/content/10.1101/2021.01.27.21250559v1