Immune complexome analysis reveals an autoimmune signature predictive of COVID-19 severity

•Six immune complex antigens were enriched in patients with severe COVID-19.•No association between COVID-19 severity and viral antigens was found.•Specific immune complex antigens were associated with COVID-19 severity. The factors contributing to the development of severe coronavirus disease 2019 (COVID-19) following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unclear. Although the presence of immune complexes (ICs), formed between antibodies and their antigens, has been linked to COVID-19 severity, their role requires further investigation, and the antigens within these ICs are yet to be characterized. Here, a C1q enzyme-liked immunosorbent assay and immune complexome analysis were used to determine IC concentrations and characterize IC antigens, respectively, in the sera of 64 unvaccinated COVID-19 patients with PCR-confirmed SARS-CoV-2 infection, enrolled at seven participating centers in 2020. For the analysis, the patients were split into the severe (n = 35) and non-severe (n = 28) groups on the basis of their COVID-19 symptoms. We found that neither serum IC concentration nor IC antigen number was associated with COVID-19 severity. However, we identified six IC antigens, which were significantly enriched in the severe versus non-severe group. These IC antigens were all derived from human proteins, namely haptoglobin, the serum amyloid A-2 protein, the serum amyloid A-1 protein, clusterin, and lipopolysaccharide-binding protein, and complement-factor-H-related protein 3. Meanwhile, we found no association between COVID-19 severity and IC antigens derived from SARS-CoV-2 proteins. Collectively, the six IC antigens predicted COVID-19 severity with a moderate degree of accuracy (area under the receiver operating characteristic curve = 0.90, sensitivity = 94 %, specificity = 79 %). The IC antigen signature identified in this study may have important implications for the diagnosis and treatment of severe COVID-19.