Deciphering the IgG Idiotype Network Through Proteomic Analysis of Potential Targets in SARS‐CoV‐2‐Induced Immune Responses

ABSTRACT The association between COVID‐19 and autoimmune diseases has gained increasing recognition, yet the specific targets of SARS‐CoV‐2‐induced IgG are currently in focus for several studies. This study aims to explore the proteomic targets of these antibodies and their potential role in autoimmunity. We utilised a human proteome microarray encompassing 23 736 unique proteins, including isoform variants and fragments, as catalogued by the Human Protein Atlas. Serum samples were analysed from four groups: healthy controls (N‐exp HC), individuals vaccinated with protein‐based vaccines (N‐Cov Vac) and patients with moderate or severe COVID‐19 (COVID‐Mod and COVID‐Sev). The evaluation of SARS‐CoV‐2‐induced IgG antibodies revealed their potential to recognise multiple human proteins. Key targets included interferon alpha (IFN‐α), tumour growth factor beta (TGF‐β), interleukin 1 (IL‐1), CXCL16, TGF‐β receptors, CD34, CD47 and BCL2. The antibodies also targeted proteins from genes overexpressed in various immune cells, such as CD4+ and CD8+ T cells, γδ T cells, B cells, dendritic cells and NK cells. Reactivity was also observed with proteins specifically expressed in multiple organs, including the brain, liver, lungs and heart. Targeting patterns differed between COVID‐19 patients and controls, with some proteins showing differential recognition in moderate versus severe cases. Furthermore, we evaluated the protein–protein interaction network (PPIN) of all targeted proteins and observed minimal structural homology and co‐expression among the evaluated proteins, with almost no relation to the SARS‐CoV‐2 immune system reactome. The results suggest that the profile of SARS‐CoV‐2‐induced IgG autoantibodies is associated with disease severity. In contrast, protein‐vaccinated individuals exhibited a profile similar to non‐exposed controls, suggesting that autoreactive IgG is specifically linked to active SARS‐CoV‐2 infection. These findings reveal a complex network of SARS‐CoV‐2‐induced IgG idiotypes capable of targeting human proteins, not merely through simple cross‐recognition of homologous proteins. This highlights the need for further investigations to determine whether they may influence COVID‐19 pathophysiology and its clinical outcomes.