The immunopathological spectrum of COVID-19: from cytokine storm to autoimmunity—a systematic review

Introduction This systematic review aimed to provide a comprehensive evaluation of the immunopathological mechanisms associated with SARS-CoV-2 infection and COVID-19 vaccination based on current evidence. Particular emphasis was placed on cytokine storm, endothelial dysfunction, complement activation, and autoimmune processes in COVID-19 pathogenesis. Methods The study was conducted as a systematic literature review in accordance with PRISMA guidelines. English-language research articles published between 2020 and 2026 were identified through a structured search of the Scopus database. A total of 1,331 records were screened, and 53 studies were included based on predefined inclusion and exclusion criteria. The findings were systematically categorized according to major immunopathological mechanisms. Results The included studies indicate that endothelial dysfunction (24.5%) and cytokine dysregulation (18.9%) are the most frequently reported mechanisms in COVID-19 immunopathogenesis. Autoimmune responses (15.1%), complement activation (17%), and immune complex–mediated inflammation also play significant roles. Elevated levels of proinflammatory cytokines, lymphopenia, and markers of vascular injury were consistently associated with increased disease severity and mortality. In addition, persistent immunological alterations and autoantibody production were observed in a subset of patients during the post-COVID period. Conclusion COVID-19 pathogenesis is driven by complex and interconnected immunopathological mechanisms rather than viral effects alone. Hyperinflammation, endothelial dysfunction, complement activation, and autoimmune processes are key determinants of disease severity and clinical outcomes. These findings underscore the importance of targeted immunomodulatory strategies and provide a comprehensive framework for future research.