The immune response as a double‐edged sword: The lesson learnt during the COVID‐19 pandemic

The COVID‐19 pandemic has represented an unprecedented challenge for the humanity, and scientists around the world provided a huge effort to elucidate critical aspects in the fight against the pathogen, useful in designing public health strategies, vaccines and therapeutic approaches. One of the first pieces of evidence characterizing the SARS‐CoV‐2 infection has been its breadth of clinical presentation, ranging from asymptomatic to severe/deadly disease, and the indication of the key role played by the immune response in influencing disease severity. This review is aimed at summarizing what the SARS‐CoV‐2 infection taught us about the immune response, highlighting its features of a double‐edged sword mediating both protective and pathogenic processes. We will discuss the protective role of soluble and cellular innate immunity and the detrimental power of a hyper‐inflammation‐shaped immune response, resulting in tissue injury and immunothrombotic events. We will review the importance of B‐ and T‐cell immunity in reducing the clinical severity and their ability to cross‐recognize viral variants. The immune response during SARS‐CoV2 infection represents a double‐edged sword. An unbalanced innate immunity induced a severe inflammation, leading to suppressor cell expansion, platelets activation, vascular damage, specific immune response paralysis and massive activation of unspecific T cells. In contrast, effective innate immunity prevents the amplification of the inflammatory response and allows the differentiation of antibody‐producing plasmacells, memory B cells, effector and memory cross‐reactive T cells, overall mediating a highly efficient, protective immune response. This fine balance between harmful and protective immunity has strongly accelerated the development of new therapeutical immune‐mediated strategies.