Abstract The emergence of mRNA vaccines represents a significant advancement in public health by conferring protection against a variety of infectious diseases. However, concerns regarding the potential risk of inducing or exacerbating autoimmune disorders, particularly connective tissue diseases (CTDs), have arisen. This paper explores the mechanisms by which mRNA vaccines may lead to the onset or worsening of CTDs, focusing on the immune responses induced by Pathogen-Associated Molecular Patterns (PAMPs), the interactions between Toll-like receptors 7/8 and 9 (TLR7/8 and TLR9), and the activation of self-reactive B cells. Furthermore, guidelines are suggested for administering vaccines to individuals at elevated risk, such as those with a positive antinuclear antibody (ANA) test or specific rheumatic disease genes. Our findings underscore the necessity for targeted vaccination strategies that mitigate risks while maintaining public health efficacy.