Chronic infections sustained by pathogen strains, including Staphylococcus aureus, may activate the innate immune system via the recognition of PAMPs by TLRs or NOD2, or following opsonization with C3 and immunoglobulins, thus fomenting the production of type I IFNs that represent a peculiar signature in SLE pathogenesis. Here, C3 is linked to systemic lupus erythematosus.