Susceptibility to autoimmune diseases is determined by a combination of genetic and environmental factors, the latter being mostly unknown. Among them, the ability of infectious agents to set off or exacerbate an autoimmune disease is still a matter of debate. If there is substantial evidence that, in some circumstances, infections may have a protective effect against autoimmune-mediated diseases, clinical observations and several experimental models have suggested for decades that autoimmune diseases may be initiated or worsened by microbial infections. However, there is no real understanding of the underlying mechanisms. For B cells, it has been known for long that bacterial or viral infection, particularly when persistent, leads to polyclonal B cell activation and hypergammaglobulinemia. The   mechanisms underlying this “nonspecific” B cell activation are far from obvious; in particular, they are most probably not limited to cytokines released from activated T cells since they may involve cognate interactions with specific T cells. The old question whether this polyclonal activation includes the turning on of anti-self and therefore may lead to autoimmune disease is still open. This review summarizes and discusses recent findings that shed light on these mechanisms and that particularly emphasize the links between the innate and adaptive immune systems resulting in B cell tolerance break during infections.