Immunoglobulins with germline sequences occur in invertebrates and vertebrates and are named 'natural antibodies' (NAbs). They may target foreign antigens, self- or altered self-components and are part of the normal immunoglobulin repertoire. NAbs can act as systemic surveillance molecules, which tag damaged or stressed cells, invading pathogens and toxic protein aggregates for elimination by the immune system. Certain NAbs actively signal in different cell types with a broad range of responses from induction of apoptosis in cancer cells, stimulation of remyelination in glial cells and...