Natural Autoantibodies—Homeostasis, Autoimmunity, and Therapeutic Potential

Natural autoantibodies (NAbs) are a seminal part of the immune system, originating from B-1a cells, and produced in the absence of external antigen stimulation. They exhibit a remarkably conserved repertoire that includes a broad specificity for self-antigens. For this reason, they are believed to be a product of natural selection. NAbs are mostly antibodies of the immunoglobulin (Ig)M isotype that demonstrate polyreactive, low-titer, low antigen-binding affinities, with germline- or close to germline-encoded variable regions that provide reactivity to both microbial and altered self-antigens. NAbs are engaged with a wide range of homeostatic “housekeeping” functions as well as roles in multiple disorders. In terms of homeostatic functions, NAbs are a crucial part of the very early innate immunity, providing an essential first line of defense against pathogens. NAbs also play a key role in clearing apoptotic cells and oxidized cellular damaged structures. Such an example is the clearance of oxidized low-density lipoproteins (OxLDL); this scavenging property contributes to the cardiovascular protection against atherosclerosis. There is also mounting evidence that NAbs take part in tumor surveillance by recognizing oligosaccharides expressed on tumor cells. In addition, the roles of NAbs in the pathogenesis of Alzheimer disease, systemic inflammatory response syndrome (SIRS), ischemia, and cryoglobulinemia are currently being investigated, whereas their significance in autoimmune conditions, such as rheumatoid arthritis and systemic lupus erythematosus, have been extensively described. These understandings may harness NAbs as future tool in the combat of disease.