Natural Autoantibodies in Health and Disease

Natural antibodies (NAbs) are immunoglobulins present in the healthy organism in the absence of intentional immunization. They belong to all Ig classes (IgM, IgG, IgA and IgE) and are found in the bloodstream as well as in other biological fluids. One of the unique features of NAbs is polyreactivity, denoting that each NAb can recognize more than one epitopes from both self and non-self-antigens. Accordingly, NAbs recognize the Fc portion or the paratope of other NAbs, thus generating a stable dynamic immune network safeguarding immune homeostasis. Polyreactivity is directly related to the remarkable biological roles of NAbs, such as the removal of cellular and molecular waste, the targeting of pathogens, and the immunoregulation and homeostasis of the immune system. The immunoregulatory role of NAbs appoint them as valuable diagnostic, prognostic and therapeutic agents. Up to now, the most effective therapeutic application of NAbs are the intravenous immunoglobulin preparations that are produced from an immense number of healthy donors and are used in the treatment of more than 100 diseases. This review discusses all aspects of NAbs; their discovery, origin and evolutionary aspects, producing cells and inherent properties, such as polyreactivity to their variable region, their biological roles, association with disease and applications in biomedicine with perspectives in therapeutic use.