Natural Antibodies


Natural antibodies are essentially antibodies of the immunoglobulin M (IgM) isotype present in the circulation of normal humans and other mammalian species. They are detectable in the serum of healthy individuals before deliberate immunisation. They are often directed against highly conserved epitopes and often bind to ligands of varying chemical composition with low affinity. This antibody subset contrasts with immune antibodies, which are produced in response to the introduction of antigens to the immune system. Natural antibodies are frequently directed to intracellular structures, rather than to cell‐surface antigens. They have been found to play an innate‐like role in protection against infectious agents and to exert homeostatic functions in a variety of experimental models. Other investigations suggest that natural antibodies can play a pathogenic role in autoinflammatory diseases.

Key Concepts

  • A natural antibody is an antibody present in the circulation of an animal or a subject that had not been previously exposed to the corresponding antigen.
  • Certain B‐lymphocyte subsets, such as B‐1a cells, are committed to natural antibody production.
  • The antibody repertoire expressed in B‐cell malignancies exhibits several features in common with those of the natural antibody repertoire of healthy subjects.
  • It is possible that natural antibody production is driven by microorganisms indigenous to the organism, such as bacteria living in the intestine.
  • Natural antibodies play a role in shaping the B‐cell repertoire and may represent the precursors of antibodies to pathogens.
  • Natural antibodies could serve as innate recognition receptors, recognising various bacterial cell‐wall components or parasites.
  • Studies of rodents rendered deficient in natural antibodies suggest that this antibody subset is endowed with a homeostatic potential and housekeeping functions, such as recognition and removal of senescent cells and other self‐antigens.
  • Circumstantial evidence suggests that natural antibodies can be associated with protection against Alzheimer disease, atherosclerosis or cancer development.
  • B lymphocytes secreting natural antibodies could represent a reservoir capable of mutating their immunoglobulin variable region genes to give rise to high‐affinity pathogenic autoantibodies.

Keywords: autoimmunity; tolerance; immunoglobulin genes; B‐1a cells; marginal zone B cells; autoimmune disease; innate immunity; homeostasis; atherosclerosis; Alzheimer disease

Figure 1. Mechanisms of B‐cell tolerance to self and their relevance to production of natural antibodies. In the B‐lymphocyte compartment, tolerance to self‐components is maintained by four mechanisms: clonal ignorance, clonal anergy, clonal deletion and receptor editing. The affinity and avidity of the interaction of the B‐cell receptor with self‐antigens determines, in part, the efficiency of induced tolerance. Clonal ignorance is postulated to underlie NAb production.
Figure 2. B cells are part of innate and adaptive immunity. Because production of NAbs precedes exposure to infectious agents, they can efficiently contribute to the innate branch of immunity. With time, secretion of affinity‐mature, somatically selected antibodies will provide the immune system with a second wave of potent adaptive defence mechanism.
Figure 3. Beneficial effects of natural antibodies.
Figure 4. Deleterious effects of natural antibodies.


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Zouali, Moncef(Dec 2015) Natural Antibodies. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001213.pub3]