Defining Natural Antibodies

Abstract

The traditional definition of natural antibodies (NAbs) states that these antibodies are present prior to the body encountering cognate antigen, providing a first line of defense against infection thereby, allowing time for a specific antibody response to be mounted. The literature has a seemingly common definition of NAbs; however, as our knowledge of antibodies and B cells is refined, re-evaluation of the common definition of Nabs may be required. Defining Nabs becomes important as the function of NAb production is used to define B cell subsets (1) and as these important molecules are shown to play numerous roles in the immune system (Figure 1). Herein, we aim to briefly summarize our current knowledge of NAbs in the context of initiating a discussion within the field of how such an important and multifaceted group of molecules should be defined.

The continuing story of T‐cell independent antibodies

“…63 Here we return to the layered immune system hypothesis. Natural antibodies are spontaneously produced immunoglobulins with broad reactivity against a variety of foreign and self-antigens.…”

Innate-like B cell subsets during immune responses: Beyond antibody production

“…Beyond these celomic cavities, these cells can also be found in the bone marrow and the spleen, accounting for just about 1% of the B cell fraction in these organs, and also a minimum representation of about 0.2–0.3% of the same lineage in blood or lymph nodes . There, they produce mostly IgM Abs directed against carbohydrate or phospholipid Ags present on commensal bacteria; such natural Abs are polyreactive or polyspecific since they usually bind to both self‐antigens and microbial Ags . An archetypal example of Abs produced by B‐1 cells are those recognizing ABO blood groups, which arise during the first months of life because of structural similarities between erythrocyte surface‐antigens and bacterial structural carbohydrates recognized by B‐1 cells .…”

“…While B cells do not secrete soluble Abs unless stimulated, serum Abs and Ab‐secreting cells are easily found prior to any previous infection, vaccination, other foreign Ag exposure or passive immunization, even in gnotobiotic mice held in the complete absence of Ags; a reason why they are known as natural Abs. Natural Abs are present in animals and humans, comprising mainly IgM isotype, along with portions of IgA and IgG . Natural Abs differ from the adaptive Abs in their repertoire and function.…”

“…Natural Abs differ from the adaptive Abs in their repertoire and function. They are often directed against highly conserved epitopes and frequently bind to ligands of variable chemical composition with low affinity . They have been found to play an innate‐like role in protection against infectious agents and to exert homeostatic functions in diverse experimental disease models …”

Regulatory T cells and co‐evolution of allele‐specific MHC recognition by the TCR

“…These Ig V elements can be considered to largely encode VH and VL sequences for antibody specificities that are specific for predicable self‐antigens that appear in each ontogeny such as those determinants on buried, effete or aged self‐components. These specificities are the familiar background, often cross‐reactive, IgM ‘natural antibodies’ detected in normal healthy plasma in humans, mice and other vertebrates . We now extend the discussion on how thymic regulatory T (tTreg) cells work by Dembic and deal directly with the implications for understanding the mechanism of germline evolution of the allele‐specific TCR V segment repertoires.…”