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.

Keywords: B cell subsets; B cells; B-1 cells; antibodies; natural antibody; natural antibody repertoire.

Figure 1

Overview of natural antibodies’ (NAbs) attributes. Graphical representation of the various NAb functions (outside green circle), epitope recognition (inside yellow circle), isotype (inside red circle), and cells shown to produce NAbs (inside blue circle).

Figure 2

Determining how to define natural antibodies (NAbs). (1) Most frequently used definition of NAbs: preimmune antibodies generated in the absence of exogenous antigenic stimulation, which are broadly reactive, low affinity, germline-like antibodies selected in the presence of endogenous antigen (depicted in green). These antibodies are pre-existing/always present in the serum. The dotted outline represents the intrinsic properties the cell might have (e.g., increased levels of IgM and/or CD86/CD80, lower activation threshold). The dark outline indicates the cell is secreting Ig. (2–4) In panels 2–4, we suggest possible antigenic experiences of NAbs; however, further investigation is required to determine whether antibodies produced after such antigenic experiences are the same as preimmune, pre-existing NAbs in terms of germline structure and/or repertoire. (2) Here, we suggest a NAb producing cell may require an extra antigen experience (light push⁽¹⁾) to start immediately (within hours) secreting. This antigen experience contrasts the strong activation required for naive B-2 cells (depicted in red) to differentiate into plasma cells (PC), which results in highly specific non-germline antibody (depicted in blue). However, it is unknown what affect this light push might have upon the antibody produced by the NAb producing cell (this is depicted by giving the cell both blue and green antibody colors). (3) We suggest a NAb producing cell that is already secreting NAbs experiences antigen, which induces differentiation into a plasma cell (PC). Again, it is unknown what affect this differentiation might have upon the antibody produced (this is depicted by giving the cell both blue and green antibody colors). (4) Finally, we depict NAb producing cells experiencing strong/specific activation and subsequently following the traditional pathway leading to memory and plasma cell differentiation.