Protective Roles of Natural IgM Antibodies

Abstract

Antibodies are a vital part of the armamentarium of the adaptive immune system for the fine-tuning of the recognition and response to foreign threats. However, in health there are some types of antibodies that instead recognize self-antigens and these contribute to the enhancement of primitive innate functions. This repertoire of natural IgM antibodies is postulated to have been selected during immune evolution for their contributions to critical immunoregulatory and housekeeping properties. The clearance of dying cells is one of the most essential responsibilities of the immune system, which is required to prevent uncontrolled inflammation and autoimmunity. In the murine immune system, natural IgM antibodies that recognize apoptotic cells have been shown to enhance the phagocytic clearance of dead and dying cells and to suppress innate immune signaling pathways. In the mouse, natural IgM are often the products of B-1 cell clones that arise during immune development without an absolute requirement for exogenous antigenic stimulation. In patients with systemic lupus erythematosus, IgM autoantibodies, which bind to neo-epitopes on apoptotic cells, have been demonstrated to be present at significantly higher levels in patients with lower disease activity and with less severe organ damage. While certain specificities of IgM autoantibodies correlate with protection from lupus renal disease, others may convey protective properties from lupus-associated atherosclerotic cardiovascular disease. New and unexpected insights into the functional roles of IgM antibodies are still emerging, especially regarding the functions of natural antibodies. Herein, we review recent progress in our understanding of the potential roles of natural IgM autoantibodies in the regulation of immune homeostasis and for protection from autoimmune and inflammatory diseases.

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

“…Using our IgM clone 9H4, we show that vimentin accumulates on the surface of senescent cells, and we demonstrate that senescence-associated cell-surface vimentin is modified by the oxidative adduct malondialdehyde (MDA). These observations are in agreement with previous studies showing that one of the major antigens of natural IgMs are oxidation-associated neo-epitopes, which become distinctively exposed on the cell surface of dysfunctional cells to allow recognition by the immune system (16,24). MS analysis confirmed the presence of MDA on senescence-associated cell-surface vimentin and identified an oxidation-associated neoepitope on cysteine 328 (C328).…”

“…Among the dozens of antibody clones that we isolated and screened for immunoreactivity toward senescent cells, many were of the IgM isotype. Germ-line-type IgMs, also termed "natural antibodies," are part of the innate immune system and are the most evolutionarily conserved antibody isotype (16)(17)(18). As the earliest isotype to be expressed during immune development, IgMs are thought to have been selected during the evolution of immunity for their contribution to critical immunoregulatory and housekeeping functions, which include clearance of apoptotic cells to prevent inflammation and autoimmunity (19,20).…”

Presence of a neo-epitope and absence of amyloid beta and tau protein in degenerative hippocampal granules of aged mice

“…These carbohydrate antigens are prominent targets of immune surveillance and natural IgM antibodies (Brändlein et al 2003;Vollmers and Brändelin 2006). Natural IgM antibodies can be present from birth without external antigenic exposure and there is mounting evidence to suggest that they contribute to critical innate immune functions involved in the maintenance of tissue homeostasis (Grönwall et al 2012). Natural IgM antibodies frequently present crossreactivity, which is a required feature associated with their function in the first line of defence (Vollmers and Brändelin 2006).…”

Reconstituted Human Polyclonal Plasma-derived Secretory-like IgM and IgA Maintain the Barrier Function of Epithelial Cells Infected with an Enteropathogen

“…As the most conserved Ab among vertebrate species, the importance of IgM has been appreciated for several decades. It is present early in immune development (5) and is known to be crucial in the primary mucosal immune response (6). Moreover, IgM is able to compensate for the lack of IgA in IgA-deficient individuals (7).…”