Fundamental roles of the innate-like repertoire of natural antibodies in immune homeostasis

Abstract

The composition of the early immune repertoire is biased with prominent expression of spontaneously arising B cell clones that produce IgM with recurrent and often autoreactive binding specificities. Amongst these naturally arising antibodies (NAbs) are IgM antibodies that specifically recognized amaged and senescent cells, often via oxidation-associated neo-determinants. These NAbs are present from birth and can be further boosted by apoptotic cell challenge. Recent studies have shown that IgM NAb to apoptotic cells can enhance phagocytic clearance, as well as suppress proinflammatory responses induced via Toll-like receptors, and block pathogenic IgG-immune complex (IC)-mediated inflammatory responses. Specific antibody effector functions appear to be involved, as these anti-inflammatory properties are dependent on IgM-mediated recruitment of the early recognition factors of complement. Clinical surveys have suggested that anti-apoptotic cell (AC) IgM NAbs may modulate disease activity in some patients with autoimmune disease. In mechanistic studies, anti-AC NAbs were shown to act in dendritic cells by inhibition of the mitogen-activated protein kinase (MAPK) pathway, a primary signal transduction pathway that controls inflammatory responses. This immunomodulatory pathway has an absolute requirement for the induction of MAPK phosphatase-1. Taken together, recent studies have elucidated the novel properties of a class of protective NAbs, which may directly blunt inflammatory responses through a primitive pathway for regulation of the innate immune system.

T cell–independent B cell activation induces immunosuppressive sialylated IgG antibodies

“…have suppressive feedback effects, as was previously suggested for IgM Abs in a different context (1,41,(49)(50)(51)(52)(53). In the present study, a desialylated monoclonal anti-TNP IgM Ab enhanced TNP-Ficollinduced B cell activation in vivo.…”

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

“…Germ-line-encoded IgM antibodies or natural antibodies are part of the innate immune system and appear without immunogenic challenge. A phenotypically distinct subset of B cells (B-1 cells) are responsible for producing natural IgMs in mice, and emerging data suggest the existence of a similar human B-cell counterpart (17,68,69). In addition to IgMs recognizing a wide range of microbial and viral components, natural antibodies contribute to immune homeostasis and perform housekeeping functions that include the recognition and removal of apoptotic cells (70).…”

“…Consequently, naturally occurring IgMs are inherently polyreactive and among the diverse antigens of natural antibodies are synthetic haptens, nucleotides, polysaccharides, oxidized lipids, and advanced glycation end products (AGEs) (17,35,36). To determine if 9H4 exhibited polyreactivity, we performed direct ELISAs using a series of haptens and antigens previously used to characterize IgMs (35).…”

“…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).…”

Immune Epitope Continuum of the Protein Relationships, Poly- And Autoreactivity of Antibodies

“…Присутствие в организме аутореактивных как ЕА, так Т-и В-клеток, ха-рактерно и считается даже обязательным практи-чески для всех здоровых лиц с самого рождения [5,23] и сегодня не рассматривается как несо-мненный маркер развивающегося аутоиммунно-го процесса. Им отводится важная роль в поддер-жании тканевого гомеостаза и активном участии в очищении организма от отмирающих под воз-действием разных механизмов [40]. Сводка некоторых возможных проявлений ИЭКРБ в функционировании ИС приведена на рисунке 2, и далее по ним будут приведены ко-роткие комментарии.…”