The science and arts of antibodies.

Abstract

Recently there have been major developments in understanding the basic mechanisms of actions of natural and adaptive antibodies, especially with regard to their anti-inflammatory and immunoregulatory properties, and the art of their clinical application in a variety of inflammatory and autoimmune disorders. This was the major theme of the International Forum of Immunoglobulin Research, held in Miami Florida on October 3–6, 2013. There have been several recent developments in the understanding of the role of natural autoantibodies in immune homeostasis, tolerance, and antimicrobial activity. Natural IgM antibodies to apoptotic-cell membrane determinants represent a distinct subset of antibodies that potentiate the phagocytic clearance of apoptotic cells and apoptotic bodies. Furthermore, these autoantibodies display potent antiinflammatory activities both in vitro and in vivo, which are mediated by MAPK phosphatase 1 signaling pathway (Caroline Gronwell, New York, USA). A role of natural IgM to be protective in human diseases comes from patients with systemic lupus erythematosus in which high levels of natural IgM to phosphocholine correlate with less active lupus disease, less organ damage, and lower risk of cardiovascular events. Srini Kaveri (Paris, France) and associates have identified and characterized the natural autoantibodies of the IgG isotype directed against the human Fc receptors. They show that the F(ab′)2 of IVIG recognizes the FcγRIII (CD16) and FcγRII (CD32). Furthermore, the immunopurified anti-FcγIII and anti-FcγII antibodies present in IVIG recognized soluble and membrane-bound FcR. These observations provide further evidence of the existence of natural autoantibodies towards a wide range of self-motifs, including those present in apoptotic bodies in immunoglobulin preparations that may participate in regulation of the immune response. Peter Lobo (Virginia, USA), using in vitro and murine knock out models, demonstrated an anti-inflammatory role of natural IgM antileucocyte antibodies (ALA). This anti-inflammatory effect of IgM is mediated, in part, by inhibiting TLR-4-induced translocation of NF-κB into the nucleus and inhibiting differentiation of naive Th0 cells into Th1 and Th17 cells. He also showed that intra-peritoneal administration of IgM prevents NODmice from developing autoimmune insulitis, which also involves Th1 and Th17 cells. Therefore, anti-inflammatory and immunoregulatory properties of natural antibodies may justify the use of polyclonal IgM preparations and/or development of monoclonal IgM for the treatment of inflammatory and autoimmune disease. Although a role of both ‘natural’ and ‘immune’ IgM antibodies in immune homeostasis, removal of self-antigen containing apoptotic cells and apoptotic bodies, and in protective immunity against pathogens is well-recognized, the mechanisms of IgM-mediated protection against microbes and immune-regulation; however, are not completely understood, Recent recognition and characterization of long since elusive Fc receptor for IgM (FcμR), in both humans and mice have shed light on some of these mechanisms. Hiromi Kubagawa (Alabama, USA) presented data on the cellular distribution of FcμR and potential functions. FcμR knock out mice are unable to secrete IgM; however, express surface IgM and other Ig isotypes on B cells, and secrete other immunoglobulins. Studies of these mice have reinforced the importance of both ‘natural’ and ‘immune’ IgM in microbial defense and in the regulation of autoimmunity. The sugar moieties attached to the IgG constant fragment (Fc) are essential for IgG functionality such as binding to cellular Fc receptors and complement activation. Presence or absence of distinct residues such as fucose and sialic acid can S. Gupta (*) University of California at Irvine, Irvine, CA, USA e-mail: sgupta@uci.edu