Secreted IgM: New tricks for an old molecule

Abstract

Secreted IgM (sIgM) is a multifunctional evolutionary conserved antibody that is critical for the maintenance of tissue homeostasis as well as the development of fully protective humoral responses to pathogens. Constitutive secretion of self- and polyreactive natural IgM, produced mainly by B-1 cells, provides a circulating antibody that engages with autoantigens as well as invading pathogens, removing apoptotic and other cell debris and initiating strong immune responses. Pathogen-induced IgM production by B-1 and conventional B-2 cells strengthens this early, passive layer of IgM-mediated immune defense and regulates subsequent IgG production. The varied effects of secreted IgM on immune homeostasis and immune defense are facilitated through its binding to numerous different cell types via different receptors. Recent studies identified a novel function for pentameric IgM, namely as a transporter for the effector protein ″apoptosis-inhibitor of macrophages″ (AIM/CD5L). This review aims to provide a summary of the known functions and effects of sIgM on immune homeostasis and immune defense, and its interaction with its various receptors, and to highlight the many critical immune regulatory functions of this ancient and fascinating immunoglobulin.

Keywords: AIM; FcµR; autoimmunity; homeostasis; inflammation; secreted IgM.

Figure 1:. A new structure for sIgM.

(A) Schematic of an IgM monomer possessing two immunoglobulin heavy and light chains each. The Fab region (fragment antibody binding) encodes the antigen binding sites, and the Fc region (fragment constant) regulates its function. The heavy chain contains five glycosylation sites, while there are no glycosylation sites encoded on the light chains. (B) Secreted IgM was thought to form a symmetric pentamer in which five monomers are joined together by a J chain and disulfide bonds. (C) New data now show that pentameric IgM is asymmetrical with a 50-degree groove that allows for one AIM (apoptosis inhibitor of macrophage/CD5L) molecules to bind, stabilizing their serum half-life.

Figure 2:. Functions of secreted IgM.

(1A). Marginal zone splenic B cells capture sIgM-antigen/complement C3 complexes and (B) migrates into the B cell follicle where it transfers the complexes onto CR1/2 expressed by follicular dendritic cells (FDCs), where (C) the FDC presents antigen to germinal cell B cells in support of T-dependent antibody production. (2) sIgM strongly supports IgG response development by additional but poorly understood processes. (3) Antigen opsonization by sIgM via complement C1q-mediated uptake by macrophages. This process can also be mediated by mannose-binding lectin (not shown). (4) Pathogen neutralization to blocking pathogen entry or inducing pathogen aggregations. Natural IgM is polyreactive and recognizes conserved antigens, such as phosphorylcholine (PC) present in the cell walls of Streptococcus pneumoniae as well as on dead or dying mammalian host cells. (5) sIgM can recruit complement components to initiate the classical pathway of complement activation, eventually leading to the formation of the Membrane Attack Complex (MAC) that can result in lysis of the pathogen. (6) Although the mechanisms are incompletely resolved, sIgM prevents autoimmune antibody formation through multiple mechanisms, including effecting central tolerance induction in the bone marrow and through the removal of DAMPS, such as dead and dying cell debris. (7) The absence of sIgM causes changes in V-gene usage encoding increased self-reactivity.

Figure 3:. Receptors that bind sIgM.

The polymeric Ig receptor can bind pentameric IgM as well as dimeric IgA via binding to the J-chain, resulting in transcytosis through epithelial cells located on mucosal surfaces and luminal excretion. Fc$\alpha /\mu$R: This receptor is expressed predominantly by macrophages and follicular dendritic cells, where it binds to IgA and IgM with moderate and high affinity, respectively, to mediate endocytosis of IgA/IgM-antigen complexes. Complement Receptors: Complement receptor 1 is the C3b/C4b receptor is expressed on a variety of immune cells, including B cells and follicular dendritic cells (FDC), where it anchors sIgM-antigen-C3 complexes onto FDCs. Complement receptor 2 binds to iC3b (inactive derivative of C3b), C3dg and/or C3b. This receptor is expressed on B cells as well as FDCs. Fc$\mu$R: The Fc$\mu$R is highly expressed on B cells and binds sIgM selectively, which is rapidly internalized. The functional consequences of FcμR/sIgM interaction remain to be fully resolved.