Secreted IgM: New tricks for an old molecule

Blandino, Rebecca; Baumgarth, Nicole

doi:10.1002/jlb.3ri0519-161r

Cited by 66 publications

(60 citation statements)

References 147 publications

(369 reference statements)

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“…Although each natural IgM monomer has relatively low affinity to antigens as it normally does not undergo somatic hypermutation and affinity maturation, the presence of multivalent antigen-binding sites in IgM pentamers or hexamers confers high avidity, which is pivotal in the capacity of IgM for agglutinating pathogens by binding to specific antigenic motifs [ 101 , 136 ]. IgM exerts its functions primarily by fixing complement C1q, activating complement-dependent cytotoxicity and facilitating IgG-mediated opsonization [ 137 ]. It also has been proposed that IgM regulates immunity and tolerance through its specific Fc receptor (FcµR) [ 138 ].…”

Section: Joining Chain (J Chain)mentioning

confidence: 99%

Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis

Hao

Wang

2021

IJMS

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Transcytosis of polymeric IgA and IgM from the basolateral surface to the apical side of the epithelium and subsequent secretion into mucosal fluids are mediated by the polymeric immunoglobulin receptor (pIgR). Secreted IgA and IgM have vital roles in mucosal immunity in response to pathogenic infections. Binding and recognition of polymeric IgA and IgM by pIgR require the joining chain (J chain), a small protein essential in the formation and stabilization of polymeric Ig structures. Recent studies have identified marginal zone B and B1 cell-specific protein (MZB1) as a novel regulator of polymeric IgA and IgM formation. MZB1 might facilitate IgA and IgM transcytosis by promoting the binding of J chain to Ig. In this review, we discuss the roles of pIgR in transcytosis of IgA and IgM, the roles of J chain in the formation of polymeric IgA and IgM and recognition by pIgR, and focus particularly on recent progress in understanding the roles of MZB1, a molecular chaperone protein.

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Section: Joining Chain (J Chain)mentioning

confidence: 99%

Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis

Hao

Wang

2021

IJMS

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“…, IgG, IgE, IgA) are expressed by various hematopoietic cell types, thereby functioning as central mediators coupling innate and adaptive immune responses ( 1 ). By contrast, FcR for IgM (FcµR), the newest member of the FcR family ( 2 ), is expressed by lymphocytes only: B, T, and NK cells in humans and only B cells in mice, although there are some conflicting data regarding FcµR expression by non-B cells in mice ( 2 – 13 ). By computational analysis of existing genomic sequence databases, the distribution of FCMR orthologues seems to be restricted to mammals ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of Amino Acid Residues in Human IgM Fc Receptor (FcµR) Critical for IgM Binding

et al. 2021

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Both non-immune “natural” and antigen-induced “immune” IgM are important for protection against infections and for regulation of immune responses to self-antigens. The roles of its Fc receptor (FcµR) in these IgM effector functions have begun to be explored. In the present study, by taking advantage of the difference in IgM-ligand binding of FcµRs of human (constitutive binding) and mouse (transient binding), we replaced non-conserved amino acid residues of human FcµR with mouse equivalents before establishment of cell lines stably expressing mutant or wild-type (WT) receptors. The resultant eight-different mutant FcµR-bearing cells were compared with WT receptor-bearing cells for cell-surface expression and IgM-binding by flow cytometric assessments using receptor-specific mAbs and IgM paraproteins as ligands. Three sites Asn66, Lys79-Arg83, and Asn109, which are likely in the CDR2, DE loop and CDR3 of the human FcµR Ig-like domain, respectively, were responsible for constitutive IgM binding. Intriguingly, substitution of Glu41 and Met42 in the presumed CDR1 with the corresponding mouse residues Gln and Leu, either single or more prominently in combination, enhanced both the receptor expression and IgM binding. A four-aa stretch of Lys24-Gly27 in the predicted A ß-strand of human FcµR appeared to be essential for maintenance of its proper receptor conformation on plasma membranes because of reduction of both receptor expression and IgM-binding potential when these were mutated. Results from a computational structural modeling analysis were consistent with these mutational data and identified a possible mode of binding of FcµR with IgM involving the loops including Asn66, Arg83 and Asn109 of FcµR interacting principally with the Cµ4 domain including Gln510 and to a lesser extent Cµ3 domain including Glu398, of human IgM. To our knowledge, this is the first experimental report describing the identification of amino acid residues of human FcµR critical for binding to IgM Fc.

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“…[45][46][47][48] What prevents auto-reactive antibodies from causing autoimmune disease? Thus, kidney and heart allografts in patients with high levels of natural IgM had better graft survival and lower incidence of acute rejection.…”

Section: S Pace and Time: A Fourth D Imen S I On Of B Cell Toler An Cementioning

confidence: 99%

“…Thus, kidney and heart allografts in patients with high levels of natural IgM had better graft survival and lower incidence of acute rejection. [45][46][47][48] What prevents auto-reactive antibodies from causing autoimmune disease? One might suppose the antibodies do not achieve the concentrations or the affinities of antibodies associated with autoimmune disease.…”

Section: S Pace and Time: A Fourth D Imen S I On Of B Cell Toler An Cementioning

confidence: 99%

The five dimensions of B cell tolerance

Platt

Barbosa

Cascalho

2019

Immunological Reviews

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B cell tolerance has been generally understood to be an acquired property of the immune system that governs antibody specificity in ways that avoid auto-toxicity.As useful as this understanding has proved, it fails to fully explain the existence of auto-reactive specificities in healthy individuals and contribution these may have to health. Mechanisms underlying B cell tolerance are considered to select a clonal repertoire that generates a collection of antibodies that do not bind self, ie tolerance operates more or less in three dimensions that largely spare autologous cells andantigens. Yet, most B lymphocytes in humans and probably in other vertebrates are auto-reactive and absence of these auto-reactive B cells is associated with disease.We suggest that auto-reactivity can be embodied by extending the concept of tolerance by two further dimensions, one of time and circumstance and one that allows healthy cells to actively resist injury. In this novel concept, macromolecular recognition by the B cell receptor leading to deletion, anergy, receptor editing or B cell activation is extended by taking account of the time of development of normal immune responses (4th dimension) and the accommodation (or tolerance) of normal cells to bound antibody, activation of complement, and interaction with inflammatory cells (fifth dimension). We discuss how these dimensions contribute to understanding B cell biology in health or disease. K E Y W O R D S

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Secreted IgM: New tricks for an old molecule

Cited by 66 publications

References 147 publications

Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis

Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis

Identification of Amino Acid Residues in Human IgM Fc Receptor (FcµR) Critical for IgM Binding

The five dimensions of B cell tolerance

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