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Anti-MAG neuropathy: From biology to clinical management

Open AccessPublished:September 28, 2021DOI:https://doi.org/10.1016/j.jneuroim.2021.577725

      Highlights

      • Discovery of antigenic targets: crucial step in understanding autoimmune neuropathies.
      • Antibodies against MAG characterize a demyelinating neuropathy.
      • B cells depleting therapies are main therapeutical mode of treatment.
      • New treatment modalities include inhibitors or antigen specific immunotherapy.

      Abstract

      The acquired chronic demyelinating neuropathies include a growing number of disease entities that have characteristic, often overlapping, clinical presentations, mediated by distinct immune mechanisms, and responding to different therapies. After the discovery in the early 1980s, that the myelin associated glycoprotein (MAG) is a target antigen in an autoimmune demyelinating neuropathy, assays to measure the presence of anti-MAG antibodies were used as the basis to diagnose the anti-MAG neuropathy. The route was open for describing the clinical characteristics of this new entity as a chronic distal large fiber sensorimotor neuropathy, for studying its pathogenesis and devising specific treatment strategies. The initial use of chemotherapeutic agents was replaced by the introduction in the late 1990s of rituximab, a monoclonal antibody against CD20+ B-cells. Since then, other anti-B cells agents have been introduced. Recently a novel antigen-specific immunotherapy neutralizing the anti-MAG antibodies with a carbohydrate-based ligand mimicking the natural HNK-1 glycoepitope has been described.

      Keywords

      1. Myelin structure and function

      The function of myelin is saltatory transmission of nerve impulse, leaping from one node of Ranvier to the next. The prevailing view since the discovery of this mechanism (
      • Huxley A.F.
      • Stämpfli R.
      Evidence for saltatory conduction in peripheral myelinated nerve fibres.
      ) has been that the role of myelin is to enable maximum conduction velocity and to reduce axonal energy consumption. Accordingly, myelin was considered a passive membrane and the fact that its composition was quite simple, consisting of mostly lipids, a few proteins and water was in line with its role as an insulator. However, as methods of myelin purification were available (
      • Norton W.T.
      • Poduslo S.E.
      Myelination in rat brain: method of myelin isolation.
      ) it became clear that the protein composition of myelin is not as simple as formerly thought. The era of myelin biology had begun, allowing the mapping of myelin constituents. The overall morphological structures of central nervous system (CNS) and peripheral nervous system (PNS) myelin are similar, even though they are formed by different cell types, oligodendrocytes, and Schwann cells. On the other hand, differences in protein composition in PNS and CNS myelin are especially important for determining the various pathologies that characterize genetic and acquired disorders of myelin (
      • Quarles R.H.
      Comparison of CNS and PNS myelin proteins in the pathology of myelin disorders.
      ). One important example is multiple sclerosis, which involves an immune attack on myelin and oligodendrocytes, but spares peripheral nerves. Myelin contains several glycoproteins, and Quarles (
      • Quarles R.H.
      • Everly J.L.
      • Brady R.O.
      Evidence for the close association of a glycoprotein with myelin in rat brain.
      ) described and characterized a glycoprotein in myelin that he called the myelin associated glycoprotein or MAG. It carries a carbohydrate epitope that is the target antigen for IgM monoclonal antibodies in patients with demyelinating neuropathy in association with gammopathy, as discussed later.
      Decades of theoretical and experimental work have defined the modern ultrastructural and molecular architecture of myelin (
      • Morell P.
      • Quarles R.H.
      Myelin formation, structure and biochemistry.
      ). Most of what we know about myelin ultrastructure is based on electron microscopy studies that illustrate its multilayered structure of alternating electron-dense and electron-light layers, the major dense line and the intraperiod line (
      • Robertson J.D.
      The ultrastructure of adult vertebrate peripheral myelinated nerve fibers in relation to myelinogenesis.
      ;
      • King R.
      Microscopic anatomy: normal structure.
      ). The major dense line represents the closely condensed cytoplasmic surfaces, whereas the intraperiod line consists of the tightly apposed outer membranes (Fig. 1). In the internodal region the myelin is compact, creating insulation that facilitates propagation of action potentials, while at the edge towards the node of Ranvier - the myelin sheath gap that allows saltatory conduction - the myelin becomes loose and builds up loops that constitute the paranodal region. The molecular anatomy of the nodal and paranodal regions in the peripheral nervous system has been described in considerable detail and this has helped unravel the pathogenesis of antibody mediated peripheral neuropathies, now often referred as nodopathies or paranodopathies of the peripheral nerve (
      • Uncini A.
      • Vallat J.M.
      Autoimmune nodo-paranodopathies of peripheral nerve: the concept is gaining ground.
      ). Myelin sheath not only facilitates the conduction velocity of nerve impulse but also confers protection and nutritional support to axons. Axons are dependent on Schwan cells, the myelin forming cell in the PNS for their metabolism and studies have demonstrated multiple signaling molecules responsible for Schwann cells axonal interaction (
      • Stadelmann C.
      • Timmler S.
      • Barrantes-Freer A.
      • Simons M.
      Myelin in the central nervous system: structure, function, and pathology.
      ;
      • Torii T.
      • Miyamoto Y.
      • Yamauchi J.
      Cellular signal-regulated schwann cell myelination and remyelination.
      ;
      • Cisterna B.A.
      • Arroyo P.
      • Puebla C.
      Role of connexin-based gap junction channels in communication of myelin sheath in schwann cells.
      ). Myelin should be viewed as a plastic structure, reliant on axonal glial interactions, further modulated, especially in the CNS, by activity dependent mechanisms (
      • Monje M.
      Myelin plasticity and nervous system function.
      ).
      Fig. 1
      Fig. 1Electron micrograph of myelin showing alternating dense (arrows) and doubled intermediate lines (arrowheads). A, normal myelin; B, widely spaced myelin as observed in anti-MAG neuropathy. Reproduced from King (
      • King R.
      Microscopic anatomy: normal structure.
      ).

      2. Myelin associated glycoprotein (MAG)

      2.1 Biochemistry, localization, and function

      MAG is a minor constituent of myelin, comprising less than1% of all myelin proteins in the CNS and PNS, respectively (
      • Trapp B.D.
      Myelin-associated glycoprotein. Location and potential functions.
      ). It was first detected in isolated rat CNS myelin by sensitive metabolic labeling experiments with radioactive fucose (
      • Quarles R.H.
      • Everly J.L.
      • Brady R.O.
      Evidence for the close association of a glycoprotein with myelin in rat brain.
      ;
      • Quarles R.H.
      • McIntyre L.J.
      • Pasnak C.F.
      Lectin-binding proteins in central-nervous-system myelin. Binding of glycoproteins in purified myelin to immobilized lectins.
      ). Subfractionation of myelin and myelin-related membranes demonstrated that MAG was enriched in membranous vesicles that were heavier than the lipid-rich fragments of multi-lamellar compact myelin indicating that MAG localization was distinct from compact myelin. This is the reason why Quarles named this glycoprotein “myelin-associated”.
      MAG is a 100 kDa transmembrane glycoprotein (Fig. 2). The detailed structure of MAG was revealed by cloning of rat MAG (
      • Arquint M.
      • Order J.
      • Chia L.S.
      • Down J.
      • Wilkinson D.
      • Bayley H.
      • Braun P.
      • Dunn R.
      Molecular cloning and primary structure of myelin-associated glycoprotein.
      ;
      • Salzer J.L.
      • Holmes W.P.
      • Colman D.R.
      The amino acid sequences of the myelin-associated glycoproteins: homology to the immunoglobulin gene superfamily.
      ) and later of human MAG (
      • Spagnol G.
      • Williams M.
      • Srinivasan J.
      • Golier J.
      • Bauer D.
      • Lebo R.V.
      • Latov N.
      Molecular cloning of human myelin-associated glycoprotein.
      ). The cloning of MAG showed that it contains five extracellular immunoglobulin (Ig)-like domains, a transmembrane domain, and a cytoplasmic domain that occurs in two developmentally regulated isoforms because of an alternative mRNA splicing. The presence of Ig-like domains defines MAG as a member of the Ig superfamily (
      • Quarles R.H.
      Myelin-associated glycoprotein (MAG): past, present and beyond.
      ). The large extracellular domain structure of MAG is ideally suited for interactions with different ligands and receptors (
      • Schachner M.
      • Bartsch U.
      Multiple functions of the myelin-associated glycoprotein MAG (siglec-4a) in formation and maintenance of myelin.
      ). Myelin-associated glycoprotein contains about 30% by weight carbohydrate, consisting of heterogeneous N-linked oligosaccharides at eight extracellular sites (
      • Quarles R.
      • Colman D.
      • Salzer J.
      • Trapp B.
      Myelin-associated glycoprotein: structure-function relationships and involvement in neurological diseases.
      ;
      • Burger D.
      • Pidoux L.
      • Steck A.J.
      Identification of the glycosylated sequons of human myelin-associated glycoprotein.
      ;
      • Georgiou J.
      • Tropak M.P.
      • Order J.C.
      Myelin-associated glycoprotein gene.
      ).
      Fig. 2
      Fig. 2The structure of MAG is shown in yellow with five extracellular immunoglobulin-like domains (circles), eight N-linked oligosaccharides (triangles), a single transmembrane domain, and a cytoplasmic domain. The extracellular domain of MAG mediates axon-glia interactions by binding to not yet well-defined components, most likely neuronal glycolipids (green). MAG plays a role in neurofilament phosphorylation signaling, by activation of cyclin dependent kinase 5 (cdk5) and the extracellular ERK1/2 protein kinase pathway, resulting in greater expression of phosphorylated neurofilaments leading to increased axonal caliber (
      • Lunn M.P.
      • Crawford T.O.
      • Hughes R.A.
      • Griffin J.W.
      • Sheikh K.A.
      Anti-myelin-associated glycoprotein antibodies alter neurofilament spacing.
      ). Adapted from Quarles (
      • Quarles R.H.
      Myelin-associated glycoprotein (MAG): past, present and beyond.
      ). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
      Many studies have provided compelling evidence confirming the localization of MAG in discrete regions of the myelin sheath. MAG is not found in compact myelin, but in the periaxonal space between myelinating cells and axons (
      • Trapp B.D.
      Myelin-associated glycoprotein. Location and potential functions.
      ). Its expression in the innermost myelin membrane wrap, directly apposed to the axon surface has suggested that MAG is involved in signalization between Schwan cells and axons and enhances long-term axon-myelin stability and attachment (
      • Quarles R.H.
      Myelin-associated glycoprotein (MAG): past, present and beyond.
      ;
      • Kinter J.
      • Lazzati T.
      • Schmid D.
      • Zeis T.
      • Erne B.
      • Lützelschwab R.
      • Steck A.J.
      • Pareyson D.
      • Peles E.
      • Schaeren-Wiemers N.
      An essential role of MAG in mediating axon-myelin attachment in Charcot-Marie-Tooth 1A disease.
      ).
      An important post-translational modification of MAG is phosphorylation by different protein kinases (
      • Afar D.E.
      • Salzer J.L.
      • Order J.
      • Braun P.E.
      • Bell J.C.
      Differential phosphorylation of myelin-associated glycoprotein isoforms in cell culture.
      ). MAG is known to signal to the axon, locally influencing the phosphorylation of axonal neurofilaments immediately beneath MAG-bearing membranes. MAG participates in defining the distribution of axon molecules at nodes of Ranvier and in MAG−/−mice the proper distribution of these molecules is delayed, with clear overlap of the paranodal and juxtaparanodal regions (
      • Marcus J.
      • Dupree J.L.
      • Popko B.
      Myelin-associated glycoprotein and myelin galactolipids stabilize developing axo-glial interactions.
      ;
      • Poliak S.
      • Peles E.
      The local differentiation of myelinated axons at nodes of Ranvier.
      ;
      • Schnaar R.L.
      • Lopez P.H.
      Myelin-associated glycoprotein and its axonal receptors.
      ). In this respect it has been shown, both in vitro and in vivo, that MAG has an axonal protective effect (
      • Trapp B.D.
      • Andrews S.B.
      • Wong A.
      • O'Connell M.
      • Griffin J.W.
      Co-localization of the myelin-associated glycoprotein and the microfilament components, F-actin and spectrin, in Schwann cells of myelinated nerve fibres.
      ;
      • Nguyen T.
      • Mehta N.R.
      • Conant K.
      • Kim K.J.
      • Jones M.
      • Calabresi P.A.
      • Melli G.
      • Hoke A.
      • Schnaar R.L.
      • Ming G.L.
      • Song H.
      • Keswani S.C.
      • Griffin J.W.
      Axonal protective effects of the myelin-associated glycoprotein.
      ). MAG−/−mice develop axonal loss in the CNS and PNS (
      • Yin X.
      • Crawford T.O.
      • Griffin J.W.
      • Tu Ph.
      • Lee V.M.
      • Li C.
      • Roder J.
      • Trapp B.D.
      Myelin-associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons.
      ;
      • Pan B.
      • Fromholt S.E.
      • Hess E.J.
      • Crawford T.O.
      • Griffin J.W.
      • Sheikh K.A.
      • Schnaar R.L.
      Myelin-associated glycoprotein and complementary axonal ligands, gangliosides, mediate axon stability in the CNS and PNS: neuropathology and behavioral deficits in single- and double-null mice.
      ), suggesting that MAG is important in axonal maintenance. An interesting finding is that in MAG-deficient mice not only myelin but also axons degenerate (
      • Fruttiger M.
      • Montag D.
      • Schachner M.
      • Martini R.
      Crucial role for the myelin-associated glycoprotein in the maintenance of axon-myelin integrity.
      ). Similar findings have been reported in patients affected with a loss of function mutation in MAG (
      • Lossos A.
      • Elazar N.
      • Lerer I.
      • Schueler-Furman O.
      • Fellig Y.
      • Glick B.
      • Zimmerman B.E.
      • Azulay H.
      • Dotan S.
      • Goldberg S.
      • Gomori J.M.
      • Ponger P.
      • Newman J.P.
      • Marreed H.
      • Steck A.J.
      • Schaeren-Wiemers N.
      • Mor N.
      • Harel M.
      • Geiger T.
      • Eshed-Eisenbach Y.
      • Meiner V.
      • Peles E.
      Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder.
      ). On the other hand, there is evidence that MAG has the ability to inhibit axonal elongation during regeneration. MAG is a member of the sialic acid-binding immunoglobulin-like lectins family. MAG inhibition of axon outgrowth in some neurons is reversed by treatment with sialidase, an enzyme that hydrolyzes sialic acids and eliminates MAG–sialoglycan binding (
      • Mountney A.
      • Zahner M.R.
      • Lorenzini I.
      • Oudega M.
      • Schramm L.P.
      • Schnaar R.L.
      Sialidase enhances recovery from spinal cord contusion injury.
      ). While the evidence for an inhibitory effect of MAG on axonal regeneration is mostly limited to in vitro studies (
      • Niederöst B.
      • Oertle T.
      • Fritsche J.
      • McKinney R.A.
      • Bandtlow C.E.
      Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1.
      ), studies in human demyelinating disorders, both in CNS and PNS, are consistent with axonal protective effects of MAG (
      • Trapp B.D.
      Myelin-associated glycoprotein. Location and potential functions.
      ;
      • Scherer S.
      Axonal pathology in demyelinating diseases.
      ;
      • Lunn M.P.
      • Crawford T.O.
      • Hughes R.A.
      • Griffin J.W.
      • Sheikh K.A.
      Anti-myelin-associated glycoprotein antibodies alter neurofilament spacing.
      ).
      A particularly interesting development for the understanding of immune mediated neuropathies was the characterization of the complex carbohydrate on MAG including the HNK-1 epitope (
      • McGarry R.C.
      • Helfand S.L.
      • Quarles R.H.
      • Order J.C.
      Recognition of myelin-associated glycoprotein by the monoclonal antibody HNK-1.
      ;
      • Poltorak M.
      • Sadoul R.
      • Keilhauer G.
      • Landa C.
      • Fahrig T.
      • Schachner M.
      Myelin-associated glycoprotein, a member of the L2/HNK-1 family of neural cell adhesion molecules, is involved in neuron-oligodendrocyte and oligodendrocyte-oligodendrocyte interaction.
      ). The antigenic HNK-1 epitope is a sulfated trisaccharide as shown in Fig. 3 (
      • Herrendorff R.
      • Hänggi P.
      • Pfister H.
      • Yang F.
      • Demeestere D.
      • Hunziker F.
      • Frey S.
      • Schaeren-Wiemers N.
      • Steck A.J.
      • Ernst B.
      Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy.
      ). This carbohydrate epitope is also expressed on glycoproteins and glycolipids in the nervous system, such as P0, PMP22, as well as SGPG and SGLPG (
      • Hamada Y.
      • Hirano M.
      • Kuwahara M.
      • Samukawa M.
      • Takada K.
      • Morise J.
      • Yabuno K.
      • Oka S.
      • Kusunoki S.
      Binding specificity of anti-HNK-1 IgM M-protein in anti-MAG neuropathy: possible clinical relevance.
      ). The HNK-1 epitope defines an antigen shared between the immune system and the nervous system since it is expressed on a subset of human lymphocytes, including natural killer cells (
      • McGarry R.C.
      • Helfand S.L.
      • Quarles R.H.
      • Order J.C.
      Recognition of myelin-associated glycoprotein by the monoclonal antibody HNK-1.
      ). The expression of the HNK-1 carbohydrate epitope on multiple glycosylation sites of MAG account for its high immunoreactivity. Because MAG is also localized in paranodal loops as well as Schmidt-Lanterman incisures and thus exposed to the extracellular space it easily accessible to autoantibodies (
      • Querol L.
      • Devaux J.
      • Rojas-Garcia R.
      • Illa I.
      Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications.
      ). Indeed, MAG was the first identified target for a monoclonal IgM found in patients with demyelinating neuropathy and gammopathy (
      • Braun P.E.
      • Frail D.E.
      • Latov N.
      Myelin-associated glycoprotein is the antigen for a monoclonal IgM in polyneuropathy.
      ;
      • Steck A.J.
      Immunological aspects of demyelination.
      ;
      • Steck A.J.
      • Murray N.
      • Meier C.
      • Page N.
      • Perruisseau G.
      Demyelinating neuropathy and monoclonal IgM antibody to myelin-associated glycoprotein.
      ).
      Fig. 3
      Fig. 3MAG and the HNK-1 carbohydrate epitope. The expression of the HNK-1 carbohydrate epitope on multiple glycosylation sites of MAG (up to eight HNK-1 epitopes) account for its high immunoreactivity. The natural HNK-1 glycoepitope is a trisaccharide with the characteristic sulfated glucuronic acid, a residue critically involved in the recognition of MAG by human anti-MAG antibodies. Adapted from Herrendorff (
      • Herrendorff R.
      • Hänggi P.
      • Pfister H.
      • Yang F.
      • Demeestere D.
      • Hunziker F.
      • Frey S.
      • Schaeren-Wiemers N.
      • Steck A.J.
      • Ernst B.
      Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy.
      ).

      3. Nodes, paranodes and neuropathy

      The nodes of Ranvier are composed of three distinct regions, that haven been characterized at the ultrastructural and molecular level (
      • Thaxton C.
      • Bhat M.A.
      Myelination and regional domain differentiation of the axon.
      ;
      • Stathopoulos P.
      • Alexopoulos H.
      • Dalakas M.C.
      Autoimmune antigenic targets at the node of Ranvier in demyelinating disorders.
      (Fig. 4). The node itself, where sodium channels accumulate; the adjacent paranode, marked by the presence of the myelin loops, and the juxtaparanode, characterized by potassium channels. The adhesion molecules neurofascin 186 (NF186), contactin1 (Cntn1), NF155, contactin-associated protein 1 (Caspr1), Cntn2, Caspr2 and MAG mediate axoglial attachment. Gap junction proteins such as connexins (Cx) and tight junction proteins such as claudins maintain the myelin loops, while extracellular matrix constituents such as gliomedin stabilize the structure of the nodal area. It is therefore not unexpected that mutations in these proteins leads to changes in the nodal architecture resulting with functional impairments and a polyneuropathy phenotype. CMTX1 is caused by missense mutations in the Cx 32 gene (
      • Li J.
      Inherited neuropathies.
      ). Cx 32 is localized in the uncompacted myelin of the paranodal loops and Schmidt-Lanterman incisures and functions as a gap junction protein. CMTX patients show clinical signs resembling those of an acquired demyelinating neuropathy. On the other hand, antibodies against nodal or paranodal antigens are found in chronic acquired demyelinating neuropathies. A number of antibodies such as anti-NF 186, anti- NF155, anti-CNTN1, and anti- CASPR1, are found in a subset of patients with a clinical phenotype mimicking chronic inflammatory demyelinating polyneuropathy (CIDP) (
      • Querol L.
      • Devaux J.
      • Rojas-Garcia R.
      • Illa I.
      Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications.
      ;
      • Ogata H.
      Anti-nodal/paranodal antibodies in human demyelinating disorders.
      ). As will be discussed later, anti-MAG antibodies bind to the paranodal region, impairing saltatory conduction (
      • Garg N.
      • Park S.B.
      • Howells J.
      • Noto Y.I.
      • Vucic S.
      • Yiannikas C.
      • Tomlinson S.E.
      • Huynh W.
      • Simon N.G.
      • Mathey E.K.
      • Spies J.
      • Pollard J.D.
      • Krishnan A.V.
      • Kiernan M.C.
      Anti-MAG neuropathy: role of IgM antibodies, the paranodal junction and juxtaparanodal potassium channels.
      ) and inducing nodal and paranodal molecular alterations that occur in early stages of the disease, preceding the morphological changes associated with demyelination in anti-MAG neuropathy (
      • Kawagashira Y.
      • Koike H.
      • Takahashi M.
      • Ohyama K.
      • Iijima M.
      • Katsuno M.
      • Niwa J.I.
      • Doyu M.
      • Sobue G.
      Aberrant expression of nodal and paranodal molecules in neuropathy associated with IgM monoclonal gammopathy with anti-myelin-associated glycoprotein antibodies.
      ).
      Fig. 4
      Fig. 4Schematic view of molecular components in the node, paranode and juxtaparanode of a peripheral myelinated fiber, including those targeted by autoantibodies in immune mediated neuropathies as explained in the text. Ion channels mediate action potential propagation. Glial adhesion molecules are linked to axonal molecules forming attachments. Gliomedin is expressed by myelinating Schwann cells and is important for long term maintenance of Na + channels at nodes of Ranvier. Abbreviations: KV, voltage gated K+ channel; NAV, voltage gated Na + channel; CNTN, contactin; CASPR, contactin associated protein; MAG, myelin associated glycoprotein; NF, neurofascin; GM1, monosialotetrahexosylganglioside. Adapted from Stathopoulos (
      • Stathopoulos P.
      • Alexopoulos H.
      • Dalakas M.C.
      Autoimmune antigenic targets at the node of Ranvier in demyelinating disorders.
      ) and
      • Querol L.
      • Devaux J.
      • Rojas-Garcia R.
      • Illa I.
      Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications.
      .

      4. Paraproteinemic neuropathies

      The association of peripheral polyneuropathy and monoclonal gammopathy is well known and represents in adults one of the most frequent cause of acquired polyneuropathies. The term paraproteinemic neuropathy describes a heterogeneous group of neuropathies characterized by the presence of homogeneous immunoglobulin in the serum or M-protein. An abnormal clonal proliferation of B-lymphocytes or plasma cells, which may or may not occur in the context of a hematologic malignancy, produces the monoclonal immunoglobulin in excess. Historically neuropathies associated with myeloma and Waldenström Macroglobulinemia (WM) were first described by Victor (
      • Victor M.
      • Banker B.Q.
      • Adams R.D.
      The neuropathy of multiple myeloma. J.
      ) and Garcin (
      • Garcin R.
      • Mallarmé J.
      • Rondot P.
      Névrites dysglobulinémiques.
      ). Of interest is the finding that often the neuropathy precedes the discovery of the hematological disease by several years. Due to the substantial prevalence of neuropathies associated with monoclonal proteins in the absence of a malignancy, the term benign monoclonal gammopathy was coined, but eventually Kyle (
      • Kyle R.A.
      Monoclonal gammopathy of undetermined significance. Natural history in 241 cases.
      ) suggested that monoclonal gammopathy of undetermined significance or MGUS was a better term because it is a premalignant disorder with a 0.5–1.5% per year risk of progression to multiple myeloma (MM) or other related hematological malignancies (
      • Kyle R.A.
      • Durie B.G.
      • Rajkumar S.V.
      • Landgren O.
      • Blade J.
      • Merlini G.
      • Kröger N.
      • Einsele H.
      • Vesole D.H.
      • Dimopoulos M.
      • San Miguel J.
      • Avet-Loiseau H.
      • Hajek R.
      • Chen W.M.
      • Anderson K.C.
      • Ludwig H.
      • Sonneveld P.
      • Pavlovsky S.
      • Palumbo A.
      • Richardson P.G.
      • Barlogie B.
      • Greipp P.
      • Vescio R.
      • Turesson I.
      • Westin J.
      • Boccadoro M.
      • International Myeloma Working Group
      Monoclonal gammopathyy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management.
      ). The prevalence of neuropathy among MGUS patients varies considerably from about 5 to 17% in the literature, depending on patient selection and diagnostic procedures (
      • Kelly Jr., J.J.
      • Kyle R.A.
      • O’Brien P.C.
      • Dyck P.J.
      Prevalence of monoclonal protein in peripheral neuropathy.
      ;
      • Nobile-Orazio E.
      Neuropathy and monoclonal gammopathy.
      ;
      • Steiner N.
      • Schwärzler A.
      • Göbel G.
      • Löscher W.
      • Wanschitz J.
      • Gunsilius E.
      Are neurological complications of monoclonal gammopathy of undetermined significance underestimated?.
      ). The association of a neuropathy in patients with monoclonal gammopathy differs according to the isotypes and is highest for IgM isotype, with a neuropathy in one-third of patients (
      • Nobile-Orazio E.
      • Barbieri S.
      • Baldini L.
      • Marmiroli P.
      • Carpo M.
      • Premoselli S.
      • Manfredini E.
      • Scarlato G.
      Peripheral neuropathy in monoclonal gammopathy of undetermined significance: prevalence and immunopathogenetic studies.
      ). MGUS associated neuropathies are heterogeneous with respect to the clinical presentation and the underlying pathophysiology. The three major forms of neuropathy in paraproteinemic disorders are axonal sensory-motor neuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP), and distal acquired demyelinating symmetric (DADS) polyneuropathy. While with IgG and IgA MGUS the link between the serum paraprotein and axonal nerve damage remains elusive, in the demyelinating entities CIDP and DADS a causal relationship with the monoclonal gammopathy could be established. Interestingly a subgroup of patients with IgM MGUS and demyelinating neuropathy, reduced conduction velocities and deposits of IgM in nerve (
      • Chazot G.
      • Berger B.
      • Carrier H.
      • Barbaret C.
      • Bady B.
      • Dumas R.
      • Creyssel R.
      • Schott B.
      Manifestations neurologiques des gammapathies monoclonales. Formes neurologiques pures. Etude en immunofluorescence [Neurological manifestations in monoclonal gammapathies. Pure neurological manifestations. Immunofluorescence study].
      ) and anti-peripheral nerve myelin antibodies in their serum (
      • Latov N.
      • Sherman W.H.
      • Nemni R.
      • Galassi G.
      • Shyong J.S.
      • Penn A.S.
      • Chess L.
      • Olarte M.R.
      • Rowland L.P.
      • Osserman E.F.
      Plasma-cell dyscrasia and peripheral neuropathy with a monoclonal antibody to peripheral-nerve myelin.
      ;
      • Latov N.
      • Braun P.E.
      • Gross R.B.
      • Sherman W.H.
      • Penn A.S.
      • Chess L.
      Plasma cell dyscrasia and peripheral neuropathy: identification of the myelin antigens that react with human paraproteins.
      ;
      • Smith I.S.
      • Kahn S.N.
      • Lacey B.W.
      • King R.H.
      • Eames R.A.
      • Whybrew D.J.
      • Thomas P.K.
      Chronic demyelinating neuropathy associated with benign IgM paraproteinaemia.
      ) were described. Eventually Latov and coworkers (
      • Braun P.E.
      • Frail D.E.
      • Latov N.
      Myelin-associated glycoprotein is the antigen for a monoclonal IgM in polyneuropathy.
      ) and Steck (
      • Steck A.J.
      Immunological aspects of demyelination.
      ;
      • Steck A.J.
      • Murray N.
      • Meier C.
      • Page N.
      • Perruisseau G.
      Demyelinating neuropathy and monoclonal IgM antibody to myelin-associated glycoprotein.
      ) demonstrated that the serum IgM M- protein from patients with a demyelinating neuropathy reacted with a nerve antigen that was characterized as the myelin associated glycoprotein (MAG). These studies lead to a flurry of confirmatory reports and established the anti-MAG neuropathy as the most common paraproteinemic neuropathy. The term anti-MAG IgM paraproteinemic demyelinating peripheral neuropathy (PDPN) is sometimes used.

      5. Anti-MAG neuropathy

      5.1 Clinical presentation and course

      The majority of patients presents with a homogeneous phenotype characterized by a chronic, slowly progressive large-fiber sensory- motor polyneuropathy, usually affecting initially the lower extremities. Sensory ataxia with gait imbalance is frequently observed, and some patients develop tremor in the fingers and hands increased by action. These patients display some distinct characteristics (
      • Melmed C.
      • Frail D.
      • Duncan I.
      • Braun P.
      • Danoff D.
      • Finlayson M.
      • Stewart J.
      Peripheral neuropathy with IgM kappa monoclonal immunoglobulin directed against myelin-associated glycoprotein.
      ;
      • Hafler D.A.
      • Johnson D.
      • Kelly J.J.
      • Panitch H.
      • Kyle R.
      • Weiner H.L.
      Monoclonal gammopathy and neuropathy: myelin-associated glycoprotein reactivity and clinical characteristics.
      ;
      • Steck A.J.
      • Murray N.
      • Dellagi K.
      • Brouet J.C.
      • Seligmann M.
      Peripheral neuropathy associated with monoclonal IgM autoantibody.
      ). The disease affects elderly males predominantly, and the presenting symptom is usually the neuropathy. Neurological signs appear insidiously, spare the cranial nerves, and worsen slowly over one or two decades. In advanced cases, signs of complete denervation of muscles of the hands and feet are observed, with marked muscle weakness and wasting and severe ataxia; intention tremor is typical. Pain is a prominent symptom, often characterized by paresthesia and dysesthesia as well as cramps (
      • Rajabally Y.A.
      • Delmont E.
      • Hiew F.L.
      • Aubé-Nathier A.C.
      • Grapperon A.M.
      • Cassereau J.
      • Attarian S.
      Prevalence, correlates and impact of pain and cramps in anti-MAG neuropathy: a multicentre European study.
      ).
      According to the largest study of 202 anti-MAG neuropathy patients (
      • Svahn J.
      • Petiot P.
      • Antoine J.C.
      • Vial C.
      • Delmont E.
      • Viala K.
      • Steck A.J.
      • Magot A.
      • Cauquil C.
      • Zarea A.
      • Echaniz-Laguna A.
      • Iancu Ferfoglia R.
      • Gueguen A.
      • Magy L.
      • Léger J.M.
      • Kuntzer T.
      • Ferraud K.
      • Lacour A.
      • Camdessanché J.P.
      Francophone anti-MAG cohort Group. Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features.
      ), 83% present with the classical DADS phenotype. Of these patients, 30% have a sensory ataxic distal neuropathy, 18% a sensory ataxic distal neuropathy with tremor, 31% a sensory ataxic distal neuropathy with progressive distal motor deficit and 19% a non-ataxic sensory or sensory motor neuropathy, often with few symptoms. An atypical clinical phenotype was found in 17% of the patients. Of these patients, 65% present with a CIDP phenotype, while 29% have an acute or asymmetric CIDP phenotype. Similar findings are reported by Magy (
      • Magy L.
      • Kaboré R.
      • Mathis S.
      • Lebeau P.
      • Ghorab K.
      • Caudie C.
      • Vallat J.M.
      Heterogeneity of polyneuropathy associated with anti-MAG antibodies.
      ), with 60% of the patients presenting with a DADS like phenotype.
      Although in some cases the disease progresses slowly, the majority of patients experience development of significant disability over time. Notermans (
      • Notermans N.C.
      • Wokke J.H.
      • Lokhorst H.M.
      • Franssen H.
      • van der Graaf Y.
      • Jennekens F.G.
      Polyneuropathy associated with monoclonal gammopathy of undetermined significance. A prospective study of the prognostic value of clinical and laboratory abnormalities.
      ) reports a disability rate of 22% after 5–10 years. Nobile-Orazio (
      • Nobile-Orazio E.
      • Meucci N.
      • Baldini L.
      • Di Troia A.
      • Scarlato G.
      Long-term prognosis of neuropathy associated with anti-MAG IgM M-proteins and its relationship to immune therapies.
      ) details disability rates of 16% at 5 years, 24% at 10 years and 50% at 15 years. A higher age at onset has been found to be associated with a higher risk of disability, though it is difficult to determine whether this can be attributed to aging itself or to a different course of the neuropathy (
      • Niermeijer J.M.
      • Fischer K.
      • Eurelings M.
      • Franssen H.
      • Wokke J.H.
      • Notermans N.C.
      Prognosis of polyneuropathy due to IgM monoclonal gammopathy: a prospective cohort study.
      ;
      • Galassi G.
      • Tondelli M.
      • Ariatti A.
      • Benuzzi F.
      • Nichelli P.
      • Valzania F.
      Long-term disability and prognostic factors in polyneuropathy associated with anti-myelin-associated glycoprotein (MAG) antibodies.
      ).

      5.2 Anti-MAG antibody tests

      Diagnosis of the anti-MAG neuropathy is based on detecting the presence of anti-MAG antibodies. The antigenic epitope of MAG resides in the carbohydrate component of the molecule because after deglycosylation of MAG the IgM reactivity is lost (
      • Shy M.E.
      • Vietorisz T.
      • Nobile-Orazio E.
      • Latov N.
      Specificity of human IgM M-proteins that bind to myelin-associated glycoprotein: peptide mapping, deglycosylation, and competitive binding studies.
      ). As described previously (Fig. 3) the reactive determinant is a sulfated trisaccharide (
      • Voshol H.
      • van Zuylen C.W.
      • Orberger G.
      • Vliegenthart J.F.
      • Schachner M.
      Structure of the HNK-1 carbohydrate epitope on bovine peripheral myelin glycoprotein P0.
      ;
      • Quarles R.H.
      Myelin-associated glycoprotein (MAG): past, present and beyond.
      ;
      • Herrendorff R.
      • Hänggi P.
      • Pfister H.
      • Yang F.
      • Demeestere D.
      • Hunziker F.
      • Frey S.
      • Schaeren-Wiemers N.
      • Steck A.J.
      • Ernst B.
      Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy.
      ), also called the HNK-1 epitope because it reacts with the mouse monoclonal antibody HNK-1(
      • McGarry R.C.
      • Helfand S.L.
      • Quarles R.H.
      • Order J.C.
      Recognition of myelin-associated glycoprotein by the monoclonal antibody HNK-1.
      ).
      Anti-MAG antibodies can be readily detected in a patient's sera using various types of assays, but mainly an ELISA using human brain purified MAG has been shown to be most effective (
      • Caudie C.
      • Kaygisiz F.
      • Jaquet P.
      • Petiot P.
      • Gonnaud P.M.
      • Antoine J.C.
      • Vial C.
      Les autoanticorps IgM anti-MAG par Elisa Bühlmann: apport diagnostique dans 117 neuropathies périphériques auto-immunes associées à une IgM monoclonale à activité anti-SGPG/SGLPG [Diagnostic value of autoantibodies to MAG by ELISA Bühlmann in 117 immune-mediated peripheral neuropathies associated with monoclonal IgM to SGPG/SGLPG].
      ;
      • Kuijf M.L.
      • Eurelings M.
      • Tio-Gillen A.P.
      • van Doorn P.A.
      • van den Berg L.H.
      • Hooijkaas H.
      • Stork J.
      • Notermans N.C.
      • Jacobs B.C.
      Detection of anti-MAG antibodies in polyneuropathy associated with IgM monoclonal gammopathy.
      ). Initially serum anti-MAG antibodies were determined by the Western blot method using purified myelin or purified MAG as antigen (
      • Braun P.E.
      • Frail D.E.
      • Latov N.
      Myelin-associated glycoprotein is the antigen for a monoclonal IgM in polyneuropathy.
      ;
      • Steck A.J.
      • Murray N.
      • Meier C.
      • Page N.
      • Perruisseau G.
      Demyelinating neuropathy and monoclonal IgM antibody to myelin-associated glycoprotein.
      ). This technique allows to verify that the antibodies are directed to the typical 100-kd MAG protein and not to a contaminant in the purified myelin fraction. Because anti-MAG–reacting sera also recognize the SGPG glycolipid, an assay using SGPG as antigen instead of purified human MAG has been used (
      • Dalakas M.C.
      Pathogenesis and treatment of anti-MAG neuropathy.
      ). It is preferable, however, to use MAG rather than SGPG as the target antigen because the IgM monoclonal anti-MAG antibodies bind to MAG 10 to 100 times more strongly than to SGPG antigen, so low-affinity anti-MAG antibodies can be missed if SGPG is used as the antigen in the assay (
      • Dalakas M.C.
      Autoimmune peripheral neuropathies.
      ). A study in a large number of samples has shown that ELISA testing for MAG is more sensitive than Western blotting (some sera that were negative on Western blotting were ELISA-positive), and it is the easiest and most preferable assay to use (
      • Kuijf M.L.
      • Eurelings M.
      • Tio-Gillen A.P.
      • van Doorn P.A.
      • van den Berg L.H.
      • Hooijkaas H.
      • Stork J.
      • Notermans N.C.
      • Jacobs B.C.
      Detection of anti-MAG antibodies in polyneuropathy associated with IgM monoclonal gammopathy.
      ).
      While most studies shows that the ELISA can be used as a sensitive and reliable screening method for determining anti-MAG antibodies, there has been debate concerning the ideal cut-off value for positivity of the anti-MAG autoantibodies ELISA from Buhlmann Diagnostics (
      • Svahn J.
      • Petiot P.
      • Antoine J.C.
      • Vial C.
      • Delmont E.
      • Viala K.
      • Steck A.J.
      • Magot A.
      • Cauquil C.
      • Zarea A.
      • Echaniz-Laguna A.
      • Iancu Ferfoglia R.
      • Gueguen A.
      • Magy L.
      • Léger J.M.
      • Kuntzer T.
      • Ferraud K.
      • Lacour A.
      • Camdessanché J.P.
      Francophone anti-MAG cohort Group. Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features.
      ;
      • Liberatore G.
      • Giannotta C.
      • Sajeev B.P.
      • Morenghi E.
      • Terenghi F.
      • Gallia F.
      • Doneddu P.E.
      • Manganelli F.
      • Cocito D.
      • Filosto M.
      • Antonini G.
      • Cosentino G.
      • Marfia G.A.
      • Clerici A.M.
      • Lauria G.
      • Rosso T.
      • Cavaletti G.
      • Nobile-Orazio E.
      Sensitivity and specificity of a commercial ELISA test for anti-MAG antibodies in patients with neuropathy.
      ). Results are expressed in Buhlmann titer units (BTU) and the cut-off of positivity established by the manufacturer is 1000 BTU. While this value is an optimal cut-off for sensitivity, there is a grey zone with false positive in the low titer range. It therefore important to perform a careful clinical as well as electrophysiological assessment in patients with low titers to differentiate CIDP from anti-MAG neuropathy.
      Because sera positive for anti-MAG antibodies recognize the HNK-1 sulfated trisaccharide epitope, a new ELISA assay using this synthetic carbohydrate moiety has been developed. The diagnostic accuracy of this test has been evaluated in a large cohort of anti-MAG neuropathy patients as well as subjects with other neuropathies (
      • Delmont E.
      • Attarian S.
      • Antoine J.C.
      • Paul S.
      • Camdessanché J.P.
      • Grapperon A.M.
      • Brodovich A.
      • Boucraut J.
      Relevance of anti-HNK1 antibodies in the management of anti-MAG neuropathies.
      ). This study showed that the anti-HNK1 ELISA assay had a high sensitivity (98%) and specificity (99%) in the diagnosis of anti-MAG neuropathy. In addition, anti-HNK1 titers were corelated to the disease severity, suggesting that this test could be used for the monitoring of patients or as secondary outcome measure in clinical trials, though these results need to be confirmed.
      Anti-MAG antibodies are found in more than 70% of patients with a typical IgM monoclonal gammopathy–related demyelinating polyneuropathy (
      • Kuijf M.L.
      • Eurelings M.
      • Tio-Gillen A.P.
      • van Doorn P.A.
      • van den Berg L.H.
      • Hooijkaas H.
      • Stork J.
      • Notermans N.C.
      • Jacobs B.C.
      Detection of anti-MAG antibodies in polyneuropathy associated with IgM monoclonal gammopathy.
      ). As anti-MAG antibodies are usually found in association with IgM monoclonal gammopathy, in clinical practice an anti-MAG antibody test is performed in patients with detectable IgM monoclonal gammopathy. Few cases of anti-MAG neuropathy lacking IgM-monoclonal gammopathy have been described (
      • Nobile-Orazio E.
      • Latov N.
      • Hays A.P.
      • Takatsu M.
      • Abrams G.M.
      • Sherman W.H.
      • Miller J.R.
      • Messito M.J.
      • Saito T.
      • Tahmoush A.
      • Lovelace R.E.
      • Rowland L.P.
      Neuropathy and anti-MAG antibodies without detectable serum M-protein.
      ;
      • Gabriel J.M.
      • Erne B.
      • Bernasconi L.
      • Tosi C.
      • Probst A.
      • Landmann L.
      • Steck A.J.
      Confocal microscopic localization of anti-myelin-associated glycoprotein autoantibodies in a patient with peripheral neuropathy initially lacking a detectable IgM gammopathy.
      ;
      • Talamo G.
      • Mir M.A.
      • Pandey M.K.
      • Sivik J.K.
      • Raheja D.
      IgM MGUS associated with anti-MAG neuropathy: a single institution experience.
      ;
      • Pascual-Goñi E.
      • Martín-Aguilar L.
      • Lleixà C.
      • Martínez-Martínez L.
      • Simón-Talero M.J.
      • Díaz-Manera J.
      • Cortés-Vicente E.
      • Rojas-García R.
      • Moga E.
      • Juárez C.
      • Illa I.
      • Querol L.
      Clinical and laboratory features of anti-MAG neuropathy without monoclonal gammopathy.
      ). In this respect the case reported by Gabriel (
      • Gabriel J.M.
      • Erne B.
      • Bernasconi L.
      • Tosi C.
      • Probst A.
      • Landmann L.
      • Steck A.J.
      Confocal microscopic localization of anti-myelin-associated glycoprotein autoantibodies in a patient with peripheral neuropathy initially lacking a detectable IgM gammopathy.
      ) is of interest. It was a patient with a chronic progressive sensory-motor demyelinating neuropathy with positive anti-MAG antibodies in whom deposition of monoclonal anti-MAG IgM was demonstrated in myelinated fibers in nerve biopsy before the appearance of a gammopathy in serum. Eventually an IgM monoclonal protein in the serum was disclosed after 2 years follow-up. These results support the findings that deposition of a monoclonal anti-MAG IgM may occur in the nerve before the appearance of gammopathy in serum. Given these observations, it is suggested to test anti-MAG antibodies in patients with distal chronic sensory-motor demyelinating neuropathy, regardless of the detection of IgM monoclonal gammopathy. Discussion about best methodology to accurately diagnose anti-MAG neuropathy patients is continuing as interest in this condition is increasing as new treatments become available.

      5.3 Electrophysiology

      The pattern of involvement in anti-MAG neuropathy is that of a demyelinating neuropathy with a disproportionate distal slowing reflecting a length-dependent process, in other words a DADS phenotype. Typically, electrophysiological studies show distal slowing and axon loss, which is more prominent in longer axons, and also a gradual increase of conduction slowing in a proximal to distal gradient along the length of the nerve, reflected by an increase in terminal latencies in long nerves (
      • Kaku D.A.
      • England J.D.
      • Sumner A.J.
      Distal accentuation of conduction slowing in polyneuropathy associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside.
      ;
      • Capasso M.
      • Torrieri F.
      • Di Muzio A.
      • De Angelis M.V.
      • Lugaresi A.
      • Uncini A.
      Can electrophysiology differentiate polyneuropathy with anti-MAG/SGPG antibodies from chronic inflammatory demyelinating polyneuropathy?.
      ). As a pathological correlation of these electrophysiological findings, a predominantly distal nerve involvement has been demonstrated in an autopsy study of a patient with anti-MAG antibodies (
      • Mendell J.R.
      • Sahenk Z.
      • Whitaker J.N.
      • Trapp B.D.
      • Yates A.J.
      • Griggs R.C.
      • Quarles R.H.
      Polyneuropathy and IgM monoclonal gammopathy: studies on the pathogenetic role of anti-myelin-associated glycoprotein antibody.
      ).
      When comparing MAG neuropathy with CIDP patients and Charcot Marie-Tooth (CMT1a) patients, the terminal latency index was significantly lower in the anti-MAG group (
      • Attarian S.
      • Azulay J.P.
      • Boucraut J.
      • Escande N.
      • Pouget J.
      Terminal latency index and modified F ratio in distinction of chronic demyelinating neuropathies.
      ). Other parameters such as a modified F-ratio or the residual latency have also been shown to distinguish anti-MAG-associated polyneuropathy from CIDP (
      • Radziwill A.J.
      • Steck A.J.
      • Renaud S.
      • Fuhr P.
      Distal motor latency and residual latency as sensitive markers of anti-MAG polyneuropathy.
      ). Electrophysiological testing remains the first line of paraclinical investigation in the distinction between CIDP and anti-MAG neuropathy.

      5.4 Mechanisms of nerve injury

      Morphological studies of sural nerve biopsy specimen show a loss of myelinated fibers, and on ultrastructural examination there are thinned myelin sheaths and variable number of fibers with widely spaced myelin lamellae (
      • Steck A.J.
      • Murray N.
      • Meier C.
      • Page N.
      • Perruisseau G.
      Demyelinating neuropathy and monoclonal IgM antibody to myelin-associated glycoprotein.
      ;
      • Vital A.
      • Vital C.
      • Julien J.
      • Baquey A.
      • Steck A.J.
      Polyneuropathy associated with IgM monoclonal gammopathy. Immunological and pathological study in 31 patients.
      ;
      • Jacobs J.M.
      • Scadding J.W.
      Morphological changes in IgM paraproteinaemic neuropathy.
      ;
      • Ellie E.
      • Vital A.
      • Steck A.
      • Boiron J.M.
      • Vital C.
      • Julien J.
      Neuropathy associated with "benign" anti-myelin-associated glycoprotein IgM gammopathy: clinical, immunological, neurophysiological pathological findings and response to treatment in 33 cases.
      ), resulting from separation of the two leaflets of the intermediate, or minor dense line, by an electron lucent material (
      • King R.H.
      • Thomas P.K.
      The occurrence and significance of myelin with unusually large periodicity.
      ). In one study, widening of myelin lamellae could be shown in all eight cases of peripheral neuropathy and WM with anti-MAG activity (
      • Vital C.
      • Vital A.
      • Deminiere C.
      • Julien J.
      • Lagueny A.
      • Steck A.J.
      Myelin modifications in 8 cases of peripheral neuropathy with Waldenström’s macroglobulinemia and anti-MAG activity.
      ). The widening usually occurs at the outermost myelin lamellae, but occasionally can be seen in the deep layers of compact myelin. This widely spaced myelin, in which the distance between intermediate lines is increased, is a nearly specific finding in the anti-MAG neuropathy. The frequency of myelin widening correlated with that of demyelination in teased-fiber preparations (
      • Kawagashira Y.
      • Koike H.
      • Tomita M.
      • Morozumi S.
      • Iijima M.
      • Nakamura T.
      • Katsuno M.
      • Tanaka F.
      • Sobue G.
      Morphological progression of myelin abnormalities in IgM-monoclonal gammopathy of undetermined significance anti-myelin-associated glycoprotein neuropathy.
      ).
      In patients with anti-MAG neuropathy, both nerve and skin biopsies (
      • Lombardi R.
      • Erne B.
      • Lauria G.
      • Pareyson D.
      • Borgna M.
      • Morbin M.
      • Arnold A.
      • Czaplinski A.
      • Fuhr P.
      • Schaeren-Wiemers N.
      • Steck A.J.
      IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy.
      ) show deposition of anti-MAG antibodies or monoclonal IgM in relationship to nerve fibers. Deposits of the IgM antibodies can be seen at the periphery of myelinated fibers (
      • Jacobs J.M.
      • Scadding J.W.
      Morphological changes in IgM paraproteinaemic neuropathy.
      ), and with confocal microscopy, at sites of uncompacted myelin, in Schmidt–Lanterman incisures and paranodal loops (
      • Mendell J.R.
      • Sahenk Z.
      • Whitaker J.N.
      • Trapp B.D.
      • Yates A.J.
      • Griggs R.C.
      • Quarles R.H.
      Polyneuropathy and IgM monoclonal gammopathy: studies on the pathogenetic role of anti-myelin-associated glycoprotein antibody.
      ;
      • Gabriel J.M.
      • Erne B.
      • Bernasconi L.
      • Tosi C.
      • Probst A.
      • Landmann L.
      • Steck A.J.
      Confocal microscopic localization of anti-myelin-associated glycoprotein autoantibodies in a patient with peripheral neuropathy initially lacking a detectable IgM gammopathy.
      ;
      • Ritz M.F.
      • Erne B.
      • Ferracin F.
      • Vital A.
      • Vital C.
      • Steck A.J.
      Anti-MAG IgM penetration into myelinated fibers correlates with the extent of myelin widening.
      ;
      • Kawagashira Y.
      • Koike H.
      • Tomita M.
      • Morozumi S.
      • Iijima M.
      • Nakamura T.
      • Katsuno M.
      • Tanaka F.
      • Sobue G.
      Morphological progression of myelin abnormalities in IgM-monoclonal gammopathy of undetermined significance anti-myelin-associated glycoprotein neuropathy.
      ). Given the convincing evidence that the patients' IgM co-localize with MAG at the paranodes, and at regions of split myelin lamellae a direct role of anti-MAG antibodies in myelin disadhesion and breakdown seems likely. Though a study has suggested that the terminal complement complex (TCC) may be involved in the anti-MAG neuropathy (
      • Monaco S.
      • Bonetti B.
      • Ferrari S.
      • Moretto G.
      • Nardelli E.
      • Tedesco F.
      • Mollnes T.E.
      • Nobile-Orazio E.
      • Manfredini E.
      • Bonazzi L.
      • Rizzuto N.
      Complement-mediated demyelination in patients with IgM monoclonal gammopathy and polyneuropathy.
      ), most studies confirmed the absence of TCC on myelin sheaths, but the presence of complement components such as C3d or C5 (
      • Ritz M.F.
      • Erne B.
      • Ferracin F.
      • Vital A.
      • Vital C.
      • Steck A.J.
      Anti-MAG IgM penetration into myelinated fibers correlates with the extent of myelin widening.
      ;
      • Lombardi R.
      • Erne B.
      • Lauria G.
      • Pareyson D.
      • Borgna M.
      • Morbin M.
      • Arnold A.
      • Czaplinski A.
      • Fuhr P.
      • Schaeren-Wiemers N.
      • Steck A.J.
      IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy.
      ;
      • Kawagashira Y.
      • Koike H.
      • Tomita M.
      • Morozumi S.
      • Iijima M.
      • Nakamura T.
      • Katsuno M.
      • Tanaka F.
      • Sobue G.
      Morphological progression of myelin abnormalities in IgM-monoclonal gammopathy of undetermined significance anti-myelin-associated glycoprotein neuropathy.
      ), suggesting that these complement components may be effectors of myelin changes, eventually resulting in detachment of terminal loops from the axolemma at the node of Ranvier and progressing to myelin widening in the internode (Fig. 5). This unzipping process is in keeping with the slow progression in anti-MAG neuropathy that evolves during many years, the involvement of TCC being on the other hand well established in acute inflammatory neuropathies such as Guillain-Barré syndrome (
      • Koski C.L.
      • Sanders M.E.
      • Swoveland P.T.
      • Lawley T.J.
      • Shin M.L.
      • Frank M.M.
      • Joiner K.A.
      Activation of terminal components of complement in patients with Guillain-Barré syndrome and other demyelinating neuropathies.
      ;
      • Goodfellow J.A.
      • Willison H.J.
      Guillain-Barré syndrome: a century of progress.
      ;
      • Davidson A.I.
      • Halstead S.K.
      • Goodfellow J.A.
      • Chavada G.
      • Mallik A.
      • Overell J.
      • Lunn M.P.
      • McConnachie A.
      • van Doorn P.
      • Willison H.J.
      Inhibition of complement in Guillain-Barré syndrome: the ICA-GBS study.
      ). Demyelination caused by detachment of terminal myelin loops from paranodal axolemma may be the primary cause of axonal atrophy and subsequent axonal damage in the anti-MAG neuropathy (
      • Stalder A.K.
      • Erne B.
      • Reimann R.
      • Renaud S.
      • Fuhr P.
      • Thomann S.
      • Arnold A.
      • Probst A.
      • Schaeren-Wiemers N.
      • Steck A.J.
      Immunoglobulin M deposition in cutaneous nerves of anti-myelin-associated glycoprotein polyneuropathy patients correlates with axonal degeneration.
      ;
      • Kawagashira Y.
      • Koike H.
      • Takahashi M.
      • Ohyama K.
      • Iijima M.
      • Katsuno M.
      • Niwa J.I.
      • Doyu M.
      • Sobue G.
      Aberrant expression of nodal and paranodal molecules in neuropathy associated with IgM monoclonal gammopathy with anti-myelin-associated glycoprotein antibodies.
      ). A study of sural nerve biopsies from anti-MAG neuropathy patients demonstrated a reduced axonal caliber and a reduced spacing of neurofilaments in demyelinated fibers (
      • Lunn M.P.
      • Crawford T.O.
      • Hughes R.A.
      • Griffin J.W.
      • Sheikh K.A.
      Anti-myelin-associated glycoprotein antibodies alter neurofilament spacing.
      ). According to these observations it has been hypothesized that axonal atrophy could be mediated by antibody-binding to MAG, inhibiting the signaling to the axon, resulting in a decreased neurofilament phosphorylation.
      Fig. 5
      Fig. 5Schematic representation of demyelination in anti-MAG neuropathy. Myelin widening with detachment and loosening of terminal myelin loops in the paranode (A) and widening in the outer layers of compact myelin in the internode (B). Corresponding electron micrograph of the paranode (A): widening of spaces between terminal myelin loops (arrows) and widening of myelin in the outermost lamellae (arrowheads). Corresponding electron micrograph of the internode (B): widening of outer layers of compact myelin. Adapted from Kawagashira (
      • Kawagashira Y.
      • Koike H.
      • Tomita M.
      • Morozumi S.
      • Iijima M.
      • Nakamura T.
      • Katsuno M.
      • Tanaka F.
      • Sobue G.
      Morphological progression of myelin abnormalities in IgM-monoclonal gammopathy of undetermined significance anti-myelin-associated glycoprotein neuropathy.
      ;
      • Kawagashira Y.
      • Koike H.
      • Ohyama K.
      • Hashimoto R.
      • Iijima M.
      • Adachi H.
      • Katsuno M.
      • Chapman M.
      • Lunn M.
      • Sobue G.
      Axonal loss influences the response to rituximab treatment in neuropathy associated with IgM monoclonal gammopathy with anti-myelin-associated glycoprotein antibody.
      ).

      6. Animal models

      Experimental studies have shown the capacity of anti-MAG antibodies to cause demyelination. Initially systemic acute and chronic passive transfer with anti-MAG paraproteins in guinea pigs, rabbits, and marmosets were negative, failing to induce demyelination and no antibody was found binding to myelin (
      • Steck A.J.
      • Murray N.
      • Justafre J.C.
      • Meier C.
      • Toyka K.V.
      • Heininger K.
      • Stoll G.
      Passive transfer studies in demyelinating neuropathy with IgM monoclonal antibodies to myelin-associated glycoprotein.
      ). However, attempts to demonstrate the demyelinating potential of these paraproteins using the strategy of bypassing the blood-nerve barrier by direct injection into the nerve were successful. Experimental demyelination has been demonstrated by direct injection of these paraproteins into cat nerve (
      • Hays A.P.
      • Latov N.
      • Takatsu M.
      • Sherman W.H.
      Experimental demyelination of nerve induced by serum of patients with neuropathy and an anti-MAG IgM M-protein.
      ;
      • Willison H.J.
      • Trapp B.D.
      • Bacher J.D.
      • Dalakas M.C.
      • Griffin J.W.
      • Quarles R.H.
      Demyelination induced by intraneural injection of human antimyelin-associated glycoprotein antibodies.
      ). They caused an extensive inflammatory, macrophage-mediated demyelination of feline peripheral nerve. This only occurred with fresh sera which had been supplemented with additional complement. Injection of sera from normal subjects failed to produce any demyelination. While these observations provided good evidence of the demyelinating potential of these antibodies, the acute sciatic nerve lesions showed little resemblance to the chronic human paraprotein demyelinating disease and were dependent on exogenous complement.
      Eventually a model of chronic systemic transfusion of chickens with monoclonal IgM antibody isolated from an anti-MAG patient demonstrated peripheral demyelination highly characteristic of the human syndrome (
      • Tatum A.H.
      Experimental paraprotein neuropathy, demyelination by passive transfer of human IgM anti-myelin-associated glycoprotein.
      ). The experimental lesions consisted of segmental demyelination and remyelination with minimal inflammation, widening of the myelin lamellae and specific antibody bound to myelin. This demonstration that human myelin-associated glycoprotein antibodies cause demyelination in vivo was the final proof that this type of human demyelinating neuropathy is antibody mediated.
      The unsuccessful attempts to establish an animal model of the anti-MAG neuropathy in rodents can be explained by the fact that the HNK1 oligosaccharide moiety is species restricted. There are species differences in glycosylation of MAG. Especially the sulfate group of the HNK-1 glycan epitope plays an essential role for the binding of the anti-MAG antibodies and is strongly expressed in human MAG, but not in rodent MAG (
      • Ilyas A.A.
      • Chou D.K.
      • Jungalwala F.B.
      • Costello C.
      • Quarles R.H.
      Variability in the structural requirements for binding of human monoclonal anti-myelin-associated glycoprotein immunoglobulin M antibodies and HNK-1 to sphingoglycolipid antigens.
      ;
      • Gao T.
      • Yan J.
      • Liu C.C.
      • Palma A.S.
      • Guo Z.
      • Xiao M.
      • Chen X.
      • Liang X.
      • Chai W.
      • Cao H.
      Chemoenzymatic synthesis of O-mannose glycans containing sulfated or nonsulfated HNK-1 epitope.
      ). It is however present in chicken as well as bovine MAG (
      • Ariga T.
      The role of sulfoglucuronosyl glycosphingolipids in the pathogenesis of monoclonal IgM paraproteinemia and peripheral neuropathy.
      ).
      The target of anti-MAG autoantibodies is the HNK-1 sulfated trisaccharide epitope, mostly expressed on MAG (
      • Burger D.
      • Perruisseau G.
      • Simon M.
      • Steck A.J.
      Comparison of the N-linked oligosaccharide structures of the two major human myelin glycoproteins MAG and P0: assessment of the structures bearing the epitope for HNK-1 and human monoclonal immunoglobulin M found in demyelinating neuropathy.
      ). Taking advantage of the molecular characteristics of the HNK1 epitope and the binding properties of anti-MAG antibodies, Herrendorff and coworkers (
      • Herrendorff R.
      • Hänggi P.
      • Pfister H.
      • Yang F.
      • Demeestere D.
      • Hunziker F.
      • Frey S.
      • Schaeren-Wiemers N.
      • Steck A.J.
      • Ernst B.
      Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy.
      ) synthesized derivatives and mimetics of the HNK1 epitope. The glycopolymer poly (phenyl disodium 3-O-sulfo-β-d-glucopyranuronate)-(1 → 3)-β-d-galactopyranoside (PPSGG) composed of a biodegradable polylysine backbone presenting multiple copies of a mimetic of the sulfated HNK-1 trisaccharide was found to be particularly effective in binding and blocking anti-MAG antibodies. It was shown that PPSGG could scavenge anti-MAG antibodies in an immunological mouse model, opening the possibility of removing the anti-MAG IgM autoantibodies in a highly selective fashion (
      • Herrendorff R.
      • Hänggi P.
      • Pfister H.
      • Yang F.
      • Demeestere D.
      • Hunziker F.
      • Frey S.
      • Schaeren-Wiemers N.
      • Steck A.J.
      • Ernst B.
      Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy.
      ;
      • Aliu B.
      • Demeestere D.
      • Seydoux E.
      • Boucraut J.
      • Delmont E.
      • Brodovitch A.
      • Oberholzer T.
      • Attarian S.
      • Théaudin M.
      • Tsouni P.
      • Kuntzer T.
      • Derfuss T.
      • Steck A.J.
      • Ernst B.
      • Herrendorff R.
      • Hänggi P.
      Selective inhibition of anti-MAG IgM autoantibody binding to myelin by an antigen-specific glycopolymer.
      ).

      7. Origin of anti-MAG B-cell clone

      Human anti-MAG antibodies are typically IgM and occur in the context of monoclonal gammopathies. They are derived from CD5+ B-cells that secrete naturally occurring low affinity autoantibodies, which are present in low levels in the normal physiological autoimmune repertoire (
      • Lee K.W.
      • Inghirami G.
      • Spatz L.
      • Knowles D.M.
      • Latov N.
      The B-cells that express anti-MAG antibodies in neuropathy and non-malignant IgM monoclonal gammopathy belong to the CD5 subpopulation.
      ). Patients with anti-MAG neuropathy show substantial clonal expansions of blood IgM memory B cells that recognize the MAG antigen (
      • Maurer M.A.
      • Rakocevic G.
      • Leung C.S.
      • Quast I.
      • Lukačišin M.
      • Goebels N.
      • Münz C.
      • Wardemann H.
      • Dalakas M.
      • Lünemann J.D.
      Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity.
      ). Development of a clonal B cell proliferation could be explained by an oncogenic event in concert with reactivity with self-antigens or bacterial antigens. It has been proposed that bacterial polypeptides express the glucuronyl sulphate determinant which is the target of the anti- MAG antibodies, thus leading in susceptible individuals to the production of bacteria-induced auto-antibodies (
      • Brouet J.C.
      • Mariette X.
      • Gendron M.C.
      • Dubreuil M.L.
      Monoclonal IgM from patients with peripheral demyelinating neuropathies cross-react with bacterial polypeptides.
      ). Molecular mimicry has been recognized as a possible mechanism in autoimmune neuropathies such as the Guillain-Barré Syndromes (
      • Willison H.J.
      2007 Gangliosides as targets for autoimmune injury to the nervous system.
      ) and one could speculate that it can indirectly trigger the development of antigen-driven B cell clones. Monoclonal anti-MAG IgM from patients with peripheral neuropathy feature a diverse repertoire for immunoglobulin chain variable regions which exhibit a number of somatic mutations suggestive of an antigen-driven process (
      • Ayadi H.
      • Mihaesco E.
      • Congy N.
      • Roy J.P.
      • Gendron M.C.
      • Laperriere J.
      • Prelli F.
      • Frangione B.
      • Brouet J.C.
      H chain V region sequences of three human monoclonal IgM with anti-myelin-associated glycoprotein activity.
      ;
      • Lee G.
      • Ware R.R.
      • Latov N.
      Somatically mutated member of the human V lambda VIII gene family encodes anti-myelin-associated glycoprotein (MAG) activity.
      ). Consequently, a two-step process has been proposed, the first one being antigen driven, the second dependent on an oncogenic mutation (
      • Brouet J.C.
      • Mariette X.
      • Gendron M.C.
      • Dubreuil M.L.
      Monoclonal IgM from patients with peripheral demyelinating neuropathies cross-react with bacterial polypeptides.
      ). Recurrent somatic point mutation of the myeloid differentiation factor 88 (MYD88) gene, leading to an amino acid change from leucine to proline (L265P), has been reported in the vast majority (>90%) of patients with WM and in 60% of anti-MAG polyneuropathy cases (
      • Vos J.M.
      • Notermans N.C.
      • D’Sa S.
      • Lunn M.P.
      • van der Pol W.L.
      • Kraan W.
      • Reilly M.M.
      • Chalker J.
      • Gupta R.
      • Kersten M.J.
      • Pals S.T.
      • Minnema M.C.
      High prevalence of the MYD88 L265P mutation in IgM anti-MAG paraprotein-associated peripheral neuropathy.
      ). The MYD88 mutation is a gain of function mutation resulting in increased cellular proliferation and survival mediated by the Bruton's tyrosine kinase (BTK). This kinase can be inhibited by ibrutinib, a novel drug used in the treatment of WM and of potential interest in the treatment of anti-MAG neuropathy (
      • Castellani F.
      • Visentin A.
      • Campagnolo M.
      • Salvalaggio A.
      • Cacciavillani M.
      • Candiotto C.
      • Bertorelle R.
      • Trentin L.
      • Briani C.
      The Bruton tyrosine kinase inhibitor ibrutinib improves anti-MAG antibody polyneuropathy.
      ).
      Secretion of anti-MAG antibodies is subject to regulation by T-cells and cytokines. Patients with anti-MAG neuropathy have higher median IL-6 and IL-10 concentrations in sera than controls (
      • Stork A.C.J.
      • Rijkers G.T.
      • Vlam L.
      • Cats E.A.
      • de Jong B.A.W.
      • Fritsch-Stork R.D.E.
      • Veldink J.H.
      • van den Berg L.H.
      • Notermans N.C.
      • van der Pol W.L.
      Serum cytokine patterns in immunoglobulin m monoclonal gammopathy-associated polyneuropathy.
      ). It has been postulated that IL-6 plays a role as a survival factor for plasma cell precursors and thus could be relevant in the pathogenesis of anti-MAG neuropathy leading to a monoclonal expansion of plasma cells (
      • Tanaka T.
      • Kishimoto T.
      The biology and medical implications of interleukin-6.
      ). IL-10 can also activate B cells and promote autoantibody production (
      • Tian G.
      • Li J.L.
      • Wang D.G.
      • Zhou D.
      Targeting IL-10 in auto-immune diseases.
      ). An interesting loop consisting of an interaction between CD70 found on activated T cells and CD27 expressed on the cell surface of memory B cells from which anti-MAG producing B cells are derived may play a significant role in disease progression as demonstrated in WM (
      • Arens R.
      • Tesselaar K.
      • Baars P.A.
      • van Schijndel G.M.
      • Hendriks J.
      • Pals S.T.
      • Krimpenfort P.
      • Borst J.
      • van Oers M.H.
      • van Lier R.A.
      Constitutive CD27/CD70 interaction induces expansion of effector-type T cells and results in IFN gamma-mediated B cell depletion.
      ;
      • Ho A.W.
      • Hatjiharissi E.
      • Ciccarelli B.T.
      • Branagan A.R.
      • Hunter Z.R.
      • Leleu X.
      • Tournilhac O.
      • Xu L.
      • O’Connor K.
      • Manning R.J.
      • Santos D.D.
      • Chemaly M.
      • Patterson C.J.
      • Soumerai J.D.
      • Munshi N.C.
      • McEarchern J.A.
      • Law C.L.
      • Grewal I.S.
      • Treon S.P.
      CD27-CD70 interactions in the pathogenesis of Waldenstrom macroglobulinemia.
      ).
      The roles of these cytokines and interactions between B cells producing anti-MAG antibodies and activated T cells which may also regulate access of autoreactive antibodies in the PNS (
      • Iwasaki A.
      Immune regulation of antibody access to neuronal tissues.
      ) and other biomarkers such as high BAFF concentrations (
      • Benedetti L.
      • Zardini E.
      • Briani C.
      • Beronio A.
      • Gastaldi S.
      • Jarius S.
      • Mancardi G.L.
      • Schenone A.
      • Franciotta D.
      B-cell-activating factor in rituximab-treated patients with anti-MAG polyneuropathy.
      ) deserve attention as potential targets for new treatment strategies. The fact that myelin, specifically MAG shares an antigenic determinant with NK cells is intriguing. Such cross reactivity could play a role in the pathogenesis of the anti-MAG neuropathy as well as other immune mediated demyelinating diseases (
      • Murray N.
      • Steck A.J.
      Indication of a possible role in a demyelinating neuropathy for an antigen shared between myelin and NK cells.
      ).

      8. Therapy

      As the anti-MAG neuropathy is the most common disabling paraproteinemic neuropathy and since the anti-MAG antibodies appear to exert a direct pathogenic effect on myelin structure and function, B cells depleting therapies have been the main therapeutical mode of treatment. Initially chemotherapy regimens with chlorambucil, cyclophosphamide or fludarabine have been used, but because of toxicity or secondary malignancies have been replaced by anti-CD20 antibodies. We review current and potential therapies, with a special interest on new treatment modalities (Table 1).
      Table 1Anti-MAG neuropathy: current and novel treatment modalities.
      TreatmentDrugIndication/action
      ChemotherapyChlorambucilBecause of toxicity no more used.
      Cyclophosphamide
      FludarabineFludarabine effective in occasional patients (
      • Wilson H.C.
      • Lunn M.P.
      • Schey S.
      • Hughes R.A.
      Successful treatment of IgM paraproteinaemic neuropathy with fludarabine.
      )
      IbrutinibEfficacy limited to MYD88 mutation (
      • Castellani F.
      • Visentin A.
      • Campagnolo M.
      • Salvalaggio A.
      • Cacciavillani M.
      • Candiotto C.
      • Bertorelle R.
      • Trentin L.
      • Briani C.
      The Bruton tyrosine kinase inhibitor ibrutinib improves anti-MAG antibody polyneuropathy.
      )
      LenalidomideInvestigational
      Anti-CD20 antibodiesRituximabImprovement in 30 to 50% of patients (
      • Dalakas M.C.
      Advances in the diagnosis, immunopathogenesis and therapies of IgM-anti-MAG antibody-mediated neuropathies.
      ;
      • Svahn J.
      • Petiot P.
      • Antoine J.C.
      • Vial C.
      • Delmont E.
      • Viala K.
      • Steck A.J.
      • Magot A.
      • Cauquil C.
      • Zarea A.
      • Echaniz-Laguna A.
      • Iancu Ferfoglia R.
      • Gueguen A.
      • Magy L.
      • Léger J.M.
      • Kuntzer T.
      • Ferraud K.
      • Lacour A.
      • Camdessanché J.P.
      Francophone anti-MAG cohort Group. Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features.
      )
      ObinutuzumabExerts greater B-cell depletion (
      • Rakocevic G.
      • Martinez-Outschoorn U.
      • Dalakas M.C.
      Obinutuzumab, a potent anti-B-cell agent, for rituximab-unresponsive IgM anti-MAG neuropathy.
      )
      Plasma exchangeAcute worsening due to IgM flare (
      • Baron M.
      • Lozeron P.
      • Harel S.
      • Bengoufa D.
      • Vignon M.
      • Asli B.
      • Malphettes M.
      • Parquet N.
      • Brignier A.
      • Fermand J.P.
      • Kubis N.
      • Arnulf B.
      Plasma exchanges for severe acute neurological deterioration in patients with IgM anti-myelin-associated glycoprotein (anti-MAG) neuropathy.
      )
      HNK-1 decoyPPSGGInvestigational (
      • Herrendorff R.
      • Hänggi P.
      • Pfister H.
      • Yang F.
      • Demeestere D.
      • Hunziker F.
      • Frey S.
      • Schaeren-Wiemers N.
      • Steck A.J.
      • Ernst B.
      Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy.
      ;
      • Steinman L.
      A sugar-coated strategy to treat a rare neurologic disease provides a blueprint for a decoy glycan therapeutic and a potential vaccine for CoViD-19: an Editorial Highlight for “Selective inhibition of anti-MAG IgM autoantibody binding to myelin by an antigen specific glycopolymer”on page 486.
      )

      8.1 Anti-CD20 antibodies

      The availability of rituximab, a monoclonal antibody suppressing B-cell clones which is not myelosuppressive and does not cause secondary malignancies, allows for early targeted intervention (
      • Onrust S.V.
      • Lamb H.M.
      • Balfour J.A.
      Rituximab.
      ). Rituximab is a chimeric murine-human monoclonal antibody against CD20, a B-cell surface antigen present on pre-B cells and throughout the B-cell life cycle, but not on plasma cells, causing a rapid depletion of circulating CD 20 positive B cells. It has been widely used and is currently the preferred mode of treatment though its efficacy is limited (
      • Dalakas M.C.
      Advances in the diagnosis, immunopathogenesis and therapies of IgM-anti-MAG antibody-mediated neuropathies.
      ). Two controlled studies using different scales and endpoints demonstrated a positive benefit, but the evidence was of low quality because of small numbers of participants and concerns about the design of one of the two studies (
      • Lunn M.P.
      • Nobile-Orazio E.
      Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies.
      ).
      As rituximab does not affect the anti-MAG antibody producing plasma cells, neurological improvement is typically delayed beginning 3 months after treatment and is clear 6 months after therapy (
      • Dalakas M.C.
      • Rakocevic G.
      • Salajegheh M.
      • Dambrosia J.M.
      • Hahn A.F.
      • Raju R.
      • McElroy B.
      Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy.
      ), coinciding with the slow reduction of anti-MAG antibodies (
      • Renaud S.
      • Gregor M.
      • Fuhr P.
      • Lorenz D.
      • Deuschl G.
      • Gratwohl A.
      • Steck A.J.
      Rituximab in the treatment of polyneuropathy associated with anti-MAG antibodies.
      ). Cumulative data from several studies show that rituximab helps 30–50% of the patients (
      • Svahn J.
      • Petiot P.
      • Antoine J.C.
      • Vial C.
      • Delmont E.
      • Viala K.
      • Steck A.J.
      • Magot A.
      • Cauquil C.
      • Zarea A.
      • Echaniz-Laguna A.
      • Iancu Ferfoglia R.
      • Gueguen A.
      • Magy L.
      • Léger J.M.
      • Kuntzer T.
      • Ferraud K.
      • Lacour A.
      • Camdessanché J.P.
      Francophone anti-MAG cohort Group. Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features.
      ;
      • Dalakas M.C.
      Advances in the diagnosis, immunopathogenesis and therapies of IgM-anti-MAG antibody-mediated neuropathies.
      ).While it has been shown that there is no direct association between anti-MAG IgM levels and the severity of anti-MAG neuropathy or the progression of the disease (
      • Svahn J.
      • Petiot P.
      • Antoine J.C.
      • Vial C.
      • Delmont E.
      • Viala K.
      • Steck A.J.
      • Magot A.
      • Cauquil C.
      • Zarea A.
      • Echaniz-Laguna A.
      • Iancu Ferfoglia R.
      • Gueguen A.
      • Magy L.
      • Léger J.M.
      • Kuntzer T.
      • Ferraud K.
      • Lacour A.
      • Camdessanché J.P.
      Francophone anti-MAG cohort Group. Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features.
      ), a retrospective analysis of 50 clinical trials in anti-MAG neuropathy (
      • Hänggi P.
      • Aliu B.
      • Martin K.
      • Herrendorff R.
      • Steck A.J.
      Retrospective study: decrease in serum anti-MAG autoantibodies is associated with therapy response in anti-MAG neuropathy patients.
      ) demonstrated that a relative reduction in anti-MAG IgM levels was associated with clinical improvement in the responder group. In this group the anti-MAG IgM titers were reduced by 57.5%, the paraprotein levels by 57.5% and the total IgM by 52.3% compared to the pre-treatment levels. On the other hand, the non-responder group exhibited no or only minimal change in anti-MAG IgM levels. On average, the group of patients presenting with acute worsening was associated with a strong increase in anti-MAG titers. Worsening of the neuropathy with rituximab is attributed to IgM flare and several cases have been documented (
      • Broglio L.
      • Lauria G.
      Worsening after rituximab treatment in anti-mag neuropathy.
      ;
      • Noronha V.
      • Fynan T.M.
      • Duffy T.
      Flare in neuropathy following rituximab therapy for Waldenstrom’s macroglobulinemia.
      ;
      • Gironi M.
      • Saresella M.
      • Ceresa L.
      • Calvo M.
      • Ferrante P.
      • Merli F.
      • Nemni R.
      Clinical and immunological worsening in a patient affected with Waldenstrom macroglobulinemia and anti-mag neuropathy after treatment with rituximab.
      ;
      • Sala E.
      • Robert-Varvat F.
      • Paul S.
      • Camdessanché J.P.
      • Antoine J.C.
      Acute neurological worsening after rituximab treatment in patients with anti-MAG neuropathy.
      ). The proposed mechanisms of this flare phenomenon include B-lymphocyte lysis with resultant release of intracellular paraprotein, disruption of idiotype-anti-idiotype network or cytokines overproduction (
      • Noronha V.
      • Fynan T.M.
      • Duffy T.
      Flare in neuropathy following rituximab therapy for Waldenstrom’s macroglobulinemia.
      ;
      • Kamburova E.G.
      • van den Hoogen M.W.
      • Koenen H.J.
      • Baas M.C.
      • Hilbrands L.B.
      • Joosten I.
      Cytokine release after treatment with rituximab in renal transplant recipients.
      ;
      • Maisons V.
      • Kaysi S.
      Rituximab-associated neuropathy: about two cases.
      ). The IgM flare phenomenon may be observed in up to 54% of patients with WM treated with rituximab (
      • Ghobrial I.M.
      • Fonseca R.
      • Greipp P.R.
      • Blood E.
      • Rue M.
      • Vesole D.H.
      • Gertz M.A.
      • Eastern Cooperative Oncology Group
      Initial immunoglobulin M ‘flare’ after rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia: an Eastern Cooperative Oncology Group Study.
      ), while its occurrence is much lower in patients with MGUS. Successful treatment with plasma exchanges in patients presenting with acute neurological deterioration and increase of anti-MAG antibody has been reported, allowing a dramatic and rapid neurological improvement (
      • Baron M.
      • Lozeron P.
      • Harel S.
      • Bengoufa D.
      • Vignon M.
      • Asli B.
      • Malphettes M.
      • Parquet N.
      • Brignier A.
      • Fermand J.P.
      • Kubis N.
      • Arnulf B.
      Plasma exchanges for severe acute neurological deterioration in patients with IgM anti-myelin-associated glycoprotein (anti-MAG) neuropathy.
      ).
      The reason why rituximab benefits less than 50% of the patients is not clear and several studies have looked at clinical features or biomarkers predicting response (
      • Dalakas M.C.
      Rituximab in anti-MAG neuropathy: more evidence for efficacy and more predictive factors.
      ). Demyelinating pattern and older age were significant risk factors for disability worsening (
      • Galassi G.
      • Tondelli M.
      • Ariatti A.
      • Benuzzi F.
      • Nichelli P.
      • Valzania F.
      Long-term disability and prognostic factors in polyneuropathy associated with anti-myelin-associated glycoprotein (MAG) antibodies.
      ). Predominantly motor deficits and subacute progression were associated with a positive response (
      • Gazzola S.
      • Delmont E.
      • Franques J.
      • Boucraut J.
      • Salort-Campana E.
      • Verschueren A.
      • Sagui E.
      • Hubert A.M.
      • Pouget J.
      • Attarian S.
      Predictive factors of efficacy of rituximab in patients with anti-MAG neuropathy.
      ). Gender, ataxia, tremor, and IgM anti-MAG antibody titer did not influence the outcome (
      • Galassi G.
      • Tondelli M.
      • Ariatti A.
      • Benuzzi F.
      • Nichelli P.
      • Valzania F.
      Long-term disability and prognostic factors in polyneuropathy associated with anti-myelin-associated glycoprotein (MAG) antibodies.
      ,
      • Svahn J.
      • Petiot P.
      • Antoine J.C.
      • Vial C.
      • Delmont E.
      • Viala K.
      • Steck A.J.
      • Magot A.
      • Cauquil C.
      • Zarea A.
      • Echaniz-Laguna A.
      • Iancu Ferfoglia R.
      • Gueguen A.
      • Magy L.
      • Léger J.M.
      • Kuntzer T.
      • Ferraud K.
      • Lacour A.
      • Camdessanché J.P.
      Francophone anti-MAG cohort Group. Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features.
      ). There is a trend between shorter symptom duration before treatment and response to rituximab (
      • Benedetti L.
      • Briani C.
      • Grandis M.
      • Vigo T.
      • Gobbi M.
      • Ghiglione E.
      • Carpo M.
      • Cocito D.
      • Caporale C.M.
      • Sormani M.P.
      • Mancardi G.L.
      • Nobile-Orazio E.
      • Schenone A.
      Predictors of response to rituximab in patients with neuropathy and anti-myelin associated glycoprotein immunoglobulin M.
      ) suggesting that patients should be treated early before permanent deficits due to axonal degeneration take place (
      • Kawagashira Y.
      • Koike H.
      • Ohyama K.
      • Hashimoto R.
      • Iijima M.
      • Adachi H.
      • Katsuno M.
      • Chapman M.
      • Lunn M.
      • Sobue G.
      Axonal loss influences the response to rituximab treatment in neuropathy associated with IgM monoclonal gammopathy with anti-myelin-associated glycoprotein antibody.
      ). New generation of humanized anti-CD20 monoclonal antibodies that cause more profound or sustained B-cell depletion are available and warrant the development of clinical trials (
      • Rakocevic G.
      • Martinez-Outschoorn U.
      • Dalakas M.C.
      Obinutuzumab, a potent anti-B-cell agent, for rituximab-unresponsive IgM anti-MAG neuropathy.
      ).

      8.2 New treatment modalities

      A somatic mutation of the MYD88 gene has been found in up to 90% of patients with WM and also in patients with IgM MGUS (
      • Treon S.P.
      • Xu L.
      • Yang G.
      • Zhou Y.
      • Liu X.
      • Cao Y.
      • Sheehy P.
      • Manning R.J.
      • Patterson C.J.
      • Tripsas C.
      • Arcaini L.
      • Pinkus G.S.
      • Rodig S.J.
      • Sohani A.R.
      • Harris N.L.
      • Laramie J.M.
      • Skifter D.A.
      • Lincoln S.E.
      • Hunter Z.R.
      MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia.
      ). This variant confers survival stimuli to tumor cells through activation of the BTK. The availability of inhibitors of BTK such as ibrutinib resulting in tumor cell killing opened the way for a new therapeutical avenue in WM (
      • Treon S.P.
      • Tripsas C.K.
      • Meid K.
      • Warren D.
      • Varma G.
      • Green R.
      • Argyropoulos K.V.
      • Yang G.
      • Cao Y.
      • Xu L.
      • Patterson C.J.
      • Rodig S.
      • Zehnder J.L.
      • Aster J.C.
      • Harris N.L.
      • Kanan S.
      • Ghobrial I.
      • Castillo J.J.
      • Laubach J.P.
      • Hunter Z.R.
      • Salman Z.
      • Li J.
      • Cheng M.
      • Clow F.
      • Graef T.
      • Palomba M.L.
      • Advani R.H.
      Ibrutinib in previously treated Waldenström’s macroglobulinemia.
      ). Ibrutinib has shown great efficacy at inducing deep and durable IgM responses, as well as improving hematologic parameters in patients with WM (
      • Castillo J.J.
      • Palomba M.L.
      • Advani R.
      • Treon S.P.
      Ibrutinib in Waldenström macroglobulinemia: latest evidence and clinical experience.
      ). Preliminary data from 2 studies point to a possible efficacy of ibrutinib in anti-MAG antibody neuropathy (
      • Treon S.P.
      • Tripsas C.K.
      • Meid K.
      • Warren D.
      • Varma G.
      • Green R.
      • Argyropoulos K.V.
      • Yang G.
      • Cao Y.
      • Xu L.
      • Patterson C.J.
      • Rodig S.
      • Zehnder J.L.
      • Aster J.C.
      • Harris N.L.
      • Kanan S.
      • Ghobrial I.
      • Castillo J.J.
      • Laubach J.P.
      • Hunter Z.R.
      • Salman Z.
      • Li J.
      • Cheng M.
      • Clow F.
      • Graef T.
      • Palomba M.L.
      • Advani R.H.
      Ibrutinib in previously treated Waldenström’s macroglobulinemia.
      ;
      • Castellani F.
      • Visentin A.
      • Campagnolo M.
      • Salvalaggio A.
      • Cacciavillani M.
      • Candiotto C.
      • Bertorelle R.
      • Trentin L.
      • Briani C.
      The Bruton tyrosine kinase inhibitor ibrutinib improves anti-MAG antibody polyneuropathy.
      ). Obviously, further studies are needed to assess the role of ibrutinib in the treatment of the anti-MAG neuropathy.
      A clinical study with lenalidomide, a medication used to treat multiple myeloma and myelodysplastic syndromes is currently evaluated in anti-MAG neuropathy (ClinicalTrials.gov Identifier: NCT03701711). Other potential therapies are in clinical use in different conditions but could be of interest for anti-MAG neuropathy. Cusatuzumab, an anti-CD70 monoclonal antibody, is a new drug for eliminating stem cells and preliminary data in acute myeloid leukemia have been reported (
      • Riether C.
      • Pabst T.
      • Höpner S.
      • Bacher U.
      • Hinterbrandner M.
      • Banz Y.
      • Müller R.
      • Manz M.G.
      • Gharib W.H.
      • Francisco D.
      • Bruggmann R.
      • van Rompaey L.
      • Moshir M.
      • Delahaye T.
      • Gandini D.
      • Erzeel E.
      • Hultberg A.
      • Fung S.
      • de Haard H.
      • Leupin N.
      • Ochsenbein A.F.
      Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents.
      ). Tocilizumab and sarilumab, targeting the IL-6 inflammatory pathway are investigated in rheumatoid arthritis (
      • Avci A.B.
      • Feist E.
      • Burmester G.R.
      Targeting IL-6 or IL-6 receptor in rheumatoid arthritis: what’s the difference?.
      ).
      So far, all strategies used to diminish anti MAG IgM antibody are non-specific. They include targeting of all CD20 B cells with rituximab, or inhibition of B-cell proliferation with ibrutinib or lenalidomide or removing autoantibodies from the circulation in the case of plasma exchange therapy. Recently a novel approach based on the development of an antigen specific molecule, a biodegradable glycopolymer offering multiple epitope-mimics of the HNK1 antigen has been successfully tested in an animal model (
      • Herrendorff R.
      • Hänggi P.
      • Pfister H.
      • Yang F.
      • Demeestere D.
      • Hunziker F.
      • Frey S.
      • Schaeren-Wiemers N.
      • Steck A.J.
      • Ernst B.
      Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy.
      ).The drug, poly(phenyl disodium 3-O-sulfo-β-D-glucopyranuronate)-(1 → 3)-β-D-galactopyranoside, known as PPSGG, serves as a glycan decoy for the anti-MAG autoantibody, which gets sequestered and rapidly eliminated from the body. It has been shown that PPSGG blocked the binding of anti-MAG IgM from patients to sciatic nerve myelin of non-human primates (
      • Aliu B.
      • Demeestere D.
      • Seydoux E.
      • Boucraut J.
      • Delmont E.
      • Brodovitch A.
      • Oberholzer T.
      • Attarian S.
      • Théaudin M.
      • Tsouni P.
      • Kuntzer T.
      • Derfuss T.
      • Steck A.J.
      • Ernst B.
      • Herrendorff R.
      • Hänggi P.
      Selective inhibition of anti-MAG IgM autoantibody binding to myelin by an antigen-specific glycopolymer.
      ). Investigations revealed that practical doses of PPSGG were able to significantly reduce IgM that binds to MAG. Doses of 10 μg PPSGG were sufficient to remove >90% of 60 and 120 μg of circulating mouse anti-MAG IgM from blood in a mouse model. Reductions in antibody were sustained as shown by measurements at 24 and 96 h post PPSGG administration, demonstrating the pharmacologic feasibility of this therapeutic approach. One can refer to such treatment as antigen-specific immunotherapy (
      • Steinman L.
      A sugar-coated strategy to treat a rare neurologic disease provides a blueprint for a decoy glycan therapeutic and a potential vaccine for CoViD-19: an Editorial Highlight for “Selective inhibition of anti-MAG IgM autoantibody binding to myelin by an antigen specific glycopolymer”on page 486.
      ).
      These experiments provide the rationale for the use of this targeted therapy for the removal of anti-MAG antibodies in clinical trials, either in vivo or ex vivo. This treatment could be used in the anti-MAG neuropathy as a standalone therapy or in combination with anti B cells therapy, so that patients would benefit from both fast removal and long-term suppression of anti-MAG IgM autoantibody production. A selective immunoadsorption column coated with the synthetic HNK-1 trisaccharide would provide a promising alternative for the rapid reduction of anti-MAG antibodies, as similar extracorporeal approaches have been used to treat a range of conditions including Guillain–Barré syndrome, CIDP or myasthenia gravis (
      • Oji S.
      • Nomura K.
      Immunoadsorption in neurological disorders.
      ).

      Declaration of competing interest

      A.J.S. is a cofounder and shareholder of Polyneuron, a spin off of the University of Basel, Switzerland.

      Acknowledgements

      I appreciate the advice of Ruben Herrendorff and insightful discussions with the Polyneuron team.

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