IgM in a human neuropathy related to paraproteinemia binds to a carbohydrate determinant in the myelin-associated glycoprotein and to a ganglioside.

Ilyas, Amjad A.; Quarles, Richard H.; MacIntosh, Tracy D.; Dobersen, Michael J.; Trapp, Bruce D.; Dalakas, Marinos C.; Brady, Roscoe O.

doi:10.1073/pnas.81.4.1225

Cited by 220 publications

(91 citation statements)

References 41 publications

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“…Monoclonal immunoglobulin of some patients with a paraprotein associated demyelinating neuropathy binds a shared carbohydrate determinant of the myelin-associated glycoprotein (MAG) and unusual sulfoglucuronyl glycosphingolipids of PNM (13)(14)(15)(16). Serum of these patients demyelinate cat sciatic nerve in the presence of complement (17).…”

Section: Introductionmentioning

confidence: 99%

Anti-peripheral nerve myelin antibodies in Guillain-Barre syndrome bind a neutral glycolipid of peripheral myelin and cross-react with Forssman antigen.

Koski

Chou²,

Jungalwala³

1989

J. Clin. Invest.

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During acute-phase illness, serum of patients with GuillainBarre syndrome (GBS) contain complement-fixing antibodies (Ab) to peripheral nerve myelin (PNM). We investigated PNM lipids as putative antigens for these Ab since GBS serum retained significant reactivity to PNM treated with protease. Ab binding to specific lipids was studied with a C1 fixation and transfer (CFIT) assay using fractions of PNM lipid reincorporated into liposomes as antigen targets or to lipids on HPTLC plates with peroxidase-labeled goat Ab to human IgM. Reactivity was detected to a neutral glycolipid (NGL) of human PNM with a similar number of carbohydrates residues to that of Forssman hapten (Forss). Anti-NGL Ab titers in GBS patients (50-220 U/ml) were significantly elevated over disease and normal controls (0-5 and 0-6 U/ml). We studied possible antigenic cross-reactivity of these Ab with Forss by first quantitating Ab activity with CiFF assay and liposomes containing Forss. All 12 GBS sera tested showed titers (54-272 U/ml) significantly elevated over 11 disease controls (0-22 U/ml) and 25 normal controls (0-11 U/mi). GBS serum Ab reacted with Forss isolated from dog nerve or sheep erythrocytes on HPTLC plates. Further, absorption of 80-100% of anti-NGL Ab activity and 17-97% of anti-PNM Ab activity from eight GBS patient serums was accomplished with liposomes containing Forss but not with control liposomes. In seven GBS patients anti-NGL Ab activity represented only a portion of anti-PNM Ab activity. These results suggest that a glycolipid with antigenic cross-reactivity to Forssman hapten may be responsible for some of the anti-PNM Ab activity in GBS.

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Section: Introductionmentioning

confidence: 99%

Anti-peripheral nerve myelin antibodies in Guillain-Barre syndrome bind a neutral glycolipid of peripheral myelin and cross-react with Forssman antigen.

Koski

Chou²,

Jungalwala³

1989

J. Clin. Invest.

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“…Binding of IgM, IgG, and IgA paraproteins with the acidic glycolipid fractions was determined by an ELISA as described previously (16), except that peroxidase-labeled goat anti-human IgG (y-chain specific) and goat anti-human IgA (a-chain specific) antibodies were used to detect the binding of IgG and IgA, respectively. IgM binding to individual glycolipids was detected by autoradiography of TLC plates that had been overlaid with the patients' sera diluted 1:100 followed by radioiodinated goat anti-human IgM (,uchain specific) (16). Gangliosides were detected by resorcinol spray (27).…”

Section: Methodsmentioning

confidence: 99%

“…Although the etiology of this type of neuropathy remains unknown, the deposition of antibodies on the myelin sheaths of nerves (2)(3)(4)(5)(6)(7)(8) and the binding of IgM and IgG paraproteins to peripheral nerve myelin (6)(7)(8)(9)(10)(11)(12) suggest that the paraproteins play a causative role in neuropathy. Moreover, IgM paraproteins from some polyneuropathy patients have been found to react with human myelin-associated glycoprotein (MAG) by several groups (13)(14)(15)(16). Recently, these antibodies have been shown to react with the carbohydrate moeities of MAG (16)(17)(18), acidic glycolipids of human peripheral nerve (16,19), and low Mr glycoproteins in the peripheral nervous system (18,20,21).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, IgM paraproteins from some polyneuropathy patients have been found to react with human myelin-associated glycoprotein (MAG) by several groups (13)(14)(15)(16). Recently, these antibodies have been shown to react with the carbohydrate moeities of MAG (16)(17)(18), acidic glycolipids of human peripheral nerve (16,19), and low Mr glycoproteins in the peripheral nervous system (18,20,21). However, the antigenic targets for most IgM paraproteins that do not react with MAG remain unknown, although IgM antibody reactivity with chondroitin sulfate C in two patients with the axonal type of neuropathy and epidermolysis has been reported (22).…”

Section: Introductionmentioning

confidence: 99%

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Polyneuropathy with monoclonal gammopathy: glycolipids are frequently antigens for IgM paraproteins.

Ilyas¹,

Quarles

Dalakas

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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Immunoglobulins from patients with paraproteinemic polyneuropathy were screened for reactivity with nerve and brain glycolipids by ELISA and/or a thin-layerchromatogram-overlay technique. The myelin-associated glycoprotein (MAG) has been shown to be an antigen in many neuropathy patients with IgM gammopathy, but this study focused on seven neuropathy patients in which the IgM paraproteins had been shown not to react with this glycoprotein. Five of these seven had IgM that reacted with components in the acidic glycolipid fraction of human sciatic nerve, and three of these IgMs also reacted with components in the acidic glycolipid fraction of human brain. Little or no reactivity with glycolipids was detected for two patients with neuropathy and IgG gammopathy or for two with neuropathy and IgA gammopathy. The results suggest that neuropathy-patient IgM paraproteins not reactive with MAG often react with acidic glycolipids and thus define a subset of paraproteinemic neuropathies. Since the IgM paraproteins that react with MAG also react with acidic glycolipids of nerve, glycolipid antigens appear to be quite common among the IgM paraproteinemic neuropathies.

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“…Antibodies from sera of patients with IgM MGUS neuropathy have been shown to react with various cell surface antigens, including glycoconjugates that express the adhesion-related HNK-1/L2 carbohydrate epitope such as myelinassociated glycoprotein, MAG (Braun et al 1981), P0 protein (Voshol et al 1996), PMP-22 (Hammer et al 1993), cell adhesion molecules (Kruse et al 1984), and sulfoglucuronyl glycolipids (Ilyas et al 1984;van den Berg et al 1996;Lawlor et al 2001). Experimental studies support a neuropathic role for some of these antibodies (Hays et al 1987;Tatum 1993;Corbo and Hays 1998).…”

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confidence: 99%

Antibodies to L‐periaxin in sera of patients with peripheral neuropathy produce experimental sensory nerve conduction deficits

Lawlor¹,

Richards

Vries

et al. 2002

Journal of Neurochemistry

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L-Periaxin is a PDZ-domain protein localized to the plasma membrane of myelinating Schwann cells and plays a key role in the stabilization of mature myelin in peripheral nerves. Mutations in L-periaxin have recently been described in some patients with demyelinating peripheral neuropathy, suggesting that disruption of L-periaxin function may result in nerve injury. In this study, we report the presence of autoantibodies to L-periaxin in sera from two of 12 patients with diabetes mellitus (type 2)-associated neuropathy and three of 17 patients with IgG monoclonal gammopathy of undetermined significance (MGUS) neuropathy, an autoimmune peripheral nerve disorder. By comparison, anti-L-periaxin antibodies were not present in sera from nine patients with IgM MGUS neuropathy or in sera from 10 healthy control subjects. The effect of anti-L-periaxin serum antibody on peripheral nerve function was tested in vivo by intraneural injection. Sera containing anti-L-periaxin antibody, but not sera from age-matched control subjects, injected into the endoneurium of rat sciatic nerve significantly (p < 0.005, n ¼ 3) attenuated sensory-evoked compound muscle action potential (CMAP) amplitudes in the absence of temporal dispersion. In contrast, motor-evoked CMAP amplitudes and latencies were not affected by intraneural injection of sera containing anti-L-periaxin antibody. Light and electron microscopy of anti-L-periaxin serum-injected nerves showed morphologic evidence of demyelination and axon enlargement. Depleting sera of anti-L-periaxin antibodies neutralized the serum-mediated effects on nerve function and nerve morphology. Together, these data support anti-L-periaxin antibody as the pathologic agent in these serum samples. We suggest that anti-L-periaxin antibodies, when present in sera of patients with IgG MGUS-or diabetesassociated peripheral neuropathy, may elicit sensory nerve conduction deficits. Keywords: antibody, diabetes, MGUS, neuropathy, periaxin. Peripheral neuropathies are a heterogeneous group of nerve disorders often characterized by a mixture of sensory and motor disturbances (Adams et al. 1997). Although the etiology of the peripheral neuropathy is often obscure, some patients exhibit strong familial histories consistent with an autosomal dominance, autosomal recessive, or X-linked pattern of inheritance. In other patients, the peripheral neuropathy is acquired such as in monoclonal gammopathy of undetermined significance (MGUS) neuropathy (Kyle 1992) or is secondary to a metabolic disturbance such as diabetes mellitus.Serum autoantibodies have been implicated as potential pathogenic agents in several autoimmune-mediated peripheral nerve disorders (Ho et al. 1998;Quarles and Weiss 1999). In addition, a role of autoimmunity in peripheral nerve disorders associated with metabolic disturbances, such as diabetic neuropathy, has been entertained (Said et al. 1994;Krendel et al. 1995). However, the antigenic specificities Abbreviations used: CMAP, compound muscle action potential; D/P, distal (ankle) to...

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IgM in a human neuropathy related to paraproteinemia binds to a carbohydrate determinant in the myelin-associated glycoprotein and to a ganglioside.

Cited by 220 publications

References 41 publications

Anti-peripheral nerve myelin antibodies in Guillain-Barre syndrome bind a neutral glycolipid of peripheral myelin and cross-react with Forssman antigen.

Anti-peripheral nerve myelin antibodies in Guillain-Barre syndrome bind a neutral glycolipid of peripheral myelin and cross-react with Forssman antigen.

Polyneuropathy with monoclonal gammopathy: glycolipids are frequently antigens for IgM paraproteins.

Antibodies to L‐periaxin in sera of patients with peripheral neuropathy produce experimental sensory nerve conduction deficits

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