IgM Monoclonal Gammopathy Research Articles

Anti-alpha- and beta-tubulin IgM antibodies in dysimmune neuropathies

An increased frequency of serum IgM antibodies to beta-tubulin has been found by ELISA in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and the Guillain-Barré syndrome (GBS). We used an immunoblot technique to compare the frequency, titer and specificity of anti-tubulin IgM antibodies in 207 patients with different neuropathies, 109 with other neurological disease (OND) and 110 non-neurological controls. High titers of serum anti-tubulin IgM antibodies (> 1:1600) were present in 2 patients with CIDP (10.5%), 1 with multifocal motor neuropathy (MMN) (11%), 1 with GBS (1.8%), two with IgM monoclonal gammopathy, one with (1.3%) and one without neuropathy (2.1%), and in two with OND (1.8%). Even if the relative binding to alpha- and beta-tubulin differed among positive patients, in all IgM bound to both tubulin subunits. All positive patients had a similarly intense IgM reactivity with tubulin by ELISA that showed high anti-tubulin IgM in 4 additional CIDP patients (total positive by ELISA 30%) and in 7 of 23 normal subjects (30%). Even if high anti-tubulin IgM were slightly more frequent by immunoblot in chronic dysimmune neuropathies than in other diseases, possibly reflecting a secondary response to neural damage during an ongoing immune response, their relatively low frequency in these diseases does not seem to justify their measurement for diagnostic application.

Avidity distribution of antibodies against peripheral nerve myelin in patients with polyneuropathy associated with IgM monoclonal gammopathy and in healthy controls

To elucidate the role and nature of antibodies against peripheral nerve myelin (PNM) we studied their avidity distribution. Twelve patients with demyelinating polyneuropathy associated with IgM monoclonal gammopathy were compared with 12 healthy blood donors previously found to have anti-PNM antibodies of IgM isotype. For comparison, the avidity distribution of IgM antibodies against the varicella zoster antigen in 10 patients with herpes zoster infection was also studied. Microtitre plates containing antibody bound to antigen were exposed to increasing concentrations of sodium thiocyanate (NaSCN) followed by an ELISA assay. NaSCN changes the ion strength and the pH, and thereby the critical conditions for antibody-antigen binding. Resistance to NaSCN was used as a measure of antibody avidity. Anti-PNM antibodies from patients with monoclonal gammopathy were of predominantly low avidity whereas antibodies from blood donors were of predominantly high avidity. Avidity index, representing the molar concentration of NaSCN required to reduce the initial absorbance values by 50%, was on average 11.7 times higher in blood donors (range 0.24-2.65, mean = 0.82) than in patients with monoclonal gammopathy (range 0.04-0.10, mean = 0.07) ( p = 0.002). On the other hand, patients with monoclonal gammopathy had on average a 100-fold higher relative concentration of antibodies against PNM compared to blood donors (range 4.1–392.6 AU, mean 85.0 AU, and range 0.2-1.7 AU, mean 0.85 AU, respectively) ( p = 0.002). Antibodies against the varicella zoster antigen from patients with herpes zoster showed a high avidity index (range 0.25-2.6, mean = 1.24). Using Western blot, several 14–30 kDa proteins in PNM were found to be the target antigen for IgM anti-PNM antibodies in both patients with monoclonal gammopathy and polyneuropathy, and in blood donors. Additional bands in the 43–67 kDa and > 94 kDa regions were commoner in blood donors than in patients with monoclonal gammopathy and polyneuropathy. These differences in staining pattern may reflect differences in avidity distribution or a qualitative difference at antigen binding sites of the anti-PNM antibodies. In conclusion, we found a strikingly low avidity of anti-PNM antibodies from patients with monoclonal gammopathy and polyneuropathy, and their pathogenetic role could apparently be questioned. However, low avidity implies reduced systemic elimination, with an increased risk of pathological depositions. This together with complement activation is an attractive pathogenetic model.

Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies.

Approximately 10% of patients with peripheral neuropathy of otherwise unknown etiology have an associated monoclonal gammopathy. Both the neuropathies and the monoclonal gammopathies in these patients are heterogeneous, but several distinct clinical syndromes that may respond to specific therapies can be recognized. It is important to recognize these syndromes because monoclonal gammopathies also occur in 1% of the normal adult population, and in some cases, monoclonal gammopathies are coincidental and unrelated to the neuropathy. In patients with IgM monoclonal gammopathies, IgM M proteins frequently have autoantibody activity and are implicated in the pathogenesis of the neuropathy. IgM M proteins that bind to myelin-associated glycoprotein (MAG) have been shown to cause demyelinating peripheral neuropathy; anti-GM1 antibody activity is associated with predominantly motor neuropathy, and anti-sulfatide or chondroitin sulfate antibodies are associated with sensory neuropathy. The IgM monoclonal gammopathies may be malignant or nonmalignant, and polyclonal antibodies with the same specificities are associated with similar clinical presentations in the absence of monoclonal gammopathy. IgG or IgA monoclonal gammopathies are associated with neuropathy in patients with osteosclerotic myeloma or the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy myeloma, and skin changes). Amyloidosis or cryoglobulinemic neuropathies can occur with either IgM or IgG and IgA monoclonal gammopathies. Therapeutic intervention depends on the specific clinical syndrome but is generally directed at removing the autoantibodies, reducing the number of monoclonal B cells, and interfering with the effector mechanisms.

Neuropathy associated with "benign" anti-myelin-associated glycoprotein IgM gammopathy: clinical, immunological, neurophysiological pathological findings and response to treatment in 33 cases.

We studied 33 patients presenting with a peripheral neuropathy associated with non-malignant anti-myelin-associated glycoprotein (MAG) IgM monoclonal gammopathy (MG) in an attempt to delineate their clinical, immunological, electrophysiological and pathological characteristics; we also reviewed our experience concerning long-term follow-up and therapy. Peripheral neuropathy associated with non-malignant anti-MAG IgM MG was observed mostly in males (sex ratio 7.2), and mean age at onset was 67 years (range 46-81). A predominantly sensory pattern was noted in more than 80% of cases, although some patients were affected by a predominantly motor peripheral neuropathy. Although disease progression was slow in most cases, 45% of patients suffered severe disability, and in 2 cases, the patient's death appeared to stem directly from the neuropathy. The electrophysiological findings were indicative of a demyelinating process in 90% of cases, and electron microscopic examination of nerve biopsy specimens demonstrated widening of the myelin lamellae in more than 95% of cases. Most of our patients showed a disappointing response to steroids and chemotherapy or plasma exchanges. Intravenous immune globulin, evaluated in 17 patients, had a transient, mostly subjective effect in 35% and led to a clear-cut improvement in 24% of cases. We did not observe any correlation between the severity of the clinical picture and the anti-sulphoglucuronyl paragloboside antibody titre; in individual cases, clinical improvement occurred without lowering of IgM levels. Although the severity and the rate of progression may greatly vary from patient to patient, the combination of clinical, electrophysiological and pathological features delineates a characteristic pattern in peripheral neuropathy associated with non-malignant anti-MAG IgM MG.

Human immunoglobulin treatment of multifocal motor neuropathy and polyneuropathy associated with monoclonal gammopathy.

Intravenous human immune globulin (IVIg) has been proposed for the treatment of various peripheral neuropathies that are considered to be immunemediated. The results are reported of an open trial conducted in multifocal motor neuropathy and polyneuropathy associated with monoclonal gammopathy. Six cases with multifocal motor neuropathy, selected on clinical and electrophysiological criteria (four of six patients also had significantly high anti-GM1 titres), received IVIg monthly, at doses varying from 1.6 to 2.5 mg/kg, over three to 13 months. The initial response to treatment was dramatic in 3/6 cases (with improvement of at least two grades on the MRC scale in the five more severely affected muscles). The final evaluation showed a good result in 4/6 cases, but the conduction blocks were not significantly reduced. In 13 other cases with polyneuropathy associated with IgM monoclonal gammopathy of unknown significance, IVIg was of benefit, with improvement of at least one grade on the Prineas score, in 4/7 cases previously treated with immunosuppression and 2/3 cases not treated before IVIg. In the last group of four patients with polyneuropathy and IgG monoclonal gammopathy, IVIg was followed by clinical improvement in the two cases with a chronic demyelinating polyneuropathy.

Frequency and clinical correlates of anti–neural IgM antibodies in neuropathy associated with IgM monoclonal gammopathy

We studied the frequency and clinical correlates of different IgM specificities in 75 patients with neuropathy associated with IgM monoclonal gammopathy. Patients were tested for IgM reactivity with the myelin-associated glycoprotein, P0, neurofilaments, and tubulin by immunoblot; with GM1, asialo-GM1, GM2, GD1a, GD1b, sulfatide, and chondroitin sulfate C by enzyme-linked immunosorbent assay; and with brain and nerve glycolipids by overlay high-performance thin-layer chromatography. Forty-two patients (56%) had high titers of IgM antibodies to MAG; 4 (5%), to sulfatide (1 also to myelin-associated glycoprotein); 4 (5%), to the 200-kd neurofilament (2 also to myelin-associated protein); and 1 each, to GD1b and chondroitin sulfate C. No reactivity was found in 26 patients (35%). More patients with anti-myelin-associated glycoprotein IgM (62%) than with unknown IgM reactivity (31%) had a predominantly sensory neuropathy (p < 0.025). Nerve conduction findings were consistent with a demyelinating neuropathy in 77% of patients reactive to myelin-associated glycoprotein and 24% with unknown reactivity (p < 0.0001) and the mean conduction velocity of peroneal nerve was lower in the former group (22.9 m/sec) than in the latter group (39.6 m/sec) (p < 0.000001). Patients with anti-sulfatide IgM had a sensorimotor neuropathy with morphological evidence of demyelination while anti-neurofilament IgM was not associated with homogeneous findings. Patients with anti-GD1b or anti-chondroitin sulfate C IgM had a predominantly motor impairment. The frequent occurrence of anti-neural IgM antibodies in neuropathy associated with IgM gammopathy, and their frequent, though not constant association with similar neuropathy features, support their possible pathogenetic role in the neuropathy.

Schnitzler's syndrome associated with sensorimotor neuropathy

We describe a patient with chronic urticaria in association with monoclonal IgM gammop-athy (Schnitzler's syndrome). Seven years after the onset of the cutaneous lesions sensorimotor neuropathy developed. Myelin-associated glycoprotein was detected in the patient's serum. High doses of corticosteroids improved the skin condition but failed to prevent the neuropathy. Six months of treatment with immunoglobulins was without benefit.

Mucosa-Associated Lymphoid Tissue Lymphoma of the Lung With Cold-reacting Autoantibody-mediated Hemolytic Anemia

Mucosa-associated lymphoid tissue lymphoma (MALT-oma) of the lung is a rare low-grade B cell lymphoma arising from bronchus-associated lymphoid tissue. This report concerns a 39-year-old woman with bilateral diffuse alveolar consolidations and cold-reacting autoantibody-mediated hemolytic anemia. Open-lung biopsy showed angulated lymphoid cells with lymphoepithelial lesions. Immunocytochemistry revealed that the lymphoid cells were positive for CD19, CD20, and IgM (lambda), which was consistent with immunophenotype of MALToma. The serum immunoelectrophoresis demonstrated IgM (lambda) monoclonal gammopathy. The association of cold-reacting auto-antibody-mediated hemolytic anemia with MALToma, to our knowledge, has never been reported before in the English language.

Peripheral neuropathy in IgM monoclonal gammopathy and Wäldenstrom's macroglobulinemia: a frequent complication in elderly males with low MAG-reactive serum monoclonal component.

Peripheral neuropathy (PN) is a frequent complication during primary macroglobulinemia (PM), whose immunological genesis has been suggested by various authors. This study involved 65 PM patients (44 men and 21 women aged 35-78), diagnostically divided into MGUS (31 cases), and indolent (IWM, 24 cases) or symptomatic (WM, 10 cases) Waldenstrom macroglobulinemia groups. All patients underwent neurological examination, including electrodiagnostic evaluation and the determination of the serum titre of antimyelin-associated glycoprotein (MAG). An evaluation was made of the prevalence of PN and its correlation with a series of hematological variables. The prevalence of PN was 31.6%: of those with PN, 73.1% manifested both clinical and electrophysiological signs of PN, primarily of the demyelinating type. Significant correlations emerged between the presence of PN and sex (M vs. F P = 0.0001), advanced age (P = 0.049), low MC levels (P = 0.025), high anti-MAG titres (P = 0.001) and high Hb levels (P = 0.001). No significant correlation with the diagnostic definition of PM was found, although the majority of cases with (particularly demyelinating) PN were MGUS or IWM. At multivariate analysis, the presence of PN significantly correlated with sex (P = 0.0001), age (P = 0.019), and anti-MAG titre (P = 0.001). Ten of the 26 PN cases showed no MAG reactivity. Significant correlations between PN and low serum MC levels/high MAG reactivity support the hypothesis of the antibody-mediated origin of many PN, and that the presence of PN depends on the characteristics of the proliferating pathological B clone, rather than on the tumor burden of the form of macroglobulinemia. Clinically, our data reconfirm the frequency of PN during PM and indicate simple clinicohematological variables useful for identifying patients at high neuropathic risk.

Polyneuropathy associated with IgA monoclonal gammopathy of undetermined significance

Although polyneuropathies associated with IgM and IgG monoclonal gammopathies have been well described, polyneuropathy with IgA monoclonal gammopathy of undetermined significance (MGUS) is less commonly seen and has not been well studied. We reviewed the clinical and electrodiagnostic features of 5 such patients, and the sural nerve biopsy findings in 4 of them. One patient was diabetic, while 4 were free of other diagnoses commonly associated with neuropathy. Clinical presentations were varied. Electrodiagnostic and histological studies ranged from primary demyelination to primary axon loss to a mixed axonal/demyelinating picture. Three patients who were treated appeared to respond to prednisone or intravenous gamma globulin, despite clear clinical, electrodiagnostic, and histological differences. We conclude that the polyneuropathy associated with IgA MGUS is heterogeneous, similar to that in IgM and IgG MGUS. A trial of immunomodulating therapy appears to be warranted in such patients if the neuropathy is sufficiently severe.

Anti-sulfatide antibodies in neurological disease: binding to rat dorsal root ganglia neurons

Increased titers of anti-sulfatide antibodies were detected by ELISA in 5 of 200 patients and control subjects. All 5 patients had sensory impairment; 4 had neuropathy, and one had multiple sclerosis. Of the patients with neuropathy, 2 had a clinical syndrome of small fiber sensory neuropathy with normal electrophysiological or nerve biopsy studies, 1 had a sensorimotor axonal neuropathy associated with IgM monoclonal gammopathy, and 1 had sensorimotor neuropathy with multifocal motor conduction block and anti-GM1 antibodies. The anti-sulfatide antibodies bound to the surface of unfixed rat dorsal root ganglia neurons and human neuroblastoma cells, and to fixed sections of central and peripheral myelin. No binding was detected following intraneural injection into rat sciatic nerves. Pre-absorption with sulfatide but not with galactocerebroside eliminated the tissue binding activity. These findings indicate that increased titers of anti-sulfatide antibodies are found in patients with sensory impairment but are not restricted to a particular neurological syndrome or type of neuropathy. The significance of anti-sulfatide antibodies is uncertain although sulfatide on dorsal root ganglia neurons may be a target antigen.

Monoclonal Proteins in Neuropathy

The presence of a monoclonal protein in the serum of a patient with peripheral neuropathy raises the suspicion of systemic amyloidosis, POEMS syndrome, macroglobulinemia, multiple myeloma, or lymphoma. If these conditions are excluded, the patient is classified as having a monoclonal gammopathy of undetermined significance (MGUS) with an associated neuropathy. Approximately one half of patients with peripheral neuropathy and IgM monoclonal gammopathy have IgM antibodies that bind to a myelin-associated glycoprotein (MAG). In addition to MAG, other antigens such as glycolipids or gangliosides represent other target antigens. Monoclonal gammopathies and motor neuron diseases have also been reported. Sensorimotor peripheral neuropathy occurs in about 15% of patients with primary amyloidosis but is uncommon in multiple myeloma.

Vasculitic neuropathy in a patient with cryoglobulinemia and anti‐MAG IGM monoclonal gammopathy

A patient with sensorimotor mononeuritis multiplex had a type II cryoglobulin with an IgM kappa M-protein that appeared to contain monoclonal anti-MAG antibodies of the same isotype. A sural nerve biopsy demonstrated necrotizing arteritis and features of both axonal degeneration and demyelination. IgM kappa and C3 deposits were present on the myelin sheath of some residual nerve fibers. The findings suggest that the anti-MAG antibodies contributed to the myelin damage, while cryoprecipitates may have caused the vasculitis and axonal degeneration.

Low-dose interferon-alpha in stage-I multiple myeloma and in IgM monoclonal gammopathy. Eastern Cooperative Study Group on Monoclonal Gammopathies.

Interferon (IFN)-alpha can induce objective responses in advanced-stage multiple myeloma (MM) and can delay disease progression in patients responsive to chemotherapy. We studied the effects of low-dose (3 MU daily) human recombinant IFN-alpha 2b for 6-12 months in 29 consecutive cases of previously untreated, stable-phase, early stage, monoclonal gammopathy (MG) (23 cases of stage I MM and six cases of IgM MG). In 25/29 patients, the disease remained stable throughout the study period. A major objective response was observed in one of five cases of IgA MG. Normal Ig levels increased in all five cases of IgA MG. A significant disease progression occurred in 2/29 cases during the 1-year study period. These data showed that the objective response rate of early-stage MG to low-dose IFN was low and suggested that further investigation should focus on IgA MG.

A clinical, electrophysiological, morphological and immunological study of chronic sensory neuropathy with ataxia and paraesthesia.

We have observed 9 patients (8 men and 1 woman), 58 to 77 years of age with neuropathy with only sensory symptoms and insidious onset. Five of them (4 men and 1 woman) aged 65 to 77 years, had normal serum electrophoretic profiles, while the others (all men), 58 to 74 years, had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinical data were consistent with a sensory neuropathy affecting predominantly the kinesthetic sense (position and vibration sensation). The electrophysiological data indicated predominant sensory axonal neuropathy. Morphological data confirmed the primary axonal damage. Western immunoblot showed that the IgG from a patient without MGUS reacted with a 55 kD protein of dorsal root ganglion homogenate. Three of four patients with IgM MGUS were serum reactive against chondroitin sulfate C (ChS-C) in double immunodiffusion. After absorption with ChS-C the monoclonal peak completely disappeared from two patients and was decreased in the third patient. Our data indicate that immunological abnormalities are part of the pathogenesis for a subgroup of chronic neuropathy with only sensory symptoms.

Axonal neuropathy in a patient with monoclonal IgM kappa reactive with Schmidt-Lantermann incisures

We report a patient with a progressive, predominantly sensory neuropathy and a IgMκ M-protein that binds to Schmidt-Lantermann incisures. A sural nerve biopsy showed primary axonal damage and IgM deposits at Schmidt-Lantermann incisures.were seen by direct immunoperoxidase. Serum from the patient injected into rat sciatic nerve reacts with the incisures as with those in the patient's nerve. The IgMκ M-protein reacts with chondroitin sulfate C and binds to a broad nerve protein band with a mobility of between 170 and 118 kDa. Peripheral neuropathy may be related to the M-protein, which had immunocytochemical reactivity not previously described for patients with polyneuropathy and IgM monoclonal gammopathy.

Spurious hyperphosphatemia in a dog with chronic lymphocytic leukemia and an IgM monoclonal gammopathy.

Spurious hyperphosphatemia was diagnosed in a 6-year-old, neutered female, mixed-breed dog with chronic lymphocytic leukemia associated with an IgM monoclonal gammopathy. The spurious hyperphosphatemia was probably caused by paraprotein precipitation which interfered with the ASTRA 8 automated analyzer measurements. Serial dilutions of the sample did not change the phosphorus value. Another analyzer system in which a protein-free sample was prepared prior to analysis gave a normal serum phosphorus concentration. There was a linear relationship between the amount of paraprotein and the measured total serum inorganic phosphate (r=0.75). A review of 700 chemistry profiles from dogs and cats and a review of 36 cases with polygonal gammopathy and 6 cases with monoclonal gammopathy did not reveal other cases of spurious hyperphosphatemia.

Anti-myelin-associated glycoprotein antibodies in patients with a monoclonal IgM gammopathy and polyneuropathy, and a simplified method for the preparation of glycolipid antigens

The two sulfated glucuronic acid containing glycolipids, sulfate-3-glucuronyl paragloboside (SGPG) and sulfate-3-glucuronyl lactosaminyl paragloboside (SGLPG), were prepared by ion exchange chromatography of lipid extracts from bovine cauda equina. Thin layer chromatography (TLC) immunostaining and an enzyme-linked immunosorbent assay (ELISA) were used to show that the SGPG/SGLPG fraction was free of crossreactive antigenic components such as gangliosides. The results obtained by ELISA demonstrate that sera of all patients were validated IgM monoclonal anti-myelin-associated glycoprotein (MAG) demyelinating neuropathy display high titer antibodies with high affinity type titration curves. These antibodies were absent from the sera of 16 patients with other neurological diseases and ten normal controls. ELISA with SGPG/SGLPG as an antigen appears to be a valuable and highly specific immunodiagnostic test for determining anti-MAG antibody titers in the sera of patients. The amount (≈ 0.4 mg) of SGPG/SGLPG partially purified from 10 g of fresh tissue is sufficient for the preparation of ≈ 100 96-well plates for ELISA procedures.

Antisulfatide antibodies are present in a subpopulation of patients with IGM monoclonal gammopathies with demyelinating neuropathies

Antisulfatide antibodies are present in a subpopulation of patients with IGM monoclonal gammopathies with demyelinating neuropathies

Antisulfatide antibodies are present in a subpopulation of patients with IGM monoclonal gammopathies with demyelinating neuropathies

Antisulfatide antibodies are present in a subpopulation of patients with IGM monoclonal gammopathies with demyelinating neuropathies