IgM Monoclonal Gammopathy Research Articles

A characteristic vesiculobullous eruption in patients with chronic lymphocytic leukemia

We report ten cases of a characteristic vesiculobullous eruption in patients with chronic lymphocytic leukemia. Clinically, six lesions were thought to represent insect bites. All ten patients had bone marrow examinations that confirmed the diagnosis of chronic lymphocytic leukemia. In six of ten patients serum protein and immunoelectrophoresis were performed. Six patients had immunoglobulin disturbances: one polyclonal IgG and IgM gammopathy, two monoclonal IgM gammopathies, two decreased levels of IgA, and one hypogammaglobulinemia. Direct and indirect immunofluorescence procedures were performed on two patients and results were negative. Immunoperoxidase procedures for IgG stained nonspecifically along torn/separated areas of the basement membrane in five patients. No immunohistochemistry was performed on the remaining three patients. The etiology and pathogenesis of these lesions are unknown. We favor the concept that they represent an unusual reaction to an arthropod bite, secondary to the underlying lymphoproliferative disorder. A second, and less likely theory, is that these lesions represent an unusual clinical presentation of bullous pemphigoid in patients with chronic lymphocytic leukemia.

Monoclonal gammopathy and neuropathy

Immunoblot analysis was performed on the serum from 29 patients with polyneuropathy and monoclonal gammopathy. Nine patients had IgM spikes, and six of the nine had reactivity against myelin-associated glycoprotein (MAG) associated with a slowly progressive, predominantly sensory neuropathy. In contrast, 23 patients who lacked anti-MAG reactivity had more severe sensory motor neuropathy. Thus, IgM monoclonal gammopathy with reactivity against MAG may define a distinct clinical entity.

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We retrospectively evaluated the clinical features, serum levels of IgM, and prevalence of IgM related diseases in patients with serum immunofixation electrophoresis (sIFE) confirmed IgM monoclonal gammopathy at our center.We included patients with sIFE confirmed IgM monoclonal gammopathy between January 2008 and December 2014 in this retrospective study. We evaluated clinical data, sIFE, serum IgM levels, and diagnosis.In total, 7107 patients had sIFE confirmed monoclonal gammopathy, with 377 (5.3%) patients having the IgM type. The median age was 62 years (range, 19–105 years). The median level of serum IgM is 8.3 g/L (range, 0.24–150 g/L). The diagnosis included monoclonal gammopathy of undetermined significance (MGUS, 157 patients, 41.6%), Waldenstrom macroglobulinemia (WM, 105 patients, 27.9%), B cell non-Hodgkin’s lymphoma (69 patients, 18.3%), primary cold agglutinin disease (pCAD, 16 patients, 4.2%), primary amyloidosis (14 patients, 3.7%), cryoglobulinaemia (six patients, 1.6%), IgM MGUS associated neuropathy (five patients, 1.3%), multiple myeloma (three patients, 0.8%), and POEMS syndrome (two patients, 0.5%). Levels of serum IgM > 15.5 g/L were 80.6% sensitive and 89.2% specific for the diagnosis of WM. Kappa type light chain indicated the diagnosis of WM, pCAD, IgM MGUS associated neuropathy and cryoglobulinaemia, while lambda type light chain indicated POEMS and amyloidosis. There were 41/157 (26.1%) MGUS patients diagnosed with complications due to IgM-unrelated autoimmune diseases.IgM monoclonal gammopathy contains a broad spectrum of diseases. Levels of serum IgM and the type of light chain can be used to help with differential diagnosis. The association between MGUS and some autoimmune diseases requires further investigation.

Pattern of reactivity of IgM from the sera of eight patients with IgM monoclonal gammopathy and neuropathy with components of neural tissues: Evidence for interaction with more than one epitope

It has been postulated that binding of monoclonal IgM from the sera of some patients with IgM monoclonal gammopathy and neuropathy to components of peripheral nerve may play a key role in the pathogenesis of the neuropathy. Serum IgM from these patients has been shown to bind to antigenic determinants shared by the myelin-associated glycoprotein (MAG) and a polar glycolipid from peripheral nerve. Here we describe a study of sera from eight patients with IgM monoclonal gammopathy and neuropathy. Five of the patients had serum IgM directed both against MAG and one or two polar glycolipids from peripheral nerve. One of the patients had serum IgM that bound to a peripheral nerve glycolipid but not to MAG; no one had serum IgM that bound to MAG but not to a peripheral nerve glycolipid. The relative affinity of IgM from the sera of the patients for proteins in peripheral nerves of chickens, dogs, and humans varied from patient to patient. These data indicate that the epitope against which the serum IgM from these patients is directed is not necessarily the same in all of the cases.

A Case of Malignant Histiocytosis with IgM Monoclonal Gammopathy and a Hypertetraploid Type of Chromosomal Abnormality

A Case of Malignant Histiocytosis with IgM Monoclonal Gammopathy and a Hypertetraploid Type of Chromosomal Abnormality

Cytogenetic studies in 77 patients with chronic lymphocytic leukemia: correlations with clinical, immunologic, and phenotypic data.

Cytogenetic analyses by G-banding and/or Q-banding techniques of polyclonal B cell mitogen-stimulated peripheral blood lymphocytes in 77 patients with chronic lymphocytic leukemia were carried out in the present study. Adequate metaphases were obtained in 65 patients (84%). Of 29 patients with abnormal karyotypes, ten (34%) had trisomy 12 as the sole abnormality, eight (28%) had trisomy 12 in combination with other karyotypic changes, and the remaining 11 had various karyotypic changes other than trisomy 12. There was a significant relationship between the abnormal karyotype and disease status, clinical stage, lymphocyte count, bone marrow infiltration pattern, monoclonal IgM gammopathy, and urinary monoclonal-free light chain status. Six of seven patients (87%) with trisomy 12 only had stage 0-11 disease, whereas all eight patients with trisomy 12 with other changes had stage III or IV disease (P less than .02). However, of nine patients with other karyotypic changes without trisomy 12, five had stage 0-II and four had stage III or IV disease. These observations suggest that trisomy 12 may be the primary or the earliest karyotypic change in a majority of aneuploid patients with chronic lymphocytic leukemia, and that other karyotypic changes in addition to trisomy 12 may develop as a result of clonal evolution, dedifferentiation, or therapy. Of nine patients in whom autopsy studies were carried out, four were found to have diffuse histiocytic lymphoma or Richter's syndrome (three with trisomy 12 in combination with other chromosome changes and one with normal karyotype). Our findings clearly demonstrate that cytogenetic study may be of value in the clinical and prognostic evaluation of patients with chronic lymphocytic leukemia.

Anti-idiotypic antibodies in a patient with monoclonal rheumatoid factor after pneumococcal bacteremia.

A 51-yr-old Japanese female patient with monoclonal IgM gammopathy with rheumatoid factor activity was admitted because of pneumococcal bacteremia. About 2 wk after admission, her rheumatoid factor activity became undetectable by RAHA test and radioimmunoassay, subsequent to the initial marked elevation. The suppressive capacity of the patient's IgG fraction on the rheumatoid activity of her monoclonal IgM on January 11 was determined. The IgG fraction obtained on February 22 blocked the binding of the rheumatoid factor to rabbit IgG. The suppressive activity in the IgG fraction of February 22 was shown to be localized within the F(ab')2 fragment. Furthermore, the specificity of the suppressive serum factor was shown by the inability to block the binding of SRBC coupled with diazotized phosphorylcholine to anti-pneumococcal antibody. Thus, the marked reduction of rheumatoid factor activity was considered to result from anti-idiotypic antibody transiently appearing in her serum after pneumococcal bacteremia.

Hyperviscosity syndrome with IgM monoclonal gammopathy and hepatic plasmacytoid lymphosarcoma in a cat

ABSTRACTA 19‐month‐old cat investigated because of depression, anorexia, polyuria, and polydipsia was found to have hepatomegaly, retinal haemorrhages, and distended tortuous retinal veins. Prolonged bleeding occurred after venipuncture, and serum was hyperviscous due to an immunoglobulin M monoclonal gammopathy. Prothrombin and activated partial thromboplastin times were prolonged, thrombin clotting time was only slightly prolonged and the activities of coagulation factors VII, VIII and IX were normal. The cat died suddenly before the origin of the immunoglobulin could be determined. Hepatic plasmacytoid lymphosarcoma was found at post‐mortem examination. The pathophysiology of hyperviscosity syndrome is discussed and the observations in this cat are compared with those reported in the dog.

IgM monoclonal gammopathy and oral lupus erythematosus — A case report

A case of an IgM monoclonal gammopathy associated with oral lesions of lupus erythematosus is described and the possible interrelationship of the lesions discussed.

Use of 2-mercaptoethanol to facilitate detection and classification of IgM abnormalities by immunoelectrophoresis

IgM immunoglobulins in elevated serum concentrations have a tendency to polymerize and form aggregates. When subjected to immunoelectrophoresis these proteins may deposit at the point of origin. This can result in failure to detect an IgM abnormality or the masking of other serum protein abnormalities migrating near the area of application. This paper demonstrates the importance of using reducing agents such as 2-mercaptoethanol not only to detect and/or to confirm the monoclonal IgM gammopathies but also to unmask other protein abnormalities.

Blast Cell Leukemia with IgM Monoclonal Gammopathy and Intracytoplasmic Vacuoles and Auerbody- like Inclusions

A patient with acute leukemia and an IgM, kappa (IgMkappa) monoclonal gammopathy, Bence-Jones proteinuria, and blasts containing intracytoplasmic vacuoles with peroxidase-positive inclusions is discussed. Special stains, immunofluorescence, and electron microscopy suggested that the vacuoles were autophagosomes containing Auer-body-like inclusions, and that the blast cells did not synthesize the paraprotein. Chemotherapy with cyclophosphamide, vincristine, and prednisone resulted in transient improvement of the leukemia, but the level of the paraprotein was unchanged. Other case reports involving monoclonal gammopathy in association with acute leukemia are reviewed and contrasted with this case.

A Case of Chronic Lymphocytic Leukemia with IgM Monoclonal Gammopathy

A Case of Chronic Lymphocytic Leukemia with IgM Monoclonal Gammopathy

Electrophoresis of human multiple myeloma and waldenström's macroglobulinemia sera in sodium dodecyl sulfate polyacrylamide gels

Sera from normal persons and patients with IgA, IgD, IgG, and IgM monoclonal gammopathies were electrophoresed in polyacrylamide gels containing sodium dodecyl sulfate. The gels were stained with Coomassie blue or were used for immunodiffusion. By this method IgG multiple myeloma and IgM Waldenström's macroglobulinemia sera were readily distinguished by electrophoresis alone, whereas IgA and IgD myeloma sera were distinguished by further immunodiffusion against anti-α-chain antibody and anti-δ-chain antibody.

Varied manifestations of a familial lymphoproliferative disorder

In a sibship of nine adults, four died of lymphocytic or histiocytic lymphomas, and one of Waldenström's macroglobullnemia (immunoglobulin M [IgM], kappa type) complicated by adenocarcinoma of the lung. In the next generation, one member died of Hodgkin's disease; four of nine healthy persons had impaired lymphocyte transformation in vitro in response to phytohemagglutinin-P (PHA-P), and three of these had polyclonal elevations in IgM levels. Subsequent to these observations, adenocarcinoma of the lung developed in one woman with immune defects, and lymphocytic leukemia developed in her 3 year old grandson. The findings in this family point to a genetically regulated defect of immunity expressed as diverse lymphoproliferative disorders, including polyclonal and monoclonal IgM gammopathies. The occurrence of pulmonary adenocarcinoma in two members suggests genetic and immunologic determinants in these instances.

Methodologic Differences in Values for M-Proteins in Serum, as Measured by Three Techniques

Accurate and reproducible measurement of M-proteins is essential for managing patients with monocional gammopathies, but serum protein electrophoresis, radial immunodiffusion, and electroimmunodiffusion yield comparatively divergent results. We have studied these differences and their causes. Sera from cases of IgG-monoclonal gammopathy, IgA-monoclonal gammopathy, and IgM-monoclonal gammopathy were assayed by each of the three techniques. Results indicated inter-method discrepancies as great as fivefold for all proteins studied. For IgG-monoclonal gammopathy, radial immunodiffusion values were less consistently so. For IgA-monoclonal gammopathy, both radial immunodiffusion and electroimmunodiffusion gave lower results than did serum protein electrophoresis. For IgM-monoclonal gammopathy, results were variable, but values by radial immunodiffusion tended to be higher than, and electroimmunodiffusion comparable to, those for serum protein electrophoresis. The differences were not correlated with protein abundance, serum freshness, immunoglobulin class, light-chain type, ultracentrifugal characteristics, or electrophoretic mobility. Clearly, values for M-protein concentration depend on the techniques used to obtain them. We postulate that subclass differences may contribute to the diversity of radial immunodiffusion results, and that for electroimmunodiffusion the fixed electrophoretic mobility of M-proteins leads to unpredictable results. We conclude that serum protein electrophoresis is the best of the three assay techniques for M-proteins.

Pleuropulmonary Manifestations of Waldenstrom’s Macroglobulinemia

aldenstrom's macroglobulinemia ( WMG ) is a rare lymphoproliferative disorder of insidious onset and relatively benign clinical course which predominantly affects the elderly. WMG is characterized by anemia, an elevated erythrocyte sedimentation rate, lymphocytic tumor infiltration of the bone marrow, and a monoclonal IGM gammop athy.' Peripheral lymphadenopathy, hepatosplenomegaly, and ocular or central nervous symptoms may variably be present. In contrast to other tumors of lymphocytic origin, the recorded incidence of pleuropulmonary involvement in patients with macroglobulinemia is quite low. Excluding congestive heart failure and infection, pulmonary involvement with WMG has varied from 0 percent to 3 percent in several seriesSu This compares to a 30 percent incidence of thoracic tumor involvement in patients with other ly~nphomas.~ Recent experience with two patients with WMG who presented as challenging pulmonary diagnostic problems stimulated this review of our experience to define the incidence and clinical features of pulmonary involvement. Surprisingly, five of the U) patients reviewed demonstrated thoracic involvement. The details of these five patients and a review of ten previously reported patients with pulmonary syndromes secondary to WMG form the basis of this report. with abnormal chest x-ray pic- in the absence of lymphadenopathy, hepatosplenomegaly, and ocular changes and inchded two patients who were not anemic. Pulmonary biopay or necropsy specimens from four pa tients showed an infiltration of hutg, pleura, or hilar lymph nodes by lymphocytes and phacytoid forms. The infiltrate tended to be patchy with sheets of lymphocytes replacing the long parenchyma In some areas, the lympbocytk infiltrate was exclusively interstitial mimicing the histologic pattern of lymphocytic interstitial peemonia In the absence of therapy tbe pulmonary abnormalities were inshliowly progressive over yervs. Three of the four patients treated with chlorambucil achieved slgnificad radiographic clearing in one to three months. One patient died from dBose pl~hnonary involvement in her eighth year of chlorambodl tberapy.

Monoclonal gammopathies associated with lymphoproliferative disorders: a morphologic study.

In 15 patients with lymphoproliferative diseases of various types, histologic studies suggested monoclonal gammopathy. This was confirmed immunoelectrophoretically in the serum, urine, or both, from 10 patients. Seven of these 10 patients had IgM (kappa), one had IgM (lambda), one had IgA (kappa), and one had Bence Jones (lambda). Of the other five patients, three had polyclonal IgM elevations and two had no detectable monoclonal or polyclonal immunoglobulin abnormalities. Nuclear periodic acid-Schiff positive globules, heretofore considered to be characteristic of macroglobulinemia of Waldenstrom, were found in only three patients with IgM monoclonal gammopathy. In two of these, the globules were found only after a prolonged search. They were also seen in one patient with IgA monoclonal gammopathy. They were abundant in one of three patients with polyclonal IgM gammopathy. A high frequency of nuclear PAS positive globules was also observed in three additional patients. One of these patients had an unclassifiable malignant lymphoma involving a submandibular lymph node, and the other two had lymphoid hyperplasias involving the skin and nasopharynx, respectively. Nuclear periodic acid-Schiff positive globules were more abundant and more consistently present in our cases of polyclonal IgM gammopathy than in cases with monoclonal IgM gammopathy, regardless of the neoplastic or non-neoplastic nature of the immunoglobulin-producing lesions.

Intracranial suppuration.

<h3>Background</h3> Treatment with anti-B cell antibody rituximab may ameliorate the disease course in a subgroup of patients with polyneuropathy associated with IgM monoclonal gammopathy. Polymorphisms of leukocyte IgG receptors (FcγR) that influence efficiency of antibody-dependent cell-mediated cytotoxicity determine rituximab efficacy in patients with lymphoma and autoimmune disease. <h3>Objective</h3> To investigate the association of FcγRIIA and FcγRIIIA polymorphisms with the response to rituximab treatment in a cohort of patients with polyneuropathy associated with IgM monoclonal gammopathy (PNP-IgM) with and without antimyelin-associated glycoprotein antibodies. <h3>Methods</h3> We determined FcγRIIA-R/H131 and FcγRIIIA-V/F158 genotypes in 27 patients with PNP-IgM using allele-specific PCR and Sanger sequencing. <h3>Results</h3> The FcγRIIIA-V/V158 genotype was associated with functional improvement (p=0.02) after 1 year. <h3>Conclusions</h3> FcγRIIIA polymorphisms are potential biomarkers for response to rituximab treatment in polyneuropathy associated with IgM monoclonal gammopathy.