Diffuse Hypergammaglobulinemia Research Articles

Polyclonal B-cell lymphocytosis and hypergammaglobulinemia in patients with Gaucher disease.

Sera from 23 individuals with Gaucher disease (GD) were analyzed for hypergammaglobulinemia and oligoclonal and monoclonal gammopathies. Serum IgG level was elevated in 15/23 (65%) patients, and a diffuse hypergammaglobulinemia was present in 10/23 (43%) patients. An oligoclonal gammopathy was noted in six patients, and a monoclonal gammopathy in two. Lymphocyte subset analysis was also carried out in eight individuals with GD. Four of five individuals showed increased surface Ig-positive lymphocytes, while 7/7 were positive for either increased CD19- and/or CD20-positive lymphocytes. An eighth patient was found to have a B-cell leukemia. Statistical analysis of kappa and lambda histograms were suggestive of a monoclonal excess. However, restriction enzyme analysis of four individuals with GD and increased B cells failed to show any evidence of Ig gene rearrangements. Serum Ig abnormalities and perhaps B-cell lymphocytosis appear to be common in the GD patient population and are not associated with circulating monoclonal lymphocytes.

Hypoalbuminemia associated with diffuse hypergammaglobulinemia in chronic diseases: lack of diagnostic specificity.

Although elevated gamma globulin is known to produce hypoalbuminemia both experimentally and in disease, a low albumin concentration in chronic liver disease often is assumed to reflect impaired liver synthetic function. Albumin and gamma globulin measurements in a series of 200 patients with a variety of chronic diseases (including cirrhosis, connective tissue disease, chronic inflammation, and malignancy) associated with diffuse hypergammaglobulinemia were combined with similar measurements from a previous study (Am J Med 1959; 29:596-616). The mean serum albumin concentration correlated inversely with mean gamma globulin, irrespective of disease category. Double reciprocal plot analysis showed that the relationship fits a rectangular hyperbola (r = -0.915, P less than 0.001), with the mean albumin concentration approaching 2.31 g/dL at infinite gamma globulin. This suggests that serum albumin decreases to a similar extent in various chronic diseases and that hypoalbuminemia has no diagnostic implications, except to the extent that it reflects the severity of hypergammaglobulinemia.

Immunoblastic sarcoma.A clinical description

We reviewed the clinical records of 33 patients with Immunoblastic Sarcoma in order to further describe this disease clinically. Several common features were found. Thirty percent of the patients had a history of a prior immune disease or lymphoproliferative malignancy. Forty-four percent of the patients tested had a diffuse hypergammaglobulinemia. Lymphopenia (less than 1,000/mm3) was found in 45%, and anemia occurred in 73%. At initial presentation, 30% of the cases were clinically staged as either stage I or II, whereas 70% were found to be stage III or IV. Forty-nine percent of the patients had systemic symptoms at presentation. The median survival was 14 months. Advanced stage of disease, lymphopenia, and presence of systemic symptomatology were associated with significantly decreased survival times (p less than .05). We conclude that IBS is a clinical entity often associated with prior immune disease and/or diffuse hypergammaglobulinemia.

Immunochemical and physical studies of the Sia test.

The Sia test was performed in strictly standardized conditions in boiled, bidistilled, deionized water (BBD) and in 0.01 M phosphate buffers pH 5.0 and 7.0. Normal human sera and sera from patients with diffuse hypergammaglobulinemia ( greater than 2.0 g/100 ml), immunoglobulin G (IgG) myeloma (M component greater than 5.0 g/100 ml), and Waldenstrom's macroglobulinemia were studied. In BBD all normal sera were Sia-negative, whereas 16 per cent of sera with diffuse hypergammaglobulinemia, 60 per cent of sera with IgG M component, and 44 per cent of macroglobulinemic sera with Sia-positive. Almost all sera from the above mentioned four groups gave positive results in phosphate buffer pH 5.0 and the majority of them, with the exception of normal human sera, gave positive results at pH 7.0. All precipitates isolated from the sera tested showed beta-alpha 2 bands in cellulose acetate electropherograms. Precipitates from the sera with diffuse hypergammaglobulinemia also showed gamma bands, and those from the myelomatous or macroglobulinemic sera showed strong bands corresponding to the M components. Whereas immunoelectrophoresis of the four-fold-concentrated precipitates showed up to 11 precipitation lines, radial immunodiffusion detected up to 18 proteins. The characteristic pattern of IgM/IgG immune complexes was observed in immunoelectrophoresis of Sia precipitates from hypergammaglobulinemic sera with rheumatoid factor. The recovery of immunoglobulins in the Sia precipitates varied greatly but that of IgM was usually greater than that of IgG or IgA. It may be concluded that the Sia test is entirely nonspecific regardless of the buffer or pH at which it is performed. The only advantages of this test seem to be the quick partial purification of IgM components and identification of their light chains, and the possible detection of immune complexes.

Human monoclonal immunoglobulins with antibody-like activity

Sera from 562 patients with IgG, IgA, IgM, IgD or IgE M-components or diffuse hypergammaglobulinemia and from 100 healthy individuals were tested for antibody activity against many or all of 115 different antigens. In low ionic strength buffer ( μ = 0·025), 99 sera (17·8%) had precipitating activity detectable by immunodiffusion against hapten-protein conjugates. DNA, bacterial antigens, carbohydrates, heparin, and phospholipids. Two normal sera gave weak precipitin reactions with nitrophenyl-protein conjugates. In high ionic strength buffer ( μ = 0·2) only 9 of the precipitating sera with M-components, and none of the others, gave strongly positive precipitin reactions with nitrophenyl-protein conjugates, pneumococcal polysaccharides, gums, heparin, cardiolipin, DNA, and nucleoprotein conjugates. M-components from 8 of the 9 precipitating sera, 4 IgG's and 4 IgM's, were purified and their peptic fragments prepared. Two IgG's and two IgM's and their divalent peptic fragments precipitated with DNP- and TNP-BGG when tested by immunodiffusion and quantitative precipitin analysis in high ionic strength buffers. The precipitin curves resembled those observed in conventional antige-antibody systems. They showed weak interaction with various nitrophenyl haptens when tested by hapten inhibition, passive hemagglutination and latex agglutination, modified Farr analyses, equilibrium dialysis, difference spectroscopy, and fluorescence quenching techniques. The low K A values, 10 3 M −1, as determined by Farr analysis and equilibrium dialysis using DNP- and TNP-haptens were consistent with the weak quantitative precipitin and agglutination results. One IgG and one IgM M-component reacted with low and high mol. wt heparins and heparin derivatives showing typical quantitative precipitin curves, but not with other mucopolysaccharides. The strongest reaction was obtained with high mol. wt heparin. This activity was abolished when the amino-sulphate groups were removed from the heparins. Another IgM M-component had antibody-like activity against cardiolipin. Another IgG M-component reacted with bacterial antigens (pneumococcal SI, III, VIII and X) and related substances (gums karaya and myrrh). The reaction could be inhibited with d-glucuronic acid (10 −3 M), d-galacturonic acid (10 −2 M), and l-rhamnose (10 −1 M).

Hepatoma associated with marked plasmacytosis and polyclonal hypergammaglobulinemia

This patient had marked polyclonal hypergammaglobulinemia associated with micronodular cirrhosis and hepatoma. Marked elevation of immunoglobulin levels appeared to be associated with the development of hepatic neoplasia. In addition to bone marrow plasmacytosis, plasma cells were associated with the regenerative cirrhotic and neoplastic hepatic nodules. The immunoglobulin and histopathologic findings suggest that the marked elevation of the gamma globulin levels was related to the neoplastic rather than to the underlying cirrhotic process. This case suggests that diffuse hypergammaglobulinemia and plasma cell hyperactivity may occur with hepatoma.

A Unique lymphoproliferative disorder associated with an IgM platelet agglutinin, diffuse hypergammaglobulinemia, amyloid deposition and excessive urinary excretion of IgG fragments

A case is reported of a lymphoproliferative disorder with autoimmune hemolytic anemia and thrombocytopenia. Platelet agglutinins were demonstrated to be 19S gamma macroglobulins, a unique observation. The disease was initially manifested by lymphocyte and reticulum cell proliferation, and eventually by plasma cell proliferation with amyloid deposition. The patient's serum exhibited extreme diffuse hypergammaglobulinemia with an increase in both IgG and IgM components. The urine was remarkable for its high content of kappa and lambda light chains, Fd-like fragments and Fc-like fragments. The interrelationships between the pathologic findings and protein abnormalities are briefly discussed and compared with the lymphoma associated dysproteinemias reported in the literature.

IMMUNE GLOBULIN LEVELS IN THE SUDDEN DEATH SYNDROME

Serum levels of γG, γM, γA, and total immune globulins were determined on 88 infants with the sudden death syndrome (SDS) and compared with levels on 16 infants who died from known cause and 177 normal age-matched controls. Immune globulin levels in all groups were similar except that SDS infants aged 4 to 6 months had higher mean levels of total gammaglobulin than controls. Immune globulin levels were not correlated with sex or milk agglutinin titers. Three SDS infants (3.5%) had hypogamma-globulinemia and 13 SDS infants (15%) had either elevated γM globulins (9 cases) or diffuse hyper-gammaglobulinemia (4 cases). We conclude that primary derangement of antibody proteins is not a frequent cause of SDS.

Idiopathic autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura associated with diffuse hypergammaglobulinemia, amyloidosis, hypoalbuminemia and plasmacytosis

A case is reported of a sixty-nine year old woman with severe, idiopathic, autoimmune hemolytic anemia which was initially controlled by splenectomy. A relapse associated with the development of severe, autoimmune, thrombocytopenic purpura failed to respond to large doses of prednisone, but was controlled to a variable degree with Imuran. Associated features included diffuse hypergammaglobulinemia, excessive gamma-U proteins in the urine, idiopathic hypoalbuminemia with a greatly reduced total exchangeable albumin pool, amyloidosis in the spleen and other organs, and diffuse plasmacytosis of the bone marrow, lymph nodes, and thoracic and peritoneal fat. These features and their interrelationships are discussed. There was no deficiency in the synthesis of specific neutralizing antibodies against viruses, indicating that a qualitative immune deficiency did not exist. The frequency of occurrence of thrombocytopenic purpura in such a case is discussed, as is the prognosis. The mechanism of action of antimetabolites in inducing a remission in autoimmune hemolytic anemia, as well as the etiology of the disease, is reviewed.

Immunoelectrophoretic Changes in Mouse γ-Globulin after Intraperitoneal Injection of Bayol F

Summary BALB/Gif mice were injected intraperitoneally with Bayol F (group 1), Bayol F and ovalbumin (group 2) or ovalbumin alone (group 3) and immunoelectrophoretic studies were performed weekly on sera of individual mice. Marked γ-globulin changes developed in groups 1 and 2 during the first 9 months of observation, before the appearance of plasmacytomas. The time of onset, incidence and nature of these changes were different in each group. Group 3 showed only minimal changes. A double γ-globulin precipitin line, reflecting an increased antigenic heterogeneity, developed in 20% of group 1 and 100% of group 2 animals. It appeared early (6th week) and abruptly in group 2 and was associated with diffuse hypergammaglobulinemia and the presence of precipitating antibodies directed against ovalbumin. Doubling appeared later and more slowly (12th to 16th week) in group 1 mice who also exhibited hypogammaglobulinemia. Both groups developed peritoneal plasmacytomas and myeloma globulins after the 9th month.