Correlation of low serum IgM levels with absence of functional splenic tissue in sickle cell disease syndromes

Serum immunoglobulin concentrations were determined in 21 patients with sickle cell disease syndromes and correlated with the size and visualization of the spleen. Whereas serum immunoglobulin A (IgA) levels were elevated in all patients studied, immunoglobulins G (IgG) and M (IgM) were elevated in those patients with demonstrable increase in splenic mass. When even minimal splenic visualization could be demonstrated, serum IgM was normal. However, when there was complete absence of splenic vi-sualization, or following splenectomy, serum IgM concentration was significantly below normal. This finding of low serum IgM concentration may explain the increased susceptibility to infection observed in some groups of patients with sickle cell disease.     

Waldenström's macroglobulinemia in a patient with a chronic biologic false-positive serologic test for syphilis

Acute and chronic biologic false-positive serologie reactions for syphilis (VDRL) have been associated with a variety of diseases. Several investigators emphasize that false-positive VDRL titers are usually very low. This report describes a 73 year old man with Waldenström's macroglobulinemia. The biologic false-positive serologic test for syphilis was recognized 33 years before the diagnosis of Waldenström's macroglobulinemia was made. VDRL titers were as high as 1:8192 and 1:32,000 during exacerbations of the macroglobulinemia. A biologic false-positive serologic test for syphilis is frequently associated with an elevated immunoglobulin M (IgM) level. It would be interesting to search for a relation between biologic false-positive serologic tests for syphilis and diseases characterized by monoclonal gammopathies.     

Hepatobiliary diseases associated with serum antimitochondrial antibody (AMA)

In an attempt to define the clinical spectrum of hepatobiliary disease associated with antimitochondrial antibody (AMA), 41 female and four male patients with AMA were investigated. On the basis of clinical criteria, 22 patients had primary biliary cirrhosis (group I), seven had extrahepatic biliary obstruction (group II) and 16 had other liver diseases including chronic active hepatitis, cryptogenic cirrhosis and minor abnormalities of liver function (group III). Elevations of serum cholesterol, alkaline phosphatase and bile acid levels separated the patients with primary biliary cirrhosis from those with miscellaneous liver disease, whereas in those with extrahepatic biliary obstruction results were intermediate. The cholestatic syndrome of primary biliary cirrhosis was further defined by a cholic to chenodoxycholic acid ratio > 1.0 which was found in 75 per cent of the patients with primary biliary cirrhosis but in none of those with miscellaneous liver disease. No significant differences in AMA titers or immunoglobulin M (IgM) levels were found between the groups, indicating that these tests are not correlated with cholestatic liver disease. Examination of liver tissue revealed features which were compatible with the clinical impression in the majority of cases. Cholelithiasis was present in 33 per cent of the patients. Common bile duct obstruction due to stones and/or stricture was found in six cases and carcinoma in one. Since four had fully developed cirrhosis at the time of presentation, extrahepatic biliary obstruction was probably a result of gallstone disease complicating AMA positive parenchymal liver disease. AMA seems to be a marker for idiopathic parenchymal liver disease, primarily in middle-aged women, but in itself gives no. further diagnostic information and does not exclude extrahepatic biliary obstruction.     

Inhibitors of leukocyte chemotaxis in alcoholic liver disease

Twenty-one of 42 patients (50 per cent) with alcoholic liver disease showed serum chemotactic inhibitory activity (CIA). CIA was not related to any single biochemical or histologic feature in the patients studied. The frequency of CIA was greatest in those with active infection. Serial studies demonstrated that CIA may be a transient phenomenon, associated with active alcoholic liver disease or appearance of infection. Nine of 15 patients showed skin test anergy; CIA was present in 8 of these 9 patients. Serum immunoglobulin A (IgA) and G (IgG) concentrations were significantly higher in patients with CIA when compared to those without CIA.Sucrose density gradient centrifugation of serums showing CIA yielded three peaks of inhibitory activity. Two had sedimentation coefficients of 10.7S and 6.8S, and the third was approximately 3S. The two higher molecular weight inhibitors were predominant in the 50 per cent ammonium sulfate precipitate. Immunoabsorption by anti-IgA but not by anti-IgG or IgM columns removed the ammonium sulfate precipitable chemotactic inhibitors. The appearance of chemotactic inhibitors in patients with alcoholic liver disease may have relevance to their apparent susceptibility to serious infections.     

Release of a low molecular weight Fc-like fragment on reduction of water-insoluble IgG myeloma proteins

Abstract. Serum from a patient with multiple myeloma exhibited an unusual concurrence of abnormalities: (1) bitypic gammopathy consisting of a whole Λ-IgG 1 paraprotein plus a circulating Λ-Bence Jones protein; (2) marked insolubility of the partially purified paraprotein under conditions of low ionic strength, but good solubility upon further purification; (3) release of an unusual low molecular weight fragment containing Fc antigenic determinants under standard conditions of mercaptoethanol reduction of the purified paraprotein. Evidence is presented supporting the origin of the Fc fragment from the paraprotein heavy chain and describing the requirement for 6 M urea for its dissociation from the reduced and alkylated heavy chain. The phenomenon is evidently not rare, since screening of 14 additional myeloma sera revealed one with similar euglobulin properties and an apparently similar Fc fragment abnormality. The nature and origin of the fragment in relation to previously described immunoglobulin fragments are discussed.     

Current concepts in the pathogenesis of the obesity-hypoventilation syndrome. Mechanical and circulatory factors

The pathogenesis of carbon dioxide retention associated with obesity, the obesity hypoventilation syndrome (OHS), remains obscure. In an attempt to Identify factors which might Initiate or contribute to this syndrome, we reviewed respiratory and circulatory function in two groups of obese subjects: those who were not hypercapnic (simple obesity) and those who were (OHS).Obese subjects in both groups display reduction of lung and chest wall compliance, normal airway resistance, closure of peripheral lung units and increased energy cost of breathing. These abnormalities are more severe in those who hypoventilate, especially the reduction In compliance. Respiratory muscle efficiency is reduced in both groups. Inspiratory muscle strength of patients with OHS is 60 to 70 per cent of normal. In OHS arterial carbon dioxide tension (PaCO₂), vital capacity and maximum voluntary ventilation improve significantly with weight toss, whereas in simple obesity there Is little change in these factors with weight loss.In both groups the major circulatory findings are increased total and pulmonary blood volume, with preservation of a normal ratio between the two; and good perfusion but marked underventilation of dependent regions of the lung. These changes are more pronounced In OHS. Left ventricular end diastolic pressure is elevated in some patients, but the rise is not confined to those with OHS. In OHS alveolar hypoxia and acidemia produce pulmonary arterial vasoconstriction and pulmonary arterial hypertension. As a consequence pulmonary artery pressure exceeds left ventricular pressure at the end of diastole.We suggest that excessive reduction of chest wall compliance and inspiratory muscle weakness interact with the circulatory abnormalities already present in simple obesity to generate carbon dioxide retention. The contribution of altered central nervous system function to this process remains controversial.     

Characterization of amyloid deposits and P component from a patient with factor X deficiency reveals proteins derived from a lambda VI light chain

Amyloid fibrils were isolated from a spleen obtained at surgery from a 58-year-old white man with primary amyloidosis presenting with factor X deficiency and responding dramatically to splenectomy. Gel filtration on Ultragel ACA 54 in 5 M guanidine 1 M acetic acid yielded components with molecular weights between 17,000 and 13,000. Two of them (17K and 15K) were studied in detail. Antigenic and amino acid sequence analysis showed that these proteins were related to lambda VI immunoglobulin light chain. The predominant protein subunits of the amyloid fibril of the deposits (17K) was processed at the carboxy terminus in the same section of the constant region as the only other lambda VI amyloid protein previously reported. Amino terminal sequence of the 15K protein revealed not only degradation at the C terminal, but also minor degradation at the amino terminal (three residues difference from the 17K species). P component was also isolated from the spleen and characterized. This represents the first antigenic and sequence analysis of tissue amyloid proteins and P component from a patient presenting with factor X deficiency and another example of amyloid proteins derived from the newly discovered amyloidogenic lambda VI light chain subgroup.     

Immunoglobulin M: Pentameric Fcμ Fragments Released by Trypsin at Higher Temperatures

Immunoglobulin M (IgM, 19S macroglobulin) is a high molecular weight antibody molecule currently thought to be composed of five identical 7S subunits linked by disulfide bonds, perhaps in a cyclic conformation. Reported molecular weights of IgM vary from 8 x 10(5) to 10(6). Proteolytic cleavage of this molecule under standard conditions with several enzymes results in the formation of ten antigen-binding (Fab) fragments per mole, each Fab having a molecular weight of 40,000. The remainder of the molecule, designated Fc by analogy with the structure of immunoglobulin G (IgG), is highly susceptible to further enzyme cleavage and breaks down to dialyzable peptides. However, under carefully controlled conditions, an intact Fc-like fragment in low yield can be isolated from short-term papain digests of IgM at 37 degrees C. Availability of the Fc portion of the molecule is important not only for structural studies but because it may determine certain important biological properties of the molecule such as complement fixation and placental permeability.We here report that trypsin cleavage of IgM at temperatures exceeding 50 degrees C results in the production of excellent yields of an intact Fc fragment, whereas no detectable Fc fragment is produced by trypsin cleavage at 37 degrees C. Fab fragments are obtained under both temperature conditions, and an Fab dimer has been identified in high temperature digests. This unusual difference in the products of enzyme digestion with temperature is unexplained but may be related to steric changes induced in the IgM molecule by heat. Fc fragment isolated from high temperature digests contains two-thirds of the carbohydrate of the intact molecule, and has a molecular weight of 342,000. The molecular weight falls to 67,300 after treatment with disulfide reducing agents, thus supporting the concept of a pentameric structure for IgM.     

Hyperimmunoglobulinemia associated with narcotic addiction. Effects of methadone maintenance treatment

Increased serum immunoglobulins were common in narcotic addicts. Immunoglobulin M (IgM) levels were high in 75 per cent of 46 adult addicts and in 65 per cent of 63 adolescent addicts seeking methadone maintenance or detoxification. Isolated hypermacroglobulinemia was found in 56 per cent. During methadone maintenance or abstinence high IgM levels were much less frequent. History of overt hepatitis, manifest liver disease, serum glutamic oxaloacetic transaminase (SGOT) or alkaline phosphatase levels did not correlate with the presence of high serum IgM levels. Serum immunoglobulin G (IgG) was more variably and less frequently increased than IgM in the untreated addicts, but was commonly increased in the patients maintained on methadone. Prospective studies of 21 patients starting methadone maintenance showed a decrease in mean serum IgM during treatment. The incidence of normal IgM levels in these patients rose to 48 per cent after one year compared to 24 per cent before treatment. The pattern of immunoglobulin changes in narcotic addiction is significantly altered during methadone maintenance treatment, perhaps as a result in the reduction of drug abuse.     

Serologic evidence for acute toxoplasmosis in polymyositis-dermatomyositis. Increased frequency of specific anti-toxoplasma IgM antibodies

Several case reports have suggested an association between acquired toxoplasmosis and polymyositis-dermatomyositis. Because the presence of anti-Toxoplasma IgM antibodies suggests recent infection, 58 patients with polymyositis-dermatomyositis (from two medical centers) were examined for the presence of IgM antibodies using a specific indirect immunofluorescent technique. Serum samples were also examined for antibodies using the Sabin-Feldman dye test and complement fixation methods. Of 58 patients with polymyositis-dermatomyositis, 29 (50 percent) had positive Sabin-Feldman dye test results and 14 (24 percent) had positive IgM immunofluorescent findings. This is higher than the expected frequency. None of the patients with negative Sabin-Feldman dye test results had IgM immunofluorescent antibodies. Furthermore, IgM immunofluorescent antibodies were associated with the presence and titer of both Sabin-Feldman dye test and complement fixation antibodies. Evidence that the presence of antinuclear antibody and rheumatoid factor did not influence these results is presented. Patients with muscular dystrophy and systemic lupus erythematosus (with or without myositis) did not have an increased frequency of anti-Toxoplasma IgM immunofluorescent antibodies.     

Renal handling of low molecular weight proteins

The renal filtration, absorption and final disposal of lysozyme (lysozyme—mol wt 14,000), insulin and growth hormone were studied to gain a better quantitative understanding of the fundamental variables involved in the renal handling of low molecular weight proteins. The glomerular barrier offers little hindrance to the filtration of lysozyme, the glomerular sieving coefficient being 0.8 ± 0.1 (SD). The intrarenal route by which injected lysozyme accumulates in the kidney is via filtration and subsequent absorption (uptake) by renal tubular cells. Uptake or adsorption from the peritubular side is negligible compared to luminal uptake. Renal clearance and renal titration experiments in the intact dog and in the isolated perfused rat kidney showed that the lysozyme absorption process can be best characterized as a high capacity, low affinity transport system which is directly or indirectly dependent on energy input. The final disposal of absorbed ¹²⁵I-lysozyme, ¹²⁵I-insulin and ¹²⁵I-growth hormone was studied in the isolated perfused rat kidney by measuring the radioactivity released from the kidney to the perfusate and analyzing the nature of the released product by gel chromatography. The rate of release of radioactivity as well as its nature was dependent on the molecular species of the absorbed protein. The rate of release was higher for ¹²⁵I-insulin and ¹²⁵I-growth hormone and lower for ¹²⁵I-lysozyme. Lysozyme absorbed from the luminal side was released to the perfusate both as intact protein molecules and as catabolic products, whereas absorbed ¹²⁵I-insulin was almost entirely released to the perfusate as catabolic products. It is concluded that low molecular weight proteins are extensively filtered by the kidney, absorbed from the luminal side by renal tubular cells and released back to the circulation either as intact molecules or as catabolic products (amino acids and polypeptides). This process contributes in an important way to the plasma turnover of low molecular weight proteins including peptides and protein hormones.     

An overview of intestinal immunity and malabsorption.

Intestinal immune responses are adapted to function at external mucosal surfaces. Specialized forms of antibody, secretory immunoglobulin A (IgA) and immunoglobulin M (IgM), provid humoral immunity but little is known of local cell mediated immune reactions. Antigens in the intestinal lumen gain preferential access via Peyer's patches in which sensitised lymphocytes proliferate before entering the lymphatic system. These lymphoblasts return to the intestinal mucosa via the bloodstream to provide predominantly IgA antibody responses. Secretory IgA antibody can neutralize viruses, bacteria and toxins, and appears to block the entry of some food antigens into the lamina propria. Disturbances of intestinal immunity may result in malabsorption. Immunodeficiency states are often associated with malabsorption due to Giardia lamblia infestation. In alpha chain disease there is a malignant expansion of plasma cells in the intestinal mucosa which secrete an abnormal heavy chain fragment of IgA. Arthus type hypersensitivity reactions to milk proteins and gluten may contribute to the mucosal injury in patients suffering from milk allergy and coeliac disease.     

The ventricular A wave: a new echocardiographic index of late diastolic filling of the left ventricle.

Echocardiography was used to evaluate the late diastolic filling period of the left ventricle in 30 normal individuals, 25 patients with left ventricular hypertrophy, normal sinus rhythm, and either a normal or delayed mitral valve closure, and 15 patients with atrial fibrillation. The echocardiographic ventricular A wave (VAW) was defined as the difference between the end-diastolic and an earlier late-diastolic internal left ventricular dimension, and it was felt to primarily reflect the atrial contribution to late diastolic filling of the left ventricle. It disappeared during ventricular pacing and was significantly smaller than normal in patients with atrial fibrillation. The VAW was significantly larger in patients with left ventricular hypertrophy and normal mitral valve closure reflecting the greater contribution by atrial contraction to late diastolic filling in these patients. In patients with left ventricular hypertrophy and delayed mitral valve closure, the VAW was normal reflecting lesser ventricular enlargement with atrial contraction than in the other patients with left ventricular hypertrophy. This suggested a greater impairment to left ventricular filling in these patients. Therefore, the VAW appears to be an indicator of abnormalities of late diastolic filling caused by left ventricular hypertrophy.     

Peak regional acceleration: a method to identify subtle regional ventricular dysfunction from gated blood pool scans at rest in patients with coronary artery disease

Peak regional acceleration images were obtained from gated blood pool scans at rest in 10 normal subjects, 16 patients who underwent cardiac catheterization for unstable angina or nontransmural infarction and were found to have normal ejection fraction and wall motion and 10 patients with prior infarction and regional dyssynergy. The second derivative of the time-activity curve of each pixel was generated and the maximal systolic value of the derivative for each pixel was displayed as a functional image (peak regional acceleration). Anterior and left anterior oblique views were evaluated for abnormalities and the presence and location of defects were correlated with the coronary anatomy. The scans from the 10 normal subjects were used to establish the normal range for regional second derivative values. Both gated blood pool scans and second derivative images showed regional abnormalities in all 10 patients with prior transmural infarction. Regional abnormalities were present in the second derivative images in the distribution of 17 of the 20 coronary arteries with greater than 50% stenosis; there were no regional abnormalities in the distribution of 7 of the 8 arteries with less than 50% stenosis. In addition, regional second derivative image abnormalities were present in 15 of the 16 patients with unstable angina and normal wall motion and global ejection fraction. These 16 patients showed regional abnormalities on second derivative images in the distribution of 19 of the 23 coronary arteries with significant stenosis and no regional abnormalities in the distribution of 21 of the 23 coronary arteries without significant stenosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of circulatory congestion in the cardiorespiratory failure of obesity.

The role of circulatory congestion in the cardiorespiratory dysfunction of massive obesity was investigated in 18 patients. They were hypervolemic and had increased cardiac outputs proportionate to their weight. The average resting left ventricular filling pressure was within the upper limits of normal, but it increased to abnormally high levels with increased venous return of passive leg raising, and further during exercise. The elevations in pressure were associated with high resting central blood volumes which increased significantly with exertion. These findings are consistent with reduced distensibility of the central circulation in these congested patients. Weight reduction was accompanied by a decrease in central blood volumes and restoration of a normal left ventricular response in three of four patients and a return toward normal in one. The improvement in ventricular function with relief of edema and dyspnea. In 14 patients with normal or only minimal alveolar hypoventilation, there were no significant transpulmonary diastolic pressure gradients despite a marked increase in left ventricular end-diastolic pressures. One patient, after regaining weight, subsequently had an abnormal gas exchange and an increased pulmonary vascular resistance. He and two others with severe alveolar hypoventilation demonstrated cor pulmonale on a background of left ventricular dysfunction and congestion of the circulation. Two other patients, the least obese of the group, had hypoventilation and cor pulmonale with normal left ventricular pressures. Hypervolemia and a hyperdynamic state are common features of the obese patients. High cardiac output is maintained despite marked circulatory congestion which may result in generalized anasarca and increased ventricular filling pressures. This clinical syndrome may be present in obese patients without intrinsic heart disease and may be reversible with weight reduction. The central circulatory congestion may contribute to the development of the alveolar hypoventilation syndrome in certain obese patients.     

IgD myeloma presenting as a testicular tumor: establishment and characterization of an IgD-secreting myeloma cell line.

A 72-year-old man presented with a left testicular tumor and underwent orchiectomy. The tumor was massively infiltrated with myeloma cells bearing monoclonal cytoplasmic IgD lambda. Three months after orchiectomy, he developed huge abdominal masses and subsequently ascites containing numerous myeloma cells. An IgD-secreting myeloma cell line, designated delta-47, was established from the ascites. This cell line expressed CD4 and CD38, but lacked Fc and complement receptors, surface immunoglobulin, CD19, HLA-DR, and PCA-1. CD30 was detected on the cultured cells but not on the ascites tumor cells. Delta-47 cells secreted the same immunoglobulin (IgD lambda) as was found in the patient's serum. The light chain had a molecular weight of 35 kD which was larger than that of the normal light chain. Chromosome analysis of delta-47 revealed an aneuploid karyotype with complex abnormalities including 1q+, 2p+, and 14q+. To our knowledge, this is the only IgD-secreting myeloma cell line and would provide a useful tool for the study of IgD production and IgD myeloma.     

Hereditary complement (C2) deficiency with dermatomyositis

A 60 year old white man in previous good health presented with a 6 month history of progressive muscle weakness. Clinical and laboratory findings were typical of dermatomyositis. Muscle biopsy confirmed the presence of inflammatory myopathy; deposits of immunoglobulin G (IgG), immunoglobulin M (IgM) or third component of complement (C3) were not detected by immunofluorescence. No evidence was found for an associated neoplasm.An unexpected finding was the total absence of serum hemolytic complement activity. Further investigation revealed that the complement defect was attributable to a selective and total absence of the second component of complement (C2), as determined by both functional and immunoprecipitin assays. Family studies indicated that the defect was inherited in an autosomal recessive manner, as has been observed in the previously reported C2-deficient kindreds.This case demonstrates that typical muscle lesions of dermatomyositis can occur in the presence of a complement defect which would preclude activation of the classic (C1-C4-C2) complement pathway. The case is of further interest as one of a series of recently reported associations of rheumatic diseases with hereditary complement deficiencies.Study of the functional properties of the propositus' C2-deficient serum demonstrated normal generation of chemotactic activity in the presence of endotoxin or aggregated IgG, and normal or near normal bactericidal activity against Salmonella typhi 0 901 and Hemophilus influenzae, type b. These findings emphasize the importance of the alternate (properdin) pathway of complement activation in these functions.     

Double myeloma. Production of both IgG type lambda and IgA type lambda myeloma proteins by a single plasma cell line

Monoclonal immunoglobulins G (IgG) and A (IgA) of the lambda light chain type were present in the serum of a patient with multiple myeloma. Three populations of myeloma cells were seen by immunofluorescence of bone marrow; those containing either IgG or IgA and those staining for both IgG and IgA. Idiotypic determinants present on the variable regions of the two myeloma proteins were immunologically identical and all the myeloma cells contained the same idiotypic determinant. The idiotypic specificity was related more closely to the variable region of the heavy chain than to the light chain. Structural and electrophoretic analysis confirmed that the light chains of the two myeloma proteins were identical. The myeloma in this patient appears to have arisen from a single clone of cells that was capable of synthesizing the constant portions of both the IgG and IgA heavy chain but only a single light and heavy chain variable region. These findings suggest that current concepts of antibody synthesis involving the sequential production of immunoglobulin M (IgM) and IgG antibodies may apply to certain cell lines synthesizing IgG and IgA antibodies as well.     

LOW MOLECULAR WEIGHT IgM IN B CELL LYMPHOPROLIFERATIVE DISORDERS

Circulating low molecular weight (LMW) IgM was demonstrated in five of 38 patients with B cell lymphoproliferative disorders. These five patients all had malignant disease and could be subdivided into two groups. In the first group were three patients, each with an associated serum IgM paraprotein; two had Waldenstrom's macroglobulinemia. and one lymphocytic lymphoma. The two patients of the second group did not have IgM paraproteins; one had lymphocytic lymphoma and one chronic lymphocytic leukemia. Both these patients also had acquired C1 esterase inhibitor deficiency, a previously recognised association with circulating LMW IgM. None of the 16 patients with benign IgM macroglobulinemia had circulating LMW IgM. In those positive sera with LMW IgM this moiety contributed between 10.5% and 37.5% of the total IgM. There was no apparent association between LMW IgM and total IgM levels, kappallambda typing or the presence of Bence Jones proteinuria. but rheumatoid factor, immune complexes and cryoglobulins occurred in many of the sera which contained LMW IgM. Pokeweed mitogen stimulated peripheral blood mononuclear cells from two patients with circulating LMW IgM secreted considerable quantities of this moiety in vitrobut this did not occur in two patients with benign IgM macroglobulinemia. We conclude that LMW IgM is found in the malignant but riot the benign forms of B cell lymphoproliferative disorders and is frequently associated with other serological abnormalities. The basic abnormality causing defective IgM polymerisation in these disorders is obscure.