Hypergammaglobulinemia in cystic fibrosis. Role of Pseudomonas endobronchial infection

Hypergammaglobulinemia, chronic endobronchial infection with Pseudomonas aeruginosa (PA), and the resulting systemic humoral immune response to PA are each associated with worsened clinical status and prognosis in patients with cystic fibrosis (CF). Major serum immunoglobulin isotype levels (IgG, IgA, IgM, and IgG1-4 subclasses) were measured in 31 CF patients and ten control subjects. Immunoglobulin levels were related to airway infection with PA and the resulting IgG antibody response against PA lipopolysaccharide (LPS). Hyperimmunoglobulinemia G was present with elevated IgG1 and IgG2 in 48 percent, IgG3 in 52 percent, and IgG4 in 42 percent of CF patients. The PA infection was associated with striking increases in IgG2. IgG2 levels correlated well with IgG2 antibodies to PA LPS (r = +0.70, p less than 0.001). However, even CF patients who were not infected with PA had an increased prevalence of high IgG3 (p less than 0.05) and IgG4 (p less than 0.01). The PA infection thus appears to be a major, but not the only factor causing hypergammaglobulinemia in CF.     

Serum immunoglobulins, including IgG subclasses, in Vietnamese leprosy patients

Levels of serum immunoglobulins were measured in healthy Vietnamese and in leprosy patients. Healthy Vietnamese had higher levels of IgG, IgA, IgM, and IgE than did healthy Dutch controls, as well as higher levels of three of the four subclasses of IgG (IgG1, IgG2, IgG3). Lepromatous leprosy patients had significant increases in all classes and subclasses of immunoglobulins, except for IgG2, in comparison with local controls. Tuberculoid leprosy patients had more IgG1, IgG3, and IgG4 than did local controls and had higher total IgG levels. The patients had no increase in autoantibodies against tissue antigens compared to local or Dutch controls.     

Serum IgG subclass antibodies to a variety of food antigens in patients with coeliac disease.

Levels of serum IgA, IgG, and IgG subclass antibodies to a variety of dietary antigens were determined by enzyme linked immunosorbent assays in 14 adults with untreated coeliac disease and in 10 disease controls selected because of raised total IgG activities. The untreated coeliacs showed somewhat higher total IgG activity (p approximately 0.05) and significantly raised IgA and IgG1 + IgG3 activities to gliadin but reduced IgG4 activity (p less than 0.02) compared with the controls. High IgA and IgG1 + IgG3 activities were positively correlated (r = 0.67, p less than 0.01), and so were IgG and IgG4 activities (r = 0.64, p less than 0.02). Conversely, a high IgG2 response to gliadin appeared related to a low IgA response (r = 0.55, p less than 0.05). The IgG2 response was most prominent to oat flour antigens, followed by IgG1; and the main response to soy antigens resided in IgG1, followed by IgG2 in both disease groups. There was no difference in antibody activities to oat and soy between the two groups, and raised activity to bovine serum albumin was seldom encountered. The IgA activity to alpha-lactalbumin and ovalbumin tended to be increased in the coeliacs compared with the controls. The IgG4 subclass dominated the IgG response to beta-lactoglobulin and ovalbumin and was often raised to alpha-lactalbumin, especially in the disease controls. The IgG subclass pattern to casein parallelled that to gliadin with dominance of the IgG1- and IgG3-subclass activities, especially in the coeliacs. The phlogistic potential of a response in these two subclasses might be relevant to the pathogenesis of coeliac disease and could contribute to a raised IgA gliadin response by increasing mucosal permeability. IgA activity seemed to be highest against antigens usually involved in IgE mediated food allergy.     

Serum immunoglobulins predict the extent of hepatic fibrosis in patients with chronic hepatitis C virus infection

Recently, we documented that immunoglobulins stimulate the proliferative activity of rat hepatic stellate cells in vitro. The aim of the present study was to determine whether there is any association between serum immunoglobulin levels and hepatic fibrosis in patients with chronic hepatitis C virus (HCV) infection. Charts from 116 patients with biochemical, serologic, virologic and histologic evidence of chronic hepatitis C infection and serum immunoglobulin levels (IgA, IgG, IgM and total) were reviewed. The mean (+/-SD) age of the study population was 46 +/- 11 years and 67 (58%) were male. There were significant correlations between serum IgA (r = 0.39, P = 0.00001), IgG (r = 0.49, P = 0.000002) and total (r = 0.51, P = 0.000003) immunoglobulin levels and the stage of hepatic fibrosis. When serum immunoglobulin levels were included into logistic regression analysis with variables known to be associated with advanced disease (male gender, age >40 years at onset of infection, duration of infection beyond 20 years and concurrent alcohol abuse) only IgA, IgG and total immunoglobulin levels (P < 0.05, <0.05 and <0.005, respectively) emerged as independent predictors of hepatic fibrosis. Our data indicate a strong association between serum immunoglobulin levels (IgA, IgG and total) and hepatic fibrosis in patients with HCV infection. This finding supports the need to further investigate whether immunoglobulins independently promote disease progression in patients with chronic HCV infection.     

Immunoglobulin-G subclasses in cystic fibrosis. IgG2 response to Pseudomonas aeruginosa lipopolysaccharide

Pulmonary macrophage phagocytosis of Pseudomonas aeruginosa is defective when this pathogen is opsonized with IgG antibodies isolated from serum samples from patients with cystic fibrosis (CF). To evaluate this defect further, IgG subclasses in the serum and lung fluids of patients with CF were quantitated. The pattern of IgG subclasses in serum specimens from patients with CF (n = 15) and in patients without CF but with chronic obstructive airway disease and recurrent P. aeruginosa infection (n = 4) was significantly altered from that found in normal subjects (n = 31). Immunoglobulin-G2 and IgG3 expressed as percentages of total IgG subclasses or in micrograms per milliliter of serum were significantly elevated in the serum specimens of these patients (p less than 0.05), and IgG1 was significantly decreased (p less than 0.01). It appears that the increase in IgG2 in the serum of patients with CF and those without CF but with chronic P. aeruginosa infection may be in response to chronic antigenic stimulation by P. aeruginosa lipopolysaccharide. Evidence presented to support this includes: (1) IgG2 is not increased in CF serum if a history of P. aeruginosa infection is absent, (2) IgG2 levels expressed as percentages of total IgG subclasses in CF lung fluids were positively correlated (r = 0.73) with the number of colony-forming units of P. aeruginosa present in CF sputum specimens, and (3) IgG antibodies specifically eluted from P. aeruginosa lipopolysaccharide ligands on affinity gels were largely restricted to IgG2. The opsonic index, ([IgG3] + [IgG1]) divided by ([IgG2] + [IgG4]), is inverted in CF lung fluids (0.73:1; normal, 2:1). Because pulmonary macrophages show surface receptors binding primarily with IgG3 and IgG1, it may be that such an alteration in IgG subclasses in the respiratory secretions of patients with CF further inhibits opsonin-mediated clearance of P. aeruginosa.     

Assessment of humoral immune response in patients with chronic hepatitis C virus infection

Hepatitis C infection is a major public health problem worldwide. Hepatitis C virus (HCV) infection has been identified as a major causative agent of post-transfusion hepatitis. The host immune response to HCV infection is composed of both non- specific immune response, including interferon (IFN) production and natural killer (NK) cell activity and a virus-specific immune response, including humoral and cellular components. Susceptibility to infection has been related to immunological disturbances. Several studies have provided experimental evidence of disorders of both cellular and humoral immunity. Humoral Immunity is dependent mainly on immunoglobulins and little data are available about serum immunoglobulin values in chronic hepatitis C. The present study aimed to evaluate humoral immune response by measuring the concentration of serum immunoglobulin isotypes (IgG, IgM, IgA) and IgG-subclasses level (IgG1-4) in chronic hepatitis C patients and healthy controls. This study included 50 patients with chronic hepatitis C. All of them had positive serum anti-HCV antibodies, positive serum HCV-RNA by PCR, and histologically-proven chronic hepatitis. The results were compared with 25 healthy controls. Total IgG, IgA and IgM were assayed by nephelometry. IgG subclasses were assayed using human IgG subclasses enzyme immunoassay. Serum protein electrophoresis was performed in agarose gel. The results showed that no significant difference in serum immunoglobulin levels were found among patients with chronic hepatitis C of minimal liver damage( Knodell index < or =3) and patients with mild liver disease (Knodell index > 3). A significant increase in total serum IgG, IgG1 and IgG2 levels were found in patients with chronic hepatitis than in healthy controls but no difference was found in IgG3 and IgG4 in both patients and controls. Mean serum IgM was increased in patients with HCV infection compared with healthy controls. No significant difference was found in IgA level in both the patients and healthy controls. Our data revealed an increase of humoral immune response in chronic hepatitis C infection. This is evidenced by an elevation in serum immunoglobulin isotypes; IgG and its subclasses IgG1 and IgG2 and IgM. These findings may provide some new insights into the antibody response to HCV.     

Human IgE Response to the Administration of Blood Components

Abstract. The analysis of IgG, IgA and IgE serum immunoglobulins in 94 cardiac surgery patients, who received massive blood transfusions during the bypass procedure, has shown a selective increase in immunoglobulin levels, a fortnight after the operation. For 85% of patients, IgE levels increased usually independently of IgA but in close correlation with IgM variations. IgG levels were not altered. 2 weeks following surgery, IgE concentrations were found, on average, to have doubled and in several sera reached five times the initial level. These modifications were early and transient. The concentrations of serum IgE and IgM returned to pretransfusion levels within 2 months of surgery. For 44% of the total population, serum IgE could partly be absorbed onto pooled platelets or polymerized immunoglobulins. This finding suggests the formation of IgE type antibodies directed against white cell or immunoglobulin antigens following blood transfusions. No significant variations in IgE levels were observed after absorptions onto red blood cells (RBC). Such modifications of IgE concentration in cardiac surgery patients were not related to the disease and seemed to occur as a primary immune response following blood transfusions. In another study of 44 blood donors, who were immunized with washed red blood cells for test sera production, only 3 showed significant transient variations in serum IgE levels. Thus, RBC antigens do not appear to be frequently involved in such IgE responses.     

Human leukocyte antigens and circulating immunoglobulin levels in Indian patients with pulmonary tuberculosis

Histocompatibility antigens (-A, -B and -C loci) and circulating antibodies (IgG, IgM, IgA and IgE) were studied in 63 pulmonary tuberculosis patients and regionally matched healthy volunteers from Uttar Pradesh, India. A previously described association with antigen B15 in an heterogeneous sample of North India was not confirmed but a slight increase of antigen B18 was found. The levels of immunoglobulins in the plasma of these patients showed a significant increase in IgG, IgA and IgE. Although the increased levels of IgG and IgA are in agreement with previous studies, the role of the increased IgE is not clear and needs further investigation. Patients who were antigen B14 and B18 positive tend to show significantly low levels of IgG, which suggests a possible genetic influence on the expression of immunoglobulin levels.     

多发性骨髓瘤血清单克隆免疫球蛋白及IgG亚类检测

目的：探讨多发性骨髓瘤（MM）患者血清单克隆免疫球蛋白（M－蛋白）及IgG亚类的分布。方法：用免疫固定电泳对236例MM患者血清中M－蛋白进行免疫球蛋白重链及轻链定性分析,并用单扩散法对其中76例IgG型MM进行IgG亚类分析。结果：236例中,IgG型104例（44．07％）,IgA型60例（25．42％）,IdD型22例（9．32％）,轻链型47例（19．92％）,未分泌型3例（1．27％）。对其中76例IgG型MM研究发现：IgG161例（80．26％）,IgG26例（7．89％）,IgG1-IgG2双克隆1例（1．32％）,IgG3 8例（10．53％）,未见IgG4。结论：血清M－蛋白重链及轻链分类及IgG亚类的检测对MM的免疫分型、指导临床治疗及判断疾病预后具有一定的意义。     

Serum immunoglobulins in acute myelogenous leukemia.

Forty-five patients with acute myelogenous leukemia have been followed sequentially for 12 months. All these patients had serum immunoglobulin IgA, IgG, IgM and IgE levels measured by immunodiffusion and radioimmunoassay prior to chemotherapy, then every month after chemotherapy. Significant differences were found in IgA and IgG levels prior chemotherapy, while no differences were found in IgM or IgE levels at any time. There was a positive correlation between percentage of blasts and IgA level. There was negative correlation between the percentage of blasts and IgM levels. These findings raise the value of measuring the levels of immunoglobulins in patients with leukemia as a guide to the subclinical relapse of the disease. These results may also support the hypothesis of the role of early immune defect in immunoglobulin metabolism in the pathogenesis of acute leukemia.     

Quantitative levels of immunoglobulin E in advanced tuberculosis.

Quantitative levels of immunoglobulin E (IgE) were determined in samples of sera obtained from 29 patients with proven moderate to far-advanced tuberculosis. The sensitive radioimmunoassay test for IgE was used. Statistical analysis of the results revealed no difference in IgE values as compared to a control group of normal sera. In contrast to other chronic pulmonary infections, such as bronchopulmonary aspergillosis, the IgE level in pulmonary tuberculous infection is of no diagnostic significance. Simultaneous determination of levels of immunoglobulins G, A, M, and D (IgG, IgA, IgM, IgD) in these same sera by radial immunodiffusion showed elevated IgG and lowered IgM levels in the tuberculous patients, confirming previous studies. The significance of these alterations in immunoglobulin levels is unclear and may represent a secondary phenomenon rather than a primary host response.     

Value of serum immunoglobulins in the diagnosis of liver disease

Serum immunoglobulins were determined in 145 consecutive patients with biopsy-proven steatosis, alcoholic hepatitis, alcoholic hepatitis with fibrosis, alcoholic hepatitis with cirrhosis, inactive cirrhosis, chronic active alcoholic hepatitis, chronic active hepatitis, primary biliary cirrhosis and nonspecific hepatitis. IgM was both a sensitive (90.5%) and specific (86.2%) marker for primary biliary cirrhosis, and mean IgM levels were higher in primary biliary cirrhosis than in other diagnostic categories (p less than 0.05). IgA levels were most commonly elevated in alcoholic liver disease (p less than 0.005). IgA detected 95% of alcoholic disease, but was poorly specific (41.1%). A trend of rising IgA with increasing severity of alcoholic injury was observed, but the differences were not significant. IgG was most commonly elevated in chronic active hepatitis and alcoholic hepatitis with cirrhosis, but the IgG values did not differ significantly from those found in other diagnostic categories. Our results substantiate assertions of a diagnostic sensitivity for elevated IgA in alcoholic liver disease and IgM in primary biliary cirrhosis. With the exception of IgM in primary biliary cirrhosis, however, serum immunoglobulins are not specific markers of liver histology.     

A comprehensive study of Candida-specific antibodies in the saliva of human immunodeficiency virus-positive individuals with oropharyngeal candidiasis

Oropharyngeal candidiasis (OPC) is a common oral opportunistic infection among human immunodeficiency virus (HIV)-positive individuals. Although most cases of OPC correlate with reduced systemic levels of CD4(+) T cells, the role of humoral immunity in protection against mucosal candidiasis, including OPC, remains questionable. In the present study, a comprehensive analysis of saliva from 33 HIV-negative and 68 HIV-positive individuals, stratified by OPC status and peripheral CD4(+) cell count, was conducted to measure levels of total and Candida-specific immunoglobulin A(IgA) and IgG antibodies, including subclasses and secretory IgA. Despite changes in total immunoglobulin levels, when levels of Candida-specific antibodies were normalized to total protein or total immunoglobulin of the corresponding isotype, no distinct differences in IgG (including subclasses), IgA (including subclasses), or secretory IgA levels were seen, regardless of HIV status, OPC status, or CD4(+) cell count. These data suggest that when a complete repertoire of antibodies is evaluated, with appropriate normalization of data, there is no evidence of appreciable changes in levels of Candida-specific antibodies in saliva that would account for the prevalence of OPC among HIV-positive individuals.     

IgG2 deficiency in sickle cell anaemia

8 patients with known sickle cell anaemia were studied immunologically. The concentrations of the main immunoglobulin classes, IgG and IgA, were significantly higher than the levels in 11 normal age- and sex-matched black subjects (P less than 0.01). IgM levels were not significantly different in the two groups. There was a heterogeneity in the interaction of the IgG subclasses with Protein A, with low levels of IgG2. The IgG2:IgG1 ratios varied from 1:3.8 to 1:6 (normals 1:3). In 4 patients the absolute levels of IgG2 as measured by radial immunodiffusion were lower than normal, thus confirming the chromatographic ratios. Since specific antibody is often restricted to a single subclass, the levels of IgG subclasses may be related to recurrent bacterial infections in these patients.     

Immunologic aspects of leprosy with special reference to the study of immunoglobulin E.

The serum levels of IgG, IgM, IgD and IgE have been determined in normal subjects, individuals suffering from ascariasis and filariasis, and in leprosy patients. Allergic and parasitic diseases were excluded in these normal subjects and in leprosy patients before they were taken for the study of their serum IgE. The circulating IgG was significantly raised in both tuberculoid and lepromatous forms of leprosy and also in filariasis; IgM was significantly elevated in only the lepromatous form of leprosy, ascariasis as well as in filariasis; while IgA was exclusively raised in both forms of leprosy. IgD was detected in the sera of more subjects with ascariasis and filariasis than in normal individuals and leprosy patients. The mean level of serum IgE in 35 normal Indian subjects was 1,025 I.U. per ml, 9 of them (25%) having serum IgE concentrations above 700 I.U. per ml. The highest mean level of serum IgE was found in ascariasis (7,328 I.U. per ml), followed by leprosy (5,180 I.U. per ml), and filariasis (4,244 I.U. per ml). Furthermore, no significant difference between the mean serum IgE levels of tuberculoid and lepromatous leprosy patients was observed. Although the rise of serum IgE level in these parasitic diseases, as well as in leprosy, was spectacular, the augmented synthesis of this unique class of immunoglobulins was not invariably present in all patients. The results have been discussed on the basis of recent ideas on immunoglobulin synthesis.     

Class specific rheumatoid factors in rheumatoid arthritis: response to chrysotherapy and relationship to disease activity

IgG rheumatoid factors (RF) may play an important role in the pathogenesis of rheumatoid arthritis (RA). Our study investigates the relationship between class specific RF levels measured by radioimmunoassay and disease activity in patients with RA undergoing chrysotherapy. Nineteen patients were treated with 20 mg disodium aurothiomalate weekly for 6 months. Rheumatoid disease activity was assessed before and after 6 months' treatment and the level of IgG, IgA and IgM RF measured. There were significant falls in disease activity (p less than 0.005), IgA RF (p less than 0.005) IgG RF (p less than 0.005) and SCAT (p less than 0.025), but not IgM RF, over the 6 month treatment period. No correlation was found between absolute levels of IgA, IgG or IgM RF and disease activity before or after 6 months' therapy but there was a highly significant linear correlation between reduction in IgG RF levels and fall in disease activity (r = 0.642, p less than 0.005) with treatment.     

Serum immunoglobulins and IgG subclasses in patients with glomerulonephritis

The serum concentrations of IgG, IgA, IgM and of the four subclasses of IgG were determined by radial immunodiffusion in 103 patients, mean age 42 (range 16-72), with various types of glomerulonephritis. Forty-nine healthy blood donors, mean age 41 years (range 19-65), served as controls. Kidney biopsies were obtained from all the patients for examination by histopathology and by immunofluorescence. The glomerulopathies were classified according to WHO criteria. The serum immunoglobulin patterns were different for the various clinical groups of patients. Patients with Wegener's granulomatosis, rapidly progressive glomerulonephritis and SLE had a significant increase in total IgG and of IgG4 (P less than 0.05-0.001). Patients with minimal change disease had low concentrations of IgG (P less than 0.001) with a significant decrease in IgG1 and IgG2 (P less than 0.001 and 0.01, respectively). Highly significant increases in IgA were noted for patients with IgA nephritis (P less than 0.001) but high levels were also seen in patients with chronic glomerulonephritis. The findings might have diagnostic implications.     

Immunologic parameters in infective endocarditis: a prospective study.

To evaluate the role of immunoglobulins, complement, circulating immune complexes (CIC), heart antibodies (HAb) and rheumatoid factor (RF) in infective endocarditis, we studied 28 consecutive patients before and after therapy. Statistically significant elevation was seen in IgG (p less than 0.001) and IgA (P less than 0.001) level prior to initiation of therapy as compared to a control group. Following drug treatment a fall was noted in IgA (P less than 0.01) and IgM (p less than 0.01) level as compared to basal values. Low C3 levels were seen in those with renal involvement (p less than 0.05). CIC levels estimated by 4% PEG precipitation assay were found to be elevated in 64% of patients. Patients with shorter duration of illness (less than three months) had higher levels of CIC containing IgG (P less than 0.005), IgA (P less than 0.05) and IgM (P less than 0.05), as compared to those with a longer duration. Initial CIC levels did not predict the clinical course and were found to be of no value in prognosis, although an improvement in congestive heart failure was associated with a rise in C3 (P less than 0.05) and IgM (P less than 0.05) containing CIC and an overall clinical improvement with a rise in IgA (p less than 0.05) containing CIC. There was no statistically significant difference in CIC level, for the entire group studied, before and after therapy. Patients who had rheumatoid factor in their initial serum sample demonstrated a fall in IgG, IgA and IgM containing CIC and a rise in C3 with therapy. The converse was true for those who lacked RF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunoglobulins and IgG subclasses in patients with inflammatory bowel disease.

BACKGROUND/AIMS: Serum immunoglobulin levels and distribution are altered in patients with inflammatory bowel disease (IBD). The purpose of this study is to examine the value of serum concentration of IgG subclasses for the diagnosis and evaluation of disease activity of IBD and to assess possible differences in the immunoglobulin changes between patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODOLOGY: We measured serum IgG and IgG subclasses concentrations as well as IgA, IgM, ESR, CRP, elastase levels and granulocyte count of 96 patients with chronic IBD (69 with CD and 27 with UC) with various levels of disease activity. RESULTS: The total IgG levels in patients with UC were significantly increased, for both active and inactive disease, compared to those of patients with CD. The IgG1 concentration in patients with UC (7+/-0.77 mg/ml) was significantly higher than in patients with CD (5.6+/-0.61 mg/ml) (p<0.02). The IgG2 levels in CD were significantly higher than those of UC (4.6+/-0.64 vs. 3.8+/-0.57 mg/ml) (p<0.05). The IgG4 levels of UC patients were significantly higher than those of the CD patients (0.39+/-0.06 vs. 0.29+/-0.05 mg/ml) (p<0.05). No significant differences were found in the serum concentrations of IgG3, IgA and IgM between the two groups. There was a negative correlation between the various indices of disease activity and the concentration of IgG3 in patients with UC (p<0.01), and a positive correlation in patients with CD for IgG1 (p<0.001), IgG2 (p<0.001) and IgA (p<0.01). CONCLUSIONS: In IBD some of the IgG immunoglobulin subclass concentration changes correlate, positively or negatively, with disease activity and therefore could be used as additional markers of it. However, serum immunoglobulin levels cannot be used to differentiate between UC and CD.     

Familial IgE deficiency associated with sinopulmonary disease

Three generations of relatives of 58-year-old nonidentical twins with chronic bronchitis and fibrotic lung disease were evaluated. Sera of 23 family members, 14 with a history of excessive sinopulmonary infections, were examined for deficiencies of immunoglobulin classes, IgG subclasses, and specific antibody to tetanus toxoid and Hemophilus influenzae type b. Of 14 symptomatic family members, 12 had serum IgE concentrations less than 5 IU/ml. Four had values less than 1 IU/ml. Serum IgE was greater than 10 IU/ml in all nine asymptomatic individuals. Inheritance of low IgE appeared to be autosomal dominant, with variable penetrance. IgA was low normal (70-90 mg/dl) in three individuals. Two of these were IgE deficient. One symptomatic child had unmeasurable IgG2 (less than 10 mg/dl) and IgE (less than 0.5 IU/ml). This kindred demonstrates that IgE deficiency can be familial, and associated with sinopulmonary disease.