High Serum IgA Levels Research Articles

Significance of high levels of serum IgA and IgA-class circulating immune complexes (IgA-CIC) in patients with non-insulin-dependent diabetes mellitus

Significance of serum IgA and IgA-class circulating immune complexes (IgA-CIC) elevation in patients with non-insulin-dependent diabetes mellitus (NIDDM) was described. Seventeen patients with NIDDM and 17 patients with diffuse mesangial proliferative glomerulonephritis without deposition of IgA (DPGN) as controls were examined. The levels of serum IgA in patients with NIDDM were significantly higher than those in patients with DPGN ( p ⩽ 0.01). The levels of IgA-CIC in patients with NIDDM were also significantly higher than those in patients with DPGN ( p ⩽ 0.01). Production of IgA derived from B cells and the proportion of IgA bearing B cells in patients with NIDDM were not significantly higher than those in patients with DPGN. Furthermore, the levels of IgA in pharyngeal washings from diabetic patients were not significantly higher than those for DPGN patients. Duration of diabetes, the level of HbA 1c, and the presence of hypertension, microalbuminuria, or retinopathy showed no significant correlations with the levels of serum IgA or IgA-CIC in patients with NIDDM. It was postulated that the elevations of serum IgA and IgA-CIC were based on subclinical infection of the mucosa and/or deterioration of IgA clearance in patiente with NIDDM.

Differences in the immune responses of mice and sheep to an aromatic-dependent mutant of Salmonella typhimurium

A live mutant aroA Salmonella serotype Typhimurium ovine strain (S25/1) could be cultured from tissues of mice for up to 90 days after oral infection. Following vaccination, high levels of Salmonella-specific serum IgM, IgG and IgA were produced in addition to high levels of specific intestinal IgA. Moreover, there was also evidence of Salmonella-specific cell-mediated immunity in vaccinated mice in the form of strong delayed-type hypersensitivity and the production of interferon-gamma (IFN-tau) by spleen cells stimulated with Salmonella antigen. The aroA strain was also recovered from the mesenteric lymph nodes and most tissues examined from sheep vaccinated by the oral route. Salmonella-specific IgM was detected in the serum; however, specific IgG responses were very low and there was an absence of specific copro-antibody. Although strong Salmonella-specific lymphocyte proliferative responses were detected, they did not result in the production of IFN-tau and flow cytometric analysis revealed that the proliferating cells were predominantly B lymphocytes. Despite the absence of strong vaccine-specific immune responses in vaccinated sheep compared with those seen in mice, both mice and sheep were protected against challenge with virulent wild-type strain S25/1.

An enzyme-linked immunosorbent assay (ELISA) for the detection of serum IgA against Candida albicans mannan

An enzyme-linked immunosorbent assay (ELISA) is described for measuring serum IgA against highly purified preparations of the Candida albicans immunodominant surface carbohydrate, mannan. Optimal assay conditions are presented for the test to be run in less than four hours. The assay is reliable and easy to use in the diagnostic laboratory with an intraassay variation of less than 10%. Blood donors showed a wide variation of serum levels. Two groups of patients awaiting organ transplants, with a high degree of mucosal colonization by Candida species, showed significantly higher levels of serum IgA against the mannan as compared to the blood donors. This test is proposed to be a useful tool in the surveillance of Candida colonization as one of the factors predisposing for infection in both immunocompetent and immunocompromised patients.

Effect of and Indication for Tonsillectomy in IgA Nephropathy

Although more than 20 years have passed since the initial report of IgA nephropathy, the etiology of this disease is still unclear. Some reports suggest that the tonsil is an important etiological factor. We performed tonsillectomy on 26 patients with IgA nephropathy associated with chronic tonsillitis, and followed up the patients for two years after the operation to evaluate its clinical effect on this disease. Twelve patients (efficacy rate 46%) showed distinct improvement in urinary findings after the operation, although the efficacy rate went down as renal injury advanced. Serum IgA levels decreased significantly after the operation both in patients who improved and in those who did not; the decrease was especially evident in patients who had high levels of serum IgA before tonsillectomy. In 4 patients who improved, the level of circulating immune complex (CIC) was extremely high before, and decreased significantly after, the operation. One patient suffered renal failure three years after tonsillectomy. When renal injury has advanced to the clinically apparent degree, as occurred in this patient, tonsillectomy is absolutely contraindicated. In reaching a decision as to whether tonsillectomy is indicated in mild cases, the change in the number of erythrocytes in urinary sediments may be a sensitive parameter of the tonsillar provocation test.

Effect of dietary administration of the trichothecene vomitoxin (deoxynivalenol) on IgA and IgG secretion by peyer's patch and splenic lymphocytes

Prolonged dietary exposure of mice to the trichothecene vomitoxin induces abnormally high levels of serum IgA and kidney mesangial IgA accumulation in a manner that is highly analogous to the human glomerulonephritis IgA nephropathy. In this study, the capacity of Peyer's patch and splenic lymphocytes to produce IgA and IgG were compared in B6C3F 1 mice that were fed diets with and without 25 ppm vomitoxin for up to 12 wk. Serum IgA increased 2-,4- and 8-fold after 4, 8 and 12 wk, respectively, of vomitoxin exposure and it became the primary serum isotype, whereas serum IgG was unaffected. On termination of the experiment there were increased numbers of IgA-secreting cells in Peyer's patches after 8 wk of toxin exposure and in the spleen after 4, 8 and 12 wk of toxin exposure. There were also increased numbers of IgG-secreting cells in Peyer's patches on termination of the experiment at 4, 8 and 12 wk but no effect was observed in the spleen. Supernatant IgA and IgA-secreting cell numbers were also markedly elevated in lymphocyte cultures obtained from Peyer's patches and, to a lesser extent, from spleens of treated mice compared with controls. Based on output of treated mice relative to corresponding controls, IgA secretion was greatest in concanavalin-A-stimulated and unstimulated Peyer's patch cultures. Enhanced IgG secretion and IgG-secreting cells were also observed in mitogen-stimulated and unstimulated Peyer's patch lymphocyte cultures of treated relative to control mice, but differences in splenocyte cultures were negligible. Based on total Ig output, IgA production was 8- to 20-fold greater than IgG production in both control and treatment Peyer's patch cultures. In contrast, vomitoxin treatment caused a shift from primarily IgG production in lipopolysaccharide-stimulated spleen cultures to equivalent IgA production. These data provide in vitro evidence that ingestion of vomitoxin promotes terminal differentiation of IgA-secreting progenitors in the Peyer's patch and, to a lesser extent, in the spleen. These functional changes are consistent with the shift from IgG to IgA as the primary serum isotype.

Amniotic Fluid Findings in Women with High Levels of Chlamydial Antibody

A study was undertaken to examine possible transplacental passage of Chlamydia trachomatis from pregnant women who were seropositive for chlamydia, but with no cervical C. trachomatis infection. Forty asymptomatic pregnant women, scheduled for diagnostic amniocentesis at 15-19 weeks of gestation, were tested for the presence of high serum IgA and IgG chlamydial specific antibodies and for cervical chlamydia infection. Five (12.5%) had both high serum IgA and IgG antibody levels and 10 (25%) had high serum IgG antibody levels. Overall, 15 (37.5%) had high serum chlamydia specific antibody levels (all were free of cervical chlamydial infection). The evaluation of the amniotic fluid specimens of these 15 seropositive pregnant women, who were free of cervical chlamydial infection, proved negative for direct C. trachomatis antigen detection and for chlamydial IgA and IgG specific antibodies. These negative results could be attributed to the lack of transplacental passage of C. trachomatis or to the antimicrobial activity of amniotic fluid against C. trachomatis, which has been previously described. The discrepancy between maternal infection and maternal serum antibody levels may suggest that the serologic test does not predict the presence of an antigen in the cervix.

Regulation of Peripheral Blood B-Cell IgA Production in Alcoholic Cirrhosis

In alcoholic cirrhosis, high levels of serum IgA make a prominent contribution to hyperglobulinaemia. Kinetic studies indicate that this predominantly reflects enhanced IgA synthesis rather than catabolism. Increase IgA synthesis might reflect increased antigenic load, diminished T-cell suppression, or T-cell independent B-cell stimulation (for example by lipopolysaccharide). To investigate this we studied T-cell control of IgA production by peripheral blood cells. Six patients with alcoholic cirrhosis were compared with six normal individuals. Serum IgA levels were significantly higher in the patients (6.6 mg/ml, SD 2.8 cf 1.7 mg/ml, SD 1.2). Seven day unstimulated cultures of peripheral blood mononuclear cells yielded supernatant IgA concentrations of 1,025 ng/ml (SD 600) in patients and 363 ng/ml (SD 222) in controls. T-cell control of IgA synthesis was explored by rosetting out T-cells, and reconstituting cultures at varying T:non-T cell ratios. Similarly shaped curves relating IgA per million non-T cells to the T:non-T cell ratio were found, with maximum IgA production at a T:non-T ratio of 8:2 in each group. IgA production at this ratio was 6.4 micrograms/ml/million non-T cells (SD 3.2) in cirrhosis of 3.2 (SD 1.0) in controls. T-cell control of IgA production thus appears normal, though set at a higher level, implying enhanced T-cell independent drive to IgA production in alcoholic cirrhosis.

Clinical and therapeutic studies in mesangial immunoglobulin A glomerulonephritis.

A long-term clinical and therapeutic study was performed in 47 patients with mesangial IgA glomerulonephritis. The male to female ration was 2.9:1. An episode of gross haematuria or the incidental discovery of asymptomatic microscopic haematuria with associated mild proteinuria heralded the apparent onset of renal disease. At the onset of observation 18 patients (38.2%) had high blood pressure. Other 17 patients developed hypertension during observation. Anaemia was uncommon. No essential abnormalities in serum protein and lipid patterns were found. Twenty-nine patients (61.6%) had higher levels of serum immunoglobulins--most frequently of IgA (42.5%). Twenty-two patients had low serum C3 levels (46.8%). The percentage of patients with renal failure increased from 21.2 to 36.1 during observation. Male sex, hypertension, proteinuria higher than 2 g/24 h, elevated ESR, high serum IgA levels, longer duration of the disease and older age of patients suggest an unfavourable outcome. Long-term treatment with a combination of azathioprine/acenocumarol, or indomethacin, or levamisole has no effect on the clinical manifestation and evolution.

Clinicopathologic correlations in a series of 143 patients with IgA glomerulonephritis.

In an unselected series of patients with IgA glomerulonephritis, old age, high blood pressure, and high urinary protein excretion at the time of renal biopsy were found to correlate with impaired renal function, whereas sex, estimated duration of the disease, or high serum IgA levels did not. The following clinical features were favorable prognostic signs: asymptomatic proteinuria, macroscopic hematuria, and isolated microscopic hematuria. The degree of diffuse mesangial alteration and the presence of segmental glomerular lesions correlated clearly with the subsequent clinical outcome. Vascular lesions, i.e. arteriosclerosis and renal vascular deposition of C3, were most often present in patients with severe glomerulopathy. The presence of electron-dense deposits in glomerular capillary walls was also an unfavorable prognostic finding. Renal biopsy findings of interstitial infiltrates of inflammatory cells and IgA distributed along glomerular capillary walls were usually associated with extrarenal manifestations of the disease.

Gut-liver interactions in the IgA system.

Recent experimental work in rodents has demonstrated that the liver can function as an 'IgA-pump', transporting polymeric IgA from serum to bile via a secretory-component mediated uptake at the surface of the hepatic parenchymal cell. Studies are surveyed which indicate that, although this process occurs in man, it is to a strikingly lesser degree, and interruption of this pathway does not explain the high serum IgA levels often seen in chronic liver disease: the explanation for this lies in enhanced synthesis of IgA, and diminished polymeric IgA catabolism unrelated to hepatobiliary transport.

La neuroacropathie éthylique Acquisitions diagnostiques et pathogéniques récentes

The authors report the results of a prospective study of 28 patients with alcoholic neuroacropathy or the Bureau and Barrière syndrome. The investigations included biochemical analysis of the alcoholism, electrophysiological studies and, in 4 cases, electron microscopy of the musculocutaneous nerve biopsy. Bone scintigraphy with foot and hand scans was carried out in all cases for a more exact and above all, earlier diagnosis of the neurological osteoarthropathy. The clinical syndrome was attributed to a polyneuropathy with a large sensory component of the alcoholic "dying back" variety in all cases. High VGM levels associated with high serum IgA levels appears to be a biochemical diagnostic criteria of this condition. The latter parameter was not closely related to the hepatocytic status of the patient but suggests a direct or indirect effect of the neuropathy on humoral immunity. All cases had characteristic bone scans with high uptake at points of mechanical stress of the anterior part of the foot (first metatarsophalangeal joint). This finding, which is also observed in alcoholic sensory neuropathy without trophic disturbances prompts the authors to define a preacropathic state and an evolutive and pathogenic outline of the disease.

T-cell dysfunctions in IgA nephropathy: Specific abnormalities in the regulation of IgA synthesis

This work was undertaken to determine the cellular abnormalities that could explain the high levels of serum IgA frequently found in patients with IgA nephropathy. Seventeen control subjects and twenty-seven patients who had received no therapy were studied. After in vitro pokeweed mitogen (PWM) stimulation, significantly higher amounts of IgA were produced by peripheral blood mononuclear cells (PBM) of patients when compared with those of the control group (560 ± 97 vs 231 ± 57 ng/ml, P < 0.0025). No differences were observed in the synthesis of IgG and IgM. Twenty out of twenty-seven patients presented an increase in the percentages of OKT4 + cells (mean + 2 SD), in relation to the control group, with normal or elevated percentages of OKT8 + cells. The OKT4 + OKT8 + cell ratio was elevated in 12 out of 27 patients. All patients presented some abnormality in the generation of IgA-specific suppressor cells at variable doses of concanavalin A (Con A) on in vitro PWM-stimulated culture of PBM. In both assays low doses of Con A (2.5 μg/ml) induced a certain suppression of IgA synthesis in patients that was not observed in the majority of the control group. At these doses some patients also showed an enhancement in the synthesis of IgG and IgM. On the contrary, higher doses of Con A (50 μg/ml) produced significantly less IgA suppression than the controls. Normal IgA-suppression values were found at 10 μg/ml of Con A. T cells obtained from patients were significantly more efficient than T cells from controls in providing IgA-helper activity for normal allogeneic enriched B cells ( P < 0.025) in PWM-stimulated cocultures. These results show that patients with IgA nephropathy present, after mitogen stimulation in vitro, a specifically increased production of IgA as well as an augmentation in the activity of IgA-helper T cell and a deregulation on IgA-suppressor T-cell function. According to these data, it is suggested that the alteration observed in helper T cells might precede that of suppressor T cells. These immunoregulatory abnormalities might contribute to the pathogenesis of the disease.

IgA nephropathy: prognostic significance of proteinuria and histological alterations.

A retrospective study of 166 patients with IgA nephropathy was undertaken to clarify possible correlations between clinical and histological features, and the severity and prognosis of the disease. At the time of biopsy, impaired renal function, with creatinine clearance (Ccr) below 90 ml/min was found in 61 cases. At the final examination, after a mean follow-up period of 34 months, 82 patients had impaired renal function, 12 of these patients went into terminal renal failure requiring hemodialysis treatment. The presence of proteinuria of more than 1.0 g/day was closely correlated with impairment of renal function both at the time of biopsy and at the final observation. An unfavorable outcome was also anticipated in the presence of hypertension. In contrast, microhematuria, macrohematuria or high serum IgA levels did not appear to be related to the outcome. Histologically, sclerotic lesions such as mesangial or global sclerosis, interstitial fibrosis and tubular atrophy, and some active changes such as mesangial hypercellularity and tuft adhesion were more frequent and severe in patients with impaired renal function. Impressive localization of IgA and C3 in the mesangium as well as in capillary loops was observed more often in these patients. These results clearly indicate that IgA nephropathy may follow a slowly progressive course in about half of the patients, and that marked proteinuria and severe histological changes appear to correlate closely with an unfavorable course.

Heterogeneity of T-CLL defined by monoclonal antibodies in nine patients

Surface markers were examined on peripheral lymphocytes from 450 patients with chronic lymphocytic leukemia (CLL). In nine (2%), the lymphocytes had the characteristics of thymus-derived cells (T-CLL). These nine patients had a milder clinical course than that usually attributed to T-CLL, lack of massive hepato- or splenomegaly, and fewer skin lesions. Lymphocytes from these patients were studied with surface markers, including a panel of monoclonal antibodies (MoAb) and also for in vitro functional activity. Whereas cells from two patients appear to represent heterogeneous proliferations, as detected by MoAb, seven cases gave a clearly recognized phenotype. Evaluation of immunoregulatory functions showed that OKT8 +, Fc IgG receptor-positive cells (three patients) were able to suppress either lymphocyte proliferation, or immunoglobulin biosynthesis, or both. In three patients with a proliferation of OKT4 + cells, in vitro help was not demonstrable, but in two of them, high levels of serum IgA were detected. Our results clearly show that T-CLL may originate from different T-cell subpopulations. Some, if not all of the T-CLL cells, seem to represent the proliferation of well-differentiated T cells, corresponding to the normal T-cell subsets. In some cases these cells retain functional activity. The expression of a given phenotype pattern, as detected by MoAb, represents a useful tool in determining the clonal origin of proliferating cells.

Epidemic meningococcal disease: synthesis of a hypothetical immunoepidemiologic model.

A hypothetical model of the epidermic behavior of Neisseria meningitidis, based upon the induction of susceptibility to disseminated disease by circulating IgA, is presented. The model is based on the assumption that epidemic susceptibility is acquired as a result of induction of serum IgA by cross-reacting enteric bacteria, the priming organism. Co-colonization with the appropriate strain of N. meningitidis then may result in disseminated disease. Colonization by either bacterium in the absence of the other results in reinforcement of the commensal relationship. Slow, silent, fecal-oral transmission of the priming organism determines the time/space characteristics of an epidemic; interruption of fecal-oral transmission aborts it. Aerosol transmission of the meningococcus determines the magnitude of an epidemic. Independent, age-related acquisition of both capsular polysaccharide and lipopolysaccharide antibodies provides immunity in the absence of aberrantly high levels of co-specific serum IgA.

Rubella-specific serum and nasopharyngeal antibodies in volunteers with naturally acquired and vaccine-induced immunity after intranasal challenge.

Thirty-nine volunteers, who were either naturally immune to rubella virus or immune as a result of vaccination with RA 27/3, Cendehill, or To-336 vaccines, were challenged intranasally with high-titered RA 27/3 virus. Before and after challenge, rubella-specific IgG and IgA in serum and nasopharyngeal washings were measured by hemagglutination inhibition, neutralization, and radioimmunoassay. The reinfection rate (at least a fourfold rise in titer of serum antibody by one or more tests) was highest among recipients of Cendehill vaccine. Significant rises in titer were most frequently detected by radioimmunoassay for rubella-specific IgG. After challenge of immune volunteers, rubella-specific IgM was detected in six of the 29 with vaccine-induced immunity. Although high levels of rubella-specific serum and nasopharyngeal IgA before challenge appeared to be associated with protection in recipients of RA 27/3 vaccine, no level of any antibody tested was invariably associated with protection. For comparison, volunteers with vaccine-induced immunity challenged intranasally with the same dose of vaccine after inactivation did not show evidence of reinfection.

Serum immunoglobulins in periodontosis patients.

This study indicates that a significantly greater percentage of periodontosis patients had high serum IgM and IgA levels compared to the control subjects plus a trend in the same direction for IgG. Paradoxically, 41% of the periodontosis subjects had no elevation of IgG, IgA or IgM.

An epidemiological survey of immunological abnormalities in asbestos workers: II. Serum immunoglobulin levels

A significant elevation of serum IgA and IgG was found in female asbestos workers below age 36. Higher values of serum IgA, IgG, and IgM were found in male asbestos workers over age 35, when compared to matched controls. Female asbestos workers, over age 35, statistically differ from their controls only with respect to IgG levels. Patients, with asbestosis and with an impairment of blood oxygen saturation, contribute greatly to the elevation of serum immunoglobulin levels in asbestos workers. The asbestosis process, but not chronic bronchitis, is responsible for high serum IgA and IgG levels.

CONTROLLED TRIAL OF PHENYTOIN THERAPY IN IgA NEPHROPATHY

IgA nephropathy, a condition thought to cause slowly progressive renal damage, is frequently associated with high serum IgA levels. As phenytoin sodium lowers serum IgA concentrations, a controlled trial of therapy with this drug was conducted over a two-year period in patients with IgA nephropathy. Despite significant depression of serum IgA concentrations in the treatment group, there was no significant change in any other clinical, biochemical or pathological parameter, in either control or treatment groups. Indeed, there was evidence for a slow progression of renal damage in both groups. These observations suggest that the elevated serum IgA concentrations in IgA nephropathy are not of primary pahtogenetic significance but are rather a consequence of a basic abnormality in antigen processing and IgA production.

Immunofluorescence of the skin in allergic diseases: an investigation of patients with contact dermatitis, allergic vasculitis and atopic dermatitis

Skin biopsies for immunofluorescent studies were taken from patients with contact dermatitis (positive patch tests), atopic dermatitis and allergic vasculitis for comparison with normal-appearing skin from the same patients, and from healthy controls. A variety of deposits of immunoglobulins, complement components and fibrinogen were demonstrated in 6 out of 20 patients with contact dermatitis, 7 out of 10 with atopic dermatitis, 8 out of 10 with allergic vasculitis, and in 4 out of 20 control individuals. No diagnostic pattern of deposits was found. Elevated serum IgE and eosinophilic counts were found in patients with atopic dermatitis, and high serum IgA and fibrinogen levels were found in the allergic vasculitis group.