Elevated Circulating Immune Complexes Research Articles

Leaky gut, circulating immune complexes, arthralgia, and arthritis in IBD: coincidence or inevitability?

Most host-microbiota interactions occur within the intestinal barrier, which is essential for separating the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. Gut inflammation allows pathogenic bacteria to enter the blood stream, forming immune complexes which may deposit on organs. Despite increased circulating immune complexes (CICs) in patients with inflammatory bowel disease (IBD) and discussions among IBD experts regarding their potential pathogenic role in extra-intestinal manifestations, this phenomenon is overlooked because definitive evidence demonstrating CIC-induced extra-intestinal manifestations in IBD animal models is lacking. However, clinical observations of elevated CICs in newly diagnosed, untreated patients with IBD have reignited research into their potential pathogenic implications. Musculoskeletal symptoms are the most prevalent extra-intestinal IBD manifestations. CICs are pivotal in various arthritis forms, including reactive, rheumatoid, and Lyme arthritis and systemic lupus erythematosus. Research indicates that intestinal barrier restoration during the pre-phase of arthritis could inhibit arthritis development. In the absence of animal models supporting extra-intestinal IBD manifestations, this paper aims to comprehensively explore the relationship between CICs and arthritis onset via a multifaceted analysis to offer a fresh perspective for further investigation and provide novel insights into the interplay between CICs and arthritis development in IBD.

Peculiar features of immunoinflammatory syndrome in patients with ulcerous colitis, depending on severity of disease attack

Aim. To study the blood serum interleukin-6 (IL) and circulating immune complexes (CIC) levels in patients with ulcerous colitis (UC), depending on the severity of disease attack, colonic inflammation dissemination, and presence of abenteric manifestations.
 Materials and methods. One hundred patients with UC in the phase of active inflammation were examined. Blood serum IL-6 and CIC concentrations were studied with IFA method.
 Results. 88,5 % of UC patients in the phase of active inflammation showed an elevated mean IL-6 index, 80 % had increased CIC concentration as compared with normal values. The highest IL-6 and CIC levels were obtained in case of severe forms of disease (11,50 (7,30–23,65) pg/ml and 115,50 (105,00–118,00), respectively); CIC and IL-6 levels were significantly higher in patients with abenteric manifestations and frequently relapsing course in comparison with patients, having rare UC relapses (p < 0,005). Strong direct correlations of IL-6 and CIC with each other (r = 0,65; p = 0,001) as well as with the severity of pathological changes in the colon were established.
 Conclusions. Among patients with UC, significantly elevated blood serum IL-6 and CIC concentrations were determined. Patients with severe attack of disease as well as those with abenteric manifestations and frequent relapses demonstrated reliably higher levels of these indices. It is recommended to use determination of blood serum IL-6 and CIC levels as an available and informative method, permitting to estimate the degree of severity of inflammatory process in the colonic wall among patients with ulcerous colitis.

Borna disease virus (BDV) infection in psychiatric patients and healthy controls in Iran.

BackgroundBorna disease virus (BDV) is an evolutionary old RNA virus, which infects brain and blood cells of humans, their primate ancestors, and other mammals. Human infection has been correlated to mood disorders and schizophrenia, but the impact of BDV on mental-health still remains controversial due to poor methodological and cross-national comparability.MethodThis first report from the Middle East aimed to determine BDV infection prevalence in Iranian acute psychiatric disorder patients and healthy controls through circulating immune complexes (CIC), antibodies (Ab) and antigen (pAg) in blood plasma using a standardized triple enzyme immune assay (EIA). Samples of 314 subjects (114 psychiatric cases, 69 blood donors, and 131 healthy controls) were assayed and data analyzed quantitatively and qualitatively.ResultsCICs revealed a BDV prevalence of one third (29.5%) in healthy Iranian controls (27.5% controls; 33.3% blood donors). In psychiatric patients CIC prevalence was higher than in controls (40.4%) and significantly correlating with bipolar patients exhibiting overt clinical symptoms (p = 0.005, OR = 1.65). CIC values were significantly elevated in bipolar (p = 0.001) and major depressive disorder (p = 0.029) patients as compared to controls, and in females compared to males (p = 0.031).ConclusionThis study supports a similarly high prevalence of subclinical human BDV infections in Iran as reported for central Europe, and provides again an indication for the correlation of BDV infection and mood disorders. Further studies should address the morbidity risk for healthy carriers and those with elevated CIC levels, along with gender disparities.

Polymorphisms of CD16A and CD32 Fcγ receptors and circulating immune complexes in Ménière's disease: a case-control study

BackgroundAutoimmune diseases with elevated circulating autoantibodies drive tissue damage and the onset of disease. The Fcγ receptors bind IgG subtypes modulating the clearance of circulating immune complexes (CIC). The inner ear damage in Ménière's disease (MD) could be mediated by an immune response driven by CIC. We examined single-nucleotide polymorphism (SNPs) in the CD16A and CD32 genes in patients with MD which may determine a Fcγ receptor with lower binding to CIC.MethodsThe functional CD16A (FcγRIIIa*559A > C, rs396991) and CD32A (FcγRIIa*519A > G, rs1801274) SNPs were analyzed using PCR-based TaqMan Genotyping Assay in two cohorts of 156 mediterranean and 112 Galicia patients in a case-control study. Data were analyzed by χ2 with Fisher's exact test and Cochran-Armitage trend test (CATT). CIC were measured by ELISA for C1q-binding CIC.ResultsElevated CIC were found in 7% of patients with MD during the intercrisis period. No differences were found in the allelic frequency for rs396991 or rs1801274 in controls subjects when they were compared with patients with MD from the same geographic area. However, the frequency of AA and AC genotypes of CD16A (rs396991) differed among mediterranean and Galicia controls (Fisher's test, corrected p = 6.9 × 10-4 for AA; corrected p = 0.02 for AC). Although genotype AC of the CD16A receptor was significantly more frequent in mediterranean controls than in patients, [Fisher's test corrected p = 0.02; OR = 0.63 (0.44-0.91)], a genetic additive effect for the allele C was not observed (CATT, p = 0.23). Moreover, no differences were found in genotype frequencies for rs396991 between patients with MD and controls from Galicia (CATT, p = 0.14). The allelic frequency of CD32 (rs1801274) was not different between patients and controls either in mediterranean (p = 0.51) or Galicia population (p = 0.11).ConclusionsElevated CIC are not found in most of patients with MD. Functional polymorphisms of CD16A and CD32 genes are not associated with onset of MD.

Evaluation of humoral immune response in adaptive immunity in ALS patients during disease progression

In ALS, evidence suggests immune reactions in disease pathogenesis. Although immunological changes point to adaptive immune response, whether humoral or cellular response dominates during disease course is unknown. The study aim was to evaluate humoral immune response in ALS patients during disease progression. Circulating immune complexes (CICs), IgG, and IgM in sera of ALS patients and matching controls were evaluated after each of two visits. Results showed significantly elevated CICs and IgG in ALS patient sera. CICs decreased to control levels at the second visit, yet IgG remained higher than controls. Serum IgM was within normal range. Results suggest a humoral immune response initiating adaptive immunity in ALS, however, cellular immune response needs verification.

Gliadin IgG antibodies and circulating immune complexes

Objective. Circulating immune complexes (CICs) in blood are associated with autoimmune-diseases such as systemic lupus erythematosus, immune complex glomerulonephritis, rheumatoid arthritis and vasculitis. However, slightly increased serum concentrations of such CICs are sometimes also found in healthy individuals. The objective of the current study was to assess whether food antigens could play a role in the formation of CICs. Material and methods. A total of 352 (265 F, 87 M), so far, healthy individuals were tested for CICs containing C1q and immunoglobulin G (IgG) as well as for gliadin IgG antibodies using the ELISA technique. Additionally, fructose and lactose malabsorption was assessed using hydrogen breath tests. Results. In our study, 15.3% (54/352) of the patients presented with elevated CIC concentrations (above 50 µg/ml) and 6.5% (23/352) of the study population were positive for gliadin IgG antibodies (above 20 U/ml). CIC concentration levels were significantly higher in the group with elevated gliadin IgG antibodies (CIC median: 49.0 µg/ml) compared with the group with normal levels of gliadin IgG antibodies (CIC median: 30.0 µg/ml; Mann-Whitney U-test, U=1992; p <0.001). As expected, there was no difference in CIC concentrations (Mann-Whitney U-test, U=6106; p=0.783) and gliadin IgG (Mann-Whitney U-test, U=3761; p=0.411) between patients in the fructose or lactose malabsorber groups and the subjects without malabsorption. Conclusions. The results of this study indicate that certain food antigens (e.g. gluten) could play a role in the formation of CICs. An association between CICs and fructose or lactose malabsorption seems to be improbable.

Silent nephritis in systemic lupus erythematosus.

Silent lupus nephritis (SLN) was investigated in 42 renal asymptomatic patients and compared with 49 untreated patients with overt lupus nephropathy (OLN). Urinary sediment, quantitative proteinuria, creatinine clearance, antinuclear antibodies (ANA), complement, circulating immune complexes (CIC) and renal biopsies were evaluated in all of the patients. Forty-one out of the 42 (97.6%) patients had SLN according to histopathological findings. Results showed that the mean age, female/male ratio and the clinical activity index (SLEDAI) were similar in both groups (P > 0.05). The prevalence of ANA, anti-ds DNA, anti-ENA autoantibodies and C4 serum levels showed no statistical differences between the two groups (P > 0.05). Conversely, in the OLN group, elevated CIC and diminished CH50 and C3 serum levels were significantly different (P < 0.01). WHO class II was the predominant renal lesion in the group with SLN (P < 0.0001), whereas class IV was in the OLN patients (P < 0.0001). We conclude that, in our series, SLN was highly prevalent in renal asymptomatic patients with otherwise systemic lupus erythematosus. Furthermore, abnormal levels of CIC, CH50 and C3 associated with WHO class II suggest a moderate but ongoing activation of immune-mediated renal injury mechanisms.

Circulating immune complexes in chronic hepatitis C.

For assessing the role of circulating immune complexes (CIC) in chronic hepatitis C, the relative frequency of CIC was determined in 54 patients with chronic hepatitis C, 15 asymptomatic hepatitis C virus (HCV) carriers, and 54 healthy controls. IgM and IgG containing CIC were studied using both C1q and conglutinin (K) in an immunoglobulin-specific solid-phase enzyme immunoassay. CIC were a common feature of chronic hepatitis C with 96.3% of patients with at least one abnormal test result. The prevalence of elevated IgG-K, IgM-K, IgG-C1q, and IgM-C1q CIC was 70.3%, 50.0%, 64.8%, and 35.1%, respectively. The prevalence of IgG class CIC was higher than IgM class CIC (P = 0.038 for K-CIC and P = 0.01 for C1q-CIC, respectively). There is correlation between IgG-K CIC and IgG-C1q CIC (r = 0.445, P = 0.002), IgG-K CIC and IgM-C1q CIC (r = 0.348, P = 0.020), IgM-K CIC and aspartic aminotransferase (r = 0.321, P = 0.015), IgM-K CIC and alanine aminotransferase (r = 0.301, P = 0.027). Compared to patients with chronic persistent hepatitis and chronic lobular hepatitis, patients with chronic active hepatitis have a higher prevalence of elevated IgG-K CIC (77.2% vs. 40.0%, P = 0.029) and IgM-K CIC (56.8% vs. 20.0%, P = 0.038). The concentration of IgG-K, IgM-K, and IgM-C1q CIC in the former was significantly higher than that in the latter, respectively. In conclusion, IgG class CIC is the major type of CIC in chronic hepatitis C.(ABSTRACT TRUNCATED AT 250 WORDS)

Immune Complexes in Pediatric Human Immunodeficiency Virus Infection

Circulating immune complexes (CIC) were analyzed in a cohort of 30 children infected with the human immunodeficiency virus. Elevated CIC were detected by the C1q assay in 70% (21/30) of all patients and by the Raji cell assay in 93% (28/30) of all patients. While only less than one third of patients with elevated CIC had free serum antibodies to Epstein-Barr virus, 80% (16/20) of them had detectable antibodies to Epstein-Barr virus associated with CIC. Enriched CIC in human immunodeficiency virus-infected children contained low levels of complement. These findings document that, as an expression of the humoral immunodeficiency, CIC in human immunodeficiency virus-infected children are deficient in complement and can thus be underestimated if complement-precipitating methods are used for their detection.

Immunoglobulin E and Circulating Immune Complexes in Endolymphatic Hydrops

Levels of circulating immune complexes (CICs) in 59 patients with Meniere's disease and total serum immunoglobulin E (IgE) levels in a subgroup of 42 of the 59 were determined quantitatively for possible abnormalities of humoral immunity. Significant differences in average IgE levels between the 42 patients with Meniere's disease and 18 normal control subjects were not determined; however, five (11.9%) of the 42 patients were found to have obviously raised IgE levels. Elevated CIC levels were found in 19 (32.2%) of the 59 patients with Meniere's disease and in one (2.3%) of the 43 control subjects. This difference was statistically significant. The possible mechanisms of immune-mediated endolymphatic hydrops are discussed.

Circulating immune complexes in patients with systemic lupus erythematosus.

Circulating immune complexes (CIC) were studied in seventy-one patients with systemic lupus erythematosus (SLE) in order to correlate CIC with the clinical manifestations and the disease activity of SLE. C1q-solid phase ELISA (C1q-SP) and microtiter plate Raji cell-ELISA (Raii cell) methods were used for measurement of CIC levels in this study. Patients with elevated CIC had a higher frequency of malar rash, CNS involvement, nephritis, and anti-dsDNA antibodies than those with normal levels of CIC. There were negative associations between CIC detected by the C1q-SP method and C1q, and factor B; while CIC detected by the Raji cell method negatively correalated with C3, C4, CH50, C3c, factor B, and factor H. The CIC levels were well correlated with the disease activity of SLE. The more active the disease, the greater the increase of CIC. These suggest that serial measurement of CIC is helpful in monitoring the disease activity of SLE.

Circulating immune complex levels in patients with schistosomiasis and complications

Circulating immune complexes (CIC), adult schistosome antibody, and total immunoglobulin concentrations were estimated in sera from 35 chronic Schistosoma mansoni patients with different infection intensities and different pathological complications. High CIC levels were present in about one-third ( 10 35 ) of the sera. Most of the patients ( 9 10 ) with elevated CIC levels also had hepatomegaly or hepatosplenomegaly. This finding is significant in the pathogenesis of schistosomal iver fibrosis and may also apply to other liver diseases, especially cirrhosis. No correlation was found between infection intensity as judged by stool egg counts and CIC levels. A reverse relationship was observed between the level of anti-adult worm IgG and CIC levels. CIC levels were elevated within 7 and 28 days after treatment in most patients. Hypergammaglobulinaemia was detected in most sera.

Detection of bovine serum albumin in the circulating IgA immune complexes of patients with IgA nephropathy

Alimentary antigenic challenge has been postulated to have a role in the genesis of IgA circulating immune complexes (CIC), resulting in mesangial IgA disease. In this study, we examined the relationship between bovine serum albumin (BSA) and IgA CIC in patients with IgA nephropathy. Of the 47 patients studied, elevated IgA CIC levels were found in 32% by the F(ab′) 2 anti-C 3 and Raji cell enzyme immunoassays (EIA). Elevated IgA anti-BSA antibody levels were found in 9 patients, and there was a positive correlation between these levels and IgA CIC as measured in the Raji cell EIA ( R = 0.60, P < 0.001). In 4 patients with elevation of both IgA CIC and IgA anti-BSA antibody levels, solubilization experiments were done to demonstrate the presence of BSA antigen in the IgA CIC. Using the Raji cell EIA, the IgA CIC levels decreased significantly after preincubating the sera with serial concentrations of excess BSA. No corresponding effect was seen with human serum albumin used as control. Hence, BSA may be the antigenic stimulus in the formation of IgA CIC in selected patients with IgA nephropathy. The pathogenic capacity of these IgA-BSA CIC remains to be determined.

Circulating immune complexes in cystic fibrosis and their correlation to clinical parameters.

Circulating immune complexes (CIC) have been found to be elevated in individuals with cystic fibrosis (CF). Previous investigators, using a variety of assays, have reported high levels of CIC in as many as 86% of these patients. Our study followed the progress of 25 patients with CF over a period of 10 months to determine which, if any, clinical parameters correlated with the occurrence and/or concentration of CIC. Immune complex determinations were performed using a coprecipitation method with equine rheumatoid-complement complex. One hundred percent of the CF patients had CIC elevated above normal levels, however, levels of CIC did not correlate with the severity of an individual's acute exacerbation. Clinical parameters including pulmonary function tests, vital signs, total serum IgG levels, and other laboratory studies, were obtained on each individual and analyzed with respect to their relationship to CIC. Only four of 38 parameters examined had p less than 0.05. Factors that showed significant correlation to elevated CIC's in the highly elevated portion of our CIC population were poor NIH score, increased patient age, low peak expiratory flow rate, and elevated total serum IgG. These clinical values are associated more with the measurement of chronic disease. These data suggest that CICs cannot be used as an indication of short-term prognosis or as a monitor to follow the course of acute severe lung infections in the CF patient. Of interest was the observation that all patients who died during the course of the investigation had CIC levels greater than 80 micrograms/ml.

Circulating immune complexes in malignant melanoma: serial studies in 130 patients.

We evaluated the ability of repeated measurements of circulating immune complexes (CIC) to predict for tumor recurrence in 130 patients with malignant melanoma. Twenty-two patients had level 2, 45 had level 3, and 51 had level 4/5, stage I disease in remission at the start of monitoring, while 12 had stage II disease. The polyethylene glycol precipitation assay was used for serial studies, based on an initial comparative evaluation with the Clq-binding and Raji assays. The study averaged 22 +/- 11 months (6-43 months) and an average of 22 +/- 5.3 assays were performed per patient (range 3-36), with a follow-up of 4 years. CIC were present in sera in recurrent, irregular 'bursts' of activity. Serial measurements doubled the incidence of CIC compared to single determinations. Only 23% of these bursts of activity were clearly related temporarily to documented recurrences, while 34% occurred with treatment events such as surgery or immunotherapy, and 42% occurred without correlation to either recurrence or treatment. CIC activity was greater and more closely related to recurrence in high-risk stage I (level 4,5) and stage II patients. Whether analyzed as positive sera or as bursts of elevated CIC activity, CIC assays predicted for recurrence at the 5% significance level. The assay was highly sensitive (97%), but with poor specificity (21%) with many false positives (79%). The assay was helpful at ruling out recurrences (95%), but poor at ruling them in (29%). The advantage was seen only in high-risk stage I and II patients, and there was no advantage to serial assays over random single determinations. Although generally, CIC in the sera of melanoma patients were found to predict for recurrence, the use of serial CIC measures monitoring of individual patients cannot be recommended.

Evaluation of circulating immune complexes in lymphomas and leukemias using two different assays.

Circulating immune complexes (CICs) have been detected in the sera of patients with non-Hodgkin's lymphoma (NHL), Hodgkin's disease, chronic myeloid leukemia, and acute lymphoblastic leukemia by using C1q-binding and L1210-binding assays. Both assays gave broadly similar patterns of reactivity in terms of frequency and magnitude, though there are some differences. Significantly elevated CIC levels were observed in all pathologic groups. However, sera from NHL patients with an unfavorable prognosis consistently exhibited the highest frequency of positive values and mean CIC levels in both these assays. The two tests showed concordance in 66.6% of the NHL patients' sera and were significantly correlated. Of the sera from NHL patients 12.7% were positive in the C1q-binding assay only and 15.9% in the L1210-binding assay only. Both the assays gave positive results in some patients, and a degree of overlap indicates the presence of different types of CIC in cancer patients' sera. The combined use of two methods for detecting CICs may be useful for evaluation of the activity, the extent, and the prognosis of the malignant disease.

Angioimmunoblastic lymphadenopathy with dysproteinemia circulating immune complexes and the review of 18 cases

Eighteen patients with angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) have been analyzed by reviewing all available biopsy, laboratory, and clinical data. Because of features suggesting the presence of circulating immune complexes (CIC), CIC serial sample determinations were performed throughout their disease in available patients. Age, sex, and clinical and laboratory characteristics were consistent with previously reported series. Six of 18 (33%) patients having a drug exposure associated with onset or exacerbation of symptoms demonstrated a significantly decreased survival (P less than 0.02). Achievement of complete remission was a significant indicator of longevity (P less than 0.001). Only one patient (6%) developed diffuse histiocytic lymphoma. Elevated CIC were detected in the four patients tested. In two patients fluctuating CIC levels could clearly be correlated to clinical remission or exacerbation. Despite the small number of patients tested, it was concluded tha CIC may provide useful information for therapy selection, prediction of relapse, and further insight into pathogenetic mechanisms in AILD.

Circulating immune complexes in patients with bladder cancer and other malignancies of the urogenital tract.

Sera from 70 patients with bladder cancer, 26 patients with kidney cancer, and 20 patients with prostate cancer were studied for the presence of circulating immune complexes (CIC) utilizing the human red blood cell (HRBC) radioimmunoassay. Elevated CIC levels were found in 32% of patients with bladder cancer, 30% of patients with kidney cancer, and 20% of patients with prostate cancer. For comparison, CIC was also measured in 37 sera from patients with bladder cancer by the polyethylene glycol precipitation complement consumption (PEG-CC) test. 13 of them (35%) had elevated CIC levels. The correlation between the results of the two tests was significant. There were significant correlations between CIC levels and the extent of tumor invasion and the degree of malignancy in patients with bladder cancer. The elevation of CIC level was also significantly associated with poor prognosis of these bladder cancer patients. It is proposed that measurement of CIC in patients with bladder cancer by the HRBC radioimmunoassay may be useful to evaluate their stage, degree of malignancy, and prognosis.

A rapid solid phase assay for the detection of circulating immune complexes

A simplified process, which we have termed Enzyme Immune Complex Assay (EICA™) for the detection of circulating immune complexes (CICs), is described herein. The method utilizes readily available reagents, small quantities of serum, and can be performed quickly with a minimal amount of equipment. Serum from 38 normal controls, 98 burn patients, 36 frostbite injury patients, and 21 patients with elevated rheumatoid factor (RF) were tested for CICs in an immune function study. Elevated immune complex levels were found in the group of patients with frostbite injury, and in the group with elevated RF. Serum from thermally injured patients had slightly depressed yet normal CIC levels. The detection of elevated CICs by the EICA™ method compared favorably with the more cumbersome Raji cell method, with the added advantage of simplicity, speed, and the ability to detect non-IgG immune complexes.

Circulating immune complexes in childhood malignancies: a Pediatric Oncology Group study.

Pretreatment serum samples obtained at diagnosis from 89 children with various pediatric malignancies were examined for circulating immune complexes (CIC) using the [125I]Clq binding assay. The study population consisted of 35 children with acute lymphocytic leukemia (ALL), 22 children with acute non-lymphocytic leukemia (ALL), 24 with neuroblastoma (NB), and eight with osteosarcoma (OS). Concomitant quantitation of immunoglobulins was performed in 55 patients, revealing normal values for age. Increased levels of CIC at diagnosis were found in 9%, 22%, 42%, and 50% of children with ALL, AML, NB, and OS, respectively. Except for a higher proportion of CIC-positive patients observed in stage IV NB (nine of 17) compared to stage I-III NB (one of seven), no correlation was observed between initial CIC level and presenting clinical features, response to treatment, prognosis, or presence of infection. Longitudinal sampling of six NB and two OS patients did not reveal a clear relationship between disease activity and quantity of CIC. For the pediatric malignancies studied, these data demonstrate minimal value in quantitating CIC as a means of assessing disease activity or predicting response to treatment and are in contrast to the apparently adverse effect of elevated pretreatment CIC on response to therapy and survival observed in adults with ALL, AML, and OS.