The tumor-associated shift in immunoglobulin G1/G2 is expressed at the messenger RNA level of peripheral blood B lymphocytes in patients with gynecologic malignancies.

BACKGROUND: Previously, it could be demonstrated that human patients with malignant diseases of various tissues exhibited characteristic and highly significant changes in the serum patterns of immunoglobulin (Ig)G subclasses, consisting of a decrease in IgG1 and an increase in IgG2 relative to total IgG. The aim of the current study was to determine whether this phenomenon was detectable at the level of IgG-producing B lymphocytes. METHODS: Using a competitive reverse transcriptase polymerase chain reaction specific to IgG1 and IgG2, the gene expression of these 2 IgG subclasses in peripheral B cells from 10 patients with carcinomas of various sites within the female reproductive tract and 10 healthy controls was quantitatively determined, in parallel with the concentrations of the respective serum proteins. RESULTS: Absolute levels of IgG subclass messenger ribonucleic acid (mRNA) showed a slight but not significant decrease in IgG1 and an increase in IgG2 in patients with gynecologic malignancies. However, the ratio of IgG1 to IgG2 expression showed a highly significant (P < 0.001) decrease in tumor patients compared with healthy controls, and corresponded to the change in the ratio of IgG1 to IgG2 serum proteins. CONCLUSIONS: These data suggest that the shifts in the serum patterns of IgG1 and IgG2 observed in patients with gynecologic malignancies are due to irregular biosynthesis of these IgG subclasses at the B-cell level.

Selective decrease of serum immunoglobulin G1 as marker for early stages of invasive breast cancer.

The diagnostic value of the decrease in percentage of immunoglobulin G1 (%lgG1) in breast cancer was analyzed with special emphasis on early tumor stages. IgG1 and total IgG were preoperatively measured in the sera of a total of 801 individuals using a modified quantitative affinity chromatography. Group A consisted of 174 healthy individuals of both sexes, group B of 324 female patients with benign breast disease, and group C of 303 patients with invasive and non-invasive breast cancer. Within group C, 13 patients presented with intraductal carcinoma, and 22 patients with a pT1a-tumour (diameter less than 0.5 cm). The %IgG1 values were compared among groups A, B and C. In addition, correlations were sought between %IgG1 values of group C and tumor size, stage (UICC), histopathological grade and oestrogen (ER) and progesteron receptor (PR) expression. The mean value of %IgG1 in group A was 63.3 +/- 0.5 s.e.m., in group B 57.75 +/- 0.4 s.e.m. and in group C 52.37 +/- 0.5 s.e.m. The differences of mean values were highly significant between all three groups. Sensitivity and specificity of %IgG1 to discriminate between group A and C were 75% and 87%, and between group B and C 62% and 63%, respectively. The significant decrease of %IgG1 in total serum IgG is able to distinguish patients with breast cancer of more than 5 mm in diameter from healthy controls and patients with benign breast diseases. Finally, calculated posterior probabilities revealed that within certain concentration limits %lgG1 may provide predictive information with high probabilities.

The IgG1/G2 subclass shift--a sensitive, tissue non-specific marker for malignancy. Diagnostic performance with squamous cell carcinoma of the head and neck.

A significant decrease in %IgG1 accompanied by an increase in %IgG2 in total serum IgG has been previously reported as a highly sensitive marker for detecting early stages of carcinomas of various localizations. Here we investigated the question as to whether this phenomenon is also observed in sera of patients with squamous cell carcinoma of the head-neck region (SCC-HN), and to evaluate its diagnostic performance in the post-operative monitoring. Using quantitative affinity chromatography, serum concentrations of IgG1, IgG2 and total IgG were determined in 81 patients with different stages of primary and untreated SCC-HN, in 51 SCC-HN patients in post-therapeutical follow up, and in 33 patients with organ matched benign diseases. The data were compared with a total of 174 healthy controls. It was found that (i) 105 SCC-HN patients exhibited a mean value of 56.0 +/- 0.7% IgG1, which likewise differed from healthy controls (63.2 +/- 0.5) and benign diseases (61.5 +/- 1.0) with P < 0.0005, (ii) sensitivities and specificities for discriminating primary malignancies from healthy controls were 70 and 74% respectively, and from benign diseases 65 and 76%, (iii) highest sensitivities and specificities were observed with post-therapeutic cases suffering from tumour recurrence (88% and 75%) or patients with distant metastases (87% and 86%), (iv) apparently tumour-free post-therapeutic patients showed a mean %IgG1 not different from the normal value. The decrease in %IgG1 accompanied by increased %IgG2 is an efficient, sensitive and early marker of SCC-HN, which appears particularly useful for the post-therapeutic monitoring.

[Quantitative changes in the immunoglobulin G subclass system--a reliable tumor marker in squamous epithelial carcinoma in the area of the head-neck]. / Quantitative Veränderungen im Immunglobulin G Subklassensystem--Ein verlässlicher Tumormarker bei Plattenepithelkarzinomen im Kopf-Hals-Bereich.

AIM: Until now no serological markers were available towards the diagnosis of squamous-cell carcinomas of the head and neck (HNSCC) particularly in the detection of posttherapeutic recurrent diseases and metastases. Previous reports described patients with malignant diseases of various tissues exhibiting a characteristic and highly significant alteration in the subclass composition of serum IgG, consisting of a reduction in %IgG1 and an increase of %IgG2. In this study we present for the first time results of this IgG-shift in patients suffering from HNSCC. PATIENTS AND METHODS: A total of 111 patients was investigated at our clinic, all suffering from primary, histopathologically verified squamous cell carcinomas of the head and neck. These patients were investigated as to %Ig G1/IgG2 prior to any treatment. A second group consisted of 35 patients with local recurrences, 15 patients with distant metastases and 27 patients without tumour at the time of investigation, who were in observation for 1 to 5 years after primary treatment (T0). Thirdly, a total of 33 patients was included who were afflicted with a variety of benign diseases of the head and neck, such as chronic rhinosinusitis, chronic tonsillitis and also lateral or median cysts of the neck. Data of the three groups were compared with those of 174 healthy volunteer controls. 5 ml blood were taken from a forearm vein and the quantitation of subclasses IgG1, IgG2 and total IgG was performed by affinity chromatography. The single values obtained with all experimental groups and healthy controls showed normal distribution for primary cancer patients versus healthy control. Accordingly, significant differences between mean values were calculated with the two-sided Students t-test, and cut-off values were calculated as the arithmetic means of mean values obtained from the groups to be compared. Diagnostic sensitivities and specificities were defined as percentages of patients with %IgG1 smaller, and of healthy controls with %IgG1 greater than the cut-off value. RESULTS: We found a highly significant alteration in the subclass composition of serum IgG, consisting of a reduction in %IgG1 and an increase in %IgG2 in our HNSCC groups. The present data suggest the changes in %IgG1 and %IgG2 as a useful serological tumour marker to detect primary or recurrent and/or metastatic squamous-cell carcinomas of the head and neck. CONCLUSION: The shift in %IgG1/%IgG2 exhibited diagnostic sensitivities and specificities comparable to, or--particularly at early tumour stages--by far higher than conventional serological tumour markers. Whereas conventional serological markers directly correspond to tumourogenically derived products, the shift in %IgG1/IgG2 represents an indirect marker, consisting of a change of the host's immune system due to the presence of malignant tumours.

Interheavy disulfide bridge in immunoglobulin G (IgG) reacting with dithionitrobenzoate. A unique feature in serum proteins.

Immunoglobulin G (IgG) of many species contains 'labile' disulfide bonds (SS*), which within 24 h undergo a disulfide exchange with dithionitrobenzoic acid (NBSSBN). Aims of the present study were to detect directly this type of SS* groups by means of 14C-labelled NBSSBN, and to investigate its possible presence in other serum proteins. NBSSBN reacts during the first 30 min of incubation with free SH groups, and thereafter with the sulfur atoms of SS* groups. The latter reaction reaches equilibrium after 24 h. The total of thionitrobenzoate residues (NBS) bound to IgG is called 'sigma S' and represents both SH and SS*. The results can be summarized as follows: (1) The measurement of the binding of 14C-NBSSBN gave identical sigma S values with IgG from humans and mice, as compared to the detection with the unlabelled reagent, which is based on the photometric determination of liberated NBS anions; whereas with IgG from rats some differences were observed which were ascribed to different batches of animals investigated; (2) experiments with electrophoretically separated serum proteins revealed only the gamma-globulins strongly binding 14C-NBSSBN in addition to the 30 min reaction, which indicates that SS* is confined to the gamma-globulin fraction; and (3) the significant decrease of sigma S in association with malignant tumors in man and animal models, which was previously described to be due to a specific alteration of the IgG subclass pattern, was likewise detected with the radiometrical method. Previous studies have identified SS* as one of the two inter-heavy disulfide bridges in IgG1, and possible implications of this group in specific functions of IgG1 are discussed.

Selective decrease of serum immunoglobulin G1 as a marker of malignant transformation in colorectal tissue.

BACKGROUND: Malignant diseases of various origins were previously shown to be associated with a characteristic and highly significant change in the serum pattern of immunoglobulin (Ig)G subclasses, comprised of a decrease in %IgG1 and an increase in %IgG2 relative to and independent of the absolute concentration of total IgG. The goal of the current study was to evaluate this phenomenon as an indirect marker in the primary diagnosis of colorectal carcinoma. METHODS: Using affinity chromatography, IgG1, IgG2, and total IgG were determined in 36 patients with colorectal carcinoma of different stages and compared with 162 apparently healthy controls. RESULTS: It was found that: 1) the mean values for %IgG1 and %IgG2 of all carcinoma patients differed significantly from those of the controls; 2) no quantitative association was found with tumor stages, and four of five patients with incipient adenocarcinoma within a polyp exhibited the characteristic shift in IgG subclasses; 3) based on a calculated cutoff, the specificity and sensitivity of %IgG1 to discriminate between controls and carcinoma patients was found to be 88% and 74%, respectively; and 4) a quantitative correlation between individual %IgG1 values and the probability of correct assignment to carcinoma patients or controls was established. CONCLUSIONS: The significant decrease in %IgG1 accompanied by an increase in %IgG2 in total serum IgG represents an indirect, tissue nonspecific, and early marker of malignant proliferation that distinguishes colorectal carcinoma patients from healthy controls with a specificity of 88% and sensitivity of 74%.

Reactive disulfide bonds in immunoglobulin G. A unique feature in serum proteins of different species.

A reactive disulfide bond (SS)* was detected and characterized in IgG of humans, rats and mice by virtue of disulfide interchange with dithionitrobenzoate. (SS)* was found exclusively in human IgG1 and rat IgG2b. In human IgG1 (SS)* was identified as the upper one of the two interheavy bridges in the hinge, where it appears to take part in complement activation. The biological significance of (SS)* in IgG was underlined by the fact that no other serum proteins were found to exhibit a similar reactivity.

Selective decrease in serum immunoglobulin G1. A tissue nonspecific tumor marker detecting early stages of gynecologic malignant disease with high efficiency.

BACKGROUND: Malignant diseases of various tissue origin have previously been found to be associated with a characteristic shift in the serum pattern of IgG subclasses, i.e., a highly significant reduction of the percent of IgG1 and an increase of the percentage of IgG2 relative to the total IgG. In the present study we examined the diagnostic performance of this indirect tumor marker in patients with carcinomas of various sites within the female reproductive tract. METHODS: Using quantitative affinity chromatography, the percents of IgG1 and IgG2 in the total IgG were determined for 207 patients with carcinoma of the ovary, cervix, or corpus uteri, prior to any treatment. The data were compared with those of 135 age matched healthy females and 52 patients with benign gynecologic diseases. RESULTS: It was found that (1) mean values for the percents of IgG1 and IgG2 of all of the cancer patients differed significantly from those of the patients with benign disease and healthy controls; (2) no differences were noted between carcinomas of the ovary, corpus or cervix uteri; (3) early stages of carcinoma exhibited the effect to the same extent as late stages; (4) the specificity of the percent of IgG1 to discriminate between controls and cancer patients ranged between 90 and 100%, regardless of localization and stage of tumor; and (5) whereas with ovarian cancer CA 125 showed a slightly greater sensitivity, the percent of IgG1 was by far more sensitive than the conventional markers CA 125, TPA, CEA, Ferritin, and SCC to diagnose carcinoma of the cervix and corpus uteri, notably at early stages. Combined analysis of the percent of IgG1 and CA 125 and/or TPA led to an increase in sensitivity with tumors of all three sites. CONCLUSIONS: Thus, the determination of the percent of IgG1 by itself and/or in combination with conventional markers may provide relevant information regarding the noninvasive detection of early stages of gynecologic carcinoma.