The Significance of Serum IgG4/IgG and IgG4/IgG1 Ratio in the Diagnosis Value of IgG4-Related Diseases.

OBJECTIVE: Elevated serum immunoglobulin G4 (IgG4) is one of the important features of patients with IgG4-related diseases (IgG4-RD). But diagnosing these diseases using IgG4 alone is tricky because the tests can sometimes give inaccurate results. Our research is focused on studying the ratio of IgG4 to two other substances, immunoglobulin G (IgG) and immunoglobulin G1 (IgG1), in the blood. We hope this approach will lead to more accurate diagnoses of IgG4-RD. METHODS: We conducted a study on 68 patients diagnosed with IgG4-related diseases (IgG4-RD) and 160 individuals suffering from other autoimmune diseases (AID) at our hospital between June 2018 and June 2022. Eighty healthy people who underwent physical examination in our hospital at the same time were randomly selected as controls, and medical records were collected for all subjects. The serum IgG and IgG subclasses were detected, and the IgG4/IgG and IgG4/IgG1 ratios were calculated. RESULTS: We found that patients with IgG4-RD have significantly higher average levels of serum IgG4 and more elevated IgG4/IgG and IgG4/IgG1 ratios compared to individuals with other AID patients and those in good health (p < 0.001). The receiver operating characteristic (ROC) curve analysis showed that the diagnostic effectiveness area under the curve (AUC) of the serum IgG4/IgG ratio for IgG4-RD was 0.906 (95% confidence interval [CI], 0.865-0.947) and 0.921 (95% CI, 0.876-0.965) when comparing with other AID patients and healthy individuals, respectively. The optimal cut-off value for the IgG4/IgG ratio was 0.147 (with 72.1% sensitivity and 94.4% specificity) compared with AID patients and 0.129 (with 77.9% sensitivity and 96.2% specificity) compared with healthy individuals. Similarly, the AUC of the serum IgG4/IgG1 ratio for diagnosing IgG4-RD was 0.919 (95% CI, 0.882-0.956) and 0.916 (95% CI, 0.870-0.962) when compared with patients with other AID and healthy individuals, respectively. When we divided our study participants into a high IgG4/IgG ratio group (>0.129) and a normal IgG4/IgG ratio group (≤0.129) using a cut-off point of 0.129, we found through logistic regression analysis that those with a high IgG4/IgG ratio were more likely to be associated with IgG4-RD (odds ratio [OR], 31.25; 95% CI, 15.31-63.79; p < 0.001). Likewise, a high IgG4/IgG1 ratio was also significantly linked to an increased risk of IgG4-RD (OR, 36.39; 95% CI, 17.57-75.38; p < 0.001). CONCLUSIONS: The serum's IgG4/IgG and IgG4/IgG1 ratios are independently linked to IgG4-RD and are valuable in its diagnosis.

The role of IgG4-positive plasma cell population in classic Hodgkin lymphoma.

The effect of IgG4, which constitutes the least of the IgG subclasses, on the pathogenesis and prognosis of lymphoma or solid tumors is one of the research topics of interest in recent years. The role of IgG4, which has been reported to suppress antitumor immunity, in classic Hodgkin's lymphoma (cHL), which is recognized by its pathognomonic microenvironment, is not yet clearly known. The aim of this study was to determine IgG4-positive plasma cell density in the cHL microenvironment and to compare it with histopathological and clinical parameters. In addition, the role of the increase in IgG4-positive cells in the development of relapse after treatment was also investigated. A retrospective cross-sectional study. Ninety-four patients with the initial diagnosis of cHL who had no comorbidity or no treatment history and forty-one reactive lymph nodes with follicular hyperplasia findings were included in the study. Three hot-spot areas were identified with reference to the IgG4 sections. Mean IgG4-positive plasmacyte counts and IgG4/IgG ratios were determined and compared with histopathological characteristics. The mean IgG4 + plasma cell count was 33.57 in cHL cases and 47.04 in the control group (p = 0.233). IgG4/IgG ratio was significantly higher in cHL compared with the control group (0.27 vs. 0.21, p = 0.021). The IgG4/IgG ratio was found to be higher in younger patients with classic Hodgkin lymphoma, with a low correlation (p = 0.028, r = - 0.226). There was no relationship with gender, lymph node location, histological subtype, EBV positivity and bone marrow infiltration. It was observed that IgG4/IgG ratio was higher in early-stage patients (p = 0.022). No significant IgG4 + cell increase was detected in the initial diagnosis and relapse slides of six patients who developed relapse after standard treatment, resulting in a cure. Novel therapeutic modalities targeting microenvironmental components have been reported to show dramatic effects, particularly in relapsed or refractory patients. Detailed characterization of the cHL inflammatory milieu will be useful for the identification of alternative targets. IgG4 subclass antibodies, which have been described to have anti-inflammatory effects, may have prognostic significance in a proportion of cHL patients.

Plasma cell IgG4 positivity in orbital biopsies of non-IgG4-related conditions.

The IgG4-related disease (IgG4-RD) is a systemic condition defined as a fibro-inflammatory disorder, characterized by the occurrence of tumor-like lesions in multiple organs including the eye adnexa. The main diagnostic criterion is based on histopathological findings, especially on the IgG4+/IgG+ plasma cell ratio. In this article, we reviewed the literature of non-IgG4-RD orbital conditions with IgG4 positivity. There were 20 reports of inflammatory non-IgG4-RD orbital lesions and 14 reports of orbital lymphoid proliferations with significant IgG4 positivity. The role of plasma cells IgG4 in the pathogenesis of non-IgG4-RD is not clear. Considering the large spectrum of diseases caused by a variety of different etiopathogenic mechanisms, we think that the common denominator of IgG4+ in these conditions might be related to the peculiar properties of down regulation of immune response of the IgG4 and not to a specific link to IgG4-RD.

Serum immunoglobulin G4 in Sjögren's syndrome: a pilot study.

Immunoglobulin IgG4 plays a role in the pathogenesis of the Mikulicz disease previously considered a form of primary Sjögren's syndrome (pSS). We investigated serum levels of IgG4, total IgG, C3, and C4 serum complementary components in patients suspected of Sjögren's syndrome. Basic laboratory and immunological tests, including IgG4 and IgG concentration, were performed on 20 healthy and 68 suspected of pSS individuals. We distinguished: group I: 48 pSS patients; group II (sicca): 20 patients with dryness without pSS. We revealed: statistical differences between groups I and II concerning hypergammaglobulinemia, ESR, RF, ANA, Ro, and La antibodies; lower IgG4 levels and IgG4/IgG ratio in group I compared to healthy individuals (p < 0.0435; 0.0035, respectively); no significant differences in the concentrations of IgG4 and IgG4/IgG ratio between sicca and control groups. significantly lower (p < 0.0002) C4 levels in group I compared to other groups; significant differences in C4 concentration and IgG4/IgG ratio between three groups (p = 0.0002 and p = 0.0090, respectively); a weak negative correlation between C4 and IgG (r =- 0.274) in the whole database; weak positive correlation between C4 and IgG4/IgG ratio (r = 0.237); a negative correlation of IgG4, IgG4/Ig ratio and C4 with focus score (r = - 0.281; r = - 0.327; r = - 0.406, respectively). IgG4 serum levels were significantly decreased compared to healthy subjects. IgG4 and C4 levels correlated with infiltrations in minor salivary glands. Hypergammaglobulinemia and decreased serum C4 component levels are typical for pSS.

Increased IgG4-positive plasma cells in nodular-sclerosing Hodgkin lymphoma: a diagnostic pitfall.

AIMS: Despite increasing interest in the recently established immunoglobulin 4-related disease (IgG4-RD), its pathogenesis and aetiology remain largely unclear. Characteristic histopathological features are one of the key elements of diagnosis, including 'storiform' fibrosis, obliterative phlebitis, increased lymphoplasmacytic infiltration and increased levels of IgG4 in serum and tissue. Histopathological features of IgG4-RD are striking but not specific, and can pose a pitfall for surgical pathologists. This paper aims to determine the actual amount of IgG4+ plasma cells in nodular-sclerosing Hodgkin lymphoma (NSHL) and its potential to be misdiagnosed in routine clinical practice. METHODS AND RESULTS: IgG4+ plasma cells per high-power field (HPF) and the ratio of IgG4+ versus IgG+ plasma cells (IgG4/IgG ratio) in lymph node biopsies of 24 patients with nodular-sclerosing Hodgkin lymphoma (NSHL) were determined using immunohistochemistry and consensus scoring criteria as used for IgG4-RD. Ten lymph node biopsies with reactive follicular hyperplasia were assessed for comparison. Higher numbers of IgG4+ plasma cells (P < 0.001) were observed in NSHL versus follicular hyperplasia (mean 34 versus 8 per HPF) with a mean IgG4/IgG ratio of 0.38 versus 0.18. Five cases (21%) fulfilled the consensus criteria of IgG4-RD, with >50 IgG4+ plasma cells per HPF and an IgG4/IgG ratio of >0.4. The mean count of IgG4+ plasma cells per HPF in NSHL varied greatly (3-88) with increased numbers of IgG4+ plasma cells seen near areas of fibrosclerosis. CONCLUSIONS: Significantly higher levels of IgG4+ plasma cells are common in NSHL, emphasising the need to exclude Reed-Sternberg cells by morphology and immunohistochemistry in biopsies where IgG4-RD is suspected.

A comparison of the diagnostic efficacy in type 1 autoimmune pancreatitis based on biopsy specimens from various organs.

BACKGROUND: Comprehensive immunostaining evaluation of the biopsy specimens from various organs with type 1 autoimmune pancreatitis (AIP) has not been elucidated. Our aim was to clarify which of these biopsy specimens and counting method could be a useful tool for supporting the diagnosis of AIP. METHODS: We retrospectively evaluated biopsy specimens from pancreas (n = 19), stomach (n = 28), duodenum (n = 27), duodenal papilla (n = 25), colon (n = 19), liver (n = 11), bile duct (n = 24), and minor salivary gland (n = 13) in 36 patients with AIP. Positive IgG4 immunostaining (>10 plasma cells/high-power field [HPF]) and positive IgG4/IgG ratio (>40%) of biopsy specimens from 8 sites of 6 organs in one HPF and an average from 3 HPFs were compared between AIP and controls. RESULTS: The sensitivity of IgG4 immunostaining for AIP in one HPF were 16% in pancreas, 14% in stomach, 15% in duodenum, 52% in duodenal papilla, 11% in colon, 27% in liver, 21% in bile duct and 8% in minor salivary gland, respectively. The positive IgG4 immunostaining of the duodenal papilla in one HPF showed the highest sensitivity (52%) and accuracy (73%) among the 8 sites. It also showed the highest sensitivity among 4 different counting methods (IgG4 immunostaining in one HPF and 3 HPFs, both IgG4 immunostaining and IgG/IgG4 ratio in one HPF and 3 HPFs), but there were no significant differences with respect to specificity and accuracy. CONCLUSIONS: IgG4 immunostaining of swollen duodenal papilla with more than 10 IgG4-positive plasma cells in at least one HPF is useful for supporting the diagnosis of AIP.

Relationship between Rosai-Dorfman disease and IgG4-related disease: study of 32 cases.

OBJECTIVES: To assess the association between Rosai-Dorfman disease (RDD) and IgG4-related disease (IgG4-RD). METHODS: We studied the number of IgG4-positive plasma cells and the IgG4/IgG ratio in 32 biopsy specimens (13 nodal, 19 extranodal) from 29 patients with RDD and compared the findings with those in IgG4-RD of the pancreas and reactive lymph nodes. We also assessed the number of FOXP3-positive regulatory T cells (Tregs) since they were reported to be increased in IgG4-RD. RESULTS: We found that RDD cases had much lower numbers of IgG4-positive plasma cells and lower IgG4/IgG ratios compared with IgG4-RD but were similar to reactive lymph nodes. Furthermore, RDD had lower numbers of FOXP3-positive Tregs than did IgG4-RD. There were no significant differences in the number of IgG4-positive plasma cells and the IgG4/IgG ratio between the nodal and extranodal RDD cases. CONCLUSIONS: Our study suggests that RDD does not belong in the spectrum of IgG4-RD.

IgG4-related disease-like fibrosis as an indicator of IgG4-related lymphadenopathy.

The significance of IgG4-related diseases including IgG4-related lymphadenopathy has recently been recognized worldwide. Inflammatory pseudotumors in lymph nodes, as well as in other organs, are also recognized as IgG4-related diseases. Only a few case reports have described IgG4-related lymphadenopathy with fibrosis (IgG4-fibrosing lymphadenopathy), and IgG4-fibrosing lymphadenopathy has not been compared clinicopathologically with non-IgG4-related lymphadenopathy with fibrosis. We have evaluated the pathologic features in 13 patients with IgG4-fibrosing lymphadenopathy, including IgG4 and IgG expression in lymph nodes, and compared these features with those of patients with non-IgG4-related lymphadenopathy with fibrosis with reactive inguinal lymphadenopathy and focal fibrosis and lymph nodes at least 10 mm in diameter. IgG4-fibrosing lymphadenopathy was characterized by lymphoplasmacytic and eosinophilic infiltration, many IgG4-positive plasma cells in fibrotic areas, and high serum IgG4 concentrations. The IgG4-positive/IgG-positive plasma cell ratio was significantly higher in the IgG4-fibrosing lymphadenopathy than in the non-IgG4-fibrosing lymphadenopathy group. The presence of even minor fibrosis with characteristics of IgG4-related disease such as IgG4-fibrosing lymphadenopathy may facilitate the diagnosis of IgG4-related lymphadenopathy.