Chest CT in the Emergency Department for Diagnosis of COVID-19 Pneumonia: Dutch Experience.

Background Clinicians need to rapidly and reliably diagnose coronavirus disease 2019 (COVID-19) for proper risk stratification, isolation strategies, and treatment decisions. Purpose To assess the real-life performance of radiologist emergency department chest CT interpretation for diagnosing COVID-19 during the acute phase of the pandemic, using the COVID-19 Reporting and Data System (CO-RADS). Materials and Methods This retrospective multicenter study included consecutive patients who presented to emergency departments in six medical centers between March and April 2020 with moderate to severe upper respiratory symptoms suspicious for COVID-19. As part of clinical practice, chest CT scans were obtained for primary work-up and scored using the five-point CO-RADS scheme for suspicion of COVID-19. CT was compared with severe acute respiratory syndrome coronavirus 2 reverse-transcription polymerase chain reaction (RT-PCR) assay and a clinical reference standard established by a multidisciplinary group of clinicians based on RT-PCR, COVID-19 contact history, oxygen therapy, timing of RT-PCR testing, and likely alternative diagnosis. Performance of CT was estimated using area under the receiver operating characteristic curve (AUC) analysis and diagnostic odds ratios against both reference standards. Subgroup analysis was performed on the basis of symptom duration grouped presentations of less than 48 hours, 48 hours through 7 days, and more than 7 days. Results A total of 1070 patients (median age, 66 years; interquartile range, 54-75 years; 626 men) were included, of whom 536 (50%) had a positive RT-PCR result and 137 (13%) of whom were considered to have a possible or probable COVID-19 diagnosis based on the clinical reference standard. Chest CT yielded an AUC of 0.87 (95% CI: 0.84, 0.89) compared with RT-PCR and 0.87 (95% CI: 0.85, 0.89) compared with the clinical reference standard. A CO-RADS score of 4 or greater yielded an odds ratio of 25.9 (95% CI: 18.7, 35.9) for a COVID-19 diagnosis with RT-PCR and an odds ratio of 30.6 (95% CI: 21.1, 44.4) with the clinical reference standard. For symptom duration of less than 48 hours, the AUC fell to 0.71 (95% CI: 0.62, 0.80; P < .001). Conclusion Chest CT analysis using the coronavirus disease 2019 (COVID-19) Reporting and Data System enables rapid and reliable diagnosis of COVID-19, particularly when symptom duration is greater than 48 hours. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Elicker in this issue.

Fab fragment glycosylated IgG may play a central role in placental immune evasion.

STUDY QUESTION: How does the placenta protect the fetus from immune rejection by the mother? SUMMARY ANSWER: The placenta can produce IgG that is glycosylated at one of its Fab arms (asymmetric IgG; aIgG) which can interact with other antibodies and certain leukocytes to affect local immune reactions at the junction between the two genetically distinct entities. WHAT IS KNOWN ALREADY: The placenta can protect the semi-allogenic fetus from immune rejection by the immune potent mother. aIgG in serum is increased during pregnancy and returns to the normal range after giving birth. aIgG can react to antigens to form immune complexes which do not cause a subsequent immune effector reaction, including fixing complements, inducing cytotoxicity and phagocytosis, and therefore has been called 'blocking antibody'. STUDY DESIGN, SIZE, DURATION: Eighty-eight human placentas, four trophoblast cell lines (TEV-1, JAR, JEG and BeWo), primary culture of human placental trophoblasts and a gene knock-out mouse model were investigated in this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: The general approach included the techniques of cell culture, immunohistochemistry, in situ hybridization, immuno-electron microscopy, western blot, quantitative PCR, protein isolation, glycosylation analysis, enzyme digestion, gene sequencing, mass spectrophotometry, laser-guided microdissection, enzyme-linked immunosorbent assay, pulse chase assay, double and multiple staining to analyze protein and DNA and RNA analysis at the cellular and molecular levels. MAIN RESULTS AND THE ROLE OF CHANCE: Three major discoveries were made: (i) placental trophoblasts and endothelial cells are capable of producing IgG, a significant portion of which is aberrantly glycosylated at one of its Fab arms to form aIgG; (ii) the asymmetrically glycosylated IgG produced by trophoblasts and endothelial cells can react to immunoglobulin molecules of human, rat, mouse, goat and rabbit at the Fc portion; (iii) asymmetrically glycosylated IgG can react to certain leukocytes in the membrane and cytoplasm, while symmetric IgG from the placenta does not have this property. LIMITATIONS, REASONS FOR CAUTION: Most of the experiments were performed in vitro. The proposed mechanism calls for verification in normal and abnormal pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: This study identified a number of new phenomena suggesting that aIgG produced by the placenta would be able to react to detrimental antibodies and leukocytes and interfere with their immune reactions against the placenta and the fetus. This opens a new dimension for further studies on pregnancy physiology and immunology. Should the mechanism proposed here be confirmed, it will have a direct impact on our understanding of the physiology and pathology of human reproduction and offer new possibilities for the treatment of many diseases including spontaneous abortion, infertility and pre-eclampsia. It also sheds light on the mechanism of immune evasion in general including that of cancer.

Expression and distribution of immunoglobulin G in the normal liver, hepatocarcinoma and postpartial hepatectomy liver.

The liver has the extraordinary properties of regeneration and immune tolerance; however, the mechanisms governing these abilities are poorly understood. To address these questions, we examined the possible expression of immunoglobulins in the human and rat liver and the relationship of IgG expression to hepatocyte proliferation, metastasis, apoptosis and immune tolerance. Immunohistochemistry, in situ hybridization, laser-guided microdissection and reverse transcription-PCR were performed to examine the expression of IgG in normal human and rat liver, severe combined immunodeficient mouse (SCID) liver and human liver cancers and corresponding cell lines. Small interfering RNA (siRNA) was transfected into cultured hepatocarcinoma cells to downregulate the expression of IgG heavy chain genes. Cell proliferation and apoptosis were assayed with flow cytometry. Cell metastasis was assayed with a Transwell cell assay. Partial hepatectomy (70%) was performed in rats to examine the relationship between hepatocyte IgG and hepatocyte proliferation. IgG, together with essential enzymes for its synthesis, were expressed in the cytoplasm of hepatocytes of normal adult human and hepatoma patients and rat livers, SCID mouse liver and BRL-3A, L-02 and HepG-2 cell lines. Downregulation of IgG inhibited cell proliferation and metastasis and promoted apoptosis. Postsurgery livers expressed significantly more IgG than the livers before surgery and decreased to the original levels when hepatocytes stopped regeneration. IgA and IgM but not IgD and IgE were also positive in hepatocytes. Our findings demonstrate that normal and malignant hepatocytes are capable of synthesizing immunoglobulin, which has important roles in hepatocyte proliferation, apoptosis and cancer growth with profound clinical implications.

Two ultrastructural distribution patterns of immunoglobulin G in human placenta and functional implications.

The placenta is known to protect the fetus from infection and maternal rejection. In a previous study, we demonstrated that placental trophoblasts can synthesize immunoglobulin G (IgG). In this study, we investigated the distribution of immunoglobulins (IgG, IgM, and IgA), IgG receptors (FcRn and FcgammaRIII), and complement proteins in placental trophoblasts at the ultrastructural level. In addition, we studied the mRNA expression of IgG1 heavy chain (IGHG1), recombination activating gene 1 (RAG1), RAG2, and activation-induced cytidine deaminase (AID) with nested RT-PCR in primary cultured trophoblasts. The mRNA transcripts of IGHG1, RAG1, RAG2, and AID were all identified in primary trophoblasts, further establishing the IgG-producing capacity of trophoblasts. At the ultrastructural level with colloidal gold-labeled antibodies, IgG was found to be distributed in two distinct locations in syncytiotrophoblasts. For one, it was colocalized with FcRn in endosome displaying low electron density, and for the other it was colocalized with complement C1q in medium-electron density irregular structures that have not been reported previously. This characteristic distribution suggests that IgG is likely processed through two molecular mechanisms in syncytiotrophoblasts: receptor-bound transportation across the syncytiotrophoblast and formation of immune complexes with locally produced IgG. The latter mechanism is probably aimed at neutralizing detrimental maternal anti-paternal major histocompatibility complex antibodies. Our findings support the hypothesis that placenta-produced IgG can selectively react with maternal anti-fetus antibodies and provide a mechanism of fetomaternal tolerance to protect the fetus from maternal immune rejection.

IgG gene expression and its possible significance in prostate cancers.

BACKGROUND: In spite of recent advances in treatment strategies, prostate cancer (PCa) remains the second leading cause of cancer death in men with its genetic and biologic behaviors still poorly understood. Recently, accumulating evidence indicates that cancer cells, as well as some normal cells can secret IgG. This study was designed to evaluate IgG gene expression and its possible significance in PCa tissue samples and cell lines. METHODS: IgG expression was assessed by immunohistochemistry, in situ hybridization, immunofluorescence, RT-PCR, and Western blot. The possible significance of IgG was evaluated on tissue array and cell lines. To assess cell viability and proliferation, MTS assay was carried out. Apoptosis was evaluated with propidium iodide and annexin-V staining. RESULTS: Expressions of IgG and its related genes were detected in cell lines. Abundant gene expressions of Igγ and Igκ chain were detected in PCa tissue samples, but not in normal prostate tissues. In addition, IgG expression was significantly higher in PCa tissues than in the benign prostate hyperplasia tissues (P < 0.001). Igγ expression was positively correlated to Gleason score and histological grade (P < 0.05). Furthermore, in vitro experiments showed that anti-human monoclonal IgG antibody suppressed cell proliferation and increased apoptosis in cultured PCa cells. CONCLUSION: IgG gene expression in PCa is related to cell differentiation and clinical status. PCa cell produced IgG is involved in the biological behavior of this cancer and may serve as a useful marker for cancer cell differentiation and prognosis. Locally produced IgG could be a potential target for therapy.

Immunoglobulin G expression and its colocalization with complement proteins in papillary thyroid cancer.

Except for the well-known immunoglobulin G (IgG) producing cell types, ie, mature B lymphocytes and plasma cells, various non-lymphoid cell types, including human cancer cells, neurons, and some specified epithelial cells, have been found to express IgG. In this study, we detected the expression of the heavy chain of IgG (IgGγ) and kappa light chain (Igκ) in papillary thyroid cancer cells. Using in situ hybridization, we detected the constant region of human IgG1 (IGHG1) in papillary thyroid cancer cells. With laser capture microdissection followed by RT-PCR, mRNA transcripts of IGHG1, Igκ, recombination activating gene 1 (RAG1), RAG2, and activation-induced cytidine deaminase genes were successfully amplified from isolated papillary thyroid cancer cells. We further confirmed IgG protein expression with immunohistochemistry and found that none of the IgG receptors was expressed in papillary thyroid cancer. Differences in the level of IgGγ expression between tumor size, between papillary thyroid cancer and normal thyroid tissue, as well as between papillary thyroid cancer with and without lymph node metastasis were significant. Taken together, these results indicate that IgG is produced by papillary thyroid cancer cells and that it might be positively related to the growth and metastasis of papillary thyroid cancer cells. Furthermore, it was demonstrated that IgGγ colocalized with complement proteins in the same cancer cells, which could indicate that immune complexes were formed. Such immune complexes might consist of IgG synthesized by the host against tumor surface antigens and locally produced anti-idiotypic IgG with specificity for the variable region of these 'primary' antibodies. The cancer cells might thus escape the host tumor-antigen-specific immune responses, hence promoting tumor progression.

Expression and distribution of immunoglobulin G and its receptors in an immune privileged site: the eye.

It has recently been demonstrated that not only mature B lymphocytes, but also non-lymphoid cells, including cancer cells and neurons, express IgG. In the eye, an important immune privileged site, the presence of IgG has been ascribed to IgG entering the eye through breaches of the blood­ocular barrier. Here we demonstrate that the eye itself can produce IgG intrinsically. Applying immunohistochemistry, in situ hybridization, and RT-PCR, several intraocular structures were found to express proteins and mRNA transcripts of IgG heavy chains, light chains, V(D)J rearrangements, and enzymes required for V(D)J recombination. IgG receptors were also detected in the intraocular epithelium and endothelium. The extensive distribution of IgG and its receptors in intraocular structures indicates that locally produced IgG could play a significant role in maintaining the ocular microenvironment and protection of the eyes, and it might also be involved in the pathogenesis of age-related macular degeneration and some inflammatory diseases.

Pandemic influenza A (H1N1) virus infection and avian influenza A (H5N1) virus infection: a comparative analysis.

The 2009 H1N1 and H5N1 influenza viruses are newly (re-) emerged influenza A viruses (2009 A(H1N1) and A(H5N1), respectively) that have recently posed tremendous health threats in many regions worldwide. With the 2009 outbreak of H1N1 influenza A, the world witnessed the first influenza pandemic of the 21st century. The disease has rapidly spread across the entire globe, and has resulted in hundreds of thousands of cases with confirmed infection. Although characterized by high transmissibility, the virulence and fatality of the 2009 A(H1N1) influenza virus have thus far remained relatively low. The reverse holds true for A(H5N1) influenza; at a fatality rate that exceeds 60%, it is known to cause severe damage to the human respiratory system, but is not presently capable of efficient transmission from human to human. Apart from the clear differences between the two types of influenza, there are some significant similarities that warrant attention. In particular, the more severe and fatal 2009 A(H1N1) influenza cases have shown symptoms similar to those reported in cases of A(H5N1) influenza. Histopathological findings for these cases, to the extent available, also appear to have similarities for both diseases in terms of damage and severity. Here we review important recent publications in this area, and we discuss some of the key commonalities and contrasts between the two influenza A types in terms of their biology, origins, clinical features, pathology and pathogenesis, and receptors and transmissibility.

Expression of cystic fibrosis transmembrane conductance regulator in paracervical ganglia.

The cystic fibrosis transmembrane conductance regulator (CFTR) is an important protein that acts as a chloride channel and regulates many physiological functions, including salt transport and fluid flow. Mutations in the gene encoding the CFTR protein cause cystic fibrosis. CFTR is expressed in the epithelial cells of the lungs, pancreas, intestines, and other organs. In the peripheral and central nervous system, CFTR expression has been detected in the neurons of rat brains, ganglion cells of rat hearts, human hypothalamus, human spinal cord, and human spinal and sympathetic ganglia. However, CFTR has not been identified in other parts of the nervous system. In this study, we used immunohistochemistry, in situ hybridization, and laser-assisted microdissection (LMD) followed by reverse transcriptase (RT) PCR to identify CFTR proteins and messenger RNA in human and rat paracervical ganglion cells. CFTR and its gene expression were both detected in paracervical ganglion cells, a finding that might link this important protein to the neuronal regulation of female urogenital function. These findings could provide new insights into the symptoms related to the reproductive system frequently observed in female cystic fibrosis patients.

Endocrine cells of the adenohypophysis in severe acute respiratory syndrome (SARS).

It is known that severe acute respiratory syndrome (SARS), a severe infectious illness, which caused an epidemic in Asia in 2003, has extensive and complex effects on human organ systems. It has been reported that the serum levels of prolactin (PRL), follicle stimulating hormone (FSH), and luteinizing hormone (LH) of SARS patients are significantly higher than those of control groups, while estradiol (E2), pregnancy hormone (P), and thyroid stimulating hormone (TSH) are considerably lower than those of normal controls. This phenomenon suggests that the adenohypophyseal endocrine cells in SARS patients may be damaged. However, up to now there has been no direct histological investigation on the endocrine cells of patients' pituitary. Here we investigated the endocrine cells in the adenohypophysis obtained from autopsies of 5 SARS patients. The immunohistochemistry and quantitative image results showed that compared with control cases, both the number of positive cells and the staining intensity of immunoreactivity for growth hormone, TSH, and adrenocorticotrophic hormone in these cells were remarkably decreased, while that of PRL, FSH, and LH were significantly increased in all SARS cases studied. These findings indicated that alterations occurred in the patients' adenohypophyseal endocrine cells, and these changes were consistent with the serum levels of relevant endocrine hormones reported previously. It appears that changes in these endocrine cells and their hormones are affected by the severity of this new infectious disease.

An unusual cause of multiple incidental lung nodules.

Cystic or cavitating lung nodules may reflect an additional diagnostic challenge in benign metastasizing leiomyoma. Our case underlines the importance of combining clinical and radiological findings with specific pulmonary pathology consultation.

Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans.

H5N1 avian influenza is a highly fatal infectious disease that could cause a potentially devastating pandemic if the H5N1 virus mutates into a form that spreads efficiently among humans. Recent findings have led to a basic understanding of cell and organ histopathology caused by the H5N1 virus. Here we review the pathology of H5N1 avian influenza reported in postmortem and clinical studies and discuss the key pathogenetic mechanisms. Specifically, the virus infects isolated pulmonary epithelial cells and causes diffuse alveolar damage and hemorrhage in the lungs of infected patients. In addition, the virus may infect other organs, including the trachea, the intestines, and the brain, and it may penetrate the placental barrier and infect the fetus. Dysregulation of cytokines and chemokines is likely to be one of the key mechanisms in the pathogenesis of H5N1 influenza. We also review the various molecular determinants of increased pathogenicity that have been identified in recent years and the role of avian and human influenza virus receptors in relation to the transmissibility of the H5N1 virus. A comprehensive appreciation of H5N1 influenza pathogenetic mechanisms should aid in the design of effective strategies for prevention, diagnosis, and treatment of this emerging disease.

Avian influenza receptor expression in H5N1-infected and noninfected human tissues.

Avian and human influenza viruses preferentially bind to alpha-2,3-linked and alpha-2,6-linked sialic acids, respectively. Until today, the distributions of these two receptor types had never been investigated in H5N1-infected human tissue samples. Here, the expression of avian (AIV-Rs) and human influenza receptors (HuIV-Rs) is studied in various organs (upper and lower respiratory tracts, brain, placenta, liver, kidney, heart, intestines, and spleen) of two H5N1 cases and 14 control cases. Histochemical stains using biotinylated Maackia amurensis lectin II and Sambucus nigra agglutinin were performed to localize AIV-Rs and HuIV-Rs, respectively. Immunohistochemical stainings were performed to identify the receptor-bearing cells. AIV-Rs were detected on type II pneumocytes; a limited number of epithelial cells of the upper respiratory tract; and the bronchi, bronchioli, and trachea; as well as on Kupffer cells, glomerular cells, splenic T cells, and neurons in the brain and intestines. HuIV-Rs were abundantly present in the respiratory tract and lungs. They were also detected on Hofbauer cells, glomerular cells, splenic B cells, and in the liver. Moreover, endothelial cells of all organs examined expressed both receptor types. In conclusion, the distribution pattern of AIV-Rs is partially inconsistent with the pattern of infected cells as detected in previous studies, which suggests there may be other receptors or mechanisms involved in H5N1 infection. In addition, the diffuse presence of receptors on endothelial cells may account for the multiple organ involvement in H5N1 influenza. Finally, the relative lack of AIV-Rs in the upper airway may be a one of the factors preventing efficient human-to-human transmission of H5N1 influenza.

H5N1 infection of the respiratory tract and beyond: a molecular pathology study.

BACKGROUND: Human infection with avian influenza H5N1 is an emerging infectious disease characterised by respiratory symptoms and a high fatality rate. Previous studies have shown that the human infection with avian influenza H5N1 could also target organs apart from the lungs. METHODS: We studied post-mortem tissues of two adults (one man and one pregnant woman) infected with H5N1 influenza virus, and a fetus carried by the woman. In-situ hybridisation (with sense and antisense probes to haemagglutinin and nucleoprotein) and immunohistochemistry (with monoclonal antibodies to haemagglutinin and nucleoprotein) were done on selected tissues. Reverse-transcriptase (RT) PCR, real-time RT-PCR, strand-specific RT-PCR, and nucleic acid sequence-based amplification (NASBA) detection assays were also undertaken to detect viral RNA in organ tissue samples. FINDINGS: We detected viral genomic sequences and antigens in type II epithelial cells of the lungs, ciliated and non-ciliated epithelial cells of the trachea, T cells of the lymph node, neurons of the brain, and Hofbauer cells and cytotrophoblasts of the placenta. Viral genomic sequences (but no viral antigens) were detected in the intestinal mucosa. In the fetus, we found viral sequences and antigens in the lungs, circulating mononuclear cells, and macrophages of the liver. The presence of viral sequences in the organs and the fetus was also confirmed by RT-PCR, strand-specific RT-PCR, real-time RT-PCR, and NASBA. INTERPRETATION: In addition to the lungs, H5N1 influenza virus infects the trachea and disseminates to other organs including the brain. The virus could also be transmitted from mother to fetus across the placenta.

Pathogenetic mechanisms of severe acute respiratory syndrome.

Severe acute respiratory syndrome (SARS) is an acute respiratory disease with significant morbidity and mortality. While its clinical manifestations have been extensively studied, its pathogenesis is not yet fully understood. A limited number of autopsy studies have revealed that the lungs and the immune system are the organs that sustain the most severe damage. Other organs affected include the kidneys, brain, digestive tract, heart, liver, thyroid gland and urogenital tract. The primary target cells are pneumocytes and enterocytes, both cell types abundantly expressing angiotensin-converting enzyme 2 which is the main SARS-CoV receptor. Other cell types infected include the epithelial cells of renal tubules, cerebral neurons, and immune cells. The pathology of this disease results from both direct and indirect injury. Direct injury is caused by infection of the target cells by the virus. Indirect injury mainly results from immune responses, circulatory dysfunction, and hypoxia. In this review, we summarize the major pathological findings at the gross, cellular and molecular levels and discuss the various possible mechanisms that may contribute to the pathogenesis of SARS. The implications of the proposed pathogenesis for prevention, diagnosis and therapy of the disease are discussed.

Pathology of the thyroid in severe acute respiratory syndrome.

The severe acute respiratory syndrome (SARS) epidemic started in November 2002 and spread worldwide. The pathological changes in several human organs of patients with SARS have been extensively described. However, to date, little has been reported about the effects of this infection on the thyroid gland. Femoral head necrosis and low serum triiodothyronine and thyroxine levels, commonly found in patients with SARS, raise the possibility of thyroid dysfunction. We have undertaken this study to evaluate for any potential injury to the thyroid gland caused by SARS on tissue samples obtained from 5 SARS autopsies. The terminal deoxynucleotidyl transferase-mediated dUPT nick end-labeling assay was performed to identify apoptotic cells. The follicular epithelium was found to be damaged with large numbers of cells exfoliated into the follicle. The terminal deoxynucleotidyl transferase-mediated dUPT nick end-labeling assay demonstrated many cells undergoing apoptosis. Follicular architecture was altered and showed distortion, dilatation, and collapse. No distinct calcitonin-positive cells were detectable in the SARS thyroids. In conclusion, both parafollicular and follicular cells were injured. This may provide an explanation both for low serum triiodothyronine and thyroxine levels and the osteonecrosis of the femoral head associated with patients with SARS. Apoptosis may play a role in the pathogenesis of SARS associated coronavirus infection in the thyroid gland.

Expression of Cystic Fibrosis Transmembrane Conductance Regulator in Ganglia of Human Gastrointestinal Tract.

CF is caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) which is an anion selective transmembrane ion channel that mainly regulates chloride transport, expressed in the epithelia of various organs. Recently, we have demonstrated CFTR expression in the brain, the spinal cord and the sympathetic ganglia. This study aims to investigate the expression and distribution of CFTR in the ganglia of the human gastrointestinal tract. Fresh tissue and formalin-fixed paraffin-embedded normal gastrointestinal tract samples were collected from eleven surgical patients and five autopsy cases. Immunohistochemistry, in situ hybridization, laser-assisted microdissection and nested reverse transcriptase polymerase chain reaction were performed. Expression of CFTR protein and mRNA was detected in neurons of the ganglia of all segments of the human gastrointestinal tract examined, including the stomach, duodenum, jejunum, ileum, cecum, appendix, colon and rectum. The extensive expression of CFTR in the enteric ganglia suggests that CFTR may play a role in the physiology of the innervation of the gastro-intestinal tract. The presence of dysfunctional CFTRs in enteric ganglia could, to a certain extent, explain the gastrointestinal symptoms frequently experienced by CF patients.

Correlation of immunoglobulin G expression and histological subtype and stage in breast cancer.

INTRODUCTION: Recently, growing evidence indicates that immunoglobulins (Igs) are not only produced by mature B lymphocytes or plasma cells, but also by various normal cells types at immune privileged sites and neoplasm, including breast cancer. However, the association of breast cancer derived IgG with genesis and development of the disease has not yet been established. METHODS: In this study we examined the expression of IgG in 186 breast cancers, 20 benign breast lesions and 30 normal breast tissues. Both immunohistochemistry with antibodies to Igκ (immunoglobulin G κ light chain) and Igγ (immunoglobulin G heavy chain) and in situ hybridization with an antisense probe to IgG1 heavy chain constant region gene were performed. Various clinicopathological features were also analyzed. RESULTS: We found that IgG is specifically expressed in human breast cancer cells. Both infiltrating ductal carcinoma and infiltrating lobular carcinoma had significantly greater numbers of Igκ and Igγ positive cancer cells as compared with medullary carcinoma, carcinoma in situ, and benign lesions (all p<0.05). In addition, IgG expression was correlated with breast cancer histological subtypes (p<0.01) and AJCC stages (p<0.05), with more abundance of IgG expression in more malignant histological subtypes or in more advanced stage of the disease. CONCLUSIONS: IgG expression in breast cancer cells is correlated with malignancy and AJCC stages of the cancers. This suggests that breast cancer derived IgG may be associated with genesis, development and prognosis of the cancer.

Expression of immunoglobulin G in esophageal squamous cell carcinomas and its association with tumor grade and Ki67.

We and other research groups have previously shown that various cancer types can express immunoglobulin G, but investigation on of immunoglobulin G expression in esophageal cancer, a highly malignant tumor, and its biological significance has been lacking. In this study, we examined immunoglobulin G protein and its messenger RNA, as well as the expressions of recombination-activating gene 1, recombination-activating gene 2, and activation-induced cytidine deaminase in 142 cases of esophageal cancer tissues, and 2 esophageal cancer cell lines (Eca109, SHEEC). We also compared their expressions with tumor grade and a proliferation marker, Ki67. We used immunohistochemistry, immunofluorescence, in situ hybridization, laser microdissection coupled with reverse transcriptase polymerase chain reaction, and Western blot analysis. We detected transcripts of immunoglobulin G 1 heavy-chain constant region, immunoglobulin-κ and λ-light chains, immunoglobulin G variable region, and recombination-activating genes 1 and 2 in both esophageal cancer tissues and cell lines, whereas activation-induced cytidine deaminase was not detected. No immunoglobulin G receptor subtypes were detected. Statistic analysis revealed that immunoglobulin G expression correlated well with tumor grades (P < .001) and with the proliferation marker Ki67 (P < .001). Our results indicate that human esophageal cancer cells are capable of synthesizing immunoglobulin G, which is likely involved in the growth and proliferation of this highly malignant cancer and might also be used as a prognostic indicator in esophageal squamous cell carcinomas.

IgG expression in human colorectal cancer and its relationship to cancer cell behaviors.

Increasing evidence indicates that various cancer cell types are capable of producing IgG. The exact function of cancer-derived IgG has, however, not been elucidated. Here we demonstrated the expression of IgG genes with V(D)J recombination in 80 cases of colorectal cancers, 4 colon cancer cell lines and a tumor bearing immune deficient mouse model. IgG expression was associated with tumor differentiation, pTNM stage, lymph node involvement and inflammatory infiltration and positively correlated with the expressions of Cyclin D1, NF-κB and PCNA. Furthermore, we investigated the effect of cancer-derived IgG on the malignant behaviors of colorectal cancer cells and showed that blockage of IgG resulted in increased apoptosis and negatively affected the potential for anchor-independent colony formation and cancer cell invasion. These findings suggest that IgG synthesized by colorectal cancer cells is involved in the development and growth of colorectal cancer and blockage of IgG may be a potential therapy in treating this cancer.