[Show abstract][Hide abstract] ABSTRACT: Approximately 80% of Merkel cell carcinomas (MCCs) harbor Merkel cell polyomavirus (MCPyV) which monoclonally integrates into the genome and has prognostic significance. The presence or absence of MCPyV is usually diagnosed using CM2B4 immunohistochemistry (IHC) for MCPyV-large T antigen (LT) protein. However, this method poses a risk of misdiagnosis.
In this study, we determined MCPyV infection in MCCs using real-time PCR for MCPyV-LT DNA and prepared 16 cases of MCPyV-DNA-positive and -negative groups. Diagnostic sensitivity and specificity of conventional PCR for MCPyV-small T antigen (MCPyV-ST), IHC using a newly developed polyclonal antibody (ST-1) for MCPyV-ST protein (MCPyV-ST) (aa: 164-177), and in situ hybridization (ISH) as well as real-time PCR for MCPyV-ST mRNA were compared against CM2B4-IHC for sensitivity (0.94, 15/16) and specificity (0.94, 15/16).
The followings are the respective sensitivity and specificity results from examinations for MCPyV-ST gene: conventional PCR for the MCPyV-ST (0.94, 1.0), ST-1-IHC (0.69, 1.0), real-time PCR for ST mRNA (1.0, no data), ST mRNA ISH (0.94, 1.0). Each of the MCPyV-pseudonegative (1/16) and -pseudopositive (1/16) diagnoses evaluated using CM2B4-IHC were accurately corrected by examinations for MCPyV-ST or its expression as well as real-time PCR for MCPyV-LT. Sensitivity of CM2B4-IHC (0.94) was superior to that of ST-1-IHC (0.69) but equal to that of ST mRNA-ISH (0.94). Specificities of ST-1-IHC (1.0) and ST mRNA-ISH (1.0) were superior to that of CM2B4-IHC (0.94).
Therefore, combined application of ST mRNA-ISH and ST-IHC as well as CM2B4-IHC is recommended and will contribute to the diagnostic accuracy for MCPyV infection in MCCs.Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9966295741144834.
[Show abstract][Hide abstract] ABSTRACT: Wallenberg syndrome was first reported by Adolf Wallenberg as arising due to the obstruction of the posterior inferior cerebellar artery (PICA), which caused an infarct in the lateral medulla oblongata (MO).
[Show abstract][Hide abstract] ABSTRACT: To clarify the pathogenesis of cerebellar Purkinje cell death in patients with Menkes kinky hair disease (MD), a disorder of copper absorption, we investigated the morphological and functional abnormalities of residual Purkinje cells in MD patients and the mechanism of cell death.
[Show abstract][Hide abstract] ABSTRACT: Abstract Graves' disease is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies (TRAbs). Because Epstein-Barr virus (EBV) persists in B cells and is occasionally reactivated, we hypothesized that EBV contributes to TRAbs production in Graves' disease patients by stimulating the TRAbs-producing B cells. In order for EBV to stimulate antibody-producing cells, EBV must be present in those cells but that have not yet been observed. We examined whether EBV-infected (EBV(+)) B cells with TRAbs on their surface (TRAbs(+)) as membrane immunoglobulin were present in peripheral blood of Graves' disease patients. We analyzed cultured or non-cultured peripheral blood mononuclear cells (PBMCs) from 13 patients and 11 healthy controls by flow-cytometry and confocal laser microscopy, and confirmed all cultured PBMCs from 8 patients really had TRAbs(+) EBV(+) double positive cells. We unexpectedly detected TRAbs(+) cells in all healthy controls, and TRAbs(+) EBV(+) double positive cells in all cultured PBMC from eight healthy controls. The frequency of TRAbs(+) cells in cultured PBMCs was significantly higher in patients than in controls (p = 0.021). In this study, we indicated the presence of EBV-infected B lymphocytes with TRAbs on their surface, a possible player of the production of excessive TRAbs, the causative autoantibody for Graves' disease. This is a basic evidence for our hypothesis that EBV contributes to TRAbs production in Graves' disease patients. Our results further suggest that healthy controls have the potential for TRAbs production. This gives us an important insight into the pathogenesis of Graves' disease.
[Show abstract][Hide abstract] ABSTRACT: Langerhans cell histiocytosis (LCH) is a group of granulomatous disorders in which abnormal Langerhans cells proliferate as either a localized lesion in a single bone or disseminated disease involving two or more organs or systems. Because the different LCH forms exhibit significantly elevated levels of inflammatory molecules, including pro-inflammatory cytokines and tissue-degrading enzymes, we investigated for a possible viral trigger in LCH pathogenesis. We looked for Merkel cell polyomavirus (MCPyV) in peripheral blood cells and tissues using quantitative real-time PCR and immunohistochemistry staining with anti-MCPyV large T-antigen antibody. Our findings revealed elevated amounts of MCPyV DNA in the peripheral blood cells of 2 of 3 patients affected by LCH with high-risk organ involvement (RO+) and absence of MCPyV DNA in the blood cells in all 12 LCH-RO- patients (P = .029). With lower viral loads (0.002-0.033 copies/cell), an elevated number of MCPyV DNA sequences was detected in 12 LCH tissues in comparison with control tissues obtained from patients with reactive lymphoid hyperplasia (0/5; P = .0007), skin diseases not related to LCH in children younger than 2 years (0/11; P = .0007), or dermatopathic lymphadenopathy (5/20; P = .0002). The data, including frequent but lower viral loads and low large-T antigen expression rate (2/13 LCH tissues), suggest that development of LCH as a reactive rather than a neoplastic process may be related to MCPyV infection.
Human pathology 01/2014; 45(1):119-26. · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Langerhans cell (LC) sarcoma (LCS) is a high-grade neoplasm with overtly malignant cytologic features and an LC phenotype. We very recently suggested that LC behaves as a reservoir for common dermotropic Merkel cell polyomavirus (MCPyV) and determined the relationship between LC histiocytosis (LCH), which has an underlining oncogenic capacity, and MCPyV as a trigger for a reactive process rather than a neoplastic process. We propose LC to be a reservoir for MCPyV and hypothesize that some LCS subtypes may be related to the MCPyV agent.
We examined seven LCS tissues using multiplex quantitative PCR (Q-PCR) and immunohistochemistry with anti MCPyV large-T (LT) antigen antibody. High viral loads of MCPyV DNA sequences (viral load = relative levels of MCPyV) were detected (0.328-0.772 copies/cell (Merkel cell carcinoma (MCC) = 1.0)) using Q-PCR in 43% (3/7) tissues, but LT antigen expression was not observed (0/7).
Frequent MCPyV-DNA amplification suggests that LCS in some patients may be related to MCPyV infection. Moreover, the higher viral load of LCS (median, 0.453 copies/cell) than low load of LCH (0.003, median of 12 cases) (P < 0.01) may suggest a virally induced tumorigenic process in some LCS. Although the absence of LT antigen expression may indicate a different role for MCPyV in this pathology, some subtypes of LCS may develop in the background of MCPyV-infected LC. To the best of our knowledge, this is the first report on the relationship between MCPyV and LCS. The recent discovery of MCPyV opened new therapeutic avenues for MCC. These data open novel possibilities for therapeutic interventions against LCS.
[Show abstract][Hide abstract] ABSTRACT: Most of merkel cell carcinomas (MCC), a rare, aggressive skin cancer with neuroendocrine features, harbor merkel cell polyomavirus (MCPyV). Seroepidemiological studies suggested high prevalence of MCPyV in the human population. More than ten sequence data on MCPyV strains in Japan have been available, whereas most sequence data were detected from patients living in Europe or European ancestry. Analysis of nine almost complete and 19 partial sequences from two oncogenes, small T antigen (ST) and large T antigen (LT) genomes obtained from 32 Japanese MCPyV-infected MCC revealed that each Japanese MCPyV-infected MCC harbored a specific MCPyV strain with some synonymous or, silent mutations and stop codons or deletions, but functional domains of T antigen had no amino acid changes. All stop codons were localized after retinoblastoma protein-binding domain. These Japanese MCPyV strains were very closely interrelated to themselves and a consensus sequence of Japanese strain was generated. Phylogenetic analysis of our nine sequences and 70 other sequences for ST and LT gene registered in GenBank indicated that Japanese or Asian MCPyV strains formed distinct clades from Caucasian clade, and phylogenetic tree of our nine and 75 other sequences for ST gene formed characteristic three clades and showed that all Japanese or Asian strains were included in the dominant clade. These suggested the possibility of geographically related genotypes of MCPyV. The genomic characterization of MCPyV variants will provide an important database and insights for illuminating their evolutional and biological differences.
[Show abstract][Hide abstract] ABSTRACT: Merkel cell polyomavirus (MCPyV) monoclonally integrates into genomes of approximately 80% of Merkel cell carcinomas (MCCs) and undergoes mutation. We previously demonstrated statistically significant differences in tumor cell morphology and biology between MCPyV-positive and MCPyV-negative MCCs. We reassessed the usefulness of our morphologic criteria in differentiating MCPyV-negative and MCPyV-positive MCCs for practical diagnosis. Two trainees and 4 pathologists challenged estimations (5-point confidence scale) of MCPyV infection in MCCs using hematoxylin and eosin-stained slides of 43 new MCC cases and 2 morphologic criteria: (1) nuclear polymorphism is higher and cytoplasm is more abundant in MCPyV-negative MCC cells, and (2) MCC combined with squamous cell carcinoma is defined as MCPyV negative, regardless of tumor cell morphology of MCC. Subsequently, immunohistochemistry for MCPyV large T antigen and polymerase chain reaction for MCPyV DNA yielded concordant results (MCPyV positivity was 30/43 and 32/43, respectively) for 41 (96%) of 43 cases. The mean accuracy, sensitivity, and specificity of the trainees and pathologists were 92.4% ± 1.5% and 81.5% ± 11.0%, 95.6% ± 6.2% and 90.2% ± 8.3%, and 83.3% ± 11.8% and 74.6% ± 14.1%, respectively. Values of the areas under the curve were 0.80 to 0.95, indicating good informative scores. Using our morphologic criteria, observers can predict the absence of MCPyV infection and diagnose MCPyV-negative MCCs with poor prognosis. Unexpectedly, the performance of trainees was superior to that of pathologists, implying that our morphologic criteria are useful even for practitioners having little experience. Our morphologic criteria will provide pathologists with convenient and reliable hallmarks for accurate MCC diagnosis.
[Show abstract][Hide abstract] ABSTRACT: Squamous cell carcinoma (SCC) of the oral region often metastasizes to the cervical lymph nodes. To investigate whether the risk of cervical lymph node metastasis are predictable through lymphatic vessel density (LVD) and vascular endothelial growth factor (VEGF) expression, we assessed the relationship between LVD and clinicopathological parameters, and VEGF expression in SCC of the oral region.
The subjects were 109 patients with SCC of the oral region including the lip. Clinicopathological parameters examined for the association with LVD in a peritumoral hot spot were lymph node metastasis, histological grade and disease stage. The association with VEGF expression was similarly studied. LVD was detected by immunohistochemistry using D2-40.
LVD was significantly higher in lip cancer than in other oral tumors (P < 0.0001), while there were no significant differences of LVD among other cancers of the oral cavity. LVD tended to decrease with disease progression, increase of tumor size and increase of metastatic lymph node size. Eighty-four of 109 tumors were positive for VEGF-C or D. VEGF-C-positive tumor lesions were also positive for VEGF-D. Significantly higher levels of VEGF-C and D expressions were associated with large size of lymph node metastases (P = 0.02).
SCC of the oral region including the lip that produces VEGF-C and D is significantly more likely to cause cervical lymph node metastasis. LVD in a peritumoral hot spot does not directly indicate the risk of cervical lymph node metastasis, but instead may reflect lymphangiogenesis due to VEGF together with loss of lymphatic vessels through tumor growth and progression.
[Show abstract][Hide abstract] ABSTRACT: Objectives: To clarify characteristics on rabbit in vivo infection with type 2 EBV nuclear antigen (EBNA-2)-deleted Epstein-Barr virus (P3HR-1-EBV) and compare infectious efficacy of P3HR-1-EBV with previously reported prototype type 1 EBV from B95-8. Methods: Twelve Japanese White rabbits were inoculated with P3HR-1-EBV via intranasal or intravenous routes and autopsied on day 70-84. Results: In only 2 of 12 P3HR-1-EBV-inoculated rabbits, EBV-DNA was detected in peripheral blood mononuclear cells (PBMCs). BamHI M rightward reading frame (BMRF)-1, EBNA-1 and BamHI Z leftward reading frame (BZLF)-1-mRNA were intermittently expressed in PBMCs. In 1 infected rabbit with continuous detection of EBV-DNA in PBMCs, many EBER-1-positive lymphocytes were observed in germinal centers and/or marginal zones in some follicles of the appendix, and for the first time a lymphocyte with EBER-1 expression infiltrating in the squamous cell layer of the tonsils was found. The other rabbit with a transient detection of EBV-DNA in PBMCs had no EBER-1-positive lymphocytes in the tissues examined. Few EBER-1-positive lymphocytes were detected in some rabbits without detection of EBV-DNA in PBMCs. Conclusions: P3HR-1-EBV showed less efficient infection in rabbits than EBV from the B95-8 cell line. However, a P3HR-1-EBV-inoculated animal model is meaningful because this is the first study of EBNA-2 function on in vivo EBV infection and it demonstrated the in vivo infectivity with lytic-type infection by EBNA-2-deleted EBV.
[Show abstract][Hide abstract] ABSTRACT: Langerhans cell histiocytosis (LCH) is a lymphoproliferative disorder consisting of abnormal Langerhans cell-like cells and other lymphoid cells. LCH presents as either a multisystem LCH (LCH-MS) or a single-system LCH (LCH-SS). Currently, neither the pathogeneses nor the factors that define these disease subclasses have been elucidated. The interleukin (IL)-17A autocrine LCH model and IL-17A-targeted therapies have been proposed and have engendered much controversy. Those authors showed high serum IL-17A levels in LCH and argued that serum IL-17A-dependent fusion activities in vitro, rather than serum IL-17A levels, correlated with LCH severity (i.e. the IL-17A paradox). In contrast, others could not confirm the IL-17A autocrine model. So began the controversy on IL-17A, which still continues. We approached the IL-17A controversy and the IL-17A paradox from a new perspective in considering the expression levels of IL-17A receptor (IL-17RA). We detected higher levels of IL-17RA protein expression in LCH-MS (n = 10) as compared to LCH-SS (n = 9) (P = 0.041) by immunofluorescence. We reconfirmed these data by re-analyzing GSE16395 mRNA data. We found that serum levels of IL-17A were higher in LCH (n = 38) as compared to controls (n = 20) (P = 0.005) with no significant difference between LCH subclasses. We propose an IL-17A endocrine model and stress that changes in IL-17RA expression levels are important for defining LCH subclasses. We hypothesize that these IL-17RA data could clarify the IL-17A controversy and the IL-17A paradox. As a potential treatment of LCH-MS, we indicate the possibility of an IL-17RA-targeted therapy.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 12/2012; · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has recently been shown that approximately 80% of Merkel cell carcinomas harbor a novel polyomavirus named Merkel cell polyomavirus (MCPyV). MCPyV has been detected in human tissue samples. However, detailed distribution of MCPyV in non-neoplastic Japanese human tissues remains unclear. To address this, we used single or real-time quantitative polymerase chain reaction (PCR) for 41 autopsy cases. PCR revealed MCPyV-DNA in non-neoplastic samples: total, 29/41 (71%); adult, 29/39 (74%); fetus or infant, 0/2; men, 24/28 (86%); women, 5/13 (38%); total human tissues, 66/572 (12%); skin, 8/15 (53%); adrenal gland, 9/33 (27%), and other 16 organs (4-25%). This study first reported the presence of MCPyV-DNA in non-neoplastic tissues of thyroid gland, adrenal gland, spleen, bone marrow, stomach, gallbladder, pancreas, heart, and aorta. PCR revealed that viral load ranged from 0.00026 to 0.22 in all MCPyV-positive tissues compared with Merkel cell carcinoma samples. These detailed PCR data showed higher prevalence of MCPyV infection in Japanese men than women (p = 0.004) and broad distribution of MCPyV with low viral load in more non-neoplastic human tissues than in the previous reports. These data provide valuable insights for further studies of MCPyV infection and MCPyV-related diseases.
[Show abstract][Hide abstract] ABSTRACT: Basophilic inclusions (BIs) are pathological features of a subset of frontotemporal lobar degeneration disorders, including sporadic amyotrophic lateral sclerosis (ALS) and familial ALS (FALS). Mutations in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene have recently been identified as a cause of FALS. The FUS/TLS-immunoreactive inclusions are consistently found in cases of frontotemporal lobar degeneration with BIs; however, the association between ALS cases with BIs and FUS/TLS accumulation is not well understood. We used immunohistochemistry to analyze 3 autopsy cases of FALS with the FUS/TLS mutation and with BIs using anti-FUS/TLS antibodies. The disease durations were 1, 3, and 9 years. As the disease duration becomes longer, there were broader distributions of neuronal and glial FUS/TLS-immunoreactive inclusions. As early as 1 year after the onset, BIs, neuronal cytoplasmic inclusions and glial cytoplasmic inclusions were found in the substantia nigra in addition to the anterior horn of the spinal cord. Glial cytoplasmic inclusions are found earlier and in a wider distribution than neuronal cytoplasmic inclusions. The distribution of FUS/TLS-immunoreactive inclusions in FUS/TLS-mutated FALS with BIs was broader than that of BIs alone, suggesting that the pathogenetic mechanism may have originated from the FUS/TLS proteinopathy.
Journal of Neuropathology and Experimental Neurology 08/2012; 71(9):779-88. · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Spinal cord tumors are rare in children. We report a novel case of pediatric intramedullary spinal cord tumor with unusual solid-cystic and papillary features. Clinically, the patient presented at the age of 3 years with motor deficit and urinary incontinence, and MRI demonstrated multilocular cystic lesions in the thoracic spine. Histologically the tumor consisted of solid, sheet-like components and branching papillary structures, and immunohistochemistry demonstrated positive reactivity for epithelial membrane antigen, cytokeratins (7, AE1/3, CAM5.2), E-cadherin and transthyretin, and negativity for GFAP, S-100 protein, synaptophysin and neurofilament. These histological and immunohistochemical findings appeared to be unique, and were not compatible with the features of classical ependymoma or choroid plexus papilloma. The clinical behavior, characterized by relatively rapid tumor regrowth after surgical resection and a relatively high MIB-1 labeling index, suggest that this tumor might have had moderate malignant potential. This pediatric case appears to be particularly informative with regard to the tumor biology or tumorigenesis of intramedullary spinal cord tumor with unusual solid-cystic and papillary features.
[Show abstract][Hide abstract] ABSTRACT: Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cell (LC)-like CD1a-positive cell (LCH cell) with unknown causes. LCH consists of two subtypes: single-system LCH (LCH-SS) with favorable prognosis and multisystem LCH (LCH-MS) with poor prognosis. LCH has been indicated as a neoplastic disorder from monoclonal characteristics of LCH cells. This study aimed to investigate an expression of tyrosine phosphatase SHP-1 in LCH, since its expression levels were variously reported in many tumors, overexpression in ovarian cancers (a candidate oncoprotein), and downregulation by methylation in gastric cancers, prostate cancers, malignant lymphomas, and leukemias (a putative tumor suppressor). By immunohistochemistry (IHC), the SHP-1 expression in LCs and LCH cells was compared in LCH (two subtypes: LCH-SS = 21, LCH-MS = 12), dermatopathic lymphadenopathy (DLA) (n = 9) and normal epidermal LCs (n = 3) near LCH lesion. IHC results were analyzed semiquantitatively using a Photoshop software. The mean intensity score (IS) of DLA, LCH-SS, LCH-MS, and LCs were 47, 100, 139, and 167 (in arbitrary unit), respectively. The IS had significant differences among LCH-SS, LCH-MS, and DLA (p < 0.01). SHP-1 is expressed significantly higher in LCH-MS than in LCH-SS. SHP-1 can be a progression marker of LCH. SHP-1 is also useful for differential diagnosis between LCH in lymph nodes and DLA.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 05/2011; 459(2):227-34. · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In Graves' disease, the IgG class autoantibody against thyrotropin receptor (TRAb) is produced excessively and induces hyperthyroidism. Epstein-Barr virus (EBV) is one of the human herpesviruses that persists for life, mainly in B lymphocytes, and is occasionally reactivated. Therefore, EBV may affect the antibody production of B lymphocytes that would normally produce TRAb. The purpose of the present study was to evaluate the association of EBV reactivation with the etiology of Graves' disease. Serum levels of EBV antibodies and IgE were determined by ELISA. TRAb levels were determined by radioreceptor assay. We performed in-situ hybridization (ISH) of EBV-encoded small RNA (EBER)1 on the thyroid tissue of one of our patients. In Graves' disease patients with TRAb levels ≥ 10%, EA antibody levels, which indicate EBV reactivation, were moderately but significantly correlated with the levels of TRAb, and weakly but significantly correlated with IgE. EBER1-ISH revealed that one of our patients had EBV-infected lymphocytes infiltrating the thyroid gland. EBV reactivation may stimulate antibody-producing B lymphocytes predisposed to make TRAb, and this may contribute to or exacerbate the disease.
[Show abstract][Hide abstract] ABSTRACT: Recently, it has been shown that approximately 80% of Merkel cell carcinomas harbor a novel polyomavirus named Merkel cell polyomavirus, thought to be a carcinogenic agent. However, it is not fully elucidated whether Merkel cell carcinomas differ with regard to the presence or absence of Merkel cell polyomavirus. To address this, we investigated morphologic differences between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas by morphometry. Using polymerase chain reaction and real-time quantitative polymerase chain reaction, Merkel cell polyomavirus was detected in 20 (77%) of 26 Merkel cell carcinoma cases, including 4 Merkel cell carcinomas combined with squamous cell carcinomas. Interestingly, Merkel cell polyomavirus was detected only in ordinary (pure) Merkel cell carcinomas; none of the 4 combined Merkel cell carcinomas + squamous cell carcinomas was positive for Merkel cell polyomavirus (P = .001). Morphometric analyses revealed that Merkel cell polyomavirus-negative Merkel cell carcinomas had more irregular nuclei (P < .001) and more abundant cytoplasm (P = .001) than Merkel cell polyomavirus-positive Merkel cell carcinomas, which had uniform round nuclei and scant cytoplasm. Reliability of the morphometry was confirmed using intraobserver and interobserver reliability tests. These results demonstrated statistically significant differences in tumor cell morphology between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas and reconfirmed the absence of Merkel cell polyomavirus in combined tumors. Furthermore, the results strongly suggest fundamental biological differences between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas, supporting that Merkel cell polyomavirus plays an important role in the pathogenesis of Merkel cell polyomavirus-positive Merkel cell carcinoma.
Human pathology 01/2011; 42(5):632-40. · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Most humans become lifelong carriers of Epstein-Barr virus (EBV) by adulthood. Primary EBV infection in adolescents causes infectious mononucleosis. EBV infection is associated with various diseases, neoplasms and hematological disorders. Recently, we reported that EBV can infect rabbits by intravenous, intranasal and/or peroral inoculation, which caused primary EBV infection in rabbits with heterogeneous host reactions. Some rabbits showed chronic and lifelong EBV infection with hemophagocytosis. In this study, to reveal detailed mechanisms in rabbit EBV infection, an in vitro investigation was performed. We elucidated that: (1) EBV can infect rabbit peripheral blood mononuclear cells and splenic lymphocytes in vitro, because EBV gene expressions were confirmed. (2) It is highly likely that the B cell is the main target cell of rabbit EBV infection and is immortalized similar to humans. (3) CD8+ T cells increased in the rabbit in vivo model after EBV inoculation, whereas an increase of B cells occurred after their transient decrease. These data suggest that EBV-infected B cells were proliferated, while CD8+ T cells increased to recognize and kill them. This system may explain the paths of rabbit EBV infection and host reaction, simulating human EBV infection. In vitro studies will be helpful to reveal the pathogenesis of rabbit EBV infection and EBV-associated diseases.
[Show abstract][Hide abstract] ABSTRACT: Most humans become lifelong carriers of Epstein-Barr virus (EBV) by adulthood. Primary EBV infection in adolescents causes in one to two-third of cases infectious mononucleosis. EBV infection is associated with various diseases, neoplasms and hematological disorders. Recently we reported that EBV can infect rabbits frequently by intravenous, intranasal or/and peroral inoculation, which caused primary EBV infection in rabbits with heterogeneous host reactions. Here we presented follow up data that of six primary EBV-infected rabbits out of seven inoculated intravenously with EBV, two out of six EBV-infected rabbits showed lifetime EBV infection. (1) EBV-DNA were detected in blood through life. (2) High antibody titers against EA-D were maintained over 1000 days. (3) A focal mass lesion was transiently observed by ultrasonography in the spleen of one rabbit. (4) Two lifelong EBV-detected rabbits died on day 1522 or 1400, and autopsy revealed proliferation of lymphocytes expressing EBER1 or LMP1 accompanied with mild hemophagocytosis in the spleen or lymph nodes. We hypothesized some EBV-infected rabbits could not eliminate EBV for life and showed somewhat similar features to persistent EBV infection, mild CAEBV and/or mild sublethal hemophagocytosis. These lifelong EBV-infected rabbits might be a new useful animal model for studying lifelong persistent EBV infection, taking place in almost all adults.
Virus Research 10/2010; 153(1):172-8. · 2.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epstein-Barr virus (EBV) is spread universally in humans, and it causes infectious mononucleosis and sometimes induces serious EBV-associated disease. The detailed mechanism of primary infection in humans has remained unclear, because it is difficult to examine the dynamics of EBV in vivo. In this study, a natural EBV-infection rabbit model by intranasal or peroral inoculation is described. Ten male rabbits were examined for EBV-DNA or mRNA expression and anti-EBV antibodies in blood. Four of 10 rabbits showed the evidence of EBV infection; detection of EBV-DNA or EBV-related genes mRNA in peripheral blood mononuclear cells, increased EBV antibodies in the plasma, and the presence of lymphocytes expressing EBER1 and EBV-related gene proteins in the lymphoid tissues of a rabbit. Three of four infected rabbits were detected transiently EBV-DNA and/or mRNA of EBV-related genes such as EBNA1, EBNA2, BZLF1, and EA in blood, while in one of four, EBV-DNA and/or mRNA were detected for more than 200 days after viral inoculation. The level of EA-IgG increased and its level was maintained in all infected rabbits, whereas those of VCA-IgM and VCA-IgG increased transiently, and EBNA-IgG was not elevated. Pathological examination of a rabbit infected transiently revealed some scattered lymphocytes expressing EBER1, LMP1, and EBNA2 in the spleen and lymph nodes. EA expression was also observed in the spleen. These findings suggest that EBV can infect the rabbit by the intranasal or peroral route, and that this rabbit model is useful for examining the pathophysiology of natural primary EBV infection in humans.
Journal of Medical Virology 05/2010; 82(6):977-86. · 2.37 Impact Factor