Cytomegalovirus infection in ulcerative colitis

Objective. Cytomegalovirus (CMV) infection has been reported as an exacerbating factor in inflammatory bowel disease but the relationship between CMV infection and ulcerative colitis (UC) remains unclear. There has been no detailed research to elucidate the clinicopathologic features of CMV infection in UC using surgical specimens. The aim of this study was to investigate the clinicopathologic features of CMV infection in UC patients who had undergone colectomy.

Material and methods. Surgical specimens taken from UC patients were examined for CMV infection. The patients were divided into three groups: severe, refractory, and UC-associated dysplasia or cancer according to the operative indications. CMV infection rates were evaluated and a comparison of clinical parameters was made between CMV-positive and CMV-negative patients, and the risk factors for CMV infection were analyzed using multivariate analyses.

Results. It was found that 25% of 32 patients were positive for CMV in the severe UC group; 8.3% of 72 patients were positive for CMV in the refractory UC group. None of the 22 patients was positive for CMV in the UC-associated dysplasia or cancer group. The CMV-positive rate in the severe UC group was significantly higher than that in the other groups (p<0.05). Patients’ age at the time of operation was higher in the CMV-positive group than in the CMV-negative group among the patients with severe UC (p<0.01), and age at operation was an independent risk factor for CMV infection.

Conclusions. CMV is found more frequently in severe UC than refractory UC and UC-associated cancer or dysplasia. Higher age can be a risk factor for CMV infection in patients with severe UC. However, a high steroid dose may not always be a risk factor for CMV infection.     

Appendix is a priming site in the development of ulcerative colitis

AIM: The role of the appendix has been highlighted in the pathogenesis of ulcerative colitis (UC). The aims of this study were to elucidate the immuno-imbalances in the appendix of UC patients, and to clarify the role of the appendix in the development of UC. METHODS: Colonoscopic biopsy specimens of the appendix, transverse colon, and rectum were obtained from 86 patients with UC: active pancolitis (A-Pan; n = 15), active left-sided colitis (A-Lt; n = 25), A-Lt with appendiceal involvement (A-Lt/Ap; n = 10), inactive pancolitis (I-Pan; n = 14), and inactive left-sided colitis (I-Lt; n = 22), and from controls. In the isolated mucosal T cells, the CD4/CD8 ratio and proportion of activated CD4+ T cells were investigated, and compared with controls. RESULTS: In the appendix, the CD4/CD8 ratio significantly increased in A-Lt and A-Lt/Ap. The ratio in the appendix also tended to increase in A-Pan. In the rectum, the ratio significantly increased in all UC groups. In the appendix, the proportion of CD4+CD69+ (early activation antigen) T cells significantly increased in all UC groups. In the rectum, the proportion of CD4+CD69+ T cells significantly increased only in A-Pan. The proportion of CD4+HLA-DR+ (mature activation antigen) T cells significantly increased only in the rectum of A-Pan, but not in the other areas of any groups. CONCLUSION: The increased CD4/CD8 ratio and predominant infiltration of CD4+CD69+ T cells in the appendix suggest that the appendix is a priming site in the development of UC.     

Primary CD56+ NK/T-cell lymphoma of the rectum accompanied with refractory ulcerative colitis

A case of primary NK/T-cell lymphoma of the rectum accompanied with ulcerative colitis (UC) in a 73-year-old man is reported. He had a 6-year history of repeated admission to our hospital for UC. Total colonoscopy performed 4 months after resolution of refractory UC complicated by cytomegalovirus colitis showed a markedly submucosal tumor in the rectum, which was histologically diagnosed as malignant lymphoma. The findings of computed tomography of the chest and abdomen, gallium scintigraphy, abdominal ultrasonography, and upper gastrointestinal endoscopy showed no abnormal lesions. Therefore, based on a diagnosis of localized rectal lymphoma with UC, proctocolectomy was performed. The resected specimen showed three submucosal tumors in the rectum with local nodal involvement. Histologically, the tumors were characterized by diffusely infiltrating sheets of large atypical lymphoid cells, which were negative for CD4, CD8, and CD20 but were positive for CD56, CD3, and granzyme B. The presence of Epstein-Barr virus (EBV) infection in neoplastic cells was shown by in situ hybridization for EBV-encoded early small RNA1 (EBER-1). Based on these findings, the patient was diagnosed with primary CD56+ NK/T-cell lymphoma of the rectum (stage IIE). This is the first case report of primary rectal NK/T-cell lymphoma accompanied with UC.     

Differential expression of CCR5 and CRTH2 on infiltrated cells in colonic mucosa of patients with ulcerative colitis

BACKGROUND AND AIM: The pathogenesis of ulcerative colitis (UC) is unclear, but abnormal infiltration of T lymphocytes in the colonic mucosa has been implicated in the mucosal tissue damage. The abnormal cytokine production because of a T helper (h)1/Th2 imbalance may play an important role in continuing inflammation in the colonic mucosa. In the present study, the expression of chemokine receptor 5 (CCR5) as a Th1 marker and a chemoattractant receptor-homologs molecule expressed on Th2 cells (CRTH2) were investigated in order to analyze impaired Th1/Th2 responses in the colonic mucosa of UC patients. METHODS: Tissue samples were obtained by colonic biopsies from patients with UC or colonic polyps, with informed consent. Immunohistochemical analysis was performed on periodate, lysine-paraformaldehyde-fixed serial cryostat sections using the labeled streptavidin biotin method. Monoclonal antibodies against CD4, CCR5 or CRTH2 were used as primary antibodies. The number of cells expressing CD4, CCR5 or CRTH2 per unit area was calculated by using an image analyzer. RESULTS: In the patients with UC, the numbers of CD4- and CCR5-positive cells were significantly increased in inflamed mucosa, and appeared to be correlated with the disease activity. The infiltration of CRTH2-positive cells was predominantly observed in the mildly inflamed or the margin of inflamed mucosa of UC patients. CONCLUSION: There is a possibility that Th1 responses significantly occur in colonic mucosa with severe inflammation, while Th2 responses mainly occur with mild inflammation in UC patients. The Th1/Th2 imbalance in colonic mucosa may be related to the disease progression of UC.     

Immunoglobulin G subclass distribution of human anticolon antibodies in ulcerative colitis

Abstract Immunoglobulin G (IgG) subclasses of anticolon antibodies were studied in patients with ulcerative colitis (UC) using enzyme-linked immunosorbent assay (ELISA). The concentrations of total serum IgG subclasses were also measured by ELISA. The values for total serum IgG subclasses in patients with UC were not significantly different from those in normal controls, while the ratio of IgG₁ to IgG₂ in the patients was significantly higher than that in normal controls. All four IgG subclasses of autoantibodies were demonstrated in the sera of the patients. IgG₄ anticolon antibodies were detected most frequently (15 out of 18 patients, 83%). IgG₂ was the next most prevalent (9 of 18 patients, 50%). The activity of anticolon antibodies in each subclass did not correlate with the concentration of the corresponding serum IgG subclass. Seven cell lines producing anticolon antibodies were obtained from the colonic mucosa of the patients by Epstein-Barr virus (EBV) transformation. IgG subclasses of anticolon antibodies secreted by these cell lines were also varied. IgG₄ subclass was secreted by three EBV transformed cell lines, all of which produced IgG₄ anticolon antibodies. These results suggest that all four different IgG subclasses could respond to the colon antigens and that various antigens in colonic mucosa or lumen may contribute to the induction of those autoantibodies. In addition, the prominence of IgG₄ anticolon antibodies may support the pathogenic role of this subclass in UC as in other autoimmune diseases.     

乙型病毒性肝炎的免疫动力学

乙型肝炎的发病机制主要是机体清除乙型肝炎病毒(hepatitis B virus,HBV)而引发的细胞免疫病理改变,机体对病毒的免疫应答有赖于一系列免疫活性细胞的相互作用.目前国内外主要就HBV感染控制者和感染持续者间的免疫差异原因进行研究.本文就乙型肝炎病毒感染状态下机体控制HBV感染下各相关免疫细胞间的作用机制以及...     

B1a lymphocytes in ulcerative colitis

Background and aims B1a lymphocytes (CD5+) are the major contributors of natural antibodies (Ab) implicated in the initial protection against several infections. The aim of this study was to assess the expression of these cells in the peripheral blood of ulcerative colitis (UC) patients who underwent restorative proctocolectomy (RPC) and others who were not operated on. Materials and methods The blood concentration of CD5+ B cells was analysed by three-colour flow cytometry. Blood was collected from 38 UC patients, 20 of whom had undergone RPC and compared with the results in 18 healthy controls and in 12 familial adenomatous polyposis (FAP) patients who had undergone RPC. We were interested in evaluating if there was any correlation between B1a blood cell concentration and ESR and CRP levels, clinical, endoscopic and histological activity, perinuclear anti-neutrophil cytoplasmic antibody (pANCA) and extra-intestinal symptoms. Results B1a cell blood concentration was reduced in non-operated UC patients (20.7 ± 4.6/μl) with respect to that in healthy controls (71.1 ± 18.0/μl, p < 0.05). It was also lower in UC patients with RPC (24.9 ± 1.0/μl) compared to RPC for FAP (48.2 ± 6.2, p < 0.05). B1a cell rate correlated inversely in UC patients with ESR (R = −0.41, p < 0.05) and CRP levels (R = −0.47, p = 0.01). Conclusion B1a cell concentration was reduced in the blood of patients with UC even after the diseased organ was surgically removed by proctocolectomy. As these cells play an important role in natural immunity against luminal stimuli, consistently lower levels that are found in UC patients could be responsible for the impaired immunologic response to gut antigens in this disease.     

Epstein-Barr virus infection in Richter's transformation

Chronic lymphocytic leukemia (CLL) may convert to a diffuse large cell lymphoma (Richter's syndrome) over time. In occasional cases of Richter's transformation, Epstein-Barr virus (EBV) has been identified in the lymphoma cells. To evaluate the association of EBV infection with Richter's syndrome, the biopsy specimens and clinical records of 25 patients who were seen at the Mayo Clinic between 1984–1996 were retrospectively evaluated for the presence of EBV by immunoperoxidase staining for expression of EBV latent membrane protein (LMP), as well as the expression of EBV RNA and DNA in the cells by in situ hybridization. Four of the 25 patients showed evidence of EBV in the diffuse large cell lymphoma cells—three patients with a B-cell phenotype were positive for LMP, EBV DNA, and RNA; and one patient with a T-cell phenotype had positive EBV RNA in the large cell lymphoma cells. The Richter's syndrome was treated with combination chemotherapy in 15 patients, three received radiotherapy, three were followed without further therapy after a splenectomy, two died before treatment could be started, and one patient had insufficient follow-up. One patient with evidence of EBV in large cell lymphoma cells was treated with acyclovir as initial therapy. The median survival of EBV-positive patients was three months compared with nine months for EBV-negative patients, but this difference was not statistically significant (P = 0.385). Evidence for EBV infection related to Richter's transformation was present in 16% of the patients in this study and may be associated with a poorer outcome. Primary therapy with acyclovir in one patient did not seem to be beneficial and other therapeutic modalities in patients with EBV-positive Richter's transformation need to be explored. Am J. Hematol. 60:99–104, 1999. © 1999 Wiley-Liss, Inc.     

鼻咽癌C666-1细胞中EBV miRNA的表达情况及其功能研究

目的观察鼻咽癌C666-1细胞中EB病毒(EBV)所编码的44个miRNA的表达情况(即BART、BHRT家族的表达情况)及BART-15对EBV的即刻早期基因(BZLF-1)表达的影响。方法培养C666-1细胞,取对数生长期的细胞,提取RNA,采用polyA加尾PCR法对EBV miRNA进行扩增,观察BHRF和BART家族的表达情况。将BART-15抑制剂转染C666-1细胞,转染成功后,用real-time PCR法检测BZLF-1的表达。结果在EBV编码的44个miRNA中,BHRF家族的表达普遍低于BART家族。BART-15抑制剂转染C666-1细胞后,转染率为77.0%,BART-15的表达降低了87%。抑制C666-1细胞中BART-15的表达后,BZLF-1的表达增高了2.54倍。结论鼻咽癌C666-1细胞中EBV的miRNA表达谱存在家族性差异,其中的BART-15可能直接或间接作用于EBV的BZLF-1,影响EBV的感染状态。     

Cholestatic hepatitis induced by Epstein-Barr virus infection in an adult

Liver involvement is nearly universal in healthy persons with Epstein-Barr Virus (EBV) infection-induced infectious mononucleosis. It is usually mild, undetected clinically and resolves spontaneously. Jaundice is distinctly uncommon and may reflect either more severe hepatitis or an associated hemolytic anemia. Cholestatic hepatitis due to EBV infection is infrequently reported and may pose a diagnostic quandary. We describe a patient who presented with jaundice and a markedly elevated serum alkaline phosphatase level due to serologically confirmed acute infection with EBV. Imaging studies excluded biliary obstruction. Symptoms and laboratory abnormalities resolved spontaneously. EBV infection should be included in the differential diagnosis of cholestatic hepatitis in adults.     

罕见成人慢性活动性EB病毒感染1例报告

正1病例资料患者男性,27岁,因反复发热7周,发现肝功能异常1个月于2014年8月20日入本院。患者于7周前无明显诱因出现发热,多发生于晚间(约16∶00~19∶00),体温最高为38.5℃,伴有咽痛,偶有咳嗽、咳痰,痰为白色泡沫样,伴有散在皮肤疱疹,约米粒大小,自服布洛芬后体温逐渐降至正常,不曾系     

High nitric oxide synthase activity in endothelial cells in ulcerative colitis

Endothelial nitric oxide (NO) synthase, a unique NO synthase (NOS) isoform that is expressed constitutively by the vascular endothelium both in vivo and in vitro, is believed to be essential to systemic and/or local vascular integrity. NOS expression by endothelial cells may indicate vascular activation. We successfully established a simple method for the culture of microvascular endothelial cells from a small amount of tissue and investigated ulcerative colitis (UC), in which condition vascular factors have not been studied extensively. We cultured endothelial cells from the mesenteries of surgical patients with UC and assayed NOS activity by reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry. Strong NOS activity was demonstrated in the cells from all UC patients (5/5), whereas no activity was detected in the cells from human umbilical veins and the mesenteries of colon cancer patients (0/10 and 0/5, respectively). This strong NOS activity was not diminished by incubation with a high concentration of glucocorticoid, suggesting that it was constitutive. These results indicate a close relationship of vascular activation (high NOS activity) with the pathogenesis of UC.     

A case of toxic megacolon in ulcerative colitis associated with cytomegalovirus infection

Cytomegalovirus (CMV) infection, which has been shown to complicate the course of ulcerative colitis (UC), has been implicated as a possible etiologic factor in the exacerbation of UC, especially in toxic megacolon. However, CMV infection in patients with UC accompanied by toxic megacolon has rarely been reported. Here we report a case of CMV infection of the colon accompanied by toxic megacolon occurring in UC. A 38-year-old woman had been treated with intravenous hydrocortisone, rectal steroid, and central venous alimentation for 6 weeks under the diagnosis of UC. She was transferred to Akita University Hospital because of increasing bloody diarrhea and abdominal pain. Toxic megacolon was identified by examinations on admission, and she underwent a total colectomy. Examination of the surgical specimen showed severe inflammation of the colon. Microscopically, cytomegalic inclusions were observed in and around the endothelial cells in the inflamed submucosal layer. It can be assumed that CMV infection was a secondary, opportunistic invader superimposed on UC, and that it played an important role in altering the clinical course of the patient.     

Bacterial invasion into the colonic mucosa in ulcerative colitis

Abstract This study investigated interactions between mucosal lesions and bacterial invasion in ulcerative colitis using the acridine-orange staining method. In all 16 cases of ulcerative colitis, the mucosa was found to be invaded by small rods and cocci. In five of 10 controls, bacteria were seen only adhering to the mucosa and no bacteria were detected in the five remaining cases. It is suggested that the presence of bacteria in the colonic mucosa may be a factor responsible for the persistence or aggravation of ulcerative colitis.     

LFA-1 subunit expression in ulcerative colitis patients

The adhesion molecule, lymphocyte function associated antigen 1 (LFA-1) consisting of two subunits, CD11a and CD18, mediates lymphocyte migration into tissue and cell effector functions. Previous observations showed no differences in LFA-1 expression by circulating lymphocytes between inflammatory bowel disease patients and controls. The aim of the present work was to study subsets of circulating LFA-1⁴ lymphocytes in ulcerative colitis (UC) patients versus healthy controls. Peripheral blood mononuclear cells were obtained from 16 UC patients and 10 healthy volunteers. The percentages of CD11a^lo, CD11a^hi; CD18^lo, CD18^hi T and B cells, as well as CD25 expression on these cells were studied using double staining with monoclonal antibodies and panning procedures. The percentage of CD11^hi and CD18^hi T cells was significantly decreased in quiescent UC patients as compared to active disease patients and healthy controls (P<0.05). The majority of CD25⁺ T cells were expressing CD11a and CD18 with low density. A detectable percentage, 2% (range 1–6%), of CD11a^hiCD25⁺ (but not CD18^hiCD25⁺) was found in UC patients with moderate to severe disease, but not in those with inactive UC or healthy controls. In conclusion, the percentage of CD11a^hi and CD18^hi T cells is decreased in peripheral blood of quiescent UC patients, which is probably associated with the effect of specific treatment. The percentage of CD11a^hi+ T cells is increased in peripheral blood of patients with active (moderate and severe) UC, which most likely reflects a sustained T-cell activation due to a persistent inflammatory process.The project was supported by grants from direktor Jacob Madsen's and Hustru Olga Madsen's Foundation.     

Comprehensive longitudinal analysis of hepatitis C virus (HCV)‐specific T cell responses during acute HCV infection in the presence of existing HIV‐1 infection

Summary. The aim of this study was to study the development of HCV‐specific T cell immunity during acute HCV infection in the presence of an existing HIV‐1 infection in four HIV‐1 infected men having sex with men. A comprehensive analysis of HCV‐specific T cell responses was performed at two time points during acute HCV infection using a T cell expansion assay with overlapping peptide pools spanning the entire HCV genome Three patients with (near) normal CD4+ T cell counts (range 400–970 × 10⁶/L) either resolved (n = 1) or temporary suppressed HCV RNA. In contrast, one patient with low CD4+ T cell counts (330 × 10⁶/L), had sustained high HCV RNA levels. All four patients had low HCV‐specific CD8+ T cell responses, and similar magnitudes of CD4+ T cell responses. Interestingly, individuals with resolved infection or temporary suppression of HCV‐RNA had HCV‐specific CD4+ T cell responses predominantly against nonstructural (NS) proteins. While the individual with high HCV RNA plasma concentrations had CD4+ T cell responses predominantly directed against Core. Our data show that an acute HCV infection in an HIV‐1 infected person can be suppressed in the presence of HCV‐specific CD4+ T cell response targeting non‐structural proteins. However further research is needed in a larger group of patients to evaluate the role of HIV‐1 on HCV‐specific T cell responses in relation to outcome of acute HCV infection.