Correlation of DEFA1 gene copy number variation with intestinal involvement in Behcet's disease

Copy number variation has been associated with various autoimmune diseases. We investigated the copy number (CN) of the DEFA1 gene encoding α-defensin-1 in samples from Korean individuals with Behcet''s disease (BD) compared to healthy controls (HC). We recruited 55 BD patients and 35 HC. A duplex Taqman® real-time PCR assay was used to assess CN. Most samples (31.1%) had a CN of 5 with a mean CN of 5.4 ± 0.2. There was no significant difference in the CN of the DEFA1 gene between BD patients and HC. A high DEFA1 gene CN was significantly associated with intestinal involvement in BD patients. Variable DEFA1 gene CNs were observed in both BD patients and HC and a high DEFA1 gene CN may be associated with susceptibility to intestinal involvement in BD.     

Serum Level of Interleukin-33 and Soluble ST2 and Their Association with Disease Activity in Patients with Behcet's Disease

Interleukin (IL)-33 is an important mediator of innate immunity. Behcet''s disease (BD) is an autoinflammatory disorder characterized by hyperactivity of the innate immune response. We measured serum levels of IL-33 and its receptor soluble ST2 (sST2) in patients with BD to investigate their association with disease activity. Serum levels of both IL-33 and sST2 were higher in patients with BD compared with those in normal controls (IL-33: 594.48±175.04 pg/mL in BD and 224.23±56.64 pg/mL in normal controls [P=0.048], sST2: 99.01±15.92 pg/mL in BD and 23.56±3.25 pg/mL in normal controls [P<0.001]). IL-33 and sST2 expression in skin tissue, as shown by immunohistochemistry, was higher in patients with BD compared with that in the normal controls. Serum sST2 level correlated significantly with the BD currently active form (BDCAF), Iranian BD dynamic activity measure (IBDDAM), erythrocyte sedimentation rate and C-reactive protein. Multiple linear regression showed that serum sST2 was an independent factor associated with IBBDAM (regression coefficient, 0.374; P=0.004), and BDCAF (regression coefficient, 0.236; P=0.047). These results demonstrate that IL-33 and sST2 are highly expressed in patients with BD and that serum sST2 is an independent factor associated with IBDDAM and BDCAF, suggesting a potential role for sST2 as a surrogate marker of disease activity in patients with BD.     

Metastatic carcinoma of the colon similar to Crohn's disease: a case report

A 68-year-old Japanese man with a history of linitis plastica carcinoma of the stomach and subsequent gastrectomy 8 years previously presented with lower abdominal pain. Radiological and endoscopic examinations showed multiple submucosal nodular lesions similar to Crohn's disease in the ileocecal area. A firm diagnosis could not be made after initial multiple biopsies. Finally, a submucosal biopsy revealed adenocarcinoma. The ileocecal lesion was diagnosed as a recurrence because of the histological findings, which included mucosal preservation, a similarity with the histologic type of stomach carcinoma, and atypical immunoreactivity for primary colon carcinoma; the lesion was negative for both cytokeratin 7 and cytokeratin 20. In cases where metastatic carcinoma of the colon is suspected, we recommend early consideration of a submucosal biopsy.     

Cytokines and Behcet's disease

Behcet's Disease (BD) is a systemic vasculitis of unknown etiology. Increasing studies find that a sophisticated interlacing cytokine network is closely implicated in the onset, evolution and even organ damages of the disease. Cytokines involved can be categorized as Th1 type, Th2 type, Th17 type, chemokines and other proinflammatory cytokines, etc. The vicious cycle of cytokine network plays a substantial role in the disease pathogenesis and even in organ lesions, and might be disorganized by blocking one of the key links of the cytokines, which in turn may provide essential clues to outlook the target therapy regimen of cytokine agents in BD. There have been a number of case reports of the positive efficacies of cytokine (and cytokine blocker) agents including Infiximab (Human murine chimeric Anti-TNF α monoclonal antibody), Anakinra (recombinant, non-glycosylated human IL1 receptor antagonist) etc in BD. IFN-α had been used clinically in treating BD with uveitis with beneficial efficacy ever since the 1980s. The studies to date suggested that IL6, IP10 are involved in BD with nervous system lesions, IL17, IL18 are relevant to the superimposed uveitis in patients with BD. Some cytokines i.e. IL8, RANTES, MIP-1α are associated with the disease activity, whereas others are exemplified by that of IL10, whose level shows negative relevance to the disease activity, might be potentially cytokine of protecting effect. According to the related genetic study, the SNPs of numerous cytokines including IL1, TNFα, IFNγ, IL12, and IL18 are pertinent to BD. The recent GWAS (Genome Wide Association Studies) demonstrated that SNPs in the IL10 and IL23R-IL12RB2 region are associated with the disease. Most studies nowadays are confined within the cytokines in the peripheral blood levels, owing to the potentially significant roles of certain cytokines in local lesions. It warrants further in-depth study to address this issue. Moreover, it deserves multi-centre study considering the unique geographical "silk road" display picture of the disease.     

Differences between tissue-associated intestinal microfloras of patients with Crohn's disease and ulcerative colitis

A leading hypothesis for the role of bacteria in inflammatory bowel diseases is that an imbalance in normal gut flora is a prerequisite for inflammation. Testing this hypothesis requires comparisons between the microbiota compositions of ulcerative colitis and Crohn's disease patients and those of healthy individuals. In this study, we obtained biopsy samples from patients with Crohn's disease and ulcerative colitis and from healthy controls. Bacterial DNA was extracted from the tissue samples, amplified using universal bacterial 16S rRNA gene primers, and cloned into a plasmid vector. Insert-containing colonies were picked for high-throughput sequencing, and sequence data were analyzed, yielding species-level phylogenetic data. The clone libraries yielded 3,305 sequenced clones, representing 151 operational taxonomical units. There was no significant difference between floras from inflamed and healthy tissues from within the same individual. Proteobacteria were significantly (P = 0.0007) increased in Crohn's disease patients, as were Bacteroidetes (P < 0.0001), while Clostridia were decreased in that group (P < 0.0001) in comparison with the healthy and ulcerative colitis groups, which displayed no significant differences. Thus, the bacterial flora composition of Crohn's patients appears to be significantly altered from that of healthy controls, unlike that of ulcerative colitis patients. Imbalance in flora in Crohn's disease is probably not sufficient to cause inflammation, since microbiotas from inflamed and noninflamed tissues were of similar compositions within the same individual.     

Subpopulations of Regulatory T Cells in Rheumatoid Arthritis, Systemic Lupus Erythematosus, and Behcet's Disease

Recently, subpopulations of regulatory T (Treg) cells, resting Treg (rTreg) and activated Treg (aTreg), have been discovered. The authors investigated the relationship between the change of Treg, aTreg and rTreg and autoimmune diseases. Treg cells and those subpopulations were analyzed by using the human regulatory T cell staining kit and CD45RA surface marker for 42 rheumatoid arthritis (RA), 13 systemic lupus sclerosis (SLE), 7 Behcet's disease (BD), and 22 healthy controls. The proportion of Treg cells was significantly lower in RA (3.8% ± 1.0%) (P < 0.001) and BD (3.3% ± 0.5%) (P < 0.01) compared to healthy controls (5.0% ± 1.3%). The proportion of aTreg cells was also significantly lower in RA (0.4% ± 0.2%) (P = 0.008) and BD (0.3% ± 0.1%) (P = 0.013) compared to healthy controls (0.6% ± 0.3%). The rTreg cells showed no significant differences. The ratio of aTreg to rTreg was lower in RA patients (0.4% ± 0.2%) than that in healthy controls (0.7% ± 0.4%) (P = 0.002). This study suggests that the decrement of aTreg not rTreg cells contributes the decrement of total Treg cells in peripheral blood of RA and BD autoimmune diseases. Detailed analysis of Treg subpopulations would be more informative than total Treg cells in investigating mechanism of autoimmune disease.     

Dura mater graft-associated Creutzfeldt-Jakob disease: the first case in Korea

Since 1987, dura mater graft-associated iatrogenic Creutzfeldt-Jakob disease (dCJD) has been reported in many countries. We report the first case of dCJD in Korea. A 54-yr-old woman, who underwent resection of the meningioma in the left frontal region and received a dura mater graft 23 yr ago presented with dysesthesia followed by psychiatric symptoms and ataxia. Her neurological symptoms rapidly progressed to such an extent that she exhibited myoclonus, dementia, and pyramidal and extrapyramidal signs within 8 weeks. The 14-3-3 protein was detected in her cerebrospinal fluid; however, an electroencephalogram did not reveal characteristic positive sharp wave complexes. Diffusion-weighted magnetic resonance images, obtained serially over 64 days, revealed the rapid progression of areas of high signal intensity in the caudate nucleus and cingulate gyrus to widespread areas of high signal intensity in the cortex and basal ganglia. Pathological examination of brain biopsy specimens confirmed the presence of spongiform changes and deposition of prion protein in the neurons and neuropils.     

Associations of distinct variants of the intestinal mucin gene MUC3A with ulcerative colitis and Crohn's disease

Ulcerative colitis (UC) and Crohn's disease (CD), the major forms of inflammatory bowel diseases (IBDs), are multifactorial disorders of unknown etiology. We reported a possible association of rare variable number of tandem repeat (VNTR) alleles of the "MUC3" gene with a susceptibility to UC. However, an entire structure of "MUC3" is still unknown because the long stretches of tandem repeats in this "gene" make its cloning extraordinarily difficult. In this study, we report evidence that "MUC3" consists of two genes, MUC3A and MUC3B, both of which encode membrane-bound mucins with two epidermal growth factor-like motifs, and we describe the complete 3′-terminal structures of these two genes. We have also analyzed the single nucleotide polymorphisms (SNPs) in the exonic sequences of the 3′ portions of these two genes to investigate whether sequence variations in these regions can cause person-to-person differences in the susceptibility to IBDs, and report here that non-synonymous SNPs of MUC3A, involving a tyrosine residue with a proposed role in cell signaling, may confer genetic predisposition to CD (P = 0.0132). Our findings suggest that variants of MUC3A may be involved in the occurrence of UC and CD in distinct manners. Received: September 28, 2000 / Accepted: October 13, 2000     

A rare aspect of Crohn's disease: Pulmonary involvement in a child

Crohn''s disease (CD), known as the disease of gastrointestinal system, is a granulamatous systemic disorder with extraintestinal manifestations including the respiratory system. The resemblance in the embriological origins and the immunities of both organ systems'' mucosae, also the circulating immune complexes and the autoantibodies are accepted as contributing factors. The shift of inflammation may become prominent when the colon is removed after colectomy and independent of the bowel disease activity; pulmonary involvement may be exarbecated. In the pediatric population, CD associated pulmonary involvement is very rare, mainly in the form of subclinical alterations and the data are limited mostly to case reports. Therefore, it is possibly overlooked since the diagnosis relies on suspicion. We represent a 5-year-old CD patient with previous bronchiolitis episodes that might have resulted from CD-associated pulmonary involvement; whom later developed severe pneumonia resulting in acute respiratory distress syndrome and bronchiectasia following a colectomy operation.     

Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn's disease

Chronic inflammation in inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) may be attributed partly to increased secretion of inflammatory cytokines. The aim of this study was to investigate simultaneously the spontaneous release patterns of tumor necrosis factor-alpha (TNF-), interleukin-1-beta (IL-1), and interleukin-6 (IL-6) by organ cultures of inflamed mucosa from IBD patients. Organ cultures of involved IBD mucosa spontaneously produced increased amounts of TNF-, IL-1, and IL-6 compared to normal mucosa. The patterns of cytokine release between Crohn's disease and ulcerative colitis organ cultures were not significantly different. Increased inflammatory cytokine production by lamina propria mononuclear cells (LPMCs) and mucosa treated with EDTA suggests that these cytokines originate mainly from LPMCs. These results confirm the role of inflammatory cytokines in IBD and shed a new light on the role of TNF- in IBD.     

A case of Behcet's disease in a patient with albinism.

A 22-year old female suffering from recurrent oral ulcers, genital ulcers, erythema nodosum, and folliculitis, was diagnosed as having Behcet's disease (BD). She has also hypopigmentation of skin and hair, and optic changes associated with albinism including hypopigmentation of the retina, nystagmus, strabismus, and reduced visual acuity. In this report, we discuss the possibility of precipitating factor in BD that the hypersensitivity, mental stress, and drug resistance which is caused by albinism.     

Serological markers to differentiate between ulcerative colitis and Crohn's disease.

AIM--To assess prospectively the value of three serological tests for differentiating between ulcerative colitis and Crohn's disease, used either alone or combined. METHODS--Coded serum samples from 63 patients with ulcerative colitis and 67 patients with Crohn's disease were analysed. Detection assays for the presence of perinuclear antineutrophil cytoplasmic antibodies (pANCA), serum agglutinating antibodies to anaerobic coccoid rods, and specific IgG antibodies against a Kd-45/48 immunological crossreactive mycobacterial antigen complex (ImCrAC) were studied. Sensitivity, specificity, pre- and post-test probabilities, likelihood ratios, and predictive values of each of these serological tests were determined. RESULTS--The sensitivity and specificity of the pANCA test for the diagnosis of ulcerative colitis were 61 and 79%, respectively. The serum agglutination test for anaerobic coccoid rods had a sensitivity of 42% and a specificity of 89% for a diagnosis of Crohn's disease. The sensitivity of specific IgG antibodies against Kd-45/48 ImCrAC in diagnosing Crohn's disease was 70% and specificity 60%. Although 100% specificity was achieved by combining all three tests in a small group of patients with Crohn's disease (n = 20), combining two or more tests had no additive clinical value. No correlation was found between the presence of any one of these antibodies and disease activity, duration, or localisation of disease. Surgery or medical treatment did not influence the presence of antibodies or the antibody titre. CONCLUSIONS--The value of these tests in the differential diagnosis between ulcerative colitis and Crohn's disease is limited, but the high predictive values and specificities of different tests for both diseases suggest that these tests may be of help in studying disease heterogeneity and in defining different subgroups of patients with different pathogenesis.     

Ultrastructure of intestinal lymphatics in Crohn's disease

The fine structure of intestinal lymphatics in four patients with Crohn's disease and in two control subjects is described. Although obstructed lacteals are considered to be of major importance in the pathogenesis of regional enteritis, no detailed electron microscopic studies of lymphatic capillaries in this disease could be found. Even though both open and closed intercellular junctions were observed in the normal intestinal lymphatics, only closed junctions were noted in the mucosal and submucosal lymphatic capillaries in patients with regional enteritis. A heavy accumulation of protein rich lymph at the abluminal surface of lymphatic capillaries was consistently seen. None of the control lymphatics showed a similar alteration. The described fine structural changes indicate a decreased permeability of the lymphatic wall. Reduced lymphatic permeability could be a contributing element in the development of submucosal edema, a major microscopic feature of Crohn's disease.     

A case of Kawasaki disease with colonic edema

Kawasaki disease (KD) is recognized as a systemic vasculitis affecting multi-organ with inflammatory changes. The commonest and most serious complication of KD is coronary artery aneurysm, but KD may cause other organic complications beside cardiac problems. Gastrointestinal tract also present complications of KD in which, for example, hepatic dysfunction, pancreatitis, intussusception, colonic obstruction, intestinal pseudo-obstruction, and bowel edema are included. Among them, colonal wall edema is left unknown in the incidence, and it has been reported even if rare. In this report, we describe a case of KD with colonal wall edema, occurred in 5-yr-old boy who complained of severe abdominal pain and vomiting.     

Associations between TNFSF15 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: A meta-analysis

Abstract

Aims: Several polymorphisms have been identified in TNFSF15, while their roles in the incidence of ulcerative colitis (UC) and Crohn's disease (CD) are conflicting. This meta-analysis was aimed to clarify the impact of these polymorphisms on UC and CD risk. Method: Databases were searched until 31 January 2014 for eligible studies on TNFSF15 polymorphisms. Data were extracted, and pooled odd ratios (ORs) as well as 95% confidence intervals (95% CIs) were calculated. Results: Fifteen studies with 8903 CD patients, 4687 UC patients and 12?606 controls were included. Except for rs4263839 polymorphism, significant associations were found between the rest six TNFSF15 polymorphisms and CD risk (rs3810936: OR?=?2.10, 95% CI, 1.47–3.00; rs6478108: OR?=?2.19, 95% CI, 1.53–3.13; rs4979462: OR?=?1.89, 95% CI, 1.42–2.52; rs6478109: OR?=?2.00, 95% CI, 1.39–2.88; rs7848647: OR?=?1.54, 95% CI, 1.15–2.06; rs7869487: OR?=?1.51, 95% CI, 1.06–2.17). And we found rs3810936, rs6478108 and rs6478109 polymorphism were significantly associated with UC risk (rs3810936: OR?=?1.19, 95% CI, 1.06–1.34; rs6478108: OR?=?1.16, 95% CI, 1.06–1.26; rs6478109: OR?=?1.16, 95% CI, 1.03–1.32). According to the subgroup analysis by ethnicity, except for rs4263839 in Caucasian and rs4979462 in Asian, all the rest investigated TNFSF15 polymorphisms were associated with CD risk and rs3810936 and rs7848647 polymorphism in Asian as well as rs6478108 polymorphism in Caucasian were associated with UC risk. Conclusion: This meta-analysis indicated that most of the seven TNFSF15 polymorphisms (except for rs4263839) were risk factors contributed to CD and UC susceptibility. The differences in ethnicity did not influence the risk obviously.     

An autopsy case of intestinal Behcet's disease with sacroiliitis accompanied by myelodysplastic syndrome with trisomy 8. ]

Here we described an autopsy case of intestinal Behcet's disease with sacroiliitis associated with myelodysplastic syndrome (RAEB-t, 8+). Over twenty cases of Behcet's disease associated with myelodysplastic syndrome have been reported in preliterature so far. The majority of them are incomplete type of Behcet's disease having intestinal ulceration. Of those, trisomy 8 is the most common chromosomal abnormality. We reviewed similar cases reported and investigated the association of intestinal Behcet's disease with trisomy 8. The association of sacroiliitis with Behcet's disease is also studied.     

Comparison of Behcet's disease and recurrent aphthous ulcer according to characteristics of gastrointestinal symptoms

Behcet's disease (BD) is a multisystemic chronic inflammatory disease. It is characterized by recurrent oral and genital ulcers, uveitis, skin lesions and other manifestations, including neurologic, vascular, joint, and gastrointestinal ulcers of variable severity. Recurrent aphthous ulcer (RAU) represents a very common, but poorly understood, mucosal disorder. If a patient of RAU without any other typical symptoms of BD has gastrointestinal symptoms, it is difficult to distinguish this RAU from true BD with gastrointestinal involvement. Because pathognomonic clinical features and tools are absent, the differential diagnosis of these two diseases relies on the characteristic clinical features and the judgement of an experienced physician. Sixty-five out of a total 960 RAU patients and forty-four of 556 BD patients with gastrointestinal symptoms between January 1996 and December 2003 participated in this study. All were evaluated with esophagogastroduodenoscopy and colonoscopy. Clinical, endoscopic and histopathologic findings were analyzed and ELISA tests were conducted to detect serum levels of ASCA and pANCA. No significant difference was found between the two groups. Differential diagnosis between RAU with gastrointestinal symptoms and BD with gastrointestinal involvement requires further prospective, large-scale study.     

Endoscopic and bioptic study of the upper gastrointestinal tract in Crohn's disease patients

In the present study, virtually all of 225 patients suffering from Crohn's disease of the lower gastrointestinal tract (small and/or large bowel) were subjected to endoscopic examination of the upper gastrointestinal tract (esophagus, stomach, duodenum); while histologic examination of the upper gastrointestinal tract was performed in a portion of the patients (54 initial esophageal, 221 initial gastric and 210 initial duodenal examinations). Statistical evaluation of the findings from the upper gastrointestinal tract revealed that: Endoscopic lesions were observed in the esophagus of 15%, the stomach of 49%, and the duodenum of 34% of the 225 Crohn's disease patients. Of the 54 patients from which esophageal biopsies were taken, 31 (57%) revealed histopathologic alterations. Of the 221 patients from which gastric biopsies were obtained, 60% revealed histopathologic alterations; the rate was 53% in the 210 patients from which duodenal biopsies were taken. Calculated from the present data, noncaseating granulomas, i.e., Crohn's disease, were present only in the stomach of 29.4% of the patients, only in the duodenum in 3.4% of patients, and in both the stomach and duodenum in 4.9% of patients. Gastric granulomas were confined to the region of the stomach body and fundus in 3.4% of the patients from which gastric biopsies were obtained and to the antrum in 15.6% of the respective patients. Both gastric regions were involved in 8.3% of the respective patients. The incidence of gastric granulomas was significantly increased in young patients, patients with enterocolic manifestations of Crohn's disease, and those with brief duration of disease. Patient sex or previous drug therapy had no effect on the incidence of granulomas. The most frequent endoscopic findings in the stomach of patients with Crohn's disease were mucosal edema, mucosal redness, and acute or chronic erosions. Only chronic erosions were of significant predictive value for the presence of granulomas, i.e., diagnosis of Crohn's disease. The most frequent endoscopic lesion in the duodenum was mucosal redness, followed by mucosal edema and aphthous lesions. Ulcers, stenosis, and mucosal redness had significant predictive values for the presence of granulomas.