Hanan Guzner-Gur

CXCL12 Is a constitutive and inflammatory chemokine in the intestinal immune system

Background: Inflammatory bowel disease (IBD) is characterized by increased lymphocytic infiltrate to the lamina propria (LP) and upregulation of inflammatory chemokines and receptors. CXCL12 is a constitutive chemokine involved in lung, brain, and joint inflammation. We hypothesized that CXCL12 and its receptor, CXCR4, would have a constitutive and inflammatory role in the gut. Methods: Intestinal epithelial cells (IECs) and T lymphocytes were isolated from intestinal mucosa of IBD and control patients undergoing bowel resection. Autologous T cells were isolated from peripheral blood (PB). CXCL12 and CXCR4 expression by IECs was assessed by polymerase chain reaction and immunohistochemistry, lymphocyte phenotype by flow cytometry, and migration by Transwells. Results: IECs expressed CXCL12 and expression was increased and more diffuse in IBD compared to normal crypts (ulcerative colitis [UC] > Crohns disease [CD], inflamed > noninflamed). CXCR4 was expressed by IECs, LP T cells (LPTs), and PB T cells (PBTs), and CXCR4+ cells were increased in IBD LP in situ. PBTs and LPTs from all patients had a high and comparable migration toward CXCL12 (P < 0.0001 and P < 0.05 vs. medium, respectively). Migration toward IBD‐IEC‐derived supernatant was significantly higher compared to normal. Antibodies against CXCR4 and CXCL12 blocked migration. Conclusions: CXCL12 is expressed by normal IECs and upregulated and differentially distributed in IBD IECs. CXCR4 is expressed by IECs and LPTs, and CXCR4+ cells are significantly increased in IBD LP. CXCL12 is chemotactic for both PBTs and LPTs. Thus, CXCL12 and CXCR4 have a constitutive and inflammatory role in the intestinal mucosa and their selective therapeutic manipulation may be considered in IBD management. (Inflamm Bowel Dis 2009;)

Involvement of CXCR4/CXCR7/CXCL12 Interactions in Inflammatory Bowel Disease

Directional movement of cells in the human body is orchestrated via chemokines. This migration was initially identified in pathological and immunological processes but quickly extended to homeostatic cell trafficking. One such chemokine is the ubiquitous CXCL12 (initially called SDF1-α) which signals via the chemokine receptors CXCR4 and CXCR7. In the last decade CXCL12 was recognized to participate not only in embryonic development and homeostatic maintenance, but also in progression of inflammation. A role for CXCL12 and its receptors CXCR4 and CXCR7 in inflammatory bowel diseases was recently shown. The current review discusses up to date knowledge of CXCL12 in inflammation, focusing on the involvement of CXCL12 and its receptors, CXCR4 and CXCR7, in inflammatory bowel diseases.

Diagnostic and prognostic significance of serum C-reactive protein levels in patients admitted to the department of medicine.

Background:Despite its apparent role as a marker of different disease processes, to date, no study has presented comprehensive comparative data regarding the distribution of serum C-reactive protein (CRP) levels in all admitted patients. We aimed to examine the distribution of serum CRP levels in internal medicine patients and to find whether initial serum CRP value had a diagnostic and prognostic significance. Methods:Serum CRP levels together with epidemiologic, clinical, and laboratory data were analyzed for 370 consecutive adult patients admitted to the department of internal medicine during a 2-month period. Results:The median CRP level on admission was 24 mg/L, with a range between 0 and 346 mg/L. Infections had significantly higher median CRP than noninfections (99 versus 11 mg/L), and bacterial infections had distinctively higher CRP (120 mg/L) compared with nonbacterial infections (32 mg/L). The highest noninfectious median CRP was recorded in inflammatory bowel disease exacerbation (107 mg/L). Moreover, serum CRP was divided into 5 ranges. Very high CRP >200 mg/L was a marker of sepsis. In contrast, low CRP range (<10 mg/L) was characteristic to cardiovascular diseases and viral infections, but included none of the patients with severe infections or sepsis. Furthermore, higher CRP was significantly associated with mortality, the need for intubation, and longer hospitalization, and had better distinguishing ability compared with erythrocyte sedimentation rate or platelets count for the comparison of major disease categories, such as bacterial infections, inflammatory and rheumatic disease, viral infections, and cardiovascular disorders. Conclusions:Initial serum CRP has an important role as a diagnostic and prognostic tool in patients admitted to internal medicine.

Human intestinal epithelial cells respond to β-glucans via Dectin-1 and Syk.

Intestinal epithelial cells (IECs) are the first to encounter luminal antigens and may be involved in intestinal immune responses. Fungi are important components of the intestinal microflora. The potential role of fungi, and in particular their cell wall component β‐glucan, in modulating human intestinal epithelial responses is still unclear. Here we examined whether human IECs are capable of recognizing and responding to β‐glucans, and the potential mechanisms of their activation. We show that human IECs freshly isolated from surgical specimens, and the human IEC lines HT‐29 and SW480, express the β‐glucan receptor Dectin‐1. The β‐glucan‐consisting glycans curdlan and zymosan stimulated IL‐8 and CCL2 secretion by IEC lines. This was significantly inhibited by a Dectin‐1 blockade using its soluble antagonist laminarin. Spleen tyrosine kinase (Syk), a signaling mediator of Dectin‐1 activation, is expressed in human IECs. β‐glucans and Candida albicans induced Syk phosphorylation, and Syk inhibition significantly decreased β‐glucan‐induced chemokine secretion from IECs. Thus, IECs may respond to β‐glucans by the secretion of pro‐inflammatory chemokines in a Dectin‐1‐ and Syk‐dependent pathway, via receptors and a signaling pathway described to date only for myeloid cells. These findings highlight the importance of fungi–IEC interactions in intestinal inflammation.

Antibodies against glycoprotein 2 are novel markers of intestinal inflammation in patients with an ileal pouch

BACKGROUND AND AIMS The Crohns disease (CD)-specific pancreatic auto-antibodies (PAB), have been recently identified to target glycoprotein 2 (GP2). Pouchitis is an inflammation of the small bowel developing in up to 60% of ulcerative colitis patients undergoing proctocolectomy and ileal pouch anal anastomosis. Occurrence of CD-specific antibodies was reported to be a predictor of pouchitis. We aimed to assess the prevalence of anti-GP2 antibodies (anti-GP2) in the serum and feces of pouch patients and to correlate them with clinical parameters. Furthermore, we examined mucosal expression of the GP2 protein in the pouch. METHODS Pouch patients were prospectively recruited and checked for clinical, endoscopic, and laboratory markers of inflammation. IgG and IgA anti-GP2 levels in serum and fecal samples were determined using ELISA. GP2 protein was assessed by immunohistochemistry. RESULTS Anti-GP2 was elevated in both serum and fecal samples of patients with inflamed compared to those with non-inflamed pouches and patients with familial-adenomatous polyposis after surgery (p<0.05, respectively). Moreover, patients with CD-like complications exhibited significantly higher anti-GP2 titers than those without CD-like complications (p≤0.01). High levels of anti-GP2 correlated with more frequent bowel movements per day and with the presence of at least one anti-glycan antibody (p≤0.05). GP2 itself was more abundant in the mucosa of patients with chronic pouchitis. CONCLUSIONS Anti-GP2 exists in the serum and feces of pouch patients and correlates with pouch inflammation, and presence of other serological markers. Thus, anti-GP2 may contribute to better stratification of pouchitis, more-so when the inflammation exhibits CD-like complications.

Prognostic Significance of Serum Uric Acid in Patients Admitted to the Department of Medicine

Background:Hyperuricemia has been linked to proatherogenic processes, including increased oxidative stress and leukocyte activation, and was shown to predict adverse prognosis in heart failure, renal failure, and hypertension. Recently, serum uric acid (SUA) was shown to be an independent predictor of long-term mortality in patients with cardiovascular diseases. However, the prognostic significance of SUA for the short-term outcome of admitted medical patients is unknown. Methods:Initial SUA, together with epidemiological, clinical, and laboratory data, was analyzed for a prospective cohort of 650 consecutive adult patients admitted to the department of internal medicine during a 3-month period. Results:The mean, median, and range of SUA at admission were 6.1 ± 2.7, 5.6, and 1.2 to 24 mg/dL, respectively. Increased SUA was significantly correlated with age, gender, comorbidities (coronary heart disease, heart failure, hypertension, diabetes, renal failure, and gout), use of diuretics, and current admission for cardiovascular diseases but not with current diagnosis of infection, malignancy, or inflammatory diseases, nor with C-reactive protein. However, SUA significantly correlated with mortality (7.7 versus 6 mg/L, P < 0.025) and was an independent predictor of mortality in a multivariate regression analysis (odds ratio: 1.11; confidence interval: 1.003-1.218; P = 0.04), with a significant difference in mortality between normal SUA (<6 mg/dL) with 5% mortality and high SUA (>12 mg/dL) with 27% mortality. Conclusions:Initial SUA is an independent predictor of mortality in admitted medical patients. Whether significant asymptomatic hyperuricemia should be treated remains to be determined in further studies.

Reciprocal regulation of CXCR4 and CXCR7 in intestinal mucosal homeostasis and inflammatory bowel disease

IBDs are characterized by increased influx of immune cells to the mucosa of genetically susceptible persons. Cellular migration to injury sites is mediated by chemokines. CXCL12 is a ubiquitous, constitutive chemokine that participates in stem cell proliferation and migration and mediates T lymphocyte migration to inflamed tissues. We have recently reported that CXCL12 and its receptor, CXCR4, are expressed in normal and more prominently, inflamed human intestinal mucosa. However, the interactions and roles of CXCL12 and its receptors, CXCR4 and the recently discovered CXCR7, in intestinal inflammation have not been defined. In the present study, we further dissected the effects of CXCL12 on lymphocytes in intestinal homeostasis and inflammation and delineated the interplay between CXCL12 and its receptors CXCR4 and CXCR7. To that end, fresh mononuclear cells were isolated from mucosa and PB of healthy or IBD patients. Phenotypical and functional assays were conducted using flow cytometry, Transwell migration chambers, and ELISA. The data show that CXCL12‐mediated migration of T cells is CXCR4‐ but not CXCR7‐dependent. T cell activation reciprocally regulates CXCR7 and CXCR4 expression and migratory capacity. IBD PBTs expressed more CXCR7 than normal PBTs. Finally, T cells attracted by CXCL12 are mostly of a memory phenotype. In conclusion, the present study suggests that the interplay between CXCL12 and its receptors affects homeostasis and inflammation in the intestinal mucosa.

Diagnostic and Prognostic Value of Thrombocytosis in Admitted Medical Patients

Introduction:Whether secondary thrombocytosis is a distinguishing clinical biomarker of various diseases, and whether it is an independent predictor of short-term outcome of admitted medical patients is unknown and has never been examined. Methods:A cohort of all 138 patients with secondary thrombocytosis (platelets count ≥ 5 x 105/&mgr;L) admitted to the department of medicine during the last 2 years was analyzed. Epidemiological and clinical data, and the final diagnosis and outcome were recorded and compared with a cohort of 684 consecutive admitted patients without thrombocytosis. Results:Thrombocytosis was not a non-specific marker of inflammation, because uncomplicated infections and most admission causes were not associated with thrombocytosis, except for inflammatory rheumatic diseases (6% versus 1%), along with anemia (9.4% versus 2.5%) and tumor comorbidity (25% versus 14%). In contrast, thrombocytosis was a distinguishing biomarker for severe pyogenic infections, especially empyema (5% vs. 0%), any abscesses (14% versus 3%), and soft tissue infections (7% versus 3%). Moreover, the thrombocytosis group had significantly more admission days, infections (45% versus 33%), sepsis (21% versus 6%), in-hospital major complications (15% versus 3%) and mortality (19% versus 5%). Finally, thrombocytosis was found to be an independent predictor of mortality, in a multivariate regression analysis. Conclusions:Thrombocytosis is not a simple marker of inflammation. Its presence warrants thorough investigation for the presence of severe underlying disease, mostly complicated pyogenic infections, inflammatory rheumatic diseases and malignancy. Moreover, thrombocytosis is a marker for major complications and is an independent predictor of mortality in admitted medical patients.

Eplerenone for chronic central serous chorioretinopathy–a randomized controlled prospective study

To evaluate the efficacy and safety of eplerenone for chronic nonresolving central serous chorioretinopathy (CSC).

Differential stimulation of peripheral blood mononuclear cells in Crohn's disease by fungal glycans

Crohns disease (CD) is characterized by loss of tolerance to intestinal microorganisms. This is reflected by serological responses to fungal glycans such as mannan and β‐glucans. Fungal glycans have various effects on immune cells. However, the evidence for their effects in CD is vague. This study aimed to assess the effects of fungal cell wall glycans on human peripheral blood mononuclear cells (PBMCs) from CD and control patients.