Profoundly Expanded T-cell Clones in the Inflamed and Uninflamed Intestine of Patients With Crohn's Disease.

BACKGROUND AND AIM: T cells are key players in the chronic intestinal inflammation that characterises Crohn's disease. Here we aim to map the intestinal T-cell receptor [TCR] repertoire in patients with Crohn's disease, using next-generation sequencing technology to examine the clonality of the T-cell compartment in relation to mucosal inflammation and response to therapy. METHODS: Biopsies were taken from endoscopically inflamed and uninflamed ileum and colon of 19 patients with Crohn's disease. From this cohort, additional biopsies were taken after 8 weeks of remission induction therapy from eight responders and eight non-responders. Control biopsies from 11 patients without inflammatory bowel disease [IBD] were included. The TCRß repertoire was analysed by next-generation sequencing of biopsy RNA. RESULTS: Both in Crohn's disease patients and in non-IBD controls, a broad intestinal T-cell repertoire was found, with a considerable part consisting of expanded clones. Clones in Crohn's disease were more expanded [p = 0.008], with the largest clones representing up to as much as 58% of the total repertoire. There was a substantial overlap of the repertoire between inflamed and uninflamed tissue and between ileum and colon. Following therapy, responders showed larger changes in the T-cell repertoire than non-responders, although a considerable part of the repertoire remained unchanged in both groups. CONCLUSIONS: The intestinal T-cell repertoire distribution in Crohn's disease is different from that in the normal gut, containing profoundly expanded T-cell clones that take up a large part of the repertoire. The T-cell repertoire is fairly stable regardless of endoscopic mucosal inflammation or response to therapy.

miR-511-3p, embedded in the macrophage mannose receptor gene, contributes to intestinal inflammation.

MiR-511-3p is embedded in intron 5 of the CD206/MRC1 gene Mrc1, expressed by macrophage and dendritic cell populations. CD206 and miR-511-3p expression are co-regulated, and their contribution to intestinal inflammation is unclear. We investigated their roles in intestinal inflammation in both mouse and human systems. Colons of CD206-deficient mice displayed normal numbers of monocytes, macrophage, and dendritic cells. In experimental colitis, CD206-deficient mice had attenuated inflammation compared with wild-type (WT) mice. However, neither a CD206 antagonist nor a blocking antibody reproduced this phenotype, suggesting that CD206 was not involved in this response. Macrophages isolated from CD206-deficient mice had reduced levels of miR-511-3p and Tlr4 compared with WT, which was associated with reduced pro-inflammatory cytokine production upon lipopolysaccharides (LPS) and fecal supernatant stimulation. Macrophages overexpressing miR-511-3p showed 50% increase of Tlr4 mRNA, whereas knockdown of miR-511-3p reduced Tlr4 mRNA levels by 60%, compared with scrambled microRNA (miRNA)-transduced cells. Response to anti-tumor necrosis factor (TNF) treatment has been associated with elevated macrophage CD206 expression in the mucosa. However, in colon biopsies no statistically significant change in miR-511-3p was detected. Taken together, our data show that miR-511-3p controls macrophage-mediated microbial responses and is involved in the regulation of intestinal inflammation.

Innate lymphoid cells in inflammatory bowel diseases.

It is generally believed that inflammatory bowel diseases (IBD) are caused by an aberrant immune response to environmental triggers in genetically susceptible individuals. The exact contribution of the adaptive and innate immune system has not been elucidated. However, recent advances in treatments targeting key inflammatory mediators such as tumour necrosis factor highlight the crucial role of the innate immune system in IBD. Innate lymphoid cells (ILCs) have recently been identified to play an important role in immune mediated inflammatory diseases. In this review we recapitulate the current knowledge on ILCs in IBD.

[Gender differences in career motivation: female doctors' ambitions benefit from family friendly work environment]. / Genderverschillen in carrièremotivatie: ambities van vrouwelijke artsen vooral gebaat bij carrièreondersteuning.

OBJECTIVE: To determine gender differences in career motivation and the effect of a family friendly work environment. DESIGN: Cross-sectional pilot investigation. METHOD: A web survey among male and female doctors (n = 107; 72 women and 35 men) in different specialties, including surgical, internal medicine and general practitioners, was used to gather information on different dimensions of career motivation and perceptions of the family friendliness of the work environment. Differences were analysed by means of t-tests and regression analyses. RESULTS: Male doctors had higher scores on career identity and on career planning than female doctors. However, male and female doctors did not differ in their willingness to achieve top positions. Female doctors were more determined concerning their career goals than their male counterparts. The family friendliness of the work environment had an overall positive effect on career motivation for both male and female doctors. However, a family friendly work environment had a negative effect on the career identity of male doctors. For male and female doctors alike, support to achieve career goals and elimination of career barriers lead to increased career identity. CONCLUSION: Male and female doctors differed in certain dimensions of career motivation. Offering support for career goals and taking away career barriers leads to a higher career motivation than offering a family friendly work environment.

Frequency and correlates of childhood sexual and physical abuse histories in adult female borderline inpatients.

Suspected complex partial seizure disorder, eating disorders, and drug abuse disorders were overrepresented among the 40% (N = 16) of female borderline inpatients who reported a history of sexual abuse. Early family disruption, more frequent hospital admissions, and concomitant antisocial personality disorder were overrepresented among those who reported past physical abuse.

Intent and lethality of suicide attempts among female borderline inpatients.

Data relevant to variations in self-destructive behavior are reported for 40 female borderline inpatients. These data were assessed in relation to measures of the patients' suicidal intent, the lethality of their attempts, and their empirically derived suicide risk. Variation in the seriousness of suicide attempts was accounted for primarily by age, number of suicide attempts, presence of an eating disorder, psychotic features, and family history variables, with generalized anxiety disorder as a mitigating factor. In addition to age and number of attempts, concomitant histrionic and antisocial features were differentially predictive of the empirically derived risk of suicide.