Antigen-driven PD-1+ TOX+ BHLHE40+ and PD-1+ TOX+ EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ.

T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro. Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA). However, the functions of T lymphocytes in established disease remain elusive. Here we dissect the transcriptional and the clonal heterogeneity of synovial T lymphocytes in JIA patients by single-cell RNA sequencing combined with T cell receptor profiling on the same cells. We identify clonally expanded subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD-1+ TOX+ EOMES+ population of CD4+ T lymphocytes expressed immune regulatory genes and chemoattractant genes for myeloid cells. A PD-1+ TOX+ BHLHE40+ population of CD4+ , and a mirror population of CD8+ T lymphocytes expressed genes driving inflammation, and genes supporting B lymphocyte activation in situ. This analysis points out that multiple types of T lymphocytes have to be targeted for therapeutic regeneration of tolerance in arthritis.

Is the age at surgery in Crohn's disease clinically relevant? Differences and peculiarities: a wide single centre experience after long-term follow-up.

PURPOSE: The Montreal classification for Crohn's disease includes "age at diagnosis" as a parameter but few is reported about the age at surgery. The aim of this study is to evaluate the short- and long-term differences in the postoperative surgical outcome and disease behaviour, according to the age at the first surgery. METHODS: Patients consecutively operated for abdominal Crohn's disease during the period 1986-2012 at our centre were systematically analysed according to their age at first surgery. In our retrospective cohort, the age at first surgery ranged from 13 to 83 years, and patients were arbitrarily divided into four groups: ≤ 19 (G1), 20-39 (G2), 40-59 (G3) and ≥ 60 (G4) years old. RESULTS: In total, 1051 patients were included with a median follow-up time of 232 months. The four groups exhibited statistically significant differences in age at diagnosis, smoke habit, time between diagnosis and surgery, disease location and behaviour, history of perianal fistula or abscess, severe malnutrition requiring total parental nutrition before surgery, type of surgery, total length of resected bowel, median duration of hospitalization, incidence of abdominal recurrences and number of surgical recurrences. G1 displays an inverse linear trend with time in the severity of clinical characteristics when compared to G4 groups. On the contrary, the incidence of short-term complications, types of abdominal recurrence and presence of concomitant perianal disease did not vary among groups. In addition, at multivariate analysis, the age at surgery and the disease location were the only independent risk factors for abdominal surgical recurrence. CONCLUSION: Despite first surgery is extremely more frequent between 20 and 59 years, patients from G1 and G4 groups showed clinical differences and peculiarities when compared to the other age groups. The most indolent CD behaviour and occurrence of surgical recurrence was observed in patients having their first abdominal surgery in the elderly, while patients operated before the age of 19 experienced a more aggressive disease course.

Long-Term Follow-Up, Association between CARD15/NOD2 Polymorphisms, and Clinical Disease Behavior in Crohn's Disease Surgical Patients.

BACKGROUND: CARD15/NOD2 is the most significant genetic susceptibility in Crohn's disease (CD) even though a relationship between the different polymorphisms and clinical phenotype has not been described yet. The study is aimed at analyzing, in a group of CD patients undergoing surgery, the relationship between CARD15/NOD2 polymorphisms and the clinical CD behavior after a long-term follow-up, in order to identify potential clinical biomarkers of prognosis. METHODS: 191 surgical CD patients were prospectively characterized both for the main single nucleotide polymorphisms of CARD15/NOD2 and for many other environmental risk factors connected with the severe disease form. After a mean follow-up of 7.3 years, the correlations between clinical features and CD natural history were analyzed. RESULTS: CARD15/NOD2 polymorphisms were significantly associated with younger age at diagnosis compared to wild type cases (p < 0.05). Moreover, patients carrying a 3020insC polymorphism presented a larger Δ between diagnosis and surgery (p = 0.0344). Patients carrying an hz881 and a 3020insC exhibited, respectively, a lower rate of responsiveness to azathioprine (p = 0.012), but no difference was found in biologic therapy. Finally, the risk of surgical recurrence was significantly associated, respectively, to age at diagnosis, to familial CD history, to diagnostic delay, to arthritis, and to the presence of perioperative complications. CONCLUSIONS: 3020insC CARD15 polymorphism is associated with an earlier CD onset, and age at CD diagnosis < 27 years was confirmed to have a detrimental effect on its clinical course. In addition, the familiarity seems to be connected with a more aggressive postoperative course. Finally, for the first time, we have observed a lower rate of responsiveness to azathioprine in patients carrying an hz881 and a 3020insC.

Preliminary study of short- and long-term outcome and quality of life after minimally invasive surgery for Crohn's disease: Comparison between single incision, robotic-assisted and conventional laparoscopy.

BACKGROUND: The feasibility of minimally invasive approach for Crohn's disease (CD) is still controversial. However, several meta-analysis and retrospective studies demonstrated the safety and benefits of laparoscopy for CD patients. Laparoscopic surgery can also be considered for complex disease and recurrent disease. The aim of this study was to investigate retrospectively the effect of three minimally invasive techniques on short- and long-term post-operative outcome. PATIENTS AND METHODS: We analysed CD patients underwent minimally invasive surgery in the Digestive Surgery Unit at Careggi University Hospital (from January 2012 to March 2017). Short-term outcome was evaluated with Clavien-Dindo classification and visual analogue scale for post-operative pain. Long-term outcome was evaluated through four questionnaires: Short Form Health Survey (SF-36), Gastrointestinal Quality Of Life Index (GIQLI), Body Image Questionnaire (BIQ) and Hospital Experience Questionnaire (HEQ). RESULTS: There were 89 patients: 63 conventional laparoscopy, 16 single-incision laparoscopic surgery and 10 robotic-assisted laparoscopy (RALS). Serum albumin <30 g/L (P = 0.031) resulted to be a risk factor for post-operative complications. HEQ had a better result for RALS (P = 0.019), while no differences resulted for SF-36, BIQ and GIQLI. CONCLUSIONS: Minimally invasive technique for CD is feasible, even for complicated and recurrent disease. Our study demonstrated low rates of post-operative complications. However, it is a preliminary study with a small sample size. Further studies should be performed to assess the best surgical technique.

New perspectives on the long-term outcome of segmental colectomy for Crohn's colitis: an observational study on 200 patients.

BACKGROUND AND AIMS: Surgical management of Crohn's colitis represents one of the most complex situations in colorectal surgery. Segmental colectomy (SC) and total abdominal colectomy with ileorectal anastomosis (TAC-IRA) are the most common procedures, but there are few available data on their long-term outcome. The aim of the present study was to analyze the long-term outcome of patients who underwent segmental colectomy for Crohn's colitis, with regard to the risk for total abdominal colectomy. METHODS: In this observational, monocentric, retrospective analysis, we analyzed patients who received a segmental colectomy for Crohn's colitis at our institution. The database was updated by asking patients to complete a questionnaire by telephone or at the outpatient clinic. Only patients followed up at our Hospital were included. Patients were followed up by a specialized multidisciplinary team (IBD Unit). The primary endpoint was the interval between segmental colectomy and, when performed, total abdominal colectomy. RESULTS: Between 1973 and 2014, 200 patients underwent segmental colectomy for Crohn's colitis. The median follow-up was 13.5 years (interquartile range [IQR] 7.8-21.5). Overall, 62 patients (31%) had a surgical recurrence, of these, 42 (21%) received total abdominal colectomy. At multivariate analysis, the presence of ≥ 3 sites (HR = 2.47; 95% CI 1.22-5.00; p = 0.018) and perianal disease (HR = 3.23; 95% CI 1.29-8.07; p = 0.006) proved to be risk factors for total abdominal colectomy. CONCLUSIONS: The risk for surgical recurrence after SC for Crohn's colitis is acceptable. We recommend a bowel-sparing policy for the treatment of Crohn's colitis in any case in which the extent of the disease at the moment of surgery makes the conservative approach achievable.

Totally robotic intracorporeal side-to-side isoperistaltic strictureplasty for Crohn's disease.

The development of bowel-sparing techniques (strictureplasties) for extended stricturing Crohn's disease (CD) and the increased use of minimally invasive surgery (wound sparing) represent the two most important improvements in inflammatory bowel disease surgery from the origin. Nevertheless, the minimally invasive approach for extended stricturing forms is usually avoided primarily because of difficulties in performing complex intracorporeal sutures. We describe a totally intracorporeal robotic ileocecal resection with a yet described modified side-to-side isoperistaltic strictureplasty for an extended ileocecal CD. The strictureplasty was 6 cm long including the stricture in its middle part. Adopting this approach, the preserved small bowel was about 10 cm longer. Operative time was about 4 h, with a blood loss of about 50 ml. The patients' post-operative course was uneventful, enteral nutrition started at post-operative day 2 and gradual oral food intake from day 3. She was discharged on post-operative day 6. Histology confirmed a stricturing CD, and the patient is recurrence free at 34 months' follow-up. Our report suggests that robotic-assisted intracorporeal strictureplasty is feasible and that robotics could represent an interesting instrument for allowing the intersection between minimally invasive and bowel-sparing surgery for CD.

Natural History of MEN1 GEP-NET: Single-Center Experience After a Long Follow-Up.

BACKGROUND: The multiple endocrine neoplasia type 1 syndrome (MEN1) natural history is poorly evaluated, and few single-institution experiences about hereditary gastroenteropancreatic neuroendocrine tumors (GEP-NET) are reported. Our purpose is to analyze the role of GEP-NET in MEN1-related death, as well as the behavior of these lesions during follow-up. METHODS: The study population consists of 77 patients diagnosed with MEN1 GEP-NET, regularly followed up since 1990. Extensive clinical data were prospectively recorded. Statistical analysis was performed both on the whole population of 77 patients and on two subgroups including patients who, during the long lasting study period, underwent GEP-NET surgery (50 pts) and who did not (27 pts), respectively. RESULTS: Twenty-five males (32.5%) and 52 females (67.5%) were enrolled. Sixty-four patients had MEN1 family history (83.1%), and genetic mutation was detected in 67 cases (87%). The mean age at GEP-NET diagnosis was 41.4 years (SD = 13.6); 16 patients (20.8%) had GEP-NET diagnosed before age 30 and 12 cases (15.6%) before 1996. The mean interval time between MEN1 diagnosis and GEP-NET detection was 5.7 years (range -11/37; SD = 8.1 years). Overall, the mean follow-up time from MEN1 diagnosis was 15.8 years (SD = 9.7 years) and from GEP-NET diagnosis was 9.6 years (SD = 6.9 years). Gastrinoma was the most frequent functioning GEP-NET and pancreatoduodenectomy the most adopted surgery. GEP-NET progression affected 12 patients within the non-surgical group, while 18 subjects developed progression after surgery. CONCLUSIONS: Our single-center data provide information on epidemiologic, clinical and pathological features of GEP-NET in MEN1 making possible to clarify their natural history.

Results of surgical treatment for jejunal Crohn's disease: choice between resection, strictureplasty, and combined treatment.

PURPOSE: The jejunum is a relatively uncommon localization of Crohn's disease (CD) compared to the terminal ileum or the large bowel. The type of surgery and the short and long-term results after surgery have not been extensively investigated. A review of patients who underwent surgery for jejunal CD in our center was examined. METHODS: Between 1986 and 2011, 110 patients underwent surgery for jejunal CD. Thirty patients (27.3 %) were surgically treated with resection, 29 patients (26.4 %) with one or more strictureplasties, and 51 patients (46.3 %) with both a resection and one or more strictureplasties. RESULTS: There was no statistical difference in terms of short-term postoperative complications between patients operated with three different options (p = 0.72). Patients were followed up for a period ranging from 2 to 18 years (mean 11 years). During this period, 42 patients had no CD recurrence, 11 patients had medical recurrences only, while 57 patients had surgical recurrences, too. There was no statistical difference in terms of medical and surgical recurrence between the three types of surgical procedures employed (p = 0.24) and between smokers and non-smokers. The recurrent CD was prevalently treated with strictureplasty. CONCLUSIONS: The most frequently employed surgery for the treatment of jejunal CD is a combined type of treatment, i.e., resection of the most affected tract and strictureplasty of the residual strictures. This approach does not imply an increased risk of postoperative complications and recurrence and can reduce the risk of the short bowel syndrome.

Results of Surgical Salvage Treatment for Anal Canal Cancer: A Retrospective Analysis with Overview of the Literature.

BACKGROUND AND AIM: Chemoradiotherapy (CRT) is the gold standard treatment for anal cancer, which permits the maintenance of the anal function. However, about 30-40% of patients develop local disease progression, for which surgery represents a good salvage therapy. The aim of this study is to evaluate survival and morbidity rate in patients who undergo salvage surgery in our single institution, with an overview of the literature. METHODS: A retrospective study was carried out on patients who underwent surgical treatment of anal canal cancer after failure of CRT. We evaluated overall survival at 1, 3, and 5 years and postoperative morbidity rate. RESULTS: Twenty patients who underwent radical surgery with abdominoperineal resection were included in the study. The survival rates at 1, 3, and 5 years were 75, 60, and 37.4%; with a disease-free survival of 67, 53, and 35%, respectively. There was no postoperative mortality. The morbidity rate was 35%. CONCLUSION: Surgery represents the recommended therapy for persistent or recurrent anal canal cancer after CRT, with a good survival rate and an acceptable morbidity.

Rationalisation of the surgical technique for minimally invasive laparoscopic ileal pouch-anal anastomosis after previous total colectomy for ulcerative colitis.

INTRODUCTION: No previous study clearly focuses on laparoscopic technique to perform the second stage surgery (proctectomy with ileal pouch-anal anastomosis [IPAA]) after total colectomy for acute/severe ulcerative colitis (UC). We describe the procedural steps for a simple and rational minimally invasive second stage surgery, reporting intra- and short-term post-operative results. PATIENTS AND METHODS: During the period December 2014-December 2015, 10 consecutive patients (8 males and 2 females) with mean age of 48 years underwent laparoscopic proctectomy and IPAA adopting our novel approach. They were operated 3 months after the previous total colectomy which has been performed, respectively, for acute (three patients) or severe (seven patients) UC. Intraoperative data and post-operative complications, divided as minor and major, were recorded and analysed. A body image questionnaire was administered to all patients to evaluate the cosmetic results of the procedure. RESULTS: Overall mean surgical time was 235 ± 49 min. During the post-operative course, three patients required morphine for >48 h, no patient needed blood transfusion and bowel movements recovery happened as mean during the 2nd day. No early major complications happened. Two patients (20%) developed peri-ileostomic wound infection at the right flank. Only one patient (10%) suffered from ileal-anal anastomotic dehiscence, conservatively treated till resolution. The average length of hospital stay was 8 ± 2 days. The body image questionnaire showed in all patients an extreme satisfaction about the results obtained (mean value = 59/64 points). CONCLUSIONS: Through three standardised surgical steps easily reproducible, we describe an almost scar-less procedure able to optimise the intraoperative time with good post-operative results in terms of complications and cosmesis.

Hepatocellular carcinoma on cirrhosis complicated with tumoral thrombi extended to the right atrium: results in three cases treated with major hepatectomy and thrombectomy under hypothermic cardiocirculatory arrest and literature review.

BACKGROUND: Hepatocellular carcinoma (HCC) with the presence of tumor thrombus in hepatic veins and vena cava, until the atrium (RATT), is correlated with poor prognosis and with risk of tricuspid valve occlusion, congestive heart failure, and pulmonary embolism. METHODS: Three patients with HCC on cirrhotic liver with RATT were studied. Operative technique, pre-operative and post-operative liver function tests, blood loss and transfusions, post-operative morbidity and mortality, and the overall survival and the disease free survival were analyzed. RESULTS: Mean operative time was 336 ± 66 min. Intra-operative blood loss was 926.6 ± 325.9 ml. No major complications occurred. The times of hospital stay were 10, 21, and 19 days, respectively. The survival times were 90, 161, and 40 days, and the disease-free survival times were 30, 141, and 30 days, respectively. CONCLUSIONS: The complete removal of HCC with RATT may be achieved with cardiopulmonary by-pass (CPB) and total hepatic vascular exclusion (THVE). Adding the hypothermic cardiocirculatory arrest (HCCA) to the use of CPB allowed us to have minimal blood loss and hemostasis of the resectional plane. So the use of CPB and HCCA should be considered a good therapeutic alternative to the normothermic CPB with THVE.

Safer intestinal invagination for a solid pancreatico-jejunal anastomosis in presence of a soft texture pancreatic remnant and non-dilated duct.

Pancreatico-jejunal anastomosis after pancreatoduodenectomy still represents the Achilles' heel of the procedure: the failure of this anastomosis is relatively common and it is the main cause of post-operative morbidity and mortality. Studies have described different reconstruction strategies for the control of the development of post-operative pancreatic fistula, but the strategy to obtain a safer pancreatico-jejunal anastomosis is still far from satisfaction. We report a novel variation of the invagination technique based on preliminary clinical experience in 8 patients who underwent pancreatico-jejunal anastomosis after pancreatoduodenectomy in our hepatobiliopancreatic center from 2008 to 2014. The variation could obtain a safer intestinal invagination for a solid pancreatico-jejunal anastomosis even in the presence of soft pancreatic remnant.

Perianal Crohn's disease and hidradenitis suppurativa: a possible common immunological scenario.

BACKGROUND: Crohn's disease (CD) and Hidradenitis suppurativa (HS) are both chronic inflammatory diseases. The pathogenesis of these diseases is multifactorial, due to the interaction of genetic and environmental factors leading to a deregulated local immune response where T lymphocytes play a major role. To the best of our knowledge, no previous study has clarified whether the pathogenetic mechanism of perianal CD and HS is the same. We therefore analyzed the cellular expression pattern and the cytokine repertoire in three patients suffering from both perianal CD and HS. METHODS: We evaluated three patients affected by concurrent HS and CD with fistulizing perianal disease. Surgical specimens have been fixed and embedded in paraffin prior to sectioning for histological examination. Inflammatory tissue curettages have been recovered during intervention from perianal fistulas and HS lesions in order to analyze the phenotypic and functional characteristics of infiltrating T cells. In particular we evaluated T cells, by flow cytometry, for cytokine production profile and expression of surface markers. Moreover, analysis of the T cell repertoire was performed by means of spectratyping, in only one patient. RESULTS: A higher frequency of CD4+ CD161+ T lymphocytes has been detected in CD fistulas and in HS lesions than in peripheral blood (PB) samples. In the patient in whom we derived enough cells from the three sources, we found higher frequency of CD4+ IL-17- producing cells in HS lesion and fistula lesion compared to PB. It is noteworthy that the same clonotypes were expanded in this patient in T cells derived from both HS lesion and fistula lesion. CONCLUSION: The presence of numerous CD4+ CD161+ lymphocytes in fistula and HS lesion curettages suggests that these cells may play a pathogenic role, and candidates CD161 as a possible biological target for medical treatment.

Intraoperative PTH monitoring: a new approach based on the identification of the "true" time origin of the decay curve.

Some published criteria for intraoperative monitoring of PTH serum concentrations may cause misleading results, since the timing of samples measured between the pre-incision and pre-excision phase of surgery is often unrecorded. In our opinion this information is critical, as the time of an intermediate sample during surgical manipulation may represent the "true" beginning of the PTH decay. We modified the usual criterion of monitoring (cut-off at 10 minutes after clamping) proposing a further check at manipulation in case the primary check at clamping produces an apparently negative result. On the basis of a mathematical model, false negative curves were simulated by means of a time shift. This shift was assumed to be the interval between manipulation and clamping. Analysing the decay curve, we used the 50% cut-off at 10 minutes after the supposed "true" origin (clamping or manipulation). Using a rapid immunochemiluminometric assay (ICMA), data were collected from 22 patients successfully operated for parathyroid adenoma. The check at clamping correctly diagnosed 13 patients. Among the 9 false negative cases, 6 were correctly diagnosed considering the manipulation as the baseline value. In the remaining 3 patients, diagnosis required prolonged observation of the curves. In case the iPTH decay does not follow the expected curve, it can be useful to check the decay normalising to a pre-excision value. The advantages of our criterion are both the prompt recognition of false negative results and the construction of a "true" decay curve for each patient, supporting the surgeon during the excision of hyperfunctioning parathyroid tissue.

Sarcomatoid carcinoma of the kidney in a MEN1 patient: case report and genetic profile.

Renal tumors are exceedingly rare in Multiple Endocrine Neoplasia type 1 (MEN1), a pleyotropic hereditary cancer disorder affecting the endocrine system. Herein we report a unique case of renal sarcomatoid carcinoma with concomitant ipsilateral non-secreting adrenal adenoma occurring in a young male MEN1 patient, previously operated for hyperparathyroidism and multiple pancreatic neuroendocrine neoplasms. Molecular analysis in the MEN1 locus at 11q13 showed loss of heterozygosity in the adrenal lesion, while kidney cancer was unrelated to MEN1 syndrome.

Social origins and post-high school institutional pathways: a cumulative dis/advantage approach.

The social stratification that takes place during the transition out of high school is traditionally explained with theoretical frameworks such as status attainment and social reproduction. In our paper, we suggest the cumulative dis/advantage hypothesis as an alternative theoretical and empirical approach that explains this divergence in institutional pathways as the result of the dynamic interplay between social institutions (in our case, schools) and individuals' resources. We use data from the NLSY79 in order to compute institutional pathways (defined by educational and occupational status) of 9,200 high school graduates. Optimal Matching Analysis and Cluster Analysis generated a typology of life course pathways. Our results show that both ascribed characteristics and students' high school characteristics and resources are predictors of post-high school pathways.

Multimodal Prehabilitation for Patients with Crohn's Disease Scheduled for Major Surgery: A Narrative Review.

Approximately 15-50% of patients with Crohn's disease (CD) will require surgery within ten years following the diagnosis. The management of modifiable risk factors before surgery is essential to reduce postoperative complications and to promote a better postoperative recovery. Preoperative malnutrition reduced functional capacity, sarcopenia, immunosuppressive medications, anemia, and psychological distress are frequently present in CD patients. Multimodal prehabilitation consists of nutritional, functional, medical, and psychological interventions implemented before surgery, aiming at optimizing preoperative status and improve postoperative recovery. Currently, studies evaluating the effect of multimodal prehabilitation on postoperative outcomes specifically in CD are lacking. Some studies have investigated the effect of a single prehabilitation intervention, of which nutritional optimization is the most investigated. The aim of this narrative review is to present the physiologic rationale supporting multimodal surgical prehabilitation in CD patients waiting for surgery, and to describe its main components to facilitate their adoption in the preoperative standard of care.

Comparison of microbial communities and the profile of sulfate-reducing bacteria in patients with ulcerative colitis and their association with bowel diseases: a pilot study.

Considerable evidence has accumulated regarding the molecular relationship between gut microbiota (GM) composition and the onset (clinical presentation and prognosis of ulcerative colitis (UC)). In addition, it is well documented that short-chain fatty acid (SCFA)-producing bacteria may play a fundamental role in maintaining an anti-inflammatory intestinal homeostasis, but sulfate- and sulfite reducing bacteria may be responsible for the production of toxic metabolites, such as hydrogen sulfide and acetate. Hence, the present study aimed to assess the GM composition - focusing on sulfate-reducing bacteria (SRB) - in patients with severe, severe-active and moderate UC. Each one of the six enrolled patients provided two stool samples in the following way: one sample was cultivated in a modified SRB-medium before 16S rRNA sequencing and the other was not cultivated. Comparative phylogenetic analysis was conducted on each sample. Percentage of detected gut microbial genera showed considerable variation based on the patients' disease severity and cultivation in the SRB medium. In detail, samples without cultivation from patients with moderate UC showed a high abundance of the genera Bacteroides, Bifidobacterium and Ruminococcus, but after SRB cultivation, the dominant genera were Bacteroides, Klebsiella and Bilophila. On the other hand, before SRB cultivation, the main represented genera in patients with severe UC were Escherichia-Shigella, Proteus, Methanothermobacter and Methanobacterium. However, after incubation in the SRB medium Bacteroides, Proteus, Alistipes and Lachnoclostridium were predominant. Information regarding GM compositional changes in UC patients may aid the development of novel therapeutic strategies (e.g., probiotic preparations containing specific bacterial strains) to counteract the mechanisms of virulence of harmful bacteria and the subsequent inflammatory response that is closely related to the pathogenesis of inflammatory bowel diseases.

Phenotypic and functional features of human Th17 cells.

T helper (Th) 17 cells represent a novel subset of CD4+ T cells that are protective against extracellular microbes, but are responsible for autoimmune disorders in mice. However, their properties in humans are only partially known. We demonstrate the presence of Th17 cells, some of which produce both interleukin (IL)-17 and interferon (IFN)-gamma (Th17/Th1), in the gut of patients with Crohn's disease. Both Th17 and Th17/Th1 clones showed selective expression of IL-23R, CCR6, and the transcription factor ROR gamma t, and they exhibited similar functional features, such as the ability to help B cells, low cytotoxicity, and poor susceptibility to regulation by autologous regulatory T cells. Interestingly, these subsets also expressed the Th1-transcription factor T-bet, and stimulation of these cells in the presence of IL-12 down-regulated the expression of ROR gamma t and the production of IL-17, but induced IFN-gamma. These effects were partially inhibited in presence of IL-23. Similar receptor expression and functional capabilities were observed in freshly derived IL-17-producing peripheral blood and tonsillar CD4+ T cells. The demonstration of selective markers for human Th17 cells may help us to understand their pathogenic role. Moreover, the identification of a subset of cells sharing features of both Th1 and Th17, which can arise from the modulation of Th17 cells by IL-12, may raise new issues concerning developmental and/or functional relationships between Th17 and Th1.