Instruct: Given a scientific claim, retrieve relevant documents that support or refute the claim.
Query: Oat tolerant coeliac patients may have oat specific inflammatory cells in their small bowel mucosa.
Background  Celiac disease is a small intestinal inflammatory disorder characterized by malabsorption, nutrient deficiency, and a range of clinical manifestations. It is caused by an inappropriate immune response to dietary gluten and is treated with a gluten-free diet. Recent feeding studies have indicated oats to be safe for celiac disease patients, and oats are now often included in the celiac disease diet. This study aimed to investigate whether oat intolerance exists in celiac disease and to characterize the cells and processes underlying this intolerance. Methods and Findings  We selected for study nine adults with celiac disease who had a history of oats exposure. Four of the patients had clinical symptoms on an oats-containing diet, and three of these four patients had intestinal inflammation typical of celiac disease at the time of oats exposure. We established oats-avenin-specific and -reactive intestinal T-cell lines from these three patients, as well as from two other patients who appeared to tolerate oats. The avenin-reactive T-cell lines recognized avenin peptides in the context of HLA-DQ2. These peptides have sequences rich in proline and glutamine residues closely resembling wheat gluten epitopes. Deamidation (glutamine→glutamic acid conversion) by tissue transglutaminase was involved in the avenin epitope formation. Conclusions  We conclude that some celiac disease patients have avenin-reactive mucosal T-cells that can cause mucosal inflammation. Oat intolerance may be a reason for villous atrophy and inflammation in patients with celiac disease who are eating oats but otherwise are adhering to a strict gluten-free diet. Clinical follow-up of celiac disease patients eating oats is advisable.
Results of experimental and genetic studies have highlighted the role of the IL-23/IL-17 axis in the pathogenesis of inflammatory bowel disease (IBD). IL-23-driven inflammation has been primarily linked to Th17 cells; however, we have recently identified a novel population of innate lymphoid cells (ILCs) in mice that produces IL-17, IL-22, and IFN-γ in response to IL-23 and mediates innate colitis. The relevance of ILC populations in human health and disease is currently poorly understood. In this study, we have analyzed the role of IL-23-responsive ILCs in the human intestine in control and IBD patients. Our results show increased expression of the Th17-associated cytokine genes IL17A and IL17F among intestinal CD3⁻ cells in IBD. IL17A and IL17F expression is restricted to CD56⁻ ILCs, whereas IL-23 induces IL22 and IL26 in the CD56⁺ ILC compartment. Furthermore, we observed a significant and selective increase in CD127⁺CD56⁻ ILCs in the inflamed intestine in Crohn's disease (CD) patients but not in ulcerative colitis patients. These results indicate that IL-23-responsive ILCs are present in the human intestine and that intestinal inflammation in CD is associated with the selective accumulation of a phenotypically distinct ILC population characterized by inflammatory cytokine expression. ILCs may contribute to intestinal inflammation through cytokine production, lymphocyte recruitment, and organization of the inflammatory tissue and may represent a novel tissue-specific target for subtypes of IBD.
Human group 1 ILCs consist of at least three phenotypically distinct subsets, including NK cells, CD127(+) ILC1, and intraepithelial CD103(+) ILC1. In inflamed intestinal tissues from Crohn's disease patients, numbers of CD127(+) ILC1 increased at the cost of ILC3. Here we found that differentiation of ILC3 to CD127(+) ILC1 is reversible in vitro and in vivo. CD127(+) ILC1 differentiated to ILC3 in the presence of interleukin-2 (IL-2), IL-23, and IL-1β dependent on the transcription factor RORγt, and this process was enhanced in the presence of retinoic acid. Furthermore, we observed in resection specimen from Crohn's disease patients a higher proportion of CD14(+) dendritic cells (DC), which in vitro promoted polarization from ILC3 to CD127(+) ILC1. In contrast, CD14(-) DCs promoted differentiation from CD127(+) ILC1 toward ILC3. These observations suggest that environmental cues determine the composition, function, and phenotype of CD127(+) ILC1 and ILC3 in the gut.
BACKGROUND Ulcerative colitis (UC) is a chronic inflammatory bowel disease in which the colonic mucosa is infiltrated with plasma cells producing IgG autoantibodies. It is not known whether this represents a local mucosal response which has switched to IgG or a peripheral response which may have been initiated by peripheral antigen which homed to the colonic mucosa. The clonal distribution of IgG secreting cells and isotype switched variants in UC is not known. AIMS To investigate the clonal distribution of mucosal IgG in UC and to search for related IgG and IgA secreting cells in normal and diseased mucosa and blood in UC. To investigate characteristics which may discriminate between the mucosal and peripheral repertoire in the normal mucosa and in UC. PATIENTS Blood and normal and diseased mucosa from two patients with UC were studied. METHODS Immunoglobulin gene analysis and clone specific polymerase chain reaction were used to study the clonal distribution and characteristics of IgG and related IgA in the mucosa and blood of patients with UC. RESULTS The IgG response in the mucosa of UC patients included widespread clones of cells that were present in both the diseased mucosa and blood but that were scarce in normal mucosa. Clonally related IgA class switch variants, all IgA1, were detected but also only in the diseased mucosa and blood. This suggests that these clones home preferentially to the diseased mucosa. We showed that J(H)1 usage was characteristic of the peripheral repertoire, and that examples of J(H)1 usage were observed in mucosal IgG in UC. CONCLUSIONS Overall, these data are consistent with a model of UC in which a peripheral response is expressed and expanded in the colonic mucosa.
We have previously demonstrated that interleukin (IL)-10–deficient (IL-10 knockout [KO]) but not wild-type (WT) mice develop colitis after infection with Helicobacter hepaticus . Here, we show that infected recombination activating gene (RAG) KO mice develop intestinal inflammation after reconstitution with CD4+ T cells from IL-10 KO animals and that the cotransfer of CD4+ T cells from H. hepaticus –infected but not uninfected WT mice prevents this colitis. The disease-protective WT CD4+ cells are contained within the CD45RBlow fraction and unexpectedly were found in both the CD25+ and the CD25− subpopulations of these cells, their frequency being higher in the latter. The mechanism by which CD25+ and CD25− CD45RBlow CD4+ cells block colitis involves IL-10 and not transforming growth factor (TGF)-β, as treatment with anti–IL-10R but not anti–TGF-β monoclonal antibody abrogated their protective effect. In vitro, CD45RBlow CD4+ cells from infected WT mice were shown to produce IL-10 and suppress interferon-γ production by IL-10 KO CD4+ cells in an H. hepaticus antigen–specific manner. Together, our data support the concept that H. hepaticus infection results in the induction in WT mice of regulatory T cells that prevent bacteria-induced colitis. The induction of such cells in response to gut flora may be a mechanism protecting normal individuals against inflammatory bowel disease.
BACKGROUND Crohn's disease (CD)-associated dysbiosis is characterised by a loss of Faecalibacterium prausnitzii, whose culture supernatant exerts an anti-inflammatory effect both in vitro and in vivo. However, the chemical nature of the anti-inflammatory compounds has not yet been determined. METHODS Peptidomic analysis using mass spectrometry was applied to F. prausnitzii supernatant. Anti-inflammatory effects of identified peptides were tested in vitro directly on intestinal epithelial cell lines and on cell lines transfected with a plasmid construction coding for the candidate protein encompassing these peptides. In vivo, the cDNA of the candidate protein was delivered to the gut by recombinant lactic acid bacteria to prevent dinitrobenzene sulfonic acid (DNBS)-colitis in mice. RESULTS The seven peptides, identified in the F. prausnitzii culture supernatants, derived from a single microbial anti-inflammatory molecule (MAM), a protein of 15 kDa, and comprising 53% of non-polar residues. This last feature prevented the direct characterisation of the putative anti-inflammatory activity of MAM-derived peptides. Transfection of MAM cDNA in epithelial cells led to a significant decrease in the activation of the nuclear factor (NF)-κB pathway with a dose-dependent effect. Finally, the use of a food-grade bacterium, Lactococcus lactis, delivering a plasmid encoding MAM was able to alleviate DNBS-induced colitis in mice. CONCLUSIONS A 15 kDa protein with anti-inflammatory properties is produced by F. prausnitzii, a commensal bacterium involved in CD pathogenesis. This protein is able to inhibit the NF-κB pathway in intestinal epithelial cells and to prevent colitis in an animal model.
Mice lacking junctional adhesion molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r(-/-)Rag1(-/-) mice to acute colitis. Although negligible contributions of adaptive immunity in F11r(+/+)Rag1(-/-) mice were observed, F11r(-/-)Rag1(-/-) mice exhibited increased microflora-dependent colitis. Elimination of T cell subsets and cytokine analyses revealed a protective role for TGF-β-producing CD4(+) T cells in F11r(-/-) mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4(+) T cells and TGF-β. Absence of IgA in F11r(+/+)Igha(-/-) mice did not affect disease, whereas F11r(-/-)Igha(-/-) mice displayed markedly increased susceptibility to acute injury-induced colitis. These data establish a role for adaptive immune-mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise.
The role of ataxia telangiectasia mutated (ATM), a DNA double-strand break recognition and response protein, in inflammation and inflammatory diseases is unclear. We have previously shown that high levels of systemic DNA damage are induced by intestinal inflammation in wild-type mice. To determine the effect of Atm deficiency in inflammation, we induced experimental colitis in Atm(-/-), Atm(+/-), and wild-type mice via dextran sulfate sodium (DSS) administration. Atm(-/-) mice had higher disease activity indices and rates of mortality compared with heterozygous and wild-type mice. Systemic DNA damage and immune response were characterized in peripheral blood throughout and after three cycles of treatment. Atm(-/-) mice showed increased sensitivity to levels of DNA strand breaks in peripheral leukocytes, as well as micronucleus formation in erythroblasts, compared with heterozygous and wild-type mice, especially during remission periods and after the end of treatment. Markers of reactive oxygen and nitrogen species-mediated damage, including 8-oxoguanine and nitrotyrosine, were present both in the distal colon and in peripheral leukocytes, with Atm(-/-) mice manifesting more 8-oxoguanine formation than wild-type mice. Atm(-/-) mice showed greater upregulation of inflammatory cytokines and significantly higher percentages of activated CD69+ and CD44+ T cells in the peripheral blood throughout treatment. ATM, therefore, may be a critical immunoregulatory factor dampening the deleterious effects of chronic DSS-induced inflammation, necessary for systemic genomic stability and homeostasis of the gut epithelial barrier.
Mice lacking the transcription factor T-bet in the innate immune system develop microbiota-dependent colitis. Here, we show that interleukin-17A (IL-17A)-producing IL-7Rα(+) innate lymphoid cells (ILCs) were potent promoters of disease in Tbx21(-/-)Rag2(-/-) ulcerative colitis (TRUC) mice. TNF-α produced by CD103(-)CD11b(+) dendritic cells synergized with IL-23 to drive IL-17A production by ILCs, demonstrating a previously unrecognized layer of cellular crosstalk between dendritic cells and ILCs. We have identified Helicobacter typhlonius as a key disease trigger driving excess TNF-α production and promoting colitis in TRUC mice. Crucially, T-bet also suppressed the expression of IL-7R, a key molecule involved in controlling intestinal ILC homeostasis. The importance of IL-7R signaling in TRUC disease was highlighted by the dramatic reduction in intestinal ILCs and attenuated colitis following IL-7R blockade. Taken together, these data demonstrate the mechanism by which T-bet regulates the complex interplay between mucosal dendritic cells, ILCs, and the intestinal microbiota.
IBD is characterized by uncontrolled immune responses in inflamed mucosa, with dominance of IL-17-producing cells and deficiency of Treg cells. The aim of this study was to explore the effect and mechanisms of RA, the ligand of RARalpha, on immune responses in human and murine colitis. Colonic biopsies from patients with UC were cultured and treated with RA as the agonist of RARalpha or LE135 as the antagonist of RARalpha. Expressions of IL-17 and FOXP3 were detected by immunohistochemistry. Murine colitis was induced by intrarectal administration with TNBS at Day 1. Mice were then i.p.-treated with RA or LE135 daily for 7 days. Cytokine levels in the cultures of mouse LPMCs were measured. Expressions of FOXP3 and IL-17 in colon tissues or MLN were detected by immunohistological analysis. Body weight and colon inflammation were evaluated. RA treatment up-regulated FOXP3 expression and down-regulated IL-17 expression in colon biopsies of patients and in colon tissues and MLN of mice with colitis compared with controls. LPMCs from RA-treated mice produced lower levels of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-17) but more regulatory cytokines (IL-10, TGF-beta) compared with that of untreated mice. LE135 showed the opposite effect of RA. Furthermore, RA ameliorated TNBS-induced colitis in a dose-dependent manner, as seen by improved body weight and colon inflammation. RA down-regulates colon inflammatory responses in patients with IBD in vitro and in murine colitis in vivo, representing a potential therapeutic approach in IBD treatment.
BACKGROUND & AIMS Various commensal enteric and potentially pathogenic bacteria may be involved in the pathogenesis of inflammatory bowel diseases (IBD). We compared the risk of IBD between a cohort of patients with documented Salmonella or Campylobacter gastroenteritis and an age- and gender-matched control group from the same population in Denmark. METHODS We identified 13,324 patients with Salmonella/Campylobacter gastroenteritis from laboratory registries in North Jutland and Aarhus counties, Denmark, from 1991 through 2003, and 26,648 unexposed controls from the same counties. Of these, 176 exposed patients with IBD before the infection, their 352 unexposed controls, and 80 unexposed individuals with IBD before the Salmonella/Campylobacter infection were excluded. The final study cohort of 13,148 exposed and 26,216 unexposed individuals were followed for up to 15 years (mean, 7.5 years). RESULTS A first-time diagnosis of IBD was reported in 107 exposed (1.2%) and 73 unexposed individuals (0.5%). By age, gender, and comorbidity adjusted Cox proportional hazards regression analysis, the hazard ratio (95% confidence interval) for IBD was 2.9 (2.2-3.9) for the whole period and 1.9 (1.4-2.6) if the first year after the Salmonella/Campylobacter infection was excluded. The increased risk in exposed subjects was observed throughout the 15-year observation period. The increased risk was similar for Salmonella (n = 6463) and Campylobacter (n = 6685) and for a first-time diagnosis of Crohn's disease (n = 47) and ulcerative colitis (n = 133). CONCLUSIONS In our population-based cohort study with complete follow-up, an increased risk of IBD was demonstrated in individuals notified in laboratory registries with an episode of Salmonella/Campylobacter gastroenteritis.
Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.
OBJECTIVE To assay the efficiency for celiac disease (CD) screening of 2 immunochromatographic visual stick assays based on human recombinant tissue transglutaminase (tTG). One was the antitissue transglutaminase antibodies (AtTGA) stick for IgA/G antibodies to tTG detection, the other was the AtTGA/antigliadin antibodies (AGA) stick for IgA antibodies for tTG and/or gliadins. PATIENTS AND METHODS In a prospective multicenter study, 4 pediatric gastroenterology units from Spain and 2 from Latin America enrolled 72 control children with a normal small bowel mucosa and 113 untreated patients with CD with Marsh type 3 lesions. RESULTS Evaluation of results by the gastroenterologists and by 2 independent observers at the coordination center showed a remarkably low interobserver variability. For the AtTGA stick, sensitivity was 96.5% and specificity was 98.6%. The AtTGA/AGA stick displayed a sensitivity of 94.5% and a specificity of 98.6% for AtTGA and a sensitivity of 63.1% and a specificity of 95.2% for AGA. The highest efficiency and positive likelihood ratio was obtained for the AtTGA stick, higher than for IgA AtTGA by enzyme-linked immunosorbent assay. One additional advantage was that previous investigation of total serum IgA levels could be eluded. The IgA AtTGA/AGA stick, with an efficiency of 95.1%, compared with 89.2% when the combined results of the 2 enzyme-linked immunosorbent assays were considered, turned out to be an excellent diagnostic tool for infants with no IgA deficiency. CONCLUSION These 2 assays are extremely efficient for CD screening, by combining a high diagnostic accuracy with the simplicity and rapidity of visual methods.
BACKGROUND Interleukin (IL)-17F, produced in IL-23R-expressing Th17 cells, is a novel member of the IL-17 cytokine family. Given the association of IL23R with inflammatory bowel disease (IBD), we characterized the role of IL-17F in IBD including its intestinal gene expression and the effect of the IL17F p. His161Arg polymorphism on disease susceptibility and phenotype of Crohn's disease (CD) and ulcerative colitis (UC). In addition, we analyzed the IL17F p. His161Arg polymorphism for potential epistasis with IL23R and NOD2/CARD15 variants. METHODS Intestinal IL-17F mRNA expression was measured by quantitative polymerase chain reaction (PCR). Genomic DNA from 1682 individuals (CD: n = 499; UC: n = 216; controls: n = 967) was analyzed for the presence of the IL17F p. His161Arg polymorphism, the 3 NOD2 variants, p. Arg702Trp, p. Gly908Arg, and p. Leu1007fsX1008, and 10 CD-associated IL23R variants. RESULTS Intestinal IL-17F mRNA expression was 4.4-fold increased in inflamed colonic lesions compared to uninflamed biopsies in CD (P = 0.016) but not in UC. However, the mean intestinal IL-17F mRNA expression was higher in UC than in CD (P < 0.0001). The IL17F p. His161Arg substitution was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype, but weakly associated with a low body mass index (BMI; P = 0.009) and an earlier age of disease onset (P = 0.039) in UC. There was no evidence for epistasis between the IL17F p. His161Arg polymorphism and IBD-associated single nucleotide polymorphisms within the IL23R gene. CONCLUSIONS Intestinal IL17F gene expression is increased in active CD. The IL17F p. His161Arg polymorphism is not associated with IBD susceptibility and has no epistatic interaction with CD-associated IL23R variants.
Mucosal tolerance has been considered a potentially important pathway for the treatment of autoimmune disease, including human multiple sclerosis and experimental conditions such as experimental autoimmune encephalomyelitis (EAE). There is limited information on the capacity of commensal gut bacteria to induce and maintain peripheral immune tolerance. Inbred SJL and C57BL/6 mice were treated orally with a broad spectrum of antibiotics to reduce gut microflora. Reduction of gut commensal bacteria impaired the development of EAE. Intraperitoneal antibiotic-treated mice showed no significant decline in the gut microflora and developed EAE similar to untreated mice, suggesting that reduction in disease activity was related to alterations in the gut bacterial population. Protection was associated with a reduction of proinflammatory cytokines and increases in IL-10 and IL-13. Adoptive transfer of low numbers of IL-10-producing CD25(+)CD4(+) T cells (>75% FoxP3(+)) purified from cervical lymph nodes of commensal bacteria reduced mice and in vivo neutralization of CD25(+) cells suggested the role of regulatory T cells maintaining peripheral immune homeostasis. Our data demonstrate that antibiotic modification of gut commensal bacteria can modulate peripheral immune tolerance that can protect against EAE. This approach may offer a new therapeutic paradigm in the treatment of multiple sclerosis and perhaps other autoimmune conditions.
Patients with inflammatory bowel disease have an increased prevalence of osteoporosis, and suffer high rates of spinal bone loss. Hormone replacement therapy (HRT) is effective in the treatment and prevention of osteoporosis but has not been studied in patients with inflammatory bowel disease. A two year prospective study of HRT in inflammatory bowel disease was performed in 47 postmenopausal women aged 44 to 67 years with ulcerative colitis (25) or Crohn's disease (22). Patients had radial and spinal bone density measured annually by single photon absorptiometry and quantitative computed tomography respectively. The mean (95% confidence intervals) annual change in radial bone density was +1.42%/yr (+0.58 to +2.26; P < 0.005) and for spinal bone +2.60%/yr (+1.06 to +4.15; p < 0.005). There was no significant correlation between rates of change of bone density at the two sites, or between the rates of change and the initial bone density either in the radius or spine. Twelve patients were given prednisolone during the study, and their rates of change for spinal bone density were lower, but values were not statistically significantly different from those who did not receive corticosteroids. Changes in bone density for patients with ulcerative colitis and Crohn's disease were not significantly different. The change in bone density did not correlate with the patients' age or number of years after the menopause. It is concluded that HRT is effective in prevention of bone loss in postmenopausal women with inflammatory bowel disease.
BACKGROUND & AIMS The therapeutic application of regulatory T cells (Tregs) for the treatment of inflammatory diseases is limited by the scarcity of antigen-specific Tregs. A preferred approach to endow effector T cells (Teff) with a desired specificity uses chimeric immune receptors with antibody-type specificity. Accordingly, employing such chimeric immune receptors to redirect Tregs to sites of inflammation may be a useful therapeutic approach to alleviate a broad scope of diseases in which an uncontrolled inflammatory response plays a major role. METHODS To enable application of the approach in clinical setting, which requires the genetic modification of the patient's own Tregs, we describe here a novel protocol that allows the efficient retroviral transduction and 2,4,6-trinitrophenol-specific expansion of murine naturally occurring regulatory T cells (nTregs), with a 2,4,6-trinitrophenol-specific tripartite chimeric receptor. RESULTS Transduced Tregs maintained their Foxp3 level, could undergo repeated expansion upon ex vivo encounter with their cognate antigen in a major histocompatibility complex-independent, costimulation-independent, and contact-dependent manner and specifically suppressed Teff cells. Adoptive transfer of small numbers of the transduced nTregs was associated with antigen-specific, dose-dependent amelioration of trinitrobenzenesulphonic acid colitis. CONCLUSIONS This study demonstrates that nTregs can be efficiently transduced to express functional, antigen-specific chimeric receptors that enable the specific suppression of effector T cells both in vitro and in vivo. This approach may enable future cell-based therapeutic application in inflammatory bowel disease, as well as other inflammatory disorders.
Innate lymphoid cells (ILCs) are immune cells that lack a specific antigen receptor yet can produce an array of effector cytokines that in variety match that of T helper cell subsets. ILCs function in lymphoid organogenesis, tissue remodeling, antimicrobial immunity, and inflammation, particularly at barrier surfaces. Their ability to promptly respond to insults inflicted by stress-causing microbes strongly suggests that ILCs are critical in first-line immunological defenses. Here, we review current data on developmental requirements, lineage relationships, and effector functions of two families of ILCs: (a) Rorγt-expressing cells involved in lymphoid tissue formation, mucosal immunity, and inflammation and (b) type 2 ILCs that are important for helminth immunity. We also discuss the potential roles of ILCs in the pathology of immune-mediated inflammatory and infectious diseases including allergy.
PURPOSE OF REVIEW To encapsulate our current understanding of the proinflammatory cytokines responsible for the inflammation underlying Crohn's disease and the prospect of using this information to devise therapy for this condition based on inhibition of these cytokines. RECENT FINDINGS Current research is shedding new light on the role of both T helper cell (Th)1 and Th17 responses in the pathogenesis of Crohn's disease. Initial studies conducted a decade ago highlighted the view that Crohn's disease inflammation is caused by an interleukin-12-driven Th1 response, which resulted in the generation of interferon-gamma, which then served as the main inflammatory mediator. In recent years, however, this view has been largely eclipsed by studies, conducted mainly in murine models, showing that a Th17 response is the main cause of Crohn's disease inflammation through the production of interleukin-17. Now, a somewhat more balanced view is emerging, which holds that interferon-gamma is still a major proinflammatory cytokine in Crohn's disease, although it may arise from both the Th1 and Th17-mediated responses at different phases of the inflammatory process. SUMMARY The new findings continue to support the idea that anti-interleukin-12p40, an antibody that inhibits both the Th1 and Th17 response, is logically the most potent anticytokine for the treatment of Crohn's disease.
BACKGROUND:It is well established that a minority of celiac patients present with “classic” symptoms due to malabsorption. However, few studies have focussed on the distribution of body mass index (BMI) in celiac populations and its relationship to clinical characteristics, or on its response to treatment. METHODS:We reviewed BMI measurements and other clinical and pathological characteristics from a database of 371 celiac patients diagnosed over a 10-yr period and seen by a single gastroenterologist. To assess response to gluten exclusion, we compared BMI at diagnosis and after 2 yr treatment in patients with serological support for dietary compliance. RESULTS:Mean BMI was 24.6 kg/m2 (range 16.3–43.5). Seventeen patients (5%) were underweight (BMI <18.5), 211 (57%) were normal, and 143 (39%) were overweight (BMI ≥25), including 48 (13% of all patients) in the obese range (BMI ≥30.0). There was a significant association between low BMI and female gender, history of diarrhea, reduced hemoglobin concentration, reduced bone mineral density (BMD), osteoporosis, and higher grades (subtotal/total) of villous atrophy. Of patients compliant with a gluten-free diet, 81% had gained weight after 2 yr, including 82% of initially overweight patients. CONCLUSIONS:Few celiac patients are underweight at diagnosis and a large minority is overweight; these are less likely to present with classical features of diarrhea and reduced hemoglobin. Failed or delayed diagnosis of celiac disease may reflect lack of awareness of this large subgroup. The increase in weight of already overweight patients after dietary gluten exclusion is a potential cause of morbidity, and the gluten-free diet as conventionally prescribed needs to be modified accordingly.
Eosinophils are abundant in inflammatory demyelinating lesions in neuromyelitis optica (NMO). We used cell culture, ex vivo spinal cord slices, and in vivo mouse models of NMO to investigate the role of eosinophils in NMO pathogenesis and the therapeutic potential of eosinophil inhibitors. Eosinophils cultured from mouse bone marrow produced antibody-dependent cell-mediated cytotoxicity (ADCC) in cell cultures expressing aquaporin-4 in the presence of NMO autoantibody (NMO-IgG). In the presence of complement, eosinophils greatly increased cell killing by a complement-dependent cell-mediated cytotoxicity (CDCC) mechanism. NMO pathology was produced in NMO-IgG-treated spinal cord slice cultures by inclusion of eosinophils or their granule toxins. The second-generation antihistamines cetirizine and ketotifen, which have eosinophil-stabilizing actions, greatly reduced NMO-IgG/eosinophil-dependent cytotoxicity and NMO pathology. In live mice, demyelinating NMO lesions produced by continuous intracerebral injection of NMO-IgG and complement showed marked eosinophil infiltration. Lesion severity was increased in transgenic hypereosinophilic mice. Lesion severity was reduced in mice made hypoeosinophilic by anti-IL-5 antibody or by gene deletion, and in normal mice receiving cetirizine orally. Our results implicate the involvement of eosinophils in NMO pathogenesis by ADCC and CDCC mechanisms and suggest the therapeutic utility of approved eosinophil-stabilizing drugs.
The human intestine is colonized by an estimated 100 trillion bacteria. Some of these bacteria are essential for normal physiology, whereas others have been implicated in the pathogenesis of multiple inflammatory diseases including IBD and asthma. This review examines the influence of signals from intestinal bacteria on the homeostasis of the mammalian immune system in the context of health and disease. We review the bacterial composition of the mammalian intestine, known bacterial-derived immunoregulatory molecules, and the mammalian innate immune receptors that recognize them. We discuss the influence of bacterial-derived signals on immune cell function and the mechanisms by which these signals modulate the development and progression of inflammatory disease. We conclude with an examination of successes and future challenges in using bacterial communities or their products in the prevention or treatment of human disease.
In 30 patients with cancer of the large bowel, 24 (80%) had detectable levels of methane in their breath, compared with 25 (39%) of 64 patients with non-malignant large-bowel disease and 83 (40%) of 208 subjects without large-bowel disease. These findings suggest that there may be a difference in anaerobic intestinal flora between patients with cancer of the large bowel and those without the disease. This difference may antedate the development of the tumour or, alternatively, result from the tumour.