Treatment Perspectives in Crohn’s Disease

Background: Crohn’s disease (CD) is a chronic immune-mediated disorder of the gastrointestinal tract. The pathophysiological understanding of this disease is limited and no curative therapy is available so far. Therefore, most patients require long-lasting or even life-long immunosuppressive therapies for the suppression of symptoms to improve quality of life and reduction of long-term risks. However, in a relevant subgroup of patients, these therapeutic goals cannot be sufficiently attained. Summary: Clinically established therapies in active CD comprise corticosteroids and immunosuppressants such as azathioprine. After the introduction of anti-TNFα (Tumor necrosis factor alpha) antibodies, other biologicals (e.g., vedolizumab and ustekinumab) have also been approved. New drugs in the pipeline like filgotinib, upadacitinib, risankizumab or rifaximin could improve the therapy of CD in the near future. Thus, an individualized therapy management, based on optimal selection of therapeutic agents will become more important. Additionally, the local application of mesenchymal stem cells might be helpful in the management of fistulas. Key Messages: The targeted biological therapeutic agents (anti-TNFα antibodies, vedolizumab, ustekinumab) are well established for therapy in CD. There are several new substances in the pipeline with promising results in phase II trials (filgotinib, rifaximin, risankizumab, upadacitinib). The upcoming extension of the therapeutic arsenal will require methods for an optimized selection of substances, thus enabling a more individualized therapy

Innate and Adaptive Immunity in Inflammatory Bowel Diseases

While barrier function and the effects of the intestinal microbiome have only recently moved into the focus of inflammatory bowel disease research, the role of the innate and the adaptive immune system in these gastrointestinal disorders has extensively been studied. Although still not completely understood, the increasing knowledge about the immune system's contribution to the pathophysiology of inflammatory bowel diseases has led to new diagnostic and therapeutic approaches. This review gives a compact overview on this important topic

Confocal Laser Endomicroscopy for Diagnosis of Barrett’s Esophagus

Barrett’s esophagus (BE) is established as a premalignant condition in the distal esophagus. Current surveillance guidelines recommend random biopsies every 1–2 cm at intervals of 3–5 years. Advanced endoscopic imaging of BE underwent several technical revolutions within the last decade including broad-field (red-flag) techniques (e.g., chromoendoscopy) and small-field techniques with confocal laser endomicroscopy (CLE) at the forefront. In this review we will focus on advanced endoscopic imaging using CLE for the diagnosis and characterization of BE and associated neoplasia. In addition, we will critically discuss the technique of CLE and provide some tricks and hints for the daily routine practice of CLE for diagnosis of BE

Functional Contribution and Targeted Migration of Group-2 Innate Lymphoid Cells in Inflammatory Lung Diseases: Being at the Right Place at the Right Time

During the last decade, group-2 innate lymphoid cells (ILC2s) have been discovered and successfully established as crucial mediators of lung allergy, airway inflammation and fibrosis, thus affecting the pathogenesis and clinical course of many respiratory diseases, like for instance asthma, cystic fibrosis and chronic rhinosinusitis. As an important regulatory component in this context, the local pulmonary milieu at inflammatory tissue sites does not only determine the activation status of lung-infiltrating ILC2s, but also influences their motility and migratory behavior. In general, many data collected in recent murine and human studies argued against the former concept of a very strict tissue residency of innate lymphoid cells (ILCs) and instead pointed to a context-dependent homing capacity of peripheral blood ILC precursors and the inflammation-dependent capacity of specific ILC subsets for interorgan trafficking. In this review article, we provide a comprehensive overview of the so far described molecular mechanisms underlying the pulmonary migration of ILC2s and thereby the numeric regulation of local ILC2 pools at inflamed or fibrotic pulmonary tissue sites and discuss their potential to serve as innovative therapeutic targets in the treatment of inflammatory lung diseases

Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells

AbstractOX40 is a member of the TNF/NGF-receptor family expressed on activated T cells, whose ligand is found on activated T and B cells. In the present study, we show that cross-linking of OX40L on CD40L-stimulated B cells, αlgD dextran-stimulated B cells, or both results in a significantly enhanced proliferative response with no change In the cell survival rate. Furthermore, OX40 stimulation increases Immunoglobulin heavy chain mRNA levels and Immunoglobulin secretion, which could not be blocked by anti-cytokine antibodies. In additional molecular studies, we show that OX40L cross-linking results In the down-regulation of the transcription factor BSAP. This, In turn, leads to a change In the In vivo binding pattern of the imunoglobulin heavy chain gene 3′ α enhancer, suggesting its activation. This effect may thus be one mechanism for OX40-induced Increase In Immunoglobulin secretion. In conclusion, our data suggest that the OX40-OX40L interaction is a novel pathway in T cell-dependent B cell proliferation and differentiation

Advanced Endoscopic Imaging for Diagnosis of Crohn's Disease

Endoscopy in IBD has tremendous importance to diagnose inflammatory activity, to evaluate therapeutic success and for the surveillance of colitis associated cancer. Thus it becomes obvious that there is a need for new and more advanced endoscopic imaging techniques for better characterization of mucosal inflammation and early neoplasia detection in IBD. This paper describes the concept of advanced endoscopic imaging for the diagnosis and characterization of Crohn's disease, including magnification endoscopy, chromoendoscopy, balloon-assisted enteroscopy, capsule endoscopy, confocal laser endomicroscopy, and endocytoscopy

Eosinophilic gastroenteritis with refractory ulcer disease and gastrointestinal bleeding as a rare manifestation of seronegative gastrointestinal food allergy

Gastrointestinal bleeding and iron deficiency anaemia may cause severe symptoms and may require extensive diagnostics and substantial amounts of health resources. This case report focuses on the clinical presentation of a 22 year old patient with recurrent gastrointestinal bleeding from multilocular non-healing ulcers of the stomach, duodenum and jejunum over a period of four years. Extensive gastroenterological and allergological standard diagnostic procedures showed benign ulcerative lesions with tissue eosinophilia, but no conclusive diagnosis. Multiple diagnostic procedures were performed, until finally, endoscopically guided segmental gut lavage identified locally produced, intestinal IgE antibodies by fluoro-enzyme-immunoassay. IgE antibody concentrations at the intestinal level were found to be more-fold increased for total IgE and food-specific IgE against nuts, rye flour, wheat flour, pork, beef and egg yolk compared with healthy controls. Thus, a diet eliminating these allergens was introduced along with antihistamines and administration of a hypoallergenic formula, which resulted in complete healing of the multilocular ulcers with resolution of gastrointestinal bleeding. All gastrointestinal lesions disappeared and total serum IgE levels dropped to normal within 9 months. The patient has been in remission now for more than two years. Eosinophilic gastroenteritis (EG) is well known to induce refractory ulcer disease. In this case, the mechanisms for intestinal damage and gastrointestinal bleeding were identified as local gastrointestinal type I allergy. Therefore, future diagnostics in EG should also be focused on the intestinal level as identification of causative food-specific IgE antibodies proved to be effective to induce remission in this patient

Group 2 Innate Lymphoid Cells (ILC2) Suppress Beneficial Type 1 Immune Responses During Pulmonary Cryptococcosis

Cryptococcus neoformans is an opportunistic fungal pathogen preferentially causing disease in immunocompromised individuals such as organ-transplant-recipients, patients receiving immunosuppressive medications or, in particular, individuals suffering from HIV infection. Numerous studies clearly indicated that the control of C. neoformans infections is strongly dependent on a prototypic type 1 immune response and classical macrophage activation, whereas type 2-biased immunity and alternative activation of macrophages has been rather implicated in disease progression and detrimental outcomes. However, little is known about regulatory pathways modulating and balancing immune responses during early phases of pulmonary cryptococcosis. Here, we analyzed the role of group 2 innate lymphoid cells (ILC2s) for the control of C. neoformans infection. Using an intranasal infection model with a highly virulent C. neoformans strain, we found that ILC2 numbers were strongly increased in C. neoformans-infected lungs along with induction of a type 2 response. Mice lacking ILC2s due to conditional deficiency of the transcription factor RAR-related orphan receptor alpha (Rora) displayed a massive downregulation of features of type 2 immunity as reflected by reduced levels of the type 2 signature cytokines IL-4, IL-5, and IL-13 at 14 days post-infection. Moreover, ILC2 deficiency was accompanied with increased type 1 immunity and classical macrophage activation, while the pulmonary numbers of eosinophils and alternatively activated macrophages were reduced in these mice. Importantly, this shift in pulmonary macrophage polarization in ILC2-deficient mice correlated with improved fungal control and prolonged survival of infected mice. Conversely, adoptive transfer of ILC2s was associated with a type 2 bias associated with less efficient anti-fungal immunity in lungs of recipient mice. Collectively, our date indicate a non-redundant role of ILC2 in orchestrating myeloid anti-cryptococcal immune responses toward a disease exacerbating phenotype

Reframing immune-mediated inflammatory diseases through signature cytokine hubs

No abstract available