No abstract

Crohn's disease [CD] is a chronic relapsing systemic disease affecting the gastrointestinal tract. An altered immune response to commensal intestinal bacteria takes place in genetically predisposed individuals, resulting in chronic inflammation in the gut. Several alterations in the innate immunity mechanisms have been described in recent years. Thus, the study of the immunological aspects of CD, specifically the role of lymphocytes, is a key element for understanding the pathogenesis of the disease.Gammadelta T cells [γδ T cells] constitute only a small proportion of the lymphocytes that circulate in the blood and peripheral organs and they are present mainly in the epithelia, where they can constitute up to 40% of intraepithelial lymphocytes [IEL] in the intestinal mucosa. Due to their lack of major histocompatibility complex [MHC] restriction and their unique plasticity and immune-regulating properties, they are considered key cells in the first line of defence against infections and in wound healing in the gut. Although there is growing experimental and clinical evidence of their implication in inflammatory bowel disease [IBD], including CD, their clinical relevance is still unclear.In this review, we address the possible involvement of γδ T cells in the pathogenesis of CD, reviewing their role against infections and in inflammation and the current evidence suggesting their implication in CD, offering a novel potential target for immunotherapy in IBD.

Inflammatory bowel disease (IBD) is a chronic disabling inflammatory process that affects young individuals, with growing incidence. The etiopathogenesis of IBD remains poorly understood. A combination of genetic and environmental factors triggers an inadequate immune response against the commensal intestinal flora in IBD patients. Thus, a better understanding of the immunological mechanisms involved in IBD pathogenesis is central to the development of new therapeutic options. Current pharmacological treatments used in clinical practice like thiopurines or anti-TNF are effective but can produce significant side effects and their efficacy may diminish over time. In fact, up to one third of the patients do not have a satisfactory response to these therapies. Consequently, the search for new therapeutic strategies targeting alternative immunological pathways has intensified. Several new oral and parenteral substances are in the pipeline for IBD. In this review we discuss novel therapies targeting alternative pro-inflammatory pathways like IL-12/23 axis, IL-6 pathway or Janus Kinase inhibitors; as well as others modulating anti-inflammatory signalling pathways like transforming growth factor-β1 (TGF-β1). We also highlight new emerging therapies targeting the adhesion and migration of leukocytes into the inflamed intestinal mucosa by blocking selectively different subunits of αβ integrins or binding alternative adhesion molecules like MAdCAM-1. Drugs reducing the circulating lymphocytes by sequestering them in secondary lymphoid organs (sphingosine-1-phosphate (S1P) receptor modulators) are also discussed. Finally, the latest advances in cell therapies using mesenchymal stem cells or engineered T regs are reviewed. In addition, we provide an update on the current status in clinical trials of these new immune-regulating therapies that open a new era in the treatment of IBD.

BackgroundThe cause of Crohn's Disease (CD) remains unknown. Recently a decrease in the global lymphocyte population in the peripheral blood of CD patients has been reported. This decrease was more evident in γδ T lymphocytes, especially γδ CD8+T subsets. Furthermore, a decrease of IL-7 was also observed in these patients. We propose the hypothesis that microsporidia, an obligate intracellular opportunistic parasite recently related to fungi, in CD patients can take advantage of the lymphocytes and IL-7 deficits to proliferate and to contribute to the pathophysiology of this disease.Methods and FindingsIn this case-control study, serum samples were collected from 36 CD patients and from 36 healthy individuals (controls), IgE and IgG anti-Encephalitozoon antibodies were determined by ELISA; and forty-four intestinal tissue samples were analyzed through real time Polymerase Chain Reaction (PCR), twenty CD patients, nine with others diseases and 15 healthy subjects.We observed that IgE anti-Encephalitozoon levels were significantly higher in patients with CD: 0.386(±0.256) vs control group, 0.201(±0.147), P<0.001. However, IgG anti-Encephalitozoon values were significantly lower in CD patients: 0.361(±0.256) vs control group, 0.876(±0.380), P<0.001. In the group of CD patients, 6/20 (30%) were positive by real time PCR for microsporidia and, all the patients of the control group were negative by real time PCR.ConclusionsThese results suggest that CD patients are a group at risk for microsporidiasis and, moreover that microsporidia may be involved as a possible etiologic factor of CD.

There is a decrease in the global lymphocyte population in the peripheral blood of patients with CD compared to healthy controls. This decrease is more evident in γδ T lymphocytes, especially γδ CD8+ T subsets. Our conclusion is that these results support the theory that a complex alteration of immune responses that affects the total numbers and function of γδ T cells is present in CD.