The abundance of innate and adaptive immune cells that reside together with trillions of beneficial commensal microorganisms in the mammalian gastrointestinal tract requires barrier and regulatory mechanisms that conserve host-microbial interactions and tissue homeostasis. This homeostasis depends on the diverse functions of intestinal epithelial cells (IECs), which include the physical segregation of commensal bacteria and the integration of microbial signals. Hence, IECs are crucial mediators of intestinal homeostasis that enable the establishment of an immunological environment permissive to colonization by commensal bacteria. In this Review, we provide a comprehensive overview of how IECs maintain host-commensal microbial relationships and immune cell homeostasis in the intestine.

Intestinal epithelial cells: regulators of barrier function and immune homeostasis

Erroneous communication between the innate and adaptive immune systems through cytokines results in exaggerated or attenuated immune response. It is not known whether the pathologic immune response in inflammatory bowel disease has its origin in a dysbalance of pro- and anti-inflammatory cytokine release or whether it is secondary in subsequence of a defective intestinal barrier or the destructive power of aggressive microbiota in the gut lumen.

Cytokines in inflammatory bowel disease

Crohn's disease

IBD is a chronic inflammatory condition of the gastrointestinal tract encompassing two main clinical entities: Crohn's disease and ulcerative colitis. Although Crohn's disease and ulcerative colitis have historically been studied together because they share common features (such as symptoms, structural damage and therapy), it is now clear that they represent two distinct pathophysiological entities. Both Crohn's disease and ulcerative colitis are associated with multiple pathogenic factors including environmental changes, an array of susceptibility gene variants, a qualitatively and quantitatively abnormal gut microbiota and a broadly dysregulated immune response. In spite of this realization and the identification of seemingly pertinent environmental, genetic, microbial and immune factors, a full understanding of IBD pathogenesis is still out of reach and, consequently, treatment is far from optimal. An important reason for this unsatisfactory situation is the currently limited comprehension of what are the truly relevant components of IBD immunopathogenesis. This article will comprehensively review current knowledge of the classic immune components and will expand the concept of IBD immunopathogenesis to include various cells, mediators and pathways that have not been traditionally associated with disease mechanisms, but that profoundly affect the overall intestinal inflammatory process.

Immunopathogenesis of IBD: current state of the art

Innate lymphoid cells (ILCs) are effectors of innate immunity and regulators of tissue modeling Recently identified ILC populations have a cytokine expression pattern that resembles that of the helper T cell subsets T(H)2, T(H)17 and T(H)22 Here we describe a distinct ILC subset similar to T(H)1 cells, which we call 'ILC1' ILC1 cells expressed the transcription factor T-bet and responded to interleukin 12 (IL-12) by producing interferon-γ (IFN-γ) ILC1 cells were distinct from natural killer (NK) cells as they lacked perforin, granzyme B and the NK cell markers CD56, CD16 and CD94, and could develop from RORγt(+) ILC3 under the influence of IL-12 The frequency of the ILC1 subset was much higher in inflamed intestine of people with Crohn's disease, which indicated a role for these IFN-γ-producing ILC1 cells in the pathogenesis of gut mucosal inflammation

http://www.dendritics.net/files/documentation/Bernink_JH_et_al,_2013,_R34-34.pdf

Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues

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.

https://rupress.org/jem/article-pdf/208/6/1127/1205034/jem_20101712.pdf

IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease

CD4 Th cells producing the proinflammatory cytokine IL-17 (Th17) have been implicated in a number of inflammatory arthritides including the spondyloarthritides. Th17 development is promoted by IL-23. Ankylosing spondylitis, the most common spondyloarthritis (SpA), is genetically associated with both HLA-B27 (B27) and IL-23R polymorphisms; however, the link remains unexplained. We have previously shown that B27 can form H chain dimers (termed B272), which, unlike classical HLA-B27, bind the killer-cell Ig-like receptor KIR3DL2. In this article, we show that B272-expressing APCs stimulate the survival, proliferation, and IL-17 production of KIR3DL2+ CD4 T cells. KIR3DL2+ CD4 T cells are expanded and enriched for IL-17 production in the blood and synovial fluid of patients with SpA. Despite KIR3DL2+ cells comprising a mean of just 15% of CD4 T in the peripheral blood of SpA patients, this subset accounted for 70% of the observed increase in Th17 numbers in SpA patients compared with control subjects. TCR-stimulated peripheral blood KIR3DL2+ CD4 T cell lines from SpA patients secreted 4-fold more IL-17 than KIR3DL2+ lines from controls or KIR3DL2− CD4 T cells. Strikingly, KIR3DL2+ CD4 T cells account for the majority of peripheral blood CD4 T cell IL-23R expression and produce more IL-17 in the presence of IL-23. Our findings link HLA-B27 with IL-17 production and suggest new therapeutic strategies in ankylosing spondylitis/SpA.

Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis.

Bacterial infections remain a leading cause of morbidity and mortality worldwide. However, only little is known about host-pathogen relationships depending on the nature of the causative species, and whether and how this interaction has implications for local immune responses and clinical outcome. cd T cells play a pivotal role in sensing ‘danger’ signals from invading pathogens through their abilityto recognize the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) produced by many Gram+ and Gram- bacteria. In this study we characterized the local immune responses in episodes of acute peritoneal dialysis-associated peritonitis by multi-color flow cytometry and multiplex ELISA and validated the clinical relevance for patient and technique survival in independent patient cohorts comprising a total of 2307 (ANZDATA Registry, Australia) and 372 PD patients (University Hospital of North Staffordshire, UK), respectively. Episodes were groupedaccording to the result of organism culture into culture-negative and HMB-PP+ (e.g. Corynebacterium, E. coli, Pseudomonas) or HMB-PP- (e.g. Enterococcus, Staphylococcus, Streptococcus) culture-positive infections. Our findings demonstrate that culture-positive peritonitis was associated with worse clinical outcome. Within the culturepositive group, the capacity of the causative pathogen to produce HMB-PP together with peritoneal infiltrates of activated cd T cells and increased peritoneal levels of TNF-a and MMP-3 during bacterial infection were indicative of detrimental inflammatory responses. Our results implicate HMB-PP responsive cd T cells in the nature and severity of the peritoneal immune response to bacterial infection, which may be of diagnostic, predictive and therapeutic value for acutely infected patients.

M Fleming

Papers

IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease

Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis.

The HMB-PP producing capacity of the causative pathogen and local gamma delta T cell numbers predict clinical outcome from bacterial peritonitis

Very extensive small bowel stricturing disease

The patient with rectal bleeding