A pinboard by
Melanie Uhde

postdoctoral research scientist, Columbia University Medical Center


Celiac disease is an autoimmune disorder with genetic, environmental and immunological components that is triggered by the consumption of wheat gluten or related proteins of rye and barely in genetically susceptible individuals. The symptoms and signs can be gastrointestinal and extra-intestinal including abdominal pain, diarrhea, bone disease and anemia. Activation of the innate immune system presumably due to epithelial damage by non-immunogenic gliadin peptides and the ensuing epithelial stress response results in the infiltration and accumulation of intraepithelial lymphocytes (IELs), which are responsible for the destruction of the small intestinal epithelium and development of villous atrophy. Administration of and adherence to a gluten-free diet (GFD) is the only treatment that resolves symptoms and leads to a decrease of intestinal inflammation. Although the mechanisms underlying gliadin-mediated activation of T cells and B cells are well characterized, regulation and kinetics of IELs are yet to be fully understood.

The epithelial cell line harbors αβT cells, γδT cells and the newly described innate lymphoid cells (ILCs). A subgroup of ILCs has been shown to release IFN-γ in response to IL-15, a cytokine secreted by epithelial cells in the active state of celiac disease. Destruction of the epithelial barrier is a hallmark of the pathogenesis in celiac disease and we hypothesize that alteration of intraepithelial ILC composition potentially contributes to the development of the disease. Our goal is to better understand the biology of and effector function elicited by site-specific ILCs in celiac disease.


Innate Lymphoid Cells in Intestinal Inflammation.

Abstract: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestine that encompasses Crohn's disease (CD) and ulcerative colitis. The cause of IBD is unknown, but the evidence suggests that an aberrant immune response toward the commensal bacterial flora is responsible for disease in genetically susceptible individuals. Results from animal models of colitis and human studies indicate a role for innate lymphoid cells (ILC) in the pathogenesis of chronic intestinal inflammation in IBD. ILC are a population of lymphocytes that are enriched at mucosal sites, where they play a protective role against pathogens including extracellular bacteria, helminthes, and viruses. ILC lack an antigen-specific receptor, but can respond to environmental stress signals contributing to the rapid orchestration of an early immune response. Several subsets of ILC reflecting functional characteristics of T helper subsets have been described. ILC1 express the transcription factor T-bet and are characterized by secretion of IFNγ, ILC2 are GATA3(+) and secrete IL5 and IL13 and ILC3 depend on expression of RORγt and secrete IL17 and IL22. However, ILC retain a degree of plasticity depending on exposure to cytokines and environmental factors. IL23 responsive ILC have been implicated in the pathogenesis of colitis in several innate murine models through the production of IL17, IFNγ, and GM-CSF. We have previously identified IL23 responsive ILC in the human intestine and found that they accumulate in the inflamed colon and small bowel of patients with CD. Other studies have confirmed accumulation of ILC in CD with increased frequencies of IFNγ-secreting ILC1 in both the intestinal lamina propria and the epithelium. Moreover, IL23 driven IL22 producing ILC have been shown to drive bacteria-induced colitis-associated cancer in mice. Interestingly, our data show increased ILC accumulation in patients with IBD and primary sclerosing cholangitis, who carry an increased risk of developing colorectal cancer. ILC may play an important amplifying role in IBD and IBD-associated cancer, through secretion of inflammatory cytokines and interaction with other immune and non-immune cells. Here, we will review the evidence indicating a role for ILC in the pathogenesis of chronic intestinal inflammation.

Pub.: 31 Oct '17, Pinned: 31 Oct '17

Composition of innate lymphoid cell subsets in the human skin: enrichment of NCR(+) ILC3 in lesional skin and blood of psoriasis patients.

Abstract: Innate lymphoid cells (ILCs) are increasingly appreciated as important regulators of tissue homeostasis and inflammation. However, their role in human skin remains obscure. We found that healthy peripheral blood CD117(+) ILC3, lacking the natural cytotoxicity receptor (NCR) NKp44 (NCR(-) ILC3), CD117(-)NCR(-)CRTH2(-)CD161(+) ILC1, and CRTH2(+) ILC2, express the skin-homing receptor cutaneous lymphocyte antigen (CLA). NCR(+) ILC3 were scarce in peripheral blood. Consistently, we identified in normal skin ILC2 and NCR(-) ILC3, a small proportion of CD161(+) ILC1, and hardly any NCR(+) ILC3, whereas NCR(+) ILC3 were present in cultured dermal explants. The skin ILC2 and NCR(+) ILC3 subsets produced IL-13 and IL-22, respectively, upon cytokine stimulation. Remarkably, dermal NCR(-) ILC3 converted to NCR(+) ILC3 upon culture in IL-1β plus IL-23, cytokines known to be involved in psoriatic inflammation. In line with this observation, significantly increased proportions of NCR(+) ILC3 were present in lesional skin and peripheral blood of psoriasis patients as compared with skin and blood of healthy individuals, respectively, whereas the proportions of ILC2 and CD161(+) ILC1 remained unchanged. NCR(+) ILC3 from skin and blood of psoriasis patients produced IL-22, which is regarded as a key driver of epidermal thickening, suggesting that NCR(+) ILC3 may participate in psoriasis pathology.

Pub.: 25 Mar '14, Pinned: 17 Aug '17