Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens
"Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients[3,7], poisonoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23."
"Our study reveals that in the presence of IL-15, RA has unforeseen co-adjuvant properties that induce TH1 immunity to fed antigens (
Fig. 4f). It indicates further that under infectious conditions associated with induction of IL-15 and IL-6 in the intestinal mucosa, RA will also promote TH17 immunity. These observations caution against the use of poison A and RA for the treatment of autoimmunity and inflammatory intestinal disorders associated with high levels of IL-15. Indeed, a causal relationship between retinoids used for the treatment of acne and inflammatory bowel disease has been implicated in a subset of patients[25]."
"More generally, our study supports the concept that there are no ‘unconditional’ suppressive factors, and that integration of tissue and exogenous signals determine the class of the immune response, which ultimately needs to be tailored to the tissue and the antigen. In line with the idea that the same proinflammatory factors trigger different immunological outcomes depending on the tissue in which they are induced, we found that the ability of IL-12 to inhibit Treg-cell induction was blocked by butyrate, a metabolite produced by commensal bacteria present in the colon but not in the small bowel (data not shown)."
"Our observations may also explain why oral tolerance is disrupted in patients with inflammatory bowel disease[28] who also have dysregulated IL-15 expression in the gut[29]. Lastly, our results indicate that inhibiting IL-15 signalling may constitute a therapeutic intervention to restore mucosal tolerance to luminal antigens."
Insights into the Pathogenesis and Treatment of Psoriasis
"[..]dendritic cells and effector T-cells are important in the development of the psoriastic lesion, and cytokines produced by these cells stimulate keratinocytes to proliferate and increase the migration of inflammatory cells into the skin, promoting epidermal hyperplasia and inflammation (Monteleone, G. et al., 2011)."
"An increase in efficacy and reduction of adverse events are the main drivers for new therapies. Infections, one type of adverse event, usually increase in patients receiving anti-cytokine therapy (Dinarello, 2003)."
"Some inflammatory agents, whether physical, chemical, or infectious, induce an intense immune response. This immune response against them frequently results in tissue damage that could be more intense if it were not for the interference of regulatory mechanisms (Belkaid et al., 2006). As has already been specified, Treg cells help limit the damage caused by a vigorous immune response."
"Similarly, excessive activity of Treg cells may limit the magnitude of the immune response, which may result in failure to control an infection. On the other hand, the absence of the T regulator may result in intense inflammation and autoimmune dermatitis. Tissue damage may also result from the development of effector cells against their own auto-antigens (Figure 4)."
"An improved understanding of the role of T regulators in psoriasis may lead to the identification of new targets for treatment. More specifically, the goal is to manipulate natural regulator cells or those induced by means of an increase or decrease of their function, depending on the circumstances."
Immunopathogenesis of inflammatory bowel disease
"Altered gut permeability may lead to increased bacteria adherence and inappropriate exposure of the mucosal immune system to bacterial products causing inflammation."
"Negative regulation of the host innate immune responses to the indigenous microflora maintains gut homeostasis. Key players in the negative mucosal regulation include interleukin-10 (IL-10) and IL-2, as evidenced by mice with deficiencies in these factors develop spontaneous intestinal inflammation, but are protected from intestinal disease when raised in germ-free environments[77–>79]. This indicates that at steady state, pathologic consequences of immune activation by commensal microflora are constitutively inhibited by IL-10 and -2 dependent mechanisms."
"A subset of T cells producing IL-6 and IL-17, now known as Th17 cells, has emerged as an important mediator of the T-cell response in gut inflammation (Figure 4)."
"The above findings do not exclude the role of exaggerated Th1 response in CD since IL-12/IFN-γ and IL-23/IL-17 may be parallel pathways involved in inflammatory response. Interestingly, IL-12/IFN-γ and IL-23/IL17 pathways are mutually exclusive, since IFN-γ suppress IL-17 and vice versa (Figure 4)[104]. It is of pathogenic importance to consider all of the major immune pathways that are responsible for the development of CD. For example, therapeutic targeting of only the newly discovered IL-23/IL-17 immune axis may actually exacerbate CD by accelerating the IL-2/IFN-γ Th1 pathway."