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New Crohn’s Disease Hypothesis and IL-2 Regulates T cells
Continue reading New Crohn’s Disease Hypothesis and IL-2 Regulates T cells
Early Anti-TNF Has Benefits and the Nervous Gut Unraveled
Hit Them Early and Hit Them Hard
Specialists treating newly diagnosed cases of Crohn’s disease (CD) in children usually follow a specific treatment regimen: corticosteroids followed by immunomodulators, like azathioprine. However, scientists funded by the Crohn’s and Colitis Foundation of America wondered if better results could be obtained with another protocol, a protocol including early use of anti-TNFα. In a huge collaborative study using patients that were matched for age and disease severity, CD severity was followed for a year after initial treatments. It was discovered that early treatment with anti-TNFα led to a significantly better clinical and growth outcomes than the typical regimen.
Rifaximin Settles Gut Nerves
Some intestinal disturbances, including irritable bowel syndrome (IBS), can be attributed to what is called “visceral hyperalgesia,” a situation of heightened nerve sensitivity. The antibiotic rifaximin has shown promise for IBS treatment, but little was known about its mechanism. Using two visceral hyperalgesia models in rats based on chronic stress, scientists from the University of Michigan determined that these models were associated with alterations in the microflora, increased intestinal permeability and mucosal inflammation. Rifaximin, unlike a control antibiotic, eliminated these dysfunctions. The benefits appeared to be linked to an increase in beneficial bacteria species in the gut after treatment that was not found after other kinds of antibiotic treatment.
Mast Cells Behind Nervous Gut Permeability
Most of us are familiar with nervous gut trouble, especially when we have to speak in front of a crowd. Belgium scientists suspected that corticotropin-releasing hormone (CRH) could be playing a role in stress-induced gut permeability. After administering CRH to volunteers, they found changes in gut permeability similar to those found after public speaking. One target of CRH is the mast cell, which has all of the right tools to cause a good case of tummy trouble. To find out if the mast cell could be the culprit behind stomach butterflies, they asked volunteers to take the mast cell blocker disodium cromoglycate and either give a presentation or take CRH. Blocking mast cells alleviated intestinal permeability in both situations.
References
- Thomas D Walters, M. D., MiOk Kim, P. D., Lee A Denson, M. D., Anne M Griffiths, M. D., Marla Dubinsky, M. D., James Markowitz, M. D., et al. (2013). Comparative Effectiveness of Early Therapy with Anti-Tumor Necrosis Factor-α vs an Immunomodulator in Children With Crohn’s Disease. Gastroenterology, 1–30. doi:10.1053/j.gastro.2013.10.027
- Vanuytsel, T., van Wanrooy, S., Vanheel, H., Vanormelingen, C., Verschueren, S., Houben, E., et al. (2013). Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. doi:10.1136/gutjnl-2013-305690
- Xu, D., Gao, J., Gillilland, M., Wu, X., Song, Il, Kao, J. Y., & Owyang, C. (2013). Rifaximin Alters Intestinal Bacteria and Prevents Stress-Induced Gut Inflammation and Visceral Hyperalgesia in Rats. Gastroenterology, 1–48. doi:10.1053/j.gastro.2013.10.026
Lungs and Aire Offer New T Cell Control
Intestinal Immunity via the Nose
Many mucosal immunologists have assumed that effector T cells in the gut must be stimulated exclusively by gut dendritic cells. A recent publication in the Journal of Experimental Medicine shows otherwise. In a publication by Ruane et al, it is shown that lung T cells, activated via antigens coming from the nose, express gut homing molecules and travel to the intestines. They were even able to vaccinate mice in this way against a common, intestinal pathogen. This opens up interesting possibilities not only for intestinally-directed vaccination via the nose, but also for the possible role of the respiratory tract in the development of intestinal inflammatory diseases.
New Ways to Control T Cells Are in the Aire
The most well known way that T helper cells are controlled is through regulatory T cells. Now, a new cell type is taking the stage: extrathymic Aire-expressing cells or eTACs. Aire is a transcription factor normally expressed by cells in the thymus and controls negative selection of young T cells by allowing the expression of self-antigens. The eTACs are described as being similar to an antigen-presenting cells with immature characteristics and are located in human lymphoid tissue. Upon antigen expression, antigen-specific T cells were functionally inactivated in a murine model of pancreatitis. The authors noted that these cells induced a robust tolerance that appeared to be resistant to external danger-signals, like pattern-recognition receptor stimulation. This could make these cells extremely useful for treating patients with chronic inflammatory diseases with known antigens.
References
Gardner, J. M., Metzger, T. C., McMahon, E. J., Au-Yeung, B. B., Krawisz, A. K., Lu, W., et al. (2013). Extrathymic Aire-Expressing CellsAre a Distinct Bone Marrow-Derived Population that Induce Functional Inactivation of CD4. Immunity, 1–13. doi:10.1016/j.immuni.2013.08.005
Ruane, D., Brane, L., Reis, B. S., Cheong, C., Poles, J., Do, Y., et al. (2013). Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract. The Journal of experimental medicine, 210(9), 1871–1888. doi:10.1084/j
NOD2, Not Just Another Boring Receptor in Crohn’s Disease
NOD2 is one the most well known genes associated with Crohn’s disease (CD). Initial research regarding its role in immunology revealed that it’s an internal pattern-recognition receptor (PRR) that allows cells to detect invading bacteria and initiate pro-inflammatory cascades. This discovery led to some confusion as the null variation of the gene was associated with CD patients. Many asked the question, “how can the loss of something pro-inflammatory lead to more inflammation in the intestinal tract?” A Nod2-/- mouse was created, and, surprisingly, it did not develop spontaneous colitis, which stumped researchers even more. Although much research has been performed since the knock-out mouse was developed in 2005, there is still a lot to be learned.
Nod2-/- Mice Have Increased Intestinal Regulatory T Cells
Amedola et al attempted to find out why Nod2-/- mice did not get spontaneous colitis. They found that the main reason appeared to an increase of regulatory T cells (Tregs) with latent transforming growth factor-β (TGFβ). The population of these cells seemed to be dependent on the intestinal flora and the increased intestinal permeability of the Nod2-/- mice. Their ability to modulate colitis susceptibility was confirmed with transfer experiments. In a nutshell, their results showed that, in actuality, Nod2-/- mice were actually more resistant to some intestinal insults than their wild type counterparts, including TNBS colitis and ethanol-induced colitis.
Pellino3, a Downstream Mediator of Nod2
Underneath it all, Nod2 is a receptor like any other that initiates a signaling pathway. Studies under the “cellular” hood are also extremely useful for learning about how this PRR functions. Yang et al has now revealed that one mediator, Pellino3, is particularly important to Nod2 signaling. Pellino3 was revealed to be an ubiquitin ligase and performed its job on RIP2. Ubiquitination of RIP2 is needed for the activation of NF-κB and MAPKs via Nod2 stimulation. Loss of Pellino3 reduced the ability of cells to produce cytokines after Nod2 stimulation. Interestingly, loss of Pellino3 was also noted in CD patients, suggesting a loss of NOD2 signaling in patients. Pellino3-/- mice were also more susceptible to TNBS and Citrobacter colitis than wild types, which combined well with the human data. However, some of you may note that this TNBS result is different than what one would expect after reading Amedola article mentioned above.
CARD9, Not Just Another CARD in the Pack
Another name for NOD2 is CARD15. CARD stands for caspase recruitment domain-containing protein. As some of you might know, caspases are enzymes needed to process large proteins into more active, small ones. A good example of this is caspase 1, which cleaves the interleukin-1β protein into its active form. Sokol et al looked at CARD9, which functions as an adaptor protein downstream of PRRs that sense fungi. Using a Card9-/- mouse, they found that Card9 was needed to induce pro-inflammatory cytokines during intestinal trauma caused by DSS-induced colitis. Contrary to what one might first think, this actually led to a more severe colitis and a slower recovery. In particular, these mice had defective Th17 responses and loss of innate lymphoid cells. This was further confirmed in the Th17-restricted Citrobacter-colitis model, where the mice were unable to shake the infection. The authors refreshingly suggest that the loss of effective Th17 is actually not helpful and may actually be the reason for increased intestinal inflammation.
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References:
Amendola, A., Butera, A., Sanchez, M., Strober, W., & Boirivant, M. (2013). Nod2 deficiency is associated with an increased mucosal immunoregulatory response to commensal microorganisms. Mucosal Immunology. doi:10.1038/mi.2013.58
Sokol, H., Conway, K. L., Zhang, M., Choi, M., Morin, B., Cao, Z., et al. (2013). Card9 Mediates Intestinal Epithelial Cell Restitution, T-Helper 17 Responses, and Control of Bacterial Infection in Mice. Gastroenterology. doi:10.1053/j.gastro.2013.05.047
Yang, S., Wang, B., Humphries, F., Jackson, R., Healy, M. E., Bergin, R., et al. (2013). Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis. Nature immunology, 14(9