Tag Archives: Dendritic cells

Regulatory T cell Development and Crohn’s Disease Siblings

Albert Anker Schreibender Knabe mit Schwesterchen I 1875
Siblings of Crohn’s disease patients have signs of inflammation.
This week on TIBDI: A gene behind very early onset inflammatory bowel disease (IBD) is uncovered, the receptor needed for colon regulatory T cell development is found and siblings of Crohn’s disease (CD) patients have signs of nascent intestinal inflammation.

Gene Behind Early Onset IBD

While many IBD cases are diagnosed during young adulthood and middle age, there is subset of patients that develop the disease before the age of six. To determine if there were certain mutated genes behind this early disease presentation, scientists from a multitude of institutions examined the DNA of children with very early onset IBD. They found that the children had loss of function mutations in the gene for tetratricopeptide repeat domain 7 (TTC7A). TTC7A is involved with phosphatidylinositol-4 kinase signaling. When the researchers specifically knocked down this gene in intestinal cell lines, they found that the cells lost adhesion and had increased apoptosis. This supported the clinical presentation in the children studied, which was marked by apoptotic enterocolitis.

Regulatory T cell development with GPR109A

Butyrate, a short chain fatty acid (SCFA) produced by intestinal bacteria, was recently shown to induce regulatory T cells in the colon. Scientists from Georgia Regents University have now clarified this effect even further by discovering the butyrate receptor behind increased regulatory T cells. This receptor is GPR109A, and it is also the receptor for the B vitamin niacin. They found that both butyrate and niacin gave anti-inflammatory properties to dendritic cells and macrophages via GPR109A, which encouraged Foxp3 and IL-10 expression in T cells. In colitis models, loss of the receptor led to severe disease. Studies using germ-free mice suggested that regulatory T cell defects caused by the loss of microbiota-derived butyrate could potentially be replaced by pharmacological doses of niacin.

CD Siblings As CD Models

Sisters and brothers of CD patients have an increased risk of developing disease. Initial studies of these potential patients show that they have some signs of intestinal inflammation like increased fecal calprotectin and intestinal permeability. Scientists from the United Kingdom have now investigated further and found that CD patients and their siblings have other striking similarities, such as abnormal changes in the intestinal microbiota and T cell phenotypes. The siblings were significantly different from control healthy populations, making them an unique “at risk” group. The researchers feel that studies of patient siblings could lead to new insights about the immune processes that lead to full blown CD.

References

Autophagy Explored and the Role of CD103+CD11b+ Dendritic Cells

Macrophage
Autophagy defects can lead to more phagocytosis in macrophages.
Deficient autophagy causes an increase of phagocytosis, micro-RNAs control autophagy genes in Crohn’s disease and surprising results after gut dendritic cell depletion.

Autophagy Mediates Phagocytosis

Mutations in genes involved in autophagy are often found in patients with Crohn’s disease (CD). Autophagy or “self eating” is the process that a cell uses to re-process its own organelles and proteins. It also is related to phagocytosis, the mechanism used by phagocytic cells to engulf particles in their direct environment. Autophagy helps direct the digestion of engulfed particles. Scientists from the Baylor College of Medicine asked themselves if deficiencies in autophagy could also be correlated with problems in phagocytosis. For this they used Atg7 deficient mice, which miss a key autophagy gene. They found that these mice had macrophages with exceptional phagocytic capacities. This was caused by an increase of scavenger receptor expression. During Mycobacteria infection, these mice also displayed worse symptoms due to the higher Mycobacteria loads in the macrophages.

Micro-RNA Mediated Loss of Autophagy in Crohn’s Disease

Micro-RNAs control gene expression by binding and blocking mRNAs needed for protein translation. Using human cell lines and CD patient colon tissues, researchers from the University of Alabama investigated if micro-RNAs were involved in the control of the gene ATG16L1, which is a known mutated autophagy gene in CD. By controlling the levels of two micro-RNAs, MIR106B and MIR93, they were able to influence the expression of ATG16L1, the formation of autophagosomes and the process of autophagy in an in vitro model of bacterial infection. An examination of CD colon tissue also found an unusual increase of MIR106B along with a decrease of ATG16L1, which would lead one to conclude that there could be reduced antibacterial activity in CD colons.

Gut Dendritic Cells: Modulate T Cells and Not Microflora

Using a complex transgenic mouse expressing human proteins in lamina propria dendritic cells (DCs), researchers from the University of Minnesota found they had the perfect model to specifically deplete CD103+CD11b+ DCs, known to be needed to generate crucial, antimicrobial T helper 17 (Th17) responses. Interestingly, the loss of these cells did not cause increased susceptibility to two well known, intestinal bacterial infections (Citrobacter and Salmonella). This is surprising as the normal generation Th17 cells was impaired in the DC deficient mice. These mice also had no changes in their microflora suggesting that the loss of DCs had no affect on bacterial populations in the gut. One caveat of this study is that they did not show the populations of Th17 cells during the bacterial infections.

Do you have an opinion about any of these findings? Please let us know in the comments below!

References

Th17 in the Human Gut and Bacteria Talk to Neurons

Unipolar Sensory Neuron
Bacteria can cause pain by interacting directly with neurons in the gut.
Crohn’s disease patients have more T helper 17-inducing lamina propria cells, bacteria activate pain neurons and retinoic acid determines the fate of pre-dendritic cells.

T helper 17 Cell Induction in the Human Gut

It’s easy to forget with the all the mouse immunology research that many things about gut Th17 cells haven’t been described with human cells. Now we are one step further. The journal Gastroenterology has an article in press that describes the induction of Th17 cells from human-derived, lamina propria cells. Using cells isolated from Crohn’s disease patient and control intestinal samples, Japanese scientists found an antigen-presenting cell population with a monocyte/macrophage lineage that was extremely good at inducing Th17 cells from naïve T cells. While both patient and control cells both could induce Th17, Crohn’s disease patient cells were the most effective. Th17 cells are suggested to play a role in Crohn’s disease, and this result supports this idea even more.

Bacteria and Nociceptors, Talking Together

Most of us have heard the term, “the second brain,” when people are referring to the neural networks within the intestinal system. Sensory neurons called nociceptors are responsible for the pain sensation. During intestinal Staphylococcus aureus infection, pain is induced, and, for a long time, it was assumed to be caused inflammatory mediators interacting with the pain neurons. Chiu et al, in the most recent issue of Nature, have now shown that, in actuality, it’s the bacteria that are directly activating the nociceptors. Furthermore, in neuron ablation experiments, they discovered that the nociceptors could influence inflammation. Interestingly, the communication wasn’t via pattern recognition receptors. Instead, the communication mediators were formylated peptides and α-haemolysis, a pore-forming toxin, produced by S. aureus. In the future, it will be interesting to find out how friendly commensals interact with nociceptors. They could form a novel way of modulating the immune response during intestinal inflammation.

Choosy Pre-Dendritic Cells Choose Retinoic Acid

Retinoic acid has a variety of effects within the gut-associated immune system, and it is known to influence the generation of different kinds of dendritic cells (DCs). However, it wasn’t known precisely when retinoic acid was having an effect on DC generation from pre-DCs or how it was affecting systemic DC populations. Scientists from the National Institute of Health now know the answer to both questions. They found that a retinoic acid deficiency caused a reduction in pre-DC-derived conventional DCs in both the spleen (CD11b+CD8α-Esamhigh DCs) and the gut (CD11b+CD103+ DCs), while populations of several other DC types were not affected. By transferring pre-DCs to different hosts with different retinoic acid levels, the scientists determined that ambient retinoic acid levels controls the fate of pre-DC. As conventional DCs are necessary for sufficient protective immune responses, this highlights the importance of vitamin A (precursor of retinoic acid) supplementation during mucosal stress.

References

 

Lungs and Aire Offer New T Cell Control

Nimm dich selbst by der Nase
The nose may be a crucial player in initiating intestinal immunity.
New, interesting ways of controlling the immune system were published this week. The nose offers a new way to direct T cells to go to the gut and myeloid cells expressing the transcription factor Aire stop T helper cells in their tracks.

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

Creeping Fat in Crohn’s Disease Leads to Creeping Dendritic Cells

Creeping fat is a form of mesenteric fat that's found in Crohn's disease patients.
Creeping fat is a form of mesenteric fat that’s found in Crohn’s disease patients.

An article in Mucosal Immunology shows that the creeping fat factor, leptin, can cause dendritic cells to become more migratory in Crohn’s disease. Could this be the key to disease progression?

Visit my recent post to learn more about creeping fat.

For this post, there was certainly no lack of interesting options. The journal, Science, just posted an article on the long-term stability of gut microbiota and an article looking at the way that microbiota control regulatory T cell populations. Immunity hosted an article about RORγt innate lymphoid cells and three additional articles about how microbiota interact with and modulate the immune system. I appreciate all of the press that microbiota are now getting, but after my last post and the whole Nature Immunology series on microbiota, it’s time to think of something else. Mucosal Immunology had something different and interesting. In an article by Al-Hassi et al., is a story about Crohn’s disease, fat and dendritic cell migration.

Dendritic cells (DCs) are the scouts of the immune system. They hide out in the peripheral regions of the body, detecting and collecting information on invaders. Once they have collected this information, they become activated and travel to local lymph nodes and alert T cells. This activation process includes the expression of receptors that allow them to detect the signals produced by lymph nodes. C-C motif chemokine receptor 7 (CCR7) is the most important of these receptors, and it recognizes three different ligands produced by lymph nodes and the lymphatic endothelia: CCL19 and two variants of CCL21.

Al-Hassi et al. noted that in Crohn’s disease (CD), there is an increase of mesenteric fat that surrounds the inflamed intestines. This fat is called “creeping fat,” and its adipocytes secrete large amounts of inflammatory mediators, including a mediator called leptin. Leptin is well-known for its ability to modulate DC behavior and encourage a T helper type 1 (Th1) response via leptin receptors (LepRs). Furthermore, leptin encourages the expression of CCR7 on DCs and prolongs their lifespan. The researchers hypothesized that creeping fat via leptin could control DC responses in CD, increasing their ability to travel to local lymph nodes and initiate pro-inflammatory responses.

They first looked at the expression of CCR7 and LepRb on DCs isolated from the colons of healthy individuals. LepRb distinguishes itself from other LepRs by being the only one that can activate the transcription factor, STAT3, which is important for initiating pro-inflammatory gene expression and preventing apoptosis. They found that DCs isolated from the small intestine of healthy individuals expressed both these receptors, but not DCs from the colon. However, in the CD patient DCs, this was different. DCs from CD colons also expressed the receptors too.

Looking at the maturation status between DCs collected from both healthy and patient intestinal samples. They found no real difference indicating that the increased expression of CCR7 and LepRb was not related to the activation status of the DCs themselves. They then performed experiments of a more mechanistic nature, by exposing colon DC from healthy donors to leptin. They found that this led to extensive CCR7 expression (10% to 60%) and the migratory capacity was also sharply increased towards CCL19.

To give the same experiment a more physiological swing, they collected culture supernatant from CD biopsies and added this to isolated, healthy colonic DCs. This also caused the upregulation of CCR7, and the addition of a LepR blocking antibody eliminated the effect, indicating that the likely factor controlling the CCR7 upregulation was the leptin secreted into the supernatant from the CD biopsies.

Although this is a small study, it has a strong message, and one that will probably lead to even more exciting studies. In the discussion, they consider that the difference of expression between small and large intestinal DC may have something to do with increased traffic for the transport of self-antigen to lymph nodes to perpetrate oral tolerance in local T cell populations, which could very well be true. Furthermore, they note that creeping fat does appear early in CD giving it an even better chance to affect CD progression in the long-term.

However, Gut published an article about macrophage populations in creeping fat in June. These researchers found that mediators secreted by the creeping fat adipocytes actually encouraged the M2 macrophage type, which is associated with IL-10 production and an anti-inflammatory function. They speculated that this would indicate a protective role for creeping fat in CD, not a story that fits with the ideas of Al-Hassi et al.

Which leaves us with a lot of questions. While I am convinced of the good intentions of the macrophages in the aforementioned study, I am not convinced about the innocence of the creeping fat. Adipocytes of creeping fat produce many more pro-inflammatory factors besides leptin, and TNFα is one of them. My opinion is that the anti-inflammatory nature of the creeping fat macrophages is more a response to being bathed consistently with pro-inflammatory factors. Their response would then be somewhat similar to the myeloid suppressor cell phenomenon.

Experiments need to be done that look at how dangerous leptin-exposed, CCR7+ DC are in CD patients and examine the real role of creeping fat. Is it the initiator, a propagator or protector in CD?

Thanks for reading. Please let me know what you think about creeping fat in IBD! If you need a bit more background in immunology, visit my basic immunology page.

References:

Al-Hassi, H. O., Bernardo, D., Murugananthan, A. U., Mann, E. R., English, N. R., Jones, A., et al. (2012). A mechanistic role for leptin in human dendritic cell migration: differences between ileum and colon in health and Crohn’s disease. Mucosal Immunology, 6(4), 751–761. doi:10.1038/mi.2012.113

Fink, C., Karagiannides, I., Bakirtzi, K., & Pothoulakis, C. (2012). Adipose Tissue and Inflammatory Bowel Disease Pathogenesis. Inflammatory Bowel Diseases, 18(8), 1550–1557. doi:10.1002/ibd.22893

Kredel, L. I., Batra, A., Stroh, T., Kuhl, A. A., Zeitz, M., Erben, U., & Siegmund, B. (2013). Adipokines from local fat cells shape the macrophage compartment of the creeping fat in Crohn’s disease. Gut, 62(6), 852–862. doi:10.1136/gutjnl-2011-301424

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