This week on TIBDI! Gene expression signatures of anti-TNFα non-responders are investigated, breast milk oligosaccharides regulate developing immune responses, and an anti-CD3 antibody offers hope for T cell regulation in the gut.
Inflammatory Signatures of Anti-TNFα Non-Responders
Even though anti-TNFα therapy for Crohn’s disease (CD) patients is very effective, up to 40% of patients are or become non-responders. To find out if there were differences in gene expression between these groups of patients, Dr. Raquel Franco Leal of the Hospital Clinic in Barcelona Spain examined mRNA levels of inflammatory genes in these two populations. She found that treatment with anti-TNFα effectively regulated many cytokines and chemokine genes despite the clinical outcome. However, those that achieved a clinical remission also had a number of changes in many other genes including IL1B, S100A8 and CXCL1. In contrast, refractory patients continued to have deregulated genes associated with pathways inducing IL17A. Besides introducing new drugs targets, these results reemphasize the importance of IL-17 pathways in CD.
Developing Immune Systems Need Milk
The complex immunoregulatory mechanisms needed to protect and control the human gut are developed early after birth, and are catalyzed by the colonization of the intestinal tract with bacteria. Suspecting that breast milk may protect the early intestinal tract from unwanted inflammatory responses, Dr. Y. He and colleagues investigated human milk oligosaccharides from colostrum (cHMOSs). Using human fetal intestine explants, they were able to determine that cHMOSs significantly altered immune gene expression. Their model suggests that cHMOSs attenuate pathogen-associated receptor signaling, simultaneously lowering immune cell activation and enhancing pathways needed for clearance, regulation and tissue repair.
T cells likely play an important role in inflammatory bowel disease (IBD) by maintaining inflammatory responses. Finding a way to specifically reduce or deactivate these cells in IBD patients could be a possible therapy. Dr. Anna Vossenkämper, together her colleagues, experimented with this idea using a special anti-CD3 antibody called otelixizumab, which is known to induce tolerance. Using mucosal biopsies from IBD patients, she was able to determine that otelixizumab could decrease pro-inflammatory cytokine production and lower the activity of multiple immune pathways. The antibody’s effects were determined to be dependent on IL-10 expression.
This week on TIBDI! Neutrophils shed a protein that disrupts the intestinal barrier, hormones and T cells are behind Crohn’s disease gender skewing, and CD31 is the newest way to make dendritic cells anti-inflammatory.
Neutrophils Bust Up the Intestinal Barrier
During inflammatory bowel disease (IBD), neutrophils gather at sites of inflammation and often migrate through the intestinal epithelial barrier. A new model described by Dr. Dominique A. Weber and Dr. Ronen Sumagin now shows how dangerous this behavior is for intestinal wound healing. They found that neutrophils shed junctional adhesion molecule-like protein (JAML) during epithelial transmigration. JAML binds to a receptor found on epithelial cells called coxsackie-adenovirus receptor (CAR), and JAML and CAR interactions cause epithelial barriers to become leaky. While this leakiness may be needed for initial efficient immune cell infiltration, shed JAML prevents the barrier from regaining normal function and stops wound closure. Experiments showed that blocking JAML-CAR interactions could lead to accelerated wound repair. This discovery could help treat IBD-induced intestinal ulcerations.
Why Crohn’s Disease Prefers Women
There is a general acceptance that the prevalence of Crohn’s disease (CD) is higher in women than in men. W.A. Goodman and R.R. Garg of Case Western Reserve University School of Medicine suspected that this gender bias might be the same in spontaneous models of CD. This is, indeed, the situation. Female SAMP1/YitFc (SAMP) mice were more predisposed to spontaneous CD and had impaired regulatory T cells with low frequencies as compared to the male SAMP mice. An investigation of the T cells revealed that male SAMP T cells responded much differently than female SAMP T cells to estrogen signals. While the male T cells responded by increasing immunosuppressive functions and expanding regulatory T cells, the female cells were resistant to these signals. Finding ways to make female T cells sensitive to estrogen signals could decrease female susceptibility to CD.
More Ways to Induce Anti-inflammatory Dendritic Cells
CD31 is expressed on many types of immune cells and endothelial cells, and it is mainly seen as an adhesion and migration molecule. Recent evidence has shown that it also has inhibitory function on T cells, which means that it might have inhibitory functions in other cells. Marc Clement of the French National Institute of Health and Medical Research (INSERM) has now found that this is, indeed, the situation with dendritic cells (DCs). Signaling via CD31 prevented DC maturation, migration and reduced pro-inflammatory signaling cascades. CD31-stimulated DC also preferentially polarized T cells towards a regulatory phenotype, and transfer of these DCs to a rodent model of multiple sclerosis delayed disease development. These results suggest that CD31 may also be potentially interesting for IBD.
This week on TIBDI: NOD2 and IFNγ work together to recruit cells to the small intestine, and a microRNA offers an interesting way to control Th17 differentiation.
NOD2 Behind Intestinal T Cell Recruitment
One of the most important receptors involved with Crohn’s disease (CD) is NOD2, a pattern recognition receptor that recognizes bacterial cell walls. Dr. Xingxin Wu of the Yale University School of Medicine investigated its involvement in an acute intestinal disease model induced by systemic anti-CD3. His results provide unique insight into infiltration dynamics of the characteristic CD8+ T cells found in the small intestine of this model. He discovered that NOD2 stimulation was needed for optimal infiltration. Without these signals, chemokines, specifically CXCR3-ligands, were not secreted by macrophages, dendritic cells and stromal cells. This prevented CD8+ T cells from leaving the circulation and entering the intestinal lamina propria. Moreover, the loss of CD8+ T cells in the small intestine led to reduced IFNγ, which also plays a role in stimulating immune cell chemotaxis.
Unexpected MicroRNA Control of Th17
During low oxygen conditions, immune cells upregulate transcription factors that turn on genes that help them cope with the hypoxia. One of these transcription factors, HIF-1α, also contributes to the differentiation of Th17 cells, which are important in the pathogenesis of inflammatory bowel disease (IBD). In an extremely interesting Nature Immunology publication, Dr. Haopeng Wang of the University of California in San Francisco described how the microRNA Mir210 inhibited HIF-1α expression and Th17 differentiation. MicroRNAs are small RNAs that prevent gene expression. By controlling the abundance of Mir210, he was also able to influence the numbers of Th17 T cells differentiated in vitro. Using the T cell transfer model of colitis with genetically manipulated T cells, which lacked Mir210 expression, he found that Mir210-deficient T cells caused increased numbers of Th17 and worsened symptoms. The authors suggest that drugs that function similarly to Mir210 could be interesting therapeutics.
Wang, H., Flach, H., Onizawa, M., Wei, L., McManus, M. T., & Weiss, A. (2014). Negative regulation of Hif1a expression and T. Nature Immunology, 1–10. doi:10.1038/ni.2846
Wu, X., Lahiri, A., Haines, G. K., Flavell, R. A., & Abraham, C. (2014). NOD2 Regulates CXCR3-Dependent CD8+ T Cell Accumulation in Intestinal Tissues with Acute Injury. The Journal of Immunology. doi:10.4049/jimmunol.1302436
This week on TIBDI: Keys to Treg homeostasis are uncovered and the killing mechanism of RegIII is brought into focus.
Survival of Memory Tregs
Regulatory T cells (Treg) may be key to controlling inflammatory bowel disease (IBD). Finding the factors that drive their growth could lead to new treatments. Scientists from the University of Washington School of Medicine may now have discovered the missing clues. They found that Treg can be divided into central and memory subsets, which are located in different regions of the body and are exposed to different signals. Central memory Treg were found to express CCR7 and enter lymphoid tissues, which allowed them to thrive on IL-2. The effector memory type, on the other hand, expressed high amounts of the costimulatory molecule ICOS and survived via signals provided from dendritic cells. The balance between the two types of Treg was controlled by inflammatory signals with inflammation encouraging increased numbers of effector Treg. If one of these types of Tregs is more important for IBD, than finding ways to expand them in vivo could be a new therapy.
RegIII Kills by Pore Formation
RegIII C-type lectins are a well-known family of antimicrobial proteins that bind bacterial targets and limit their activities. Now research from the University of Texas Southwestern Medical Center shows why. Using crystal structures of RegIIIα, they show that this antimicrobial protein drills a pore into gram-positive bacteria leading to their death. Monomers of RegIIIα assemble to form a tube of approximately 100 angstroms in diameter with a pore size of 18 angstroms. Gram-negative bacteria were protected from RegIIIα pores by lipopolysaccharide. Lowered RegIII expression is associated with null NOD2 mutations, which are often found in Crohn’s disease patients.
This week, we learn more about how mesenchymal stem cells affect the immune system, why CX3CR1 is needed to clear a yeast infection and how the body stops helminths in their tracks.
Stem Cells and Immunosuppression
A recent study on mesenchymal stem cell (MSC) therapy has uncovered a novel mechanism of immunosuppression in the colon. The French group was using MSC therapy to counter gastrointestinal complications caused during tumor radiotherapy. They found that the treatment reduced colon epithelial damage, but also reduced the relative proportion of infiltrating CD4+ and CD8+ T cells. There was also a marked reduction of T cell activation and proliferation. This downregulation was parallel with significant increases of corticosterone secretion and subsequent interleukin-10 expression. Experiments with a glucocorticoid receptor blocker pointed towards an impaired TCR signal transduction initiated by the MSC treatment. It will be interesting to see if this finding can help improve MSC treatment of inflammatory bowel disease (IBD).
CX3CR1 and Candida
Crohn’s disease (CD) is often associated with harmful Candida albicans infections. Unlocking the secrets behind how the body controls Candida infections could be beneficial for CD patients. In this study, performed by the NIH, it was determined that the chemokine receptor CX3CR1 is crucial for macrophage survival in the kidney, the preferred hideout for Candida. During an infection, it was found that CX3CR1 was upregulated in the kidney macrophages. Mice deficient in CX3CR1 had a high mortality and were found to have uncontrolled Candida growth in the kidneys. The loss of the receptor prevented macrophages from accumulating in the kidney and engulfing the yeast. Given the growing role CX3CR1 in the pathogenesis of IBD, it will be interesting to consider if this receptor forms a link between CD and associated Candidiasis.
Helminth Induced Immune Reactions
As intestinal worms are becoming a new therapeutic for IBD, it’s interesting to learn about the immune responses that are induced upon their introduction to the body. A Japanese study in the Journal of Experimental Medicine has now shown that the skin does its best to prevent reinfection of Nippostrongylus brasiliensis. This species is similar to Necator americanus, which is used in IBD therapy. These worms enter through the skin. The scientists found that during the first exposure the skin had a limited response. However during a second application, there was a huge immune reaction, which was characterized by cellular infiltrates that trapped the larvae. The key immune cell mediating this trapping was the basophil, which detected worm antigens (bound to antibodies) using FcεRI and elicited the help of macrophages. It will be useful to determine if this process hinders worm treatment in IBD patients who have already had helminth infections.