Regulation of Autoimmunity and Inflammation by microRNAs and Environmental Factors

Tolerance is crucial for maintaining immunological balance and avoid autoimmune diseases like type 1 diabetes and the inflammatory bowel disease, ulcerative colitis (UC). In Study I, we have investigated the regulatory role of a class of noncoding RNAs, the miRNAs, during thymocyte development of the where central tolerance is established. We used the non-obese diabetic mouse (NOD) which is spontaneously developing T1D and have been described to have defects in the T cell maturation. By studying the apoptosis response of NOD lymphocytes (which activates similar cell-cycle checkpoints and apoptosis pathways as during thymocyte maturation) we showed differential expression of the miRNA-34a/b/c gene family, miR-125 and miR-155 in the DNA damage response between NOD and wild-type mice. We believe that these differentially expressed miRNAs may contribute to defect p53 expression in NOD thymocytes after DNA damage, which we also demonstrated in this study. In Study II, we studied the importance of global canonical miRNA regulation in the NOD mice for the development of T1D development by deleting Dicer1 (an enzyme needed for miRNA maturation) early in thymocyte development. We showed that these NOD.Lck-Cre Dicer KO mice had phenotype alterations including markedly decreased amount of αβ CD4+ and CD8+ T cells in the secondary lymph nodes but not a similarly large decrease in nTregs. No difference in diabetes incidence between female NOD.Lck-Cre Dicer KO mice and control littermates could be found as a result of these phenotypic changes but surprisingly a significant increase in the male mice diabetes incidence. In Study III, we investigated whether the maternal intestinal microbiota is an environmental factor influencing T1D development in the offspring. By modulating the intestinal gut microbiota with antibiotics during pregnancy of NOD mice we showed decreased diversity and a persistent modulation of the intestinal microbial pattern in the offspring. Possibly resulting in the immunological alterations of CD8+ and CD4+CD25+ T cell frequencies in the mesenteric lymph nodes respectively Peyer’s patches, which we demonstrated. The diabetes incidence seems to have increased in the offspring to treated mothers at 20 weeks of age but the effect was not persistent. In study IV, the relationship between the global intestinal microbiota and the immune system was investigated in the dextran sulfate sodium induced UC mouse model. We demonstrated changes in the colonic intestinal microbiota pattern and immunological alterations of different populations of T cells, dendritic cells and natural killer cells after UC induction

Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment

Microbes, including viruses, influence type 1 diabetes (T1D) development, but many such influences remain undefined. Previous work on underlying immune mechanisms has focussed on cytokines and T cells. Here, we compared two nonobese diabetic (NOD) mouse colonies, NODlow and NODhigh, differing markedly in their cumulative T1D incidence (22% vs. 90% by 30 weeks in females). NODhigh mice harbored more complex intestinal microbiota, including several pathobionts; both colonies harbored segmented filamentous bacteria (SFB), thought to suppress T1D. Young NODhigh females had increased B-cell activation in their mesenteric lymph nodes. These phenotypes were transmissible. Co-housing of NODlow with NODhigh mice after weaning did not change T1D development, but T1D incidence was increased in female offspring of co-housed NODlow mice, which were exposed to the NODhigh environment both before and after weaning. These offspring also acquired microbiota and B-cell activation approaching those of NODhigh mice. In NODlow females, the low rate of T1D was unaffected by cyclophosphamide but increased by PD-L1 blockade. Thus, environmental exposures that are innocuous later in life may promote T1D progression if acquired early during immune development, possibly by altering B-cell activation and/or PD-L1 function. Moreover, T1D suppression in NOD mice by SFB may depend on the presence of other microbial influences. The complexity of microbial immune regulation revealed in this murine model may also be relevant to the environmental regulation of human T1D

Near-ground Effect of Height on Pollen Exposure

The effect of height on pollen concentration is not well documented and little is known about the near-ground vertical profile of airborne pollen. This is important as most measuring stations are on roofs, but patient exposure is at ground level. Our study used a big data approach to estimate the near-ground vertical profile of pollen concentrations based on a global study of paired stations located at different heights. We analyzed paired sampling stations located at different heights between 1.5 and 50m above ground level (AGL). This provided pollen data from 59 Hirst-type volumetric traps from 25 different areas, mainly in Europe, but also covering North America and Australia, resulting in about 2,000,000 daily pollen concentrations analyzed. The daily ratio of the amounts of pollen from different heights per location was used, and the values of the lower station were divided by the higher station. The lower station of paired traps recorded more pollen than the higher trap. However, while the effect of height on pollen concentration was clear, it was also limited (average ratio 1.3, range 0.7–2.2). The standard deviation of the pollen ratio was highly variable when the lower station was located close to the ground level (below 10m AGL). We show that pollen concentrations measured at >10m are representative for background near-ground levels

Regionalized Development and Maintenance of the Intestinal Adaptive Immune Landscape

The intestinal immune system has the daunting task of protecting us from pathogenic insults while limiting inflammatory responses against the resident commensal microbiota and providing tolerance to food antigens. This role is particularly impressive when one considers the vast mucosal surface and changing landscape that the intestinal immune system must monitor. In this review, we highlight regional differences in the development and composition of the adaptive immune landscape of the intestine and the impact of local intrinsic and environmental factors that shape this process. To conclude, we review the evidence for a critical window of opportunity for early-life exposures that affect immune development and alter disease susceptibility later in life

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut-brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.GB Rogers, DJ Keating, RL Young, M-L Wong, J Licinio, and S Wesseling

Antibiotic treatment of pregnant non-obese diabetic (NOD) mice leads to altered gut microbiota and intestinal immunological changes in the offspring.

The intestinal microbiota is important for tolerance induction through mucosal immunological responses. The composition of the gut microbiota of an infant is affected by environmental factors like diet, disease and antibiotic treatment. However, already in utero these environmental factors can affect the immunological development of the fetus and influence the future gut microbiota of the infant. To investigate the effects of antibiotic treatment of pregnant mothers on the offspring's gut microbiome and diabetes development, we treated non-obese diabetic (NOD) mice with a cocktail of antibiotics during gestation and the composition of the gut microbiota, diabetes incidence and major gut-related T lymphocyte populations were investigated in the offspring. We observed a persistent reduction in the general diversity of the gut microbiota in the offspring from NOD mothers treated with antibiotics during gestation compared to offspring from control mothers. In addition, by clustering the present bacterial taxa with principal component analysis we found a differential clustering of gut microbiota in the offspring from NOD mothers treated with antibiotics during gestation compared to offspring from control mothers. Offspring from NOD mothers treated with antibiotics during gestation also showed some immunological alterations in the gut immune system, which could be related to the diversity of the gut microbiome and influence modulation of diabetes development at 20 weeks. Our data point out maternal derangement of the intestinal microbiota as a potential environmental risk factor for T1D development. This article is protected by copyright. All rights reserved