Throughout the twentieth century, there were striking increases in the incidences of many chronic inflammatory disorders in the rich developed countries. These included autoimmune disorders such as ...Type 1 diabetes and multiple sclerosis. Although genetics and specific triggering mechanisms such as molecular mimicry and viruses are likely to be involved, the increases have been so rapid that any explanation that omits environmental change is incomplete. This chapter suggests that a series of environmental factors, most of them microbial, have led to a decrease in the efficiency of our immunoregulatory mechanisms because we are in a state of evolved dependence on organisms with which we co-evolved (and that had to be tolerated) as inducers of immunoregulatory circuits. These organisms (“Old Friends”) are depleted from the modern urban environment. Rather than considering fetal programming by maternal microbial exposures, neonatal programming, the hygiene hypothesis, gut microbiota, and diet as separate and competing hypotheses, I attempt here to integrate these ideas under a single umbrella concept that can provide the missing immunoregulatory environmental factor that is needed to explain the recent increases in autoimmune disease.
Review on three IL‐4‐related branch points for immune regulation: alternative splicing of IL‐4, differential receptor engagement, and differential regulation of macrophage activation by IL‐4.
Studies ...of IL‐4 have revealed a wealth of information on the diverse roles of this cytokine in homeostatic regulation and disease pathogenesis. Recent data suggest that instead of simple linear regulatory pathways, IL‐4 drives regulation that is full of alternatives. In addition to the well‐known dichotomous regulation of Th cell differentiation by IL‐4, this cytokine is engaged in several other alternative pathways. Its own production involves alternative mRNA splicing, yielding at least two functional isoforms: full‐length IL‐4, encoded by the IL‐4 gene exons 1–4, and IL‐4δ2, encoded by exons 1, 3, and 4. The functional effects of these two isoforms are in some ways similar but in other ways quite distinct. When binding to the surface of target cells, IL‐4 may differentially engage two different types of receptors. By acting on macrophages, a cell type critically involved in inflammation, IL‐4 induces the so‐called alternative macrophage activation. In this review, recent advances in understanding these three IL‐4‐related branch points—alternative splicing of IL‐4, differential receptor engagement by IL‐4, and differential regulation of macrophage activation by IL‐4—are summarized in light of their contributions to inflammation.
Man has moved rapidly from the hunter-gatherer environment to the living conditions of the rich industrialized countries. The hygiene hypothesis suggests that the resulting changed and reduced ...pattern of exposure to microorganisms has led to disordered regulation of the immune system, and hence to increases in certain inflammatory disorders. The concept began with the allergic disorders, but there are now good reasons for extending it to autoimmunity, inflammatory bowel disease, neuroinflammatory disorders, atherosclerosis, depression associated with raised inflammatory cytokines, and some cancers. This review discusses these possibilities in the context of Darwinian medicine, which uses knowledge of evolution to cast light on human diseases. The Darwinian approach enables one to correctly identify some of the organisms that are important for the 'Hygiene' or 'Old Friends' hypothesis, and to point to the potential exploitation of these organisms or their components in novel types of prophylaxis with applications in several branches of medicine.
As man has moved rapidly from the hunter-gatherer environment to the living conditions of the industrialized countries, the incidences of some cancers have increased alarmingly. Recent increases are ...usually attributed to dietary changes or to altered exposures to putative carcinogens associated with the modern lifestyle. However, the changes in cancer incidence parallel similar increases in non-neoplastic chronic inflammatory disorders (inflammatory bowel disease, allergies, and autoimmunity), and the epidemiology is often strikingly similar. This parallel is worth exploring, because the increases in chronic inflammatory disorders are at least partly explained by immunoregulatory defects resulting from diminished exposure to microorganisms that co-evolved with mammals and developed a role in driving immunoregulatory circuits (the hygiene hypothesis). Dysregulated chronic inflammation can drive oncogenesis and also provides growth and angiogenic factors that enhance the subsequent proliferation and spread of tumor cells. Thus, a modern failure to downregulate inappropriate inflammation could underlie increases in some cancers in parallel with the increases in chronic inflammatory disorders. This possibility is supported by recent work showing that in some circumstances regulatory T cells protect against cancer, rather than aggravating it, as previously assumed. A greater understanding of these interactions might pave the way to improved microbe-based immunotherapies.
The evolution of the gut-microbiota-brain axis in animals reveals that microbial inputs influence metabolism, the regulation of inflammation and the development of organs, including the brain. ...Inflammatory, neurodegenerative and psychiatric disorders are more prevalent in people of low socioeconomic status (SES). Many aspects of low SES reduce exposure to the microbial inputs on which we are in a state of evolved dependence, whereas the lifestyle of wealthy citizens maintains these exposures. This partially explains the health deficit of low SES, so focussing on our evolutionary history and on environmental and lifestyle factors that distort microbial exposures might help to mitigate that deficit. But the human microbiota is complex and we have poor understanding of its functions at the microbial and mechanistic levels, and in the brain. Perhaps its composition is more flexible than the microbiota of animals that have restricted habitats and less diverse diets? These uncertainties are discussed in relation to the encouraging but frustrating results of attempts to treat psychiatric disorders by modulating the microbiota.
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•Evolution and functions of microbiota illuminated by the study of insects, fish etc.•Microbial exposures modulate the immune system and immunoregulation.•Mother and natural environment are the sources of essential microbial exposures.•Low socioeconomic status (SES) disrupts essential microbial exposures.•Disrupted microbial inputs impair brain development & increase psychiatric disorders.
In a hierarchical Universe clusters grow via the accretion of galaxies from the field, groups and even other clusters. As this happens, galaxies can lose and/or consume their gas reservoirs via ...different mechanisms, eventually quenching their star formation. We explore the diverse environmental histories of galaxies through a multiwavelength study of the combined effect of ram-pressure stripping and group ‘processing’ in Abell 963, a massive growing cluster at z = 0.2 from the Blind Ultra Deep H i Environmental Survey (BUDHIES). We incorporate hundreds of new optical redshifts (giving a total of 566 cluster members), as well as Subaru and XMM–Newton data from LoCuSS, to identify substructures and evaluate galaxy morphology, star formation activity, and H i content (via H i deficiencies and stacking) out to 3 × R
200. We find that Abell 963 is being fed by at least seven groups, that contribute to the large number of passive galaxies outside the cluster core. More massive groups have a higher fraction of passive and H i-poor galaxies, while low-mass groups host younger (often interacting) galaxies. For cluster galaxies not associated with groups we corroborate our previous finding that H i gas (if any) is significantly stripped via ram-pressure during their first passage through the intracluster medium, and find mild evidence for a starburst associated with this event. In addition, we find an overabundance of morphologically peculiar and/or star-forming galaxies near the cluster core. We speculate that these arise from the effect of groups passing through the cluster (post-processing). Our study highlights the importance of environmental quenching and the complexity added by evolving environments.
It is often suggested that hygiene is not compatible with the microbial exposures that are necessary for establishment of the immune system in early life. However, when we analyze the microbial ...exposures of modern humans in the context of human evolution and history, it becomes evident that whereas children need exposure to the microbiotas of their mothers, other family members, and the natural environment, exposure to the unnatural microbiota of the modern home is less relevant. In addition, any benefits of exposure to the infections of childhood within their household setting are at least partly replaced by the recently revealed nonspecific effects of vaccines. This article shows how targeting hygiene practices at key risk moments and sites can maximize protection against infection while minimizing any impact on essential microbial exposures. Moreover, this targeting must aim to reduce direct exposure of children to cleaning agents because those agents probably exert TH2-adjuvant effects that trigger allergic responses to normally innocuous antigens. Finally, we need to halt the flow of publications in the scientific literature and the media that blame hygiene for the increases in immunoregulatory disorders. Appropriately targeted hygiene behavior is compatible with a healthy lifestyle that promotes exposure to essential microorganisms.
The differing Mbh–L relations presented in McLure & Dunlop, Marconi & Hunt and Erwin et al. have been investigated. A number of issues have been identified and addressed in each of these studies, ...including but not limited to the removal of a dependency on the Hubble constant, a correction for dust attenuation in the bulges of disc galaxies, the identification of lenticular galaxies previously treated as elliptical galaxies and the application of the same (Y∣X) regression analysis. These adjustments result in relations which now predict similar black hole masses. The optimal K-band relation is log(Mbh/M⊙) =−0.37(±0.04)(MK+ 24) + 8.29(±0.08), with a total (not intrinsic) scatter in logMbh equal to 0.33 dex. This level of scatter is similar to the value of 0.34 dex from the relation of Tremaine et al. and compares favourably with the value of 0.31 dex from the Mbh–n relation of Graham & Driver. Using different photometric data, consistent relations in the B and R band are also provided, although we do note that the small (N= 13)R-band sample used by Erwin et al. is found here to have a slope of −0.30 ± 0.06. Performing a symmetrical regression on the larger K-band sample gives a slope of ∼−0.40, implying Mbh∝L1.00. Implications for galaxy–black hole co-evolution, in terms of dry mergers, are briefly discussed, as are the predictions for intermediate mass black holes. Finally, as noted by others, a potential bias in the galaxy sample used to define the Mbh–L relations is shown and a corrective formula provided.
Abstract The immune system influences brain development and function. Hygiene and other early childhood influences impact the subsequent function of the immune system during adulthood, with ...consequences for vulnerability to neurodevelopmental and psychiatric disorders. Inflammatory events during pregnancy can act directly to cause developmental problems in the central nervous system (CNS) that have been implicated in schizophrenia and autism. The immune system also acts indirectly by “farming” the intestinal microbiota, which then influences brain development and function via the multiple pathways that constitute the gut–brain axis. The gut microbiota also regulates the immune system. Regulation of the immune system is crucial because inflammatory states in pregnancy need to be limited, and throughout life inflammation needs to be terminated completely when not required; for example, persistently raised levels of background inflammation during adulthood (in the presence or absence of a clinically apparent inflammatory stimulus) correlate with an increased risk of depression. A number of factors in the perinatal period, notably immigration from rural low-income to rich developed settings, caesarean delivery, breastfeeding and antibiotic abuse have profound effects on the microbiota and on immunoregulation during early life that persist into adulthood. Many aspects of the modern western environment deprive the infant of the immunoregulatory organisms with which humans co-evolved, while encouraging exposure to non-immunoregulatory organisms, associated with more recently evolved “crowd” infections. Finally, there are complex interactions between perinatal psychosocial stressors, the microbiota, and the immune system that have significant additional effects on both physical and psychiatric wellbeing in subsequent adulthood. This article is part of a Special Issue entitled Neuroimmunology in Health And Disease.
Genomic profiling studies suggest that triple-negative breast cancer (TNBC) is a heterogeneous disease. In this study, we sought to define TNBC subtypes and identify subtype-specific markers and ...targets.
RNA and DNA profiling analyses were conducted on 198 TNBC tumors estrogen receptor (ER) negativity defined as Allred scale value ≤ 2 with >50% cellularity (discovery set: n = 84; validation set: n = 114) collected at Baylor College of Medicine (Houston, TX). An external dataset of seven publically accessible TNBC studies was used to confirm results. DNA copy number, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed independently using these datasets.
We identified and confirmed four distinct TNBC subtypes: (i) luminal androgen receptor (AR; LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS), and (iv) basal-like immune-activated (BLIA). Of these, prognosis is worst for BLIS tumors and best for BLIA tumors for both DFS (log-rank test: P = 0.042 and 0.041, respectively) and DSS (log-rank test: P = 0.039 and 0.029, respectively). DNA copy number analysis produced two major groups (LAR and MES/BLIS/BLIA) and suggested that gene amplification drives gene expression in some cases FGFR2 (BLIS). Putative subtype-specific targets were identified: (i) LAR: androgen receptor and the cell surface mucin MUC1, (ii) MES: growth factor receptors platelet-derived growth factor (PDGF) receptor A; c-Kit, (iii) BLIS: an immunosuppressing molecule (VTCN1), and (iv) BLIA: Stat signal transduction molecules and cytokines.
There are four stable TNBC subtypes characterized by the expression of distinct molecular profiles that have distinct prognoses. These studies identify novel subtype-specific targets that can be targeted in the future for the effective treatment of TNBCs.
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