Teratological trilobites from the Silurian (Wenlock and Ludlow) of Australia.

Documentation of malformed trilobites has presented invaluable insight into the palaeobiology of a wholly extinct euarthropod group. Although the northern hemisphere record is relatively well documented, examples of abnormal trilobites from Australia are limited. Furthermore, most recorded specimens are from Cambrian-aged rocks. To extend this limited record, we document five new examples of malformed Australian trilobites from the Middle and Late Silurian (Wenlock and Ludlow) deposits of the Yarralumla Formation of the Australian Capital Territory and Yarwood Siltstone Member, Black Bog Shale in New South Wales. We record the first examples of abnormal pygidial and thoracic nodes and present new evidence for bifurcating pygidial ribs. These abnormal features are considered teratological morphologies. The aberrant nodes likely arose through developmental malfunctions, while the bifurcating ribs represent either similar defects, or an injury that developed into a teratological feature. Explanations for the limited record of malformed Australian trilobites and for the decrease in injured trilobites after the end-Ordovician are presented. Further documentation of malformed Australian trilobites from the middle-to-late Paleozoic will undoubtedly paint a more complete picture of how Gondwanan taxa recovered from injuries or unfortunate developmental complications.

Minor genomic differences between related B6 and B10 mice affect severity of schistosome infection by governing the mode of dendritic cell activation.

Infection with the helminth Schistosoma mansoni results in hepatointestinal granulomatous inflammation mediated by CD4 T cells directed against parasite eggs. The severity of disease varies greatly in humans and mice; however, the genetic basis of such a heterogenous immune response remains poorly understood. Here we show that, despite their close genetic relationship, C57BL/10SnJ (B10) mice developed significantly more pronounced immunopathology and higher T helper 17 cell responses than C57BL/6J (B6) mice. Similarly, live egg-stimulated B10-derived dendritic cells (DCs) produced significantly more IL-1ß and IL-23, resulting in higher IL-17 production by CD4 T cells. Gene expression analysis disclosed a heightened proinflammatory cytokine profile together with a strikingly lower expression of Ym1 in B10 versus B6 mice, consistent with failure of B10 DCs to attain alternative activation. To genetically dissect the differential response, we developed and analyzed congenic mouse strains that capture major regions of allelic variation, and found that the level of inflammation was controlled by a relatively small number of genes in a locus mapping to chromosome 4 117-143 MB. Our study has thus identified novel genomic regions that regulate the severity of the schistosome infection by way of controlling the mode of DC activation and consequent CD4 T-cell subset development.

Dysfunctional Cognitions among Offspring of Individuals with Bipolar Disorder.

BACKGROUND: Individuals with bipolar disorder often endorse dysfunctional beliefs consistent with cognitive models of bipolar disorder (Beck, 1976; Mansell, 2007). AIMS: The present study sought to assess whether young adult offspring of those with bipolar disorder would also endorse these beliefs, independent of their own mood episode history. METHOD: Participants (N = 89) were young adult college students with a parent with bipolar disorder (n = 27), major depressive disorder (MDD; n = 30), or no mood disorder (n = 32). Semi-structured interviews of the offspring were used to assess diagnoses. Dysfunctional beliefs related to Beck and colleagues' (2006) and Mansell's (2007) cognitive models were assessed. RESULTS: Unlike offspring of parents with MDD or no mood disorder, those with a parent with bipolar disorder endorsed significantly more dysfunctional cognitions associated with extreme appraisal of mood states, even after controlling for their own mood diagnosis. Once affected by a bipolar or depressive disorder, offspring endorsed dysfunctional cognitions across measures. CONCLUSIONS: Dysfunctional cognitions, particularly those related to appraisals of mood states and their potential consequences, are evident in young adults with a parent who has bipolar disorder and may represent targets for psychotherapeutic intervention.

IRAK-2 regulates IL-1-mediated pathogenic Th17 cell development in helminthic infection.

Infection with the trematode parasite Schistosoma mansoni results in distinct heterogeneity of disease severity both in humans and in mice. In the experimental mouse model, severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation mediated by CD4 Th17 cells, whereas mild disease is associated with reduced hepatic inflammation in a Th2-skewed cytokine environment. Even though the host's genetic background significantly impacts the clinical outcome of schistosomiasis, specific gene(s) that contribute to disease severity remain elusive. We investigated the schistosome infection in wild-derived mice, which possess a more diverse gene pool than classically inbred mouse strains and thus makes them more likely to reveal novel mechanisms of immune regulation. We now show that inbred wild-derived MOLF mice develop severe hepatic inflammation with high levels of IL-17. Congenic mice with a MOLF locus in chromosome 6, designated Why1, revealed high pathology and enabled the identification of Irak2 as the pathogenic gene. Although IRAK-2 is classically associated with TLR signaling, adoptive transfer of CD4 T cells revealed that IRAK-2 mediates pathology in a CD4 T cell specific manner by promoting Th17 cell development through enhancement of IL-1ß-induced activation of transcription factors RORγt and BATF. The use of wild-derived mice unravels IRAK-2 as a novel regulator of IL-1-induced pathogenic Th17 cells in schistosomiasis, which likely has wide-ranging implications for other chronic inflammatory and autoimmune diseases.

The pathogenic Th17 cell response to major schistosome egg antigen is sequentially dependent on IL-23 and IL-1ß.

CBA/J mice infected with the helminth Schistosoma mansoni develop severe CD4 T cell-mediated hepatic granulomatous inflammation against parasite eggs associated with a robust Th17 cell response. We investigated the requisites for Th17 cell development using novel CD4 T cells expressing a transgenic TCR specific for the major Sm-p40 egg Ag, which produce IL-17 when stimulated with live schistosome eggs. Neutralization of IL-23 or blockade of the IL-1 receptor, but not IL-6 neutralization, abrogated egg-induced IL-17 secretion by transgenic T cells, whereas exogenous IL-23 or IL-1ß reconstituted their ability to produce IL-17 when stimulated by syngeneic IL-12p40-deficient dendritic cells. Kinetic analysis demonstrated that IL-17 production was initiated by IL-23 and amplified by IL-1ß. Significantly, schistosome-infected IL-12p40-deficient or IL-1R antagonist-treated CBA/J mice developed markedly reduced hepatic immunopathology with a dampened egg Ag-specific IL-17 response. These results demonstrate that the IL-23-IL-1-IL-17 axis has a central role in the development of severe schistosome egg-induced immunopathology.

Five new malformed trilobites from Cambrian and Ordovician deposits from the Natural History Museum.

Injured trilobites present insight into how a completely extinct group of arthropods responded to traumatic experiences, such as failed predation and moulting complications. These specimens are therefore important for more thoroughly understanding the Paleozoic predator-prey systems that involved trilobites. To expand the record of injured trilobites, we present new examples of injured Ogygopsis klotzi and Olenoides serratus from the Campsite Cliff Shale Member of the Burgess Shale Formation (Cambrian, Miaolingian, Wuliuan), Paradoxides (Paradoxides) paradoxissimus gracilis from the Jince Formation (Cambrian, Miaolingian, Drumian), Ogygiocarella angustissima from the Llanfawr Mudstones Formation (Middle-Late Ordovician, Darriwilian-Sandbian), and Ogygiocarella debuchii from the Meadowtown Formation, (Middle-Late Ordovician, Darriwilian-Sandbian). We consider the possible origins of these malformations and conclude that most injuries reflect failed predation. Within this framework, possible predators are presented, and we uncover a marked shift in the diversity of animals that targeted trilobites in the Ordovician. We also collate other records of injured Ogygo. klotzi and Ol. serratus, and Ogygi. debuchii, highlighting that these species are targets for further understanding patterns and records of trilobite injuries.

Malformed trilobites from the Cambrian, Ordovician, and Silurian of Australia.

Biomineralised remains of trilobites provide important insight into the evolutionary history of a diverse, extinct group of arthropods. Their exoskeletons are also ideal for recording malformations, including evidence of post-injury repair. Re-examination of historic collections and the study of new specimens is important for enhancing knowledge on trilobite malformations across this diverse clade. To expand the records of these abnormalities and present explanations for their formation, we document eight malformed trilobite specimens, as well as one carcass, housed within the Commonwealth Palaeontological Collection at Geoscience Australia in Canberra. We present examples of Asthenopsis, Burminresia, Centropleura, Coronocephalus, Dolicholeptus, Galahetes, Papyriaspis, and Xystridura from Cambrian, Ordovician, and Silurian deposits of Australia. Most of the malformed specimens show W-, U-, or L-shaped indentations that reflect injuries from either failed predation or complications during moulting, and a mangled carcass is ascribed to either successful predation or post-mortem scavenging. We also uncover examples of teratologies, such as bifurcated pygidial ribs and pygidial asymmetry, in addition to evidence of abnormal recovery (i.e., fusion of thoracic segments) from a traumatic incident.

Examining abnormal Silurian trilobites from the Llandovery of Australia.

Abnormal trilobites present insight into how arthropods with fully biomineralised exoskeletons recovered from injuries, genetic malfunctions, and pathologies. Records of abnormal Silurian trilobites in particular show an abundance of specimens with teratologies and a limited record of injuries. Here we expand the record of abnormal Silurian trilobites by presenting seven new abnormal specimens of Odontopleura (Sinespinaspis) markhami from the early Silurian (Llandovery, Telychian) Cotton Formation, New South Wales. We use these specimens to illustrate novel evidence for asymmetric distribution of pleural thoracic spine bases. These abnormal bases likely reflect genetic complications, resulting in morphologies that would unlikely have aided the fitness of abnormal individuals. In considering records of malformed Silurian trilobites more broadly, we propose that the largest trilobites may have been prey at this time. This indicates a possible change in the trophic position of trilobites when compared to Cambrian and Ordovician palaeoecosystems.

An earliest Triassic age for Tasmaniolimulus and comments on synchrotron tomography of Gondwanan horseshoe crabs.

Constraining the timing of morphological innovations within xiphosurid evolution is central for understanding when and how such a long-lived group exploited vacant ecological niches over the majority of the Phanerozoic. To expand the knowledge on the evolution of select xiphosurid forms, we reconsider the four Australian taxa: Austrolimulus fletcheri, Dubbolimulus peetae, Tasmaniolimulus patersoni, and Victalimulus mcqueeni. In revisiting these taxa, we determine that, contrary to previous suggestion, T. patersoni arose after the Permian and the origin of over-developed genal spine structures within Austrolimulidae is exclusive to the Triassic. To increase the availability of morphological data pertaining to these unique forms, we also examined the holotypes of the four xiphosurids using synchrotron radiation X-ray tomography (SRXT). Such non-destructive, in situ imaging of palaeontological specimens can aid in the identification of novel morphological data by obviating the need for potentially extensive preparation of fossils from the surrounding rock matrix. This is particularly important for rare and/or delicate holotypes. Here, SRXT was used to emphasize A. fletcheri and T. patersoni cardiac lobe morphologies and illustrate aspects of the V. mcqueeni thoracetronic doublure, appendage impressions, and moveable spine notches. Unfortunately, the strongly compacted D. peetae precluded the identification of any internal structures, but appendage impressions were observed. The application of computational fluid dynamics to high-resolution 3D reconstructions are proposed to understand the hydrodynamic properties of divergent genal spine morphologies of austrolimulid xiphosurids.

A Lagerstätte from Australia provides insight into the nature of Miocene mesic ecosystems.

Reduced precipitation in the Miocene triggered the geographic contraction of rainforest ecosystems around the world. In Australia, this change was particularly pronounced; mesic rainforest ecosystems that once dominated the landscape transformed into the shrublands, grasslands, and deserts of today. A lack of well-preserved fossils has made it difficult to understand the nature of Australian ecosystems before the aridification. Here, we report on an exceptionally well-preserved rainforest biota from New South Wales, Australia. This Konservat-Lagerstätte hosts a rich diversity of microfossils, plants, insects, spiders, and vertebrate remains preserved in goethite. We document evidence for several species interactions including predation, parasitism, and pollination. The fossils are indicative of an oxbow lake in a mesic rainforest and suggest that rainforest distributions have shifted since the Miocene. The variety of fossils preserved, together with high fidelity of preservation, allows for unprecedented insights into the mesic ecosystems that dominated Australia during the Miocene.

Genetic control of severe egg-induced immunopathology and IL-17 production in murine schistosomiasis.

Infection with the trematode parasite Schistosoma mansoni results in a distinct heterogeneity of disease severity, both in humans and in an experimental mouse model. Severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation in a proinflammatory cytokine environment, whereas mild disease corresponds with reduced hepatic inflammation in a Th2 skewed cytokine environment. This marked heterogeneity indicates that genetic differences play a significant role in disease development, yet little is known about the genetic basis of dissimilar immunopathology. To investigate the role of genetic susceptibility in murine schistosomiasis, quantitative trait loci analysis was performed on F(2) progeny derived from SJL/J and C57BL/6 mice, which develop severe and mild pathology, respectively. In this study, we show that severe liver pathology in F(2) mice 7 wk after infection significantly correlated with an increase in the production of the proinflammatory cytokines IL-17, IFN-gamma, and TNF-alpha by schistosome egg Ag-stimulated mesenteric lymph node cells. Quantitative trait loci analysis identified several genetic intervals controlling immunopathology as well as IL-17 and IFN-gamma production. Egg granuloma size exhibited significant linkage to two loci, D4Mit203 and D17Mit82, both of which were inherited in a BL/6 dominant manner. Furthermore, a significant reduction of hepatic granulomatous inflammation and IL-17 production in interval-specific congenic mice demonstrated that the two identified genetic loci have a decisive effect on the development of immunopathology in murine schistosomiasis.

T-bet protects against exacerbation of schistosome egg-induced immunopathology by regulating Th17-mediated inflammation.

C57BL/6 mice infected with Schistosoma mansoni naturally develop mild CD4(+) T-cell-mediated immunopathology characterized by small hepatic granulomas around parasite eggs. However, immunization with soluble egg Ag in CFA markedly exacerbates the lesions by inducing a potent proinflammatory environment with high levels of IFN-gamma and IL-17, which are signature cytokines of distinct Th1- versus Th17-cell lineages. To determine the relative role of these subsets in disease exacerbation, we examined mice deficient in T-bet (T-bet(-/-)), which is required for Th1 differentiation and IFN-gamma production. We now report that immunization with soluble egg Ag in CFA caused a significantly greater enhancement of egg-induced hepatic immunopathology in T-bet(-/-) mice compared with WT controls, and analysis of their granulomas disclosed a higher proportion of activated DC and CD4(+) T cells, as well as a marked influx of neutrophils. The absence of IFN-gamma in the T-bet(-/-) mice correlated with a marked increase in IL-23p19, IL-17 and TNF-alpha in granulomas and MLN. In contrast, T-bet(-/-) mice had lower levels of IL-4, IL-5 and IL-10 and a reduction in FIZZ1 and FoxP3 expression, suggesting diminished regulatory activity, respectively, by alternatively activated macrophages and Treg. These findings demonstrate that T-bet-dependent signaling negatively regulates Th17-mediated immunopathology in severe schistosomiasis.

Dendritic cell IL-23 and IL-1 production in response to schistosome eggs induces Th17 cells in a mouse strain prone to severe immunopathology.

Infection with schistosomes results in a CD4 T cell-mediated inflammatory reaction against parasite eggs that varies greatly in magnitude both in humans as well as in mice. In the murine disease, the severe form of immunopathology correlates with high levels of IL-17. We now report that live schistosome eggs stimulate dendritic cells from high pathology-prone CBA mice to produce IL-12p40, IL-6, and TGF-beta, whereas those from low pathology-prone BL/6 mice only make TGF-beta. Moreover, egg-stimulated dendritic cells plus naive CD4 T cells from CBA mice resulted in increased levels of IL-6, IL-23, IL-1beta, as well as IL-17 and the chemokines CXCL1, CXCL2, and CCL2, whereas similarly treated BL/6 cell cocultures instead expressed higher IL-4, IL-5, IL-10, and the transcription factor Foxp3. Neutralization of IL-23 and IL-1, but not of IL-6 or IL-21, profoundly inhibited egg-induced IL-17 production in the CBA cocultures. Conversely, stimulation with schistosome eggs in the presence of exogenous IL-23 and IL-1beta induced BL/6 cells to make IL-17. These findings identify IL-23 and IL-1 as critical host factors that drive IL-17 production, and suggest that parasite recognition followed by a genetically determined innate proinflammatory response induces the development of Th17 cells and thus controls the outcome of immunopathology in schistosomiasis.

Coinfection with the intestinal nematode Heligmosomoides polygyrus markedly reduces hepatic egg-induced immunopathology and proinflammatory cytokines in mouse models of severe schistosomiasis.

Infection with the trematode helminth Schistosoma mansoni results in a parasite egg-induced, CD4 T-cell-mediated, hepatointestinal granulomatous and fibrosing inflammation that varies greatly in severity, with a higher frequency of milder forms typically occurring in regions where the disease is endemic. One possible explanation for this is that in these regions the degree of inflammation is lessened by widespread concurrent infection with gastrointestinal nematodes. We tested this hypothesis by establishing a murine coinfection model in which mice were infected with the intestinal nematode parasite Heligmosomoides polygyrus prior to infection with S. mansoni. In CBA mice that naturally display a severe form of schistosomiasis, preinfection with H. polygyrus resulted in a marked reduction in schistosome egg-induced hepatic immunopathology, which was associated with significant decreases in the levels of interleukin-17 (IL-17), gamma interferon, tumor necrosis factor alpha, IL-23, IL-6, and IL-1beta and with increases in the levels of IL-4, IL-5, IL-10, and transforming growth factor beta in mesenteric lymph node cells, purified CD4 T cells, and isolated liver granuloma cells. There also were increases in liver Ym1 and forkhead box P3 transcription factor expression. In another model of high-pathology schistosomiasis induced in C57BL/6 mice by immunization with schistosome egg antigens in complete Freund's adjuvant, coinfection with the nematodes also resulted in a marked inhibition of hepatic immunopathology accompanied by similar shifts in cytokine production. These findings demonstrate that intestinal nematodes prevent Th1- and Th17-cell-mediated inflammation by promoting a strong Th2-polarized environment associated with increases in the levels of alternatively activated macrophages and T regulatory cells, which result in significant amelioration of schistosome-induced immunopathology.

Trilobites and agnostids from the Goyder Formation (Cambrian Series 3, Guzhangian; Mindyallan), Amadeus Basin, central Australia.

A new assemblage containing twenty-two species of trilobites and agnostids is described from the Goyder Formation (Cambrian Series 3) in the Ross River Syncline and Gardiner Ranges of the Amadeus Basin, Northern Territory, central Australia. New trilobite taxa described include the genus, Trephina gen. nov., and four new species Adelogonus prichardi sp. nov., Hebeia stewarti sp. nov., Liostracina joyceae sp. nov., and Trephina ranfordi sp. nov. Two agnostid taxa previously known only from Antarctica, Ammagnostus antarcticus Bentley, Jago Cooper, 2009 and Hadragnostus helixensis Jago Cooper, 2005, are also documented. Of the two agnostid species, the latter is the most age diagnostic, previously reported from the Cambrian Series 3 (Guzhangian; late Mindyallan; Glyptagnostus stolidotus Zone) Spurs Formation in Northern Victoria Land. This age for the Goyder Formation assemblage is supported by the co-occurrence of the trilobites Biaverta reineri Öpik, 1967, Blackwelderia repanda Öpik, 1967, Henadoparia integra Öpik, 1967, Monkaspis cf. travesi (Öpik, 1967), Nomadinis pristinus Öpik, 1967, Paraacidaspis? priscilla (Öpik, 1967), and Polycyrtaspis cf. flexuosa Öpik, 1967, also known from the late Mindyallan (G. stolidotus Zone) successions of the neighbouring Georgina Basin (Northern Territory and Queensland). The generic assemblage of the Goyder Formation is also similar to those from the Guzhangian (Mindyallan) of other parts of Australia (New South Wales, South Australia, and Western Australia), in addition to East Antarctica and North and South China.

HCMV activates PI(3)K in monocytes and promotes monocyte motility and transendothelial migration in a PI(3)K-dependent manner.

Human cytomegalovirus (HCMV) is a leading cause of morbidity and mortality in immunocompromised hosts. In immunocompetent hosts, HCMV is associated with chronic inflammatory diseases including atherosclerosis. Monocytes and macrophages are proposed to play key roles in HCMV dissemination to host tissue, and their infection provides a biological link between the lifecycle of HCMV and disease pathology. We hypothesize that viral spread occurs via a mechanism in which infected peripheral blood monocytes, which are nonpermissive for viral replication, extravasate into host tissue and subsequently differentiate into permissive macrophages. Supporting this hypothesis, we recently showed that HCMV specifically induced the differentiation of monocytes into macrophages that become permissive for viral replication. To expand our understanding of HCMV pathogenesis, we next examined monocyte activation and migration, the first events in viral pathogenesis. We show here that HCMV up-regulates phosphatidylinositol 3,4,5 triphosphate kinase [PI(3)K] activity and that this increased PI(3)K activity is essential for infected monocyte-transendothelial migration. This increase in migration occurs through the up-regulation of cell motility in a PI(3)K-dependent process. Last, we show that these activated monocytes express a number of inflammatory mediators via PI(3)K signaling. We propose that the up-regulation of monocyte migration and immune mediators by HCMV infection is required for the hematogenous dissemination of the virus and as a consequence, could promote chronic inflammatory diseases associated with HCMV infection.

Contribution of gene products encoded within the unique short segment of equine herpesvirus 1 to virulence in a murine model.

The pathogenesis of three equine herpesvirus 1 (EHV-1) recombinants was assessed in a CBA mouse model. Sequences encoding the majority of glycoproteins I (gI) and E (gE) were deleted from the pathogenic EHV-1 strain RacL11 (L11deltagIdeltagE), and sequences comprising the 3859 bp deletion within the strain KyA U(S) segment, which includes genes 73 (gI), 74 (gE), and 75 (putative 10 kDa protein 75), were re-inserted into attenuated KyA (KgI/gE/75). In addition, genes gE and 75 were inserted into KyA to generate the EHV-1 recombinant KgE/75. The insertion of the 3859 bp U(S) segment was sufficient to confer virulence to KyA, as indicated by pronounced signs of clinical disease including substantial weight loss. A large plaque morphology was observed in cells infected with KgI/gE/75 compared with KyA, and a small plaque phenotype was observed in cells infected with L11deltagIdeltagE compared with RacL11. These data indicate that gI and/or gI and gE contribute to the ability of EHV-1 to spread directly from cell-to-cell. The deletion of both gI and gE from the pathogenic RacL11 strain did not reduce clinical signs of disease in infected mice, but did decrease mortality compared with RacL11. Furthermore, the insertion of genes 74 (gE) and 75 into the vaccine strain KyA did not alter the attenuated phenotype of this virus. Finally, KgI/gE/75 and RacL11 elicited the production of the proinflammatory chemokines MIP-1alpha, MIP-1beta, and MIP-2 in the lungs of infected mice, while KyA did not, suggesting that gI and/or gI and gE contribute to the up-regulation of these mediators of inflammation. These findings show that gI, and/or gI and gE restore a virulent phenotype to the EHV-1 KyA strain, and indicate that virulence factors, in addition to gI and gE, contribute to the pathogenesis of the RacL11 strain.

Cytokine profiles and long-term virus-specific antibodies following immunization of CBA mice with equine herpesvirus 1 and viral glycoprotein D.

Equine herpesvirus 1 (EHV-1)-specific antibody-secreting cells (ASC) isolated from the lung and spleen of mice at 12 months after immunization with attenuated EHV-1 KyA, heat-killed KyA, or recombinant viral glycoprotein D (rgD) assessed by ELISPOT showed a three- to fivefold increase in three immunoglobulin isotypes at 3 days post-challenge with pathogenic EHV-1 RacL11 as compared to control mice. ELISPOT assays demonstrated a high frequency of cells secreting proinflammatory tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and interleukin 4 (IL-4) in the lungs in response to infection with KyA or RacL11 or immunization with rgD. Cytokine production elicited by EHV-1 KyA or RacL11 infection revealed similar frequencies of EHV-1-specific IFN-gamma and IL-4 spot forming cells in the mediastinal lymph nodes and spleen. However, KyA induced significantly greater amounts of IFN-gamma producing cells in the lungs than did RacL11. Intranasal immunization with KyA or rgD induced long-term immunity that provided protection against pathogenic EHV-1 challenge infection at 12 months post-immunization. Overall, the data indicate that immunization with infectious KyA or rgD induces significant levels of cytokines, virus-specific ASC in the lungs and spleen, and long-term virus specific B-cell responses.

The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.

Regulatory T cells (Tregs) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate Treg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic Tregs. We determined that short-chain fatty acids, gut microbiota-derived bacterial fermentation products, regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2-dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.

Induction and regulation of pathogenic Th17 cell responses in schistosomiasis.

Schistosomiasis is a major tropical disease caused by trematode helminths in which the host mounts a pathogenic immune response against tissue-trapped parasite eggs. The immunopathology consists of egg antigen-specific CD4 T cell-mediated granulomatous inflammation that varies greatly in magnitude in humans and among mouse strains in an experimental model. New evidence, covered in this review, intimately ties the development of severe pathology to IL-17-producing CD4 T helper (Th17) cells, a finding that adds a new dimension to the traditional CD4 Th1 vs. Th2 cell paradigm. Most examined mouse strains, in fact, develop severe immunopathology with substantial Th17 as well as Th1 and Th2 cell responses; a solely Th2-polarized response is an exception that is only observed in low-pathology strains such as the C57BL/6. The ability to mount pathogenic Th17 cell responses is genetically determined and depends on the production of IL-23 and IL-1ß by antigen presenting cells following recognition of egg antigens; analyses of several F2 progenies of (high × low)-pathology strain crosses demonstrated that quantitative trait loci governing IL-17 levels and disease severity vary substantially from cross to cross. Low pathology is dominant, which may explain the low incidence of severe disease in humans; however, coinfection with intestinal nematodes can also dampen pathogenic Th17 cell responses by promoting regulatory mechanisms such as those afforded by alternatively activated macrophages and T regulatory cells. A better understanding of the pathways conducive to severe forms of schistosomiasis and their regulation should lead to interventions similar to those presently used to manage other immune-mediated diseases.