How does the microbiota control systemic innate immunity?

The intestinal microbiota has a pervasive influence on mammalian innate immunity fortifying defenses to infection in tissues throughout the host. How intestinal microbes control innate defenses in systemic tissues is, however, poorly defined. In our opinion, there are three core challenges that need addressing to advance our understanding of how the intestinal microbiota controls innate immunity systemically: first, deciphering how signals from intestinal microbes are transmitted to distal tissues; second, unraveling how intestinal microbes prime systemic innate immunity without inducing widespread immunopathology; and third, identifying which intestinal microbes control systemic immunity. Here, we propose answers to these problems which provide a framework for understanding how microbes in the intestine can regulate innate immunity systemically.

Symbiotic Firmicutes establish mutualism with the host via innate tolerance and resistance to control systemic immunity.

The intestinal microbiota regulates immunity across organ systems. Which symbionts control systemic immunity, the mechanisms they use, and how they avoid widespread inflammatory damage are unclear. We uncover host tolerance and resistance mechanisms that allow Firmicutes from the human microbiota to control systemic immunity without inducing immunopathology. Intestinal processing releases Firmicute glycoconjugates that disseminate, resulting in release of cytokine IL-34 that stimulates macrophages and enhances defenses against pneumonia, sepsis, and meningitis. Despite systemic penetration of Firmicutes, immune homeostasis is maintained through feedback control whereby IL-34-mediated mTORC1 activation in macrophages clears polymeric glycoconjugates from peripheral tissues. Smaller glycoconjugates evading this clearance mechanism are tolerated through sequestration by albumin, which acts as an inflammatory buffer constraining their immunological impact. Without these resistance and tolerance mechanisms, Firmicutes drive catastrophic organ damage and cachexia via IL-1ß. This reveals how Firmicutes are safely assimilated into systemic immunity to protect against infection without threatening host viability.

Protein tyrosine phosphatase PTPN22 regulates IL-1ß dependent Th17 responses by modulating dectin-1 signaling in mice.

A single nucleotide polymorphism within the PTPN22 gene is a strong genetic risk factor predisposing to the development of multiple autoimmune diseases. PTPN22 regulates Syk and Src family kinases downstream of immuno-receptors. Fungal ß-glucan receptor dectin-1 signals via Syk, and dectin-1 stimulation induces arthritis in mouse models. We investigated whether PTPN22 regulates dectin-1 dependent immune responses. Bone marrow derived dendritic cells (BMDCs) generated from C57BL/6 wild type (WT) and Ptpn22-/- mutant mice, were pulsed with OVA323-339 and the dectin-1 agonist curdlan and co-cultured in vitro with OT-II T-cells or adoptively transferred into OT-II mice, and T-cell responses were determined by immunoassay. Dectin-1 activated Ptpn22-/- BMDCs enhanced T-cell secretion of IL-17 in vitro and in vivo in an IL-1ß dependent manner. Immunoblotting revealed that compared to WT, dectin-1 activated Ptpn22-/- BMDCs displayed enhanced Syk and Erk phosphorylation. Dectin-1 activation of BMDCs expressing Ptpn22R619W (the mouse orthologue of human PTPN22R620W ) also resulted in increased IL-1ß secretion and T-cell dependent IL-17 responses, indicating that in the context of dectin-1 Ptpn22R619W operates as a loss-of-function variant. These findings highlight PTPN22 as a novel regulator of dectin-1 signals, providing a link between genetically conferred perturbations of innate receptor signaling and the risk of autoimmune disease.

Protein tyrosine phosphatase PTPN22 is dispensable for dendritic cell antigen processing and promotion of T-cell activation by dendritic cells.

The PTPN22R620W single nucleotide polymorphism increases the risk of developing multiple autoimmune diseases including type 1 diabetes, rheumatoid arthritis and lupus. PTPN22 is highly expressed in antigen presenting cells (APCs) where the expression of the murine disease associated variant orthologue (Ptpn22R619W) is reported to dysregulate pattern recognition receptor signalling in dendritic cells (DCs) and promote T-cell proliferation. Because T-cell activation is dependent on DC antigen uptake, degradation and presentation, we analysed the efficiency of these functions in splenic and GM-CSF bone marrow derived DC from wild type (WT), Ptpn22-/- or Ptpn22R619W mutant mice. Results indicated no differential ability of DCs to uptake antigen via macropinocytosis or receptor-mediated endocytosis. Antigen degradation and presentation was also equal as was WT T-cell conjugate formation and subsequent T-cell proliferation. Despite the likely presence of multiple phosphatase-regulated pathways in the antigen uptake, processing and presentation pathways that we investigated, we observed that Ptpn22 and the R619W autoimmune associated variant were dispensable. These important findings indicate that under non-inflammatory conditions there is no requirement for Ptpn22 in DC dependent antigen uptake and T-cell activation. Our findings reveal that perturbations in antigen uptake and processing, a fundamental pathway determining adaptive immune responses, are unlikely to provide a mechanism for the risk associated with the Ptpn22 autoimmune associated polymorphism.

DNA methylation governs the dynamic regulation of inflammation by apoptotic cells during efferocytosis.

Efficient clearance of apoptotic cells (AC) is pivotal in preventing autoimmunity and is a potent immunosuppressive stimulus. However, activation of cells prior to apoptosis abolishes their immunoregulatory properties. Here we show using the antigen-induced model of arthritis that the degree of DNA methylation within AC confers their immunomodulatory plasticity. DNA isolated from resting and activated AC mimicked their respective immune effects. Demethylation of DNA abrogated the protective effect of AC whereas remethylation of AC DNA reversed the effects of activation and restored the ability to inhibit inflammation. Disease suppression or lack thereof was associated with TGFß and IL-6 production respectively. Apoptotic CD4+ T cells from patients with rheumatoid arthritis and systemic lupus erythematosus were demethylated compared to healthy controls and favoured production of IL-6 when cultured with healthy macrophages, in contrast to the TGFß produced in response to healthy AC. Our data implicate AC DNA methylation as the molecular switch that imprints their regulatory properties.

Engulfment of activated apoptotic cells abolishes TGF-ß-mediated immunoregulation via the induction of IL-6.

Phagocytosis of apoptotic cells (ACs) is usually a potent immunoregulatory signal but can also promote inflammation. In this article, we show that administration of apoptotic dendritic cells (DCs) inhibited inflammation in vivo through increasing production of TGF-ß from intrinsic DCs and B cells. However, ACs derived from LPS-activated DCs failed to restrain inflammation because of a short-lived but marked IL-6 response, which abolished the increase in TGF-ß. Inhibition of IL-6 restored the protective anti-inflammatory properties of aACs and the TGF-ß response. DCs isolated from mice that had received resting but not activated ACs could transfer the suppression of inflammation to recipient mice. These transferred DCs stimulated B cell TGF-ß production and relied on an intact B cell compartment to limit inflammation. These results highlight how the activation state of AC governs their ability to control inflammation through reciprocal regulation of IL-6 and TGF-ß.

Evolution of the magnetic field structure of the Crab pulsar.

Pulsars are highly magnetized rotating neutron stars and are well known for the stability of their signature pulse shapes, allowing high-precision studies of their rotation. However, during the past 22 years, the radio pulse profile of the Crab pulsar has shown a steady increase in the separation of the main pulse and interpulse components at 0.62° ± 0.03° per century. There are also secular changes in the relative strengths of several components of the profile. The changing component separation indicates that the axis of the dipolar magnetic field, embedded in the neutron star, is moving toward the stellar equator. This evolution of the magnetic field could explain why the pulsar does not spin down as expected from simple braking by a rotating dipolar magnetic field.

Telemedicine and Pediatric Obesity Treatment: Review of the literature and lessons learned.

Pediatric obesity is more prevalent in rural areas, yet rural families may not have access to pediatric obesity treatment programs. Use of new technologies, particularly telemedicine, has proven effective in other behavioral fields, such as psychiatry. This paper reviews the literature on the use of telemedicine in pediatric obesity treatment, and describes one tertiary-care pediatric obesity telemedicine program. We performed a systematic review of the literature from 1990-2011 using the following criteria: pediatric age group, overweight or obesity care or treatment, and use of telemedicine technology. Of 2873 abstracts identified, four studies met all inclusion criteria; all were published after 2008. The limited evidence suggests that telemedicine to be a promising approach to pediatric weight management, particularly for rural families with limited access to treatments. We also provide important lessons learned from one pediatric obesity treatment clinic offering services to rural families via telemedicine. Few studies have examined the use of telemedicine for pediatric obesity treatment, but the available data favor this method for treating rural patients. There are several unique key factors influencing successful delivery of a pediatric obesity telemedicine treatment program. This review identifies a potential avenue for expanded treatment, and highlights the need for further investigation.

TeleFIT: adapting a multidisciplinary, tertiary-care pediatric obesity clinic to rural populations.

Pediatric obesity occurs most frequently in underserved communities where families have difficulty accessing healthcare. Disproportionate obesity rates in rural children denote significant disparities warranting innovative solutions. However, intensive, tertiary-care treatment options outlined in recent expert recommendations may not be available to families living in rural areas. Telemedicine may be useful for providing pediatric obesity treatment to rural families. The aim of this study was to assess the impact of a new outreach program (TeleFIT), which placed telemonitors in four rural satellite clinics to increase access to a pediatric obesity clinic (Brenner Families In Training [FIT]). Before TeleFIT began, of five patients from rural counties enrolled in treatment over a 1-year period, all dropped out by their third visit. Within the first year of TeleFIT, the number of rural patients increased nearly threefold (to 14) and increased again in the second year by an additional 16 new patients (n=35). Preliminary outcomes indicate comparable attrition rates and improvement in weight status compared with patients in conventional treatment. Telemedicine allows rural families to access intensive obesity treatment from local pediatric offices, eliminating geographic barriers. Systems delivering state-of-the-art care in rural areas have tremendous potential for reducing health disparities in rural populations. Further research is needed to test the efficacy of such interventions.