Cytosolic DNA sensing via the stimulator of interferon genes adaptor: Yin and Yang of immune responses to DNA

DNA is immunogenic and many cells express cytosolic DNA sensors that activate the stimulator of interferon genes (STING) adaptor to trigger interferon type I (IFN‐β) release, a potent immune activator. DNA sensing to induce IFN‐β triggers host immunity to pathogens but constitutive DNA sensing can induce sustained IFN‐β release that incites autoimmunity. Here, we focus on cytosolic DNA sensing via the STING/IFN‐β pathway that regulates immune responses. Recent studies reveal that cytosolic DNA sensing via the STING/IFN‐β pathway induces indoleamine 2,3 dioxygenase (IDO), which catabolizes tryptophan to suppress effector and helper T‐cell responses and activate Foxp3‐lineage CD4⁺ regulatory T (Treg) cells. During homeostasis, and in some inflammatory settings, specialized innate immune cells in the spleen and lymph nodes may ingest and sense cytosolic DNA to reinforce tolerance that prevents autoimmunity. However, malignancies and pathogens may exploit DNA‐induced regulatory responses to suppress natural and vaccine‐induced immunity to malignant and infected cells. In this review, we discuss the biologic significance of regulatory responses to DNA and novel approaches to exploit DNA‐induced immune responses for therapeutic benefit. The ability of DNA to drive tolerogenic or immunogenic responses highlights the need to evaluate immune responses to DNA in physiologic settings relevant to disease progression or therapy.     

Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

Tolerance to self-antigens present in apoptotic cells is critical to maintain immune-homeostasis and prevent systemic autoimmunity. However, mechanisms that sustain self-tolerance are poorly understood. Here we show that systemic administration of apoptotic cells to mice induced splenic expression of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO expression was confined to the splenic marginal zone and was abrogated by depletion of CD169(+) cells. Pharmacologic inhibition of IDO skewed the immune response to apoptotic cells, resulting in increased proinflammatory cytokine production and increased effector T-cell responses toward apoptotic cell-associated antigens. Presymptomatic lupus-prone MRL(lpr/lpr) mice exhibited abnormal elevated IDO expression in the marginal zone and red pulp and inhibition of IDO markedly accelerated disease progression. Moreover, chronic exposure of IDO-deficient mice to apoptotic cells induced a lupus-like disease with serum autoreactivity to double-stranded DNA associated with renal pathology and increased mortality. Thus, IDO limits innate and adaptive immunity to apoptotic self-antigens and IDO-mediated regulation inhibits inflammatory pathology caused by systemic autoimmune disease.     

Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease,achalasia and hypertension

Moyamoya disease (MMD) is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory moyamoya collateral vessels. Homozygous mutations in GUCY1A3 have been reported as a cause of MMD and achalasia. Probands (n = 96) from unrelated families underwent sequencing of GUCY1A3. Functional studies were performed to confirm the pathogenicity of identified GUCY1A3 variants. Two affected individuals from the unrelated families were found to have compound heterozygous mutations in GUCY1A3. MM041 was diagnosed with achalasia at 4 years of age, hypertension and MMD at 18 years of age. MM149 was diagnosed with MMD and hypertension at the age of 20 months. Both individuals carry one allele that is predicted to lead to haploinsufficiency and a second allele that is predicted to produce a mutated protein. Biochemical studies of one of these alleles, GUCY1A3 Cys517Tyr, showed that the mutant protein (a subunit of soluble guanylate cyclase) has a significantly blunted signaling response with exposure to nitric oxide (NO). GUCY1A3 missense and haploinsufficiency mutations disrupt NO signaling leading to MMD and hypertension, with or without achalasia.     

Cell-autonomous control of interferon type I expression by indoleamine 2,3-dioxygenase in regulatory CD19+ dendritic cells

Following CD80/86 (B7) and TLR9 ligation, small subsets of splenic dendritic cells expressing CD19 (CD19(+) DC) acquire potent T cell regulatory functions due to induced expression of the intracellular enzyme indoleamine 2,3-dioxygenase (IDO), which catabolizes tryptophan. In CD19(+) DC, IFN type I (IFN-alpha) is the obligate inducer of IDO. We now report that IFN-alpha production needed to stimulate high-level expression of IDO following B7 ligation is itself dependent on basal levels of IDO activity. Genetic and pharmacologic ablation of IDO completely abrogated IFN-alpha production by CD19(+) DC after B7 ligation. In contrast, IDO ablation did not block IFN-alpha production by CD19(+) DC after TLR9 ligation. IDO-mediated control of IFN-alpha production depended on tryptophan depletion as adding excess tryptophan also blocked IFN-alpha expression after B7 ligation. Consistent with this, DC from mice deficient in general control of non-derepressible-2 (GCN2)-kinase, a component of the cellular stress response to amino acid withdrawal, did not produce IFN-alpha following B7 ligation, but produced IFN-alpha after TLR9 ligation. Thus, B7 and TLR9 ligands stimulate IFN-alpha expression in CD19(+) DC via distinct signaling pathways. In the case of B7 ligation, IDO activates cell-autonomous signals essential for IFN-alpha production, most likely by activating the GCN2-kinase-dependent stress response.     

An apparent paradox: chemokine receptor agonists can be used for anti-inflammatory therapy

Inflammation plays an important role in a wide range of human diseases. Chemokines are a group of proteins which control the migration and activation of the immune cells involved in all aspects of the inflammatory response. Chemokines bind to specific receptors of the seven-transmembrane spanning type on target leukocytes and also bind to cell-surface glycosaminoglycans (GAG). Leukocytes express a range of chemokine receptors which can cross-desensitise each other, potentially allowing a single chemokine receptor agonist to desensitise all the chemokine receptors on a cell. If an appropriate single receptor agonist is engineered to be non-chemotactic itself, then a treated cell will lose the potential to migrate in response to chemokines towards any developing site of inflammation. A non-GAG-binding but receptor agonistic form of the chemokine CCL7 can inhibit leukocyte recruitment in response to a diverse range of chemokines in vitro and in vivo. We hypothesise that this modified chemokine mediates its effect by inducing homologous and heterologous receptor desensitisation and further propose that other suitable candidates could include agonistic chemokine receptor-specific antibodies or small molecule chemokine receptor agonists. Hence, an appropriate chemokine receptor agonist could be used to inhibit multiple chemokine receptors, thereby producing a powerful and robust anti-inflammatory effect. This review considers the mechanisms leading to chemokine receptor desensitisation and discusses the potential to develop a new class of anti-inflammatory agents based on targeted stimulation of chemokine receptors.     

Appropriate household water treatment methods in Ethiopia: household use and associated factors based on 2005, 2011, and 2016 EDHS data

Background

Diarrheal disease attributable to water and sanitation can be prevented using point-of-use water treatment. In Ethiopia, a small number of households treat water at point-of-use with appropriate methods. However, evidence on factors associated with household use of these treatment methods is scarce. Therefore, this study is intended to explore the household use of appropriate point-of-use water treatment and associated factors in Ethiopia.

Methods

The data of 2005, 2011, and 2016 Ethiopian demographic and health surveys were used for analysis. Households reportedly treating water with bleach, boiling, filtration, and solar disinfection in each survey are considered as treating with appropriate treatment methods. Household water treatment with these treatment methods and factors associated was assessed using bivariate and multivariable regression. In addition, a region level difference in the treatment use was assessed by using multilevel modeling.

Results

The number of households that reported treating water with appropriate water treatment methods was 3.0%, 8.2%, and 6.5% respectively in 2005, 2011, and 2016. Household heads with higher education had 5.99 (95% CI?=?3.48, 10.33), 3.61 (95% CI?=?2.56, 5.07), and 3.43 (95% CI?=?2.19, 6.37) times higher odds of using the treatment methods respectively in 2005, 2011, and 2016 compared to household heads who had no education. There was a significantly high number of households that used appropriate water treatment methods in 2011 (AOR?=?2.78, 95% CI?=?2.16, 3.57) and 2016 (AOR?=?2.18, 95% CI?=?1.64, 3.89) compared to 2005 data. In pooled data analysis, the reported use of the treatment methods is associated with household head education, residency, drinking water sources, and owning radio and television. From a multilevel modeling, within-region variation is higher than between-region variations in the use of treatment methods in each survey.

Conclusions

Below 10% of households reportedly treating water at point-of-use in each survey attributable to different factors. Designing intervention strategies for wide-scale use of treatment methods at the country level is fundamental.

     

Expression of a second receptor rescues self-specific T cells from thymic deletion and allows activation of autoreactive effector function.

Allelic exclusion at the T-cell receptor alpha chain locus is incomplete resulting in the generation of T cells that express two T-cell receptors. The potential involvement of such T cells in autoimmunity has been suggested [Padovan, E., Casorati, G., Dellabona, P., Meyer, S., Brockhaus, M. & Lanzavecchia, A. (1993) Science 262, 422-424; Heath, W. R. & Miller, J. F. A. P. (1993) J. Exp. Med. 178, 1807-1811]. Here we show that expression of a second T-cell receptor can rescue T cells with autospecific receptors from thymic deletion and allow their exit into the periphery. Dual receptor T cells, created by constitutive expression of two transgenic T-cell receptors on a Rag1-/- background, are tolerant to self by maintaining low levels of autospecific receptor, but selfreactive effector function (killing) can be induced through activation via the second receptor. This opens the possibility that T cells carrying two receptors in the periphery of normal individuals contain putatively autoreactive cells that could engage in autoimmune effector functions after recognition of an unrelated environmental antigen.