Cytokines in chronic heart failure: possible interaction in the neurohormonal and the cytokine system at the cAMP level?

In recent years, the pathophysiological concept of chronic heart failure (CHF) has changed from an isolated hemodynamic view to a more complex concept involving neuroendocrine and inflammatory pathways. New therapeutic strategies, such as beta-blocker therapy, are based on these new concepts and provide clinical evidence for a clinical benefit in patients with CHF. The survival benefit of beta-blocker therapy in CHF has been related to neurohumoral regulation. Thus, evidence evolved showing that following beta-blocker therapy cytokine levels in CHF patients are altered. We have shown that the levels of soluble TNF receptor type 2 correlated well with cAMP in leukocytes. Data from clinical studies in adult and infant CHF patients have demonstrated that beta-blocker therapy is accompanied by altered cytokine, cytokine antagonist, and/or soluble cytokine receptor levels. These alterations may result from a dysregulated interaction of beta-adrenergic pathways and the cytokine system, and are possibly related to cAMP-dependent regulation of the release or shedding of these mediators.     

Unexpected prion phenotypes in experimentally transfused animals: predictive models for humans?

ABSTRACT

The recently reevaluated high prevalence of healthy carriers (1/2,000 in UK) of variant Creutzfeldt-Jakob Disease (v-CJD), whose blood might be infectious, suggests that the evolution of this prion disease might not be under full control as expected. After experimental transfusion of macaques and conventional mice with blood derived from v-CJD exposed (human and animal) individuals, we confirmed in these both models the transmissibility of v-CJD, but we also observed unexpected neurological syndromes transmissible by transfusion: despite their prion etiology confirmed through transmission experiments, these original cases would escape classical prion diagnosis, notably in the absence of detectable abnormal PrP with current techniques. It is noteworthy that macaques developed an original, yet undescribed myelopathic syndrome associating demyelination and pseudo-necrotic lesions of spinal cord, brainstem and optical tract without affecting encephalon, which is rather evocative of spinal cord disease than prion disease in human medicine. These observations strongly suggest that the spectrum of human prion diseases may extend the current field restricted to the phenotypes associated to protease-resistant PrP, and may notably include spinal cord diseases.     

Distinct profiles of human B cell effector cytokines: a role in immune regulation?

There is growing interest in the fundamental roles that B cells may play in regulating immune responses. Emerging animal studies point to an important contribution of B cell effector cytokines to immune modulation, yet little is known about the factors regulating such cytokine production. We report that the profile of human B cell cytokine production is context dependent, being critically influenced by the balance of signals through the B cell receptor and CD40. B cells appropriately stimulated by sequential B cell receptor and CD40 stimulation proliferate and secrete TNF-alpha, lymphotoxin, and IL-6, which can act not only as autocrine growth and differentiation factors, but also serve to amplify the ongoing immune response. In contrast, CD40 stimulation alone, a mimic of a B cell receiving bystander T cell help in the absence of specific Ag recognition, induces negligible proinflammatory cytokines, but significant production of IL-10 that serves to suppress inappropriate immune responses. We thus describe a novel paradigm of reciprocal regulation of B cell effector cytokines, and ascribe active roles for human B cells in either promoting or suppressing local immune responses through context-dependent cytokine production.     

Life after death: are autophagy genes involved in cell death and survival during plant innate immune responses?

It has not escaped the attention of the plant disease resistance community that the vacuole is rapidly emerging as a central player in the execution of cell death. On the one hand the targeted destruction of the vacuole-from the inside out-by vacuolar processing enzymes (VPE) is required to induce PCD in pathogen-infected cells. On the other hand, an intact vacuole is vital for a functional autophagic response to ensure survival of uninfected cells. At face value, the two responses seem to represent distinct resistance mechanisms that operate at divergent branch points and their use of the vacuole merely coincidental. However, closer examination has led us to propose an interesting hypothesis that accounts for these two opposing roles of the vacuole in both VPE-mediated PCD and autophagydependent cell survival. During initial infection, we propose a mechanism similar to the CPY transport pathway in yeast wherein a select set of genes, including several which encode a phosphatidylinositol 3-kinase complex that is needed for autophagy, are needed for VPE transport, vacuolar processing and initiation of PCD. Later during infection, autophagyspecific genes are needed for autophagosome formation, sequestration of VPE preproteins and VPE degradation.     

Shigella's ways of manipulating the host intestinal innate and adaptive immune system: a tool box for survival?

Shigella, a Gram-negative invasive enteropathogenic bacterium, causes the rupture, invasion and inflammatory destruction of the human colonic epithelium. This complex and aggressive process accounts for the symptoms of bacillary dysentery. The so-called invasive phenotype of Shigella is linked to expression of a type III secretory system (TTSS) injecting effector proteins into the epithelial cell membrane and cytoplasm, thereby inducing local but massive changes in the cell cytoskeleton that lead to bacterial internalization into non-phagocytic intestinal epithelial cells. The invasive phenotype also accounts for the potent pro-inflammatory capacity of the microorganism. Recent evidence indicates that a large part of the mucosal inflammation is initiated by intracellular sensing of bacterial peptidoglycan by cytosolic leucine-rich receptors of the NOD family, particularly NOD1, in epithelial cells. This causes activation of the nuclear factor kappa B and c-JunNH(2)-terminal-kinase pathways, with interleukin-8 appearing as a major chemokine mediating the inflammatory burst that is dominated by massive infiltration of the mucosa by polymorphonuclear leukocytes. Not unexpectedly, this inflammatory response, which is likely to be very harmful for the invading microbe, is regulated by the bacterium itself. A group of proteins encoded by Shigella, which are injected into target cells by the TTSS, has been recently recognized as a family of potent regulators of the innate immune response. These enzymes target key cellular functions that are essential in triggering the inflammatory response, and more generally defense responses of the intestinal mucosa. This review focuses on the mechanisms employed by Shigella to manipulate the host innate response in order to escape early bacterial killing, thus ensuring establishment of its infectious process. The escape strategies, the possible direct effect of Shigella on B and T lymphocytes, their impact on the development of adaptive immunity, and how they may help explain the limited protection induced by natural infection are discussed.     

Sex and asymmetry in humans: what is the role of developmental instability?

Because asymmetric individuals are less attractive and may suffer from reduced fitness, bilateral asymmetry is widely believed to affect human sexual selection. Its evolutionary significance is based on the presumed relationship with developmental instability (DI). Yet, relationships between DI and bilateral asymmetry are often weak and possibly confounded by asymmetric mechanical loadings because of handedness. We related asymmetry in hands and faces to degrees of handedness and sexual behaviour in 100 humans. Handedness correlated to levels of asymmetry, thereby likely invalidating the use of asymmetry to estimate DI. For facial asymmetry, applying existing theoretical models refuted a link between asymmetry and DI. Explicit statistical modelling at the level of DI confirmed the absence of a link between DI and aspects of sexual behaviour. Nevertheless, asymmetries in both hands and face correlated significantly with sexual behaviour. We conclude that bilateral asymmetry per se, rather than its presumed link with DI, more likely relates to measures of human sexual behaviour. Because lateralization of behaviour appears widespread, evaluating the role of DI in evolution and ecology relies on a very critical selection of traits whose asymmetry can reliably reflect DI.     

Roles of human β-defensins in innate immune defense at the ocular surface: arming and alarming corneal and conjunctival epithelial cells

Human β-defensins are cationic peptides produced by epithelial cells that have been proposed to be an important component of immune function at mucosal surfaces. In this study, the expression and inducibility of β-defensins at the ocular surface were investigated in vitro and in vivo. Expression of human β-defensins (hBD) was determined by RT-PCR and immunohistochemistry in tissues of the ocular surface and lacrimal apparatus. Cultured corneal and conjunctival epithelial cells were stimulated with proinflammatory cytokines and supernatants of different ocular pathogens. Real-time PCR and ELISA experiments were performed to study the effect on the inducibility of hBD2 and 3. Expression and inducibility of mouse β-defensins-2, -3 and -4 (mBD2–4) were tested in a mouse ocular surface scratch model with and without treatment of supernatants of a clinical Staphylococcus aureus (SA) isolate by means of immunohistochemistry. Here we show that hBD1, -2, -3 and -4 are constitutively expressed in conjunctival epithelial cells and also partly in cornea. Healthy tissues of the ocular surface, lacrimal apparatus and human tears contain measurable amounts of hBD2 and -3, with highest concentrations in cornea and much lower concentrations in all other tissues, especially tears, suggesting intraepithelial storage of β-defensins. Exposure of cultured human corneal and conjunctival epithelial cells to proinflammatory cytokines and supernatants of various bacteria revealed that IL-1β is a very strong inductor of hBD2 and Staphylococcus aureus increases both hBD2 and hBD3 production in corneal and conjunctival epithelial cells. A murine corneal scratch model demonstrated that β-defensins are only induced if microbial products within the tear film come into contact with a defective epithelium. Our finding suggests that the tear film per se contains so much antimicrobial substances that epithelial induction of β-defensins occurs only as a result of ocular surface damage. These findings widen our knowledge of the distribution, amount and inducibility of β-defensins at the ocular surface and lacrimal apparatus and show how β-defensins are regulated specifically.     

Of mice and humans: how good are HLA transgenic mice as a model of human immune responses?

Background

Previous studies have defined vaccinia virus (VACV)-derived T cell epitopes in VACV-infected human leukocyte antigen-A*0201 (HLA-A2.1) transgenic (Tg) mice and A2.1-positive human Dryvax vaccinees. A total of 14 epitopes were detected in humans and 16 epitopes in A2.1 Tg mice; however, only two epitopes were independently reported in both systems. This limited overlap raised questions about the suitability of using HLA Tg mice as a model system to map human T cell responses to a complex viral pathogen. The present study was designed to investigate this issue in more detail.

Results

Re-screening the panel of 28 A2.1-restricted epitopes in additional human vaccinees and in A2.1 Tg mice revealed that out of the 28 identified epitopes, 13 were detectable in both systems, corresponding to a 46% concordance rate. Interestingly, the magnitude of responses in Tg mice against epitopes originally identified in humans is lower than for epitopes originally detected in mice. Likewise, responses in humans against epitopes originally detected in Tg mice are of lower magnitude.

Conclusion

These data suggest that differences in immunodominance patterns might explain the incomplete response overlap, and that with limitations; HLA Tg mice represent a relevant and suitable model system to study immune responses against complex pathogens.     

Melanocyte-specific immune response in melanoma and vitiligo: two faces of the same coin?

The appearance of depigmentation during the course of malignant melanoma has been considered a good prognostic sign. Is it only a side-effect, informative of the immune system's response to the treatment, or does it act as a necessary amplifier of these clinically important anti-tumor responses? The current review will attempt to tackle this question by reviewing the current literature, as well as by posing some novel hypotheses. Understanding the nature of humoral and cellular immune responses directed against normal melanocytes and their malignant counterparts may lead to the design of improved therapeutic strategies relevant to both vitiligo and melanoma.     

Cryptosporidiosis and Cryptosporidium species in animals and humans: A thirty colour rainbow?

Parasites of the genus Cryptosporidium (Apicomplexa) cause cryptosporidiosis in humans and animals worldwide. The species names used for Cryptosporidium spp. are confusing for parasitologists and even more so for non-specialists. Here, 30 named species of the genus Cryptosporidium are reviewed and proposed as valid. Molecular and experimental evidence suggests that humans and cattle are the hosts for 14 and 13 out of 30 named species, respectively. Two, four and eight named species are considered of major, moderate and minor public health significance, respectively. There are at least nine named species that are shared between humans and cattle. The aim of this review is to outline available species information together with the most commonly used genetic markers enabling the identification of named Cryptosporidium spp. Currently, 28 of 30 named species can be identified using the complete or partial ssrRNA, serving as a retrospective ‘barcode’. Currently, the ssrRNA satisfies the implicit assumption that the reference databases used for comparison are sufficiently complete and applicable across the whole genus. However, due to unreliable annotation in public DNA repositories, the reference nucleotide entries and alignment of named Cryptosporidium spp. has been compiled. Despite its known limitations, ssrRNA remains the optimal marker for species identification.     

Inflammatory obstruction of the olfactory clefts and olfactory loss in humans: a new syndrome?

The first step in the olfactory perception is the activation by odorants of sensory neurones in the olfactory epithelium. In humans, this sensory epithelium is located at 2 narrow passages, the olfactory clefts, at the upper part of the nasal cavities. Little is known about the physiology of these clefts. We examined, in 34 patients, the impact of obstructed clefts upon detection and postlearning identification of 5 odorants. The location and extension of the obstructions were assessed using endoscopy, CT scans, and MRI. The inflammatory obstruction was usually bilateral, extending anteroposteriorly, and confined to the clefts, with no sign of obstruction or any inflammatory disease in the rest of the nasal cavities and sinuses. When tested with 5 odorants, these patients showed greatly impaired olfaction compared with a group of 73 normosmic subjects. The majority of these 34 patients had sensory deficits equivalent to that found in another group of 41 congenital anosmic patients, where inspection with MRI indicated the lack of olfactory bulbs. This study demonstrates that the olfactory clefts, in human, function as an entity that is different from other regions of the nasal cavity and is the target for local inflammatory events that are apparently not responding to corticoid and antibiotic treatments.     

Mitochondria,endoplasmic reticulum and innate immune dysfunction in mood disorders: Do Mitochondria-Associated Membranes (MAMs) play a role?

Mood disorders like major depression and bipolar disorder (BD) are among the most prevalent forms of mental illness. Current knowledge of the neurobiology and pathophysiology of these disorders is still modest and clear biological markers are still missing. Thus, a better understanding of the underlying pathophysiological mechanisms to identify potential therapeutic targets is a prerequisite for the design of new drugs as well as to develop biomarkers that help in a more accurate and earlier diagnosis.Multiple pieces of evidence including genetic and neuro-imaging studies suggest that mood disorders are associated with abnormalities in endoplasmic-reticulum (ER)-related stress responses, mitochondrial function and calcium signalling. Furthermore, deregulation of the innate immune response has been described in patients diagnosed with mood disorders, including depression and BD. These disease-related events are associated with functions localized to a subdomain of the ER, known as Mitochondria-Associated Membranes (MAMs), which are lipid rafts-like domains that connect mitochondria and ER, both physically and biochemically.This review will outline the current understanding of the role of mitochondria and ER dysfunction under pathological brain conditions, particularly in major depressive disorder (MDD) and BD, that support the hypothesis that MAMs can act in these mood disorders as the link connecting ER-related stress response and mitochondrial impairment, as well as a mechanisms behind sterile inflammation arising from deregulation of innate immune responses. The role of MAMs in the pathophysiology of these pathologies and its potential relevance as a potential therapeutic target will be discussed.     

Developmental rules in the hematopoietic and immune systems of birds: how general are they?

Fundamental rules about the development of the hematopoietic and immune systems have been established in birds, some of which are reviewed here. The organ rudiments belonging to this system provide the stroma, that has to be seeded by extrinsic stem cells. This particular developmental pattern makes it possible to create chimeric organs with stromal cells and stem cells from different origins. Grafting the thymic epithelium alone in a young embryo is sufficient to induce tolerance to tissues of the same origin as that of epithelium, even in a xenogeneic combination. Stem cells that seed the rudiments during development are born in the embryo rather than in the yolk sac and are responsible for definitive hematopoiesis. Data in frog and mouse indicate that these conclusions may be valid in other classes of vertebrates.     

Improvement of innate immune responses and defense activity in mitten crab (Eriocheir sinensis) by oral administration of β-glucan

The beta-glucan (BG), extracted from Saccharomyces cerevisiae cell wall, was orally administrated to the mitten crab (Eriocheir sinensis) at 0, 1, 5 and 10 g BG/kg diet for 28 days, followed by a challenge with Vibrio mimicus by intramuscular injection. Growth, phenoloxidase, superoxide dismutase, acid phosphatase and alkaline phosphatase activity were monitored after 14 and 28 days. The results showed an immunomodulatory effect and protection against V. mimicus by dietary supplementation of BG. The recommended concentration is 5 g BG/kg diet.     

Circulating cytokine profile in anti-neutrophilic cytoplasmatic autoantibody-associated vasculitis: prediction of outcome?

AIMS: The anti-neutrophilic cytoplasmatic autoantibody-associated vasculitides (AASV) are diseases of relapsing-remitting inflammation. Here we explore the cytokine profile in different phases of disease, looking for pathogenic clues of possible prognostic value. RESULTS: Interleukin (IL)-6, IL-8 and IL-10 were significantly elevated in plasma. Patients in the stable phase who subsequently developed adverse events had higher IL-8 values. Patients in the stable phase who relapsed within 3 months had lower IL-10 values and higher IL-6 levels. CONCLUSIONS: Patients with AASV have raised circulating cytokine levels compared with healthy controls, even during remission. Raised IL-8 seems associated with poor prognosis. Lower levels of IL-10 and higher levels of IL-6 herald a greater risk of relapse. Patients with systemic vasculitis in clinical remission have persistent disease activity, kept under control by inhibitory cytokines.     

Monocyte epigenetics and innate immunity to malaria: yet another level of complexity?

Children under the age of 5 years living in areas of moderate to high malaria transmission are highly susceptible to clinical malaria with fever that prompts treatment of blood stage infection with anti-malarial drugs. In contrast, older school age children frequently experience subclinical malaria, i.e. chronic Plasmodium falciparum parasitemia without fever or other clinical symptoms. The role of innate immune cells in regulating inflammation at a level that is sufficient to control the parasite biomass, while at the same time maintaining a disease-tolerant clinical phenotype, i.e., subclinical malaria, is not well understood. Recent studies suggest that host epigenetic mechanisms underlie the innate immune homeostasis associated with subclinical malaria. This Current Opinion article presents evidence supporting the notion that modifications of the host monocyte/macrophage epigenome regulate innate immune functions pertinent to subclinical malaria.     

UFD1L and CDC45L: a role in DiGeorge syndrome and related phenotypes?

Molecular genetics is contributing to the understanding of normal and abnormal cardiovascular development and morphogenesis. Deletions of chromosome 22q11.2 have been associated with distinct phenotypes that result from a failure to form derivatives of third and fourth branchial arches, including DiGeorge syndrome (DGS) and velo-cardio-facial syndrome (VCFS). The biochemical mechanisms underlying these phenotypes remain undetermined. A recent study provides new insight into the mechanism by which gene deletions produce the DGS and VCFS phenotypes.