Endocrine, Metabolic & Immune Disorders-Drug Targets (v.12, #1)
Preface by Emilio Jirillo (1-1).
Dear Readers and Contributors, It is a real pleasure at the beginning of this year to provide you with some information on the current status of Endocrine Metabolic Immune Disorders-Drug Targets (EMID-DT). In the last year, EMID-DT took a very impressive step forward due to the following circumstances. On the one hand, the journal has offered the opportunity to the scientific community to submit original articles in addition to review articles. This has increased the number of submissions as well as the dissemination of novel findings about the endocrine immune axis and its modulation with drugs or natural products. Also in the case of original paper submissions we have applied very strict criteria of acceptance through a peer-reviewing in order to publish top articles. On the other hand, according to SCImago Journal and Country Rank, the cites per doc (2 years) were equivalent to 2.85 Impact Factor (IF) in 2010. The journal has been scheduled to receive its conventional IF in 2013 and, therefore, these figures seem to be predictive of a quite high IF in the immediate future. Also in view of these concepts, the journal must maintain and improve its current status via high standard publications in the form of special issues, single reviews and original articles. Finally, I wish to thank all the editorial board members and external reviewers who have contributed to the progress of EMID-DT. Also, I wish to acknowledge the strenuous work of the Editorial Office collaborators who are constantly contributing to the success of the journal and timely interact with contributors and readers. I would also want to express my appreciation to Dr. Matthew Honan for his great support and wise advices in all these years....
Editorial [ Hot Topic:Immunomodulation in Helminth Infections (Guest Editor: Prof. Fabrizio Bruschi)] by Fabrizio Bruschi (2-3).
Helminths, particularly those localized at intestinal level, represent a major public health problem at global level, with an estimation of over 3.5 billion of human infections . This Hot topic issue of ENDOCRINE, METABOLIC AND IMMUNE DISORDERS-DRUG TARGETS is entirely devoted to immunomodulation of helminth infections. It is intended to illustrate the recent results obtained in the field of host-parasite relations in these infections. These are characterised usually by a persistent Th2 polarization, with eosinophilia and increased total IgE levels, and for this reason they represent ideal models to study allergy and other Th2-mediated pathological conditions. Epidemiological evidence has accumulated suggesting that helminth infection or products derived by these parasites protect against the development of autoimmune and allergic diseases. The mechanisms underlying this protection may include regulatory cells and cytokines . Furthermore, many of these parasites have been studied for the ability to produce molecules modulating host immune response, hookworm is a typical example. This parasite in fact produces the so-called N.I.F. (neutrophil inhibitory factor) a protein which is the ligand of the integrin CD11b/CD18 molecule, present on the surface of neutrophil granulocytes, blocking the adherence of inflammatory cells to endothelium. For this reason, it has been postulated a possible therapeutic use of the protein in neutrophil-mediated human pathology . Many other molecules helminth-derived have been described, representing a real pharmacopoeia . Immunomodulation will be considered in different helminth infections. Trichinellosis is a widely spread zoonotic infection caused by Trichinella spp. in mammals, birds as well as in reptiles. In experimental model of such infection, it was recently shown that eosinophils, considered until now only for effector functions may play also a regulatory role . Data are accumulating which show that infection with this helminth may affect the evolution of experimental models of human diseases such as diabetes, multiple sclerosis and respiratory allergy or inflammation ....
Immunomodulation in Trichinellosis: Does Trichinella Really Escape the Host Immune System? by Fabrizio Bruschi (4-15).
This review describes different aspects of the host immune response to Trichinella. The role of antibodies, T cells, mast cells, eosinophils and neutrophils in immune reaction to this nematode is considered, in the light of the recent data derived from experimental models, both in in vivo and in vitro. The knowledge of immune response mechanisms against Trichinella is fundamental to understand how the parasite can escape such mechanisms. The principal evasion mechanisms of host immune response occurring in trichinellosis are described, some of which are shared by other parasites, some others are peculiar of this parasite, but particular attention is focused on immunomodulation and the possibilities to exploit this parasite ability to verify the effects on immuno-mediated diseases. In conclusion, some considerations on the actual ability to escape the host immune response by the parasite are discussed, taking into account the recent data that shows that the parasite might rather drive immune system of the host towards a less dangerous response.
Cystic Echinococcosis: Aspects of Immune Response, Immunopathogenesis and Immune Evasion from the Human Host by Alessandra Siracusano (16-23).
Cystic echinococcosis (CE) is a neglected infectious disease caused by the larval stage of Echinococcus granulosus. It constitutes a major public health problem in developing countries. During CE, the distinguishing feature of the host-parasite relationship is that chronic infection coexists with detectable humoral and cellular responses against the parasite. In order to establish successfully an infection, E. granulosus releases molecules that directly modulate the host immune responses favoring a strong anti-inflammatory response and perpetuating parasite survival in the host. In vitro and in vivo immunological approaches, together with molecular biology and immunoproteomic technologies provided us exciting insights into the mechanisms involved in the initiation of E. granulosus infection and the consequent induction and regulation of the immune response. Here, we review some of the recent developments and discuss how these observations helped to understand the immunology of E. granulosus infection in man. Although the last decade has clarified many aspects of host-relationship in human CE, establishing the full mechanisms that cause the disease require more studies. We need to define more clearly the events that manipulate the host immune response to protect the E. granulosus from elimination and minimizing severe pathology in the host.
Schistosoma mansoni Antigens as Modulators of the Allergic Inflammatory Response in Asthma by Luciano S. Cardoso (24-32).
Epidemiologic evidence has accumulated suggesting that helminth infection or their products protect against the development of autoimmune and allergic diseases. The mechanisms underlying this protection may include regulatory cells and cytokines. Both helminth infection and allergic diseases drive the immune system toward the Th2 type response with high production of IgE. However, while this antibody response is associated with the pathogenesis of allergic diseases, IgE production in regions endemic for parasite diseases, such as schistosomiasis, might be associated with a protection against infection. In individuals chronically exposed to Schistosoma sp infection, regulatory cells and cytokines which may develop to protect the host against harmful parasite antigens may also protect the host against allergic diseases. We have demonstrated that helminthic infections are associated with a poor response to allergy skin-prick tests and with low asthma pathology. This review summarizes the immune response that is associated with the pathology of allergic diseases such as asthma and with the resistance to helminth infections. Moreover, it is discussed how helminth infection, particularly Schistosoma mansoni or their products may influence the development of atopic asthma.
Toxocara infection and its Association with Allergic Manifestations by Elena Pinelli (33-44).
Toxocara canis and Toxocara cati are roundworms of dogs and cats that can also infect humans worldwide. Although these parasites do not reach the adult stage in the human host the larvae migrate to different organs and can persist for many years. Migration of larvae through the lungs may result in respiratory distress such as wheezing, coughs, mucous production and hyper-reactivity of the airways. Epidemiological and experimental studies suggest that infection with this helminth contributes to the development of allergic manifestations, including asthma. These findings are however conflicting since in others studies no association between these two immunopathologies has been found. This article reviews information on Toxocara spp. and findings from epidemiological and experimental studies on the association between Toxocara infection and allergic manifestations. In addition, the immunological mechanisms and the factors involved in the helminth allergy-association are discussed.
Immunomodulatory Properties of ES-62, a Phosphorylcholine - Containing Glycoprotein Secreted by Acanthocheilonema viteae by Lamyaa Al-Riyami (45-52).
Filarial nematodes are parasites that have the ability to persist in their hosts for extended periods of time due to the employment of various mechanisms to divert or down-regulate the host's immune responses. One of these mechanisms is the production of immunomodulatory excretory-secretory (ES) products. This review will discuss the properties of one such product, ES-62, which over the years, has been shown to interact with and modulate the activities of a variety of cells of the immune system including B and T lymphocytes, dendritic cells, macrophages and mast cells. Overall, ES-62 diverts the immune system towards an anti-inflammatory phenotype and consistent with this it has been shown to have therapeutic potential in models of inflammatory disease associated with autoimmunity and allergy.
Wolbachia and Its Implications for the Immunopathology of Filariasis by Claudio Genchi (53-56).
Filarial infections are characterized by immunopathological phenomena, that are responsible for the onset of often dramatic pathological outcomes, such as blindness (Onchocerca volvulus) and elephantiasis (W. bancrofti). In addition, the long-term survival (as long as 10 years) of these parasites in otherwise immunocompetent hosts indicates that these nematodes are capable of manipulating the host immune response. The ground-breaking discovery of the bacterial endosymbiont Wolbachia, which resides in most filarial nematodes causing disease, has led to increasing interest in the role it may play in immuno-modulation, pro-inflammatory pathology and other aspects of filarial infection. Indeed, Wolbachia has been shown to be responsible for exacerbating inflammation (as in river blindness), while at the same time blocking efficient elimination of parasites through the host immune response (Onchocerca ochengi). While studies aimed at identifying Wolbachia as a potential target for anti-filarial therapy are at the forefront of current research, understanding its role in the immunology of filarial infection is a fascinating field that has yet to uncover many secrets.
Regulation of Leptin Receptor Expression in Human Polarized Caco-2/15 Cells by Philippe G. Cammisotto (57-70).
Background: Leptin receptors (LEPR) are expressed in intestinal epithelial cells from the duodenum to the colon. Since their role is fundamental for the proper control of nutrient absorption, mucus secretion and mucosa renewal, the regulation of LEPR expression is for the first time investigated as a function of various potential effectors. Methodology/Principal Findings: Fully differentiated Caco-2/15 cells were incubated for 24 hours with nutrients [carbohydrates, fatty acids (FA), amino acids and sterols], hormones (leptin, insulin, hydrocortisone and epithelial growth factor), inflammatory agents (Interferon-γ, LPS, TNF-α), and PPAR agonists (rosiglitazone and WY14643). Levels of LEPR mRNA and protein expressions were measured by RT-PCR and Western blots, respectively. Results: Long (219.1) and short (219.3) isoforms of the LEPR were detected in Caco-2/15 cells, while absence of the isoform 219.2 was noted. Their gene expression was modulated by carbohydrates, FA, PPAR agonists, biliary salts, insulin and leptin itself. On the other hand, LEPR protein expression was modulated by FA, cholesterol, biliary salts, PPAR agonists and insulin. Interestingly, the same effectors may have opposite effects on the short and the long LEPR isoforms, as well as on mRNA and protein levels. Finally, Caco-2/15 cells were found to be sensitive to the effector location, i.e. apical or basolateral compartment. Conclusions/Significance: Our results suggest that (i) the expression of LEPR in Caco-2/15 cell line is not constitutive; (ii) the agents present in the apical or basolateral medium have different effects on LEPR mRNA and/or protein levels; and (iii) short and long isoforms of LEPR follow different patterns of regulation.
Immune Modulation by Regulatory T Cells in Helicobacter pylori-Associated Diseases by Sukanya Raghavan (71-85).
Regulatory T cells (Treg) have the ability to suppress the activity of most other lymphoid cells as well as dendritic cells through cell-cell contact dependent mechanisms, which have not yet been fully defined. Treg are a key component of a functional immune system, and Treg deficiency is associated with severe autoimmunity and allergies. Antigen-specific Treg accumulate in gastric tissue during both Helicobacter pylori-induced gastritis and peptic ulcer disease (PUD). Several studies suggest that the local Treg response protects the gastric mucosa from exaggerated inflammation and tissue damage, and the risk of PUD is inversely related to Treg frequencies. At the same time the reduction of the inflammatory response achieved by Treg leads to increased bacterial density. Furthermore, the inability to mount a protective inflammatory response will lead to chronic infection and in some patients to the development of atrophic gastritis and gastric cancer progression. Treg actively infiltrate gastric adenocarcinomas and are predicted to promote tumor escape from cytotoxic immune responses. In addition, the presence of a potent Treg response will probably be an obstacle when constructing a future therapeutic vaccine against H. pylori. In this article, we will review the proposed mechanisms of action for Treg, their accumulation in the gastric mucosa in the different H. pylori-associated diseases, and how they may affect the immune response induced by H. pylori infection and the course of PUD and gastric adenocarcinomas.
Incidence and Prevalence of Hypothyroidism in Patients Affected by Chronic Heart Failure: Role of Amiodarone by Vincenzo Triggiani (86-94).
Background: It has been demonstrated that hypothyroidism can lead to significant hemodynamic alterations favoring the onset of chronic heart failure (CHF) as well as its progression. Furthermore, amiodarone, an iodinecontaining antiarhythmic drug frequently used in CHF patients, is often the cause of primary hypothyroidism. Aim of the Study: To define the prevalence and incidence of hypothyroidism in a group of CHF outpatients in stable clinical conditions, with particular reference to the role of amiodarone therapy. Results: Among the 422 enrolled patients (326 males, aged 65±12 years), 51 (12%) had a previous diagnosis of hypothyroidism while 21 (5%) were newly diagnosed at the enrolment. Then, the overall prevalence of hypothyroidism at the first evaluation was 17%and, as expected, it was significantly higher in females than males (33% vs 13%; p < 0.001). During follow-up (median 28 months) hypothyroidism occurred in further 19 patients (incidence rate: 26/1000/year) and it was mainly attributable to amiodarone therapy. Considering all together the hypothyroid patients, either those affected by thyroid failure at the enrolment than those developing hypothyroidism during the follow-up, levothyroxine therapy was continued or started in 69% of them; however, normal serum TSH values were obtained only in 76% of treated cases (mean levothyroxine dose: 69±44 mcg/day). In any case, in the group of patients affected by hypothyroidism a significantly greater occurrence of heart failure progression was observed. Conclusions: Hypothyroidism, especially the subclinical form, frequently occurs in patients affected by CHF receiving amiodarone therapy. Given the unfavorable impact of hypothyroidism on the progression and prognosis of CHF, and the opportunity to adequately manage thyroid failure by means of levothyroxine replacement therapy without the need to withdraw amiodarone, we recommend regular testing of thyroid function in CHF patients, in particular in those submitted to amiodarone therapy, in order to early diagnose a condition of hypothyroidism and titrate substitutive treatment.
Glucocorticoid Analogues: Potential Therapeutic Alternatives for Treating Inflammatory Muscle Diseases by Erica K.M. Reeves (95-103).
Glucocorticoids (GCs) have been prescribed to treat a variety of diseases, including inflammatory myopathies and Duchenne muscular dystrophy for over 50 years. However, their prescription remains controversial due to the significant side effects associated with the chronic treatment. It is a common belief that the clinical efficacy of GCs is due to their transrepression of pro-inflammatory genes through inhibition of inflammatory transcription factors (i.e. NF-κB, AP-1) whereas the adverse side effects are attributed to the glucocorticoid receptor (GR) -mediated transcription of target genes (transactivation). The past decade has seen an increased interest in the development of GR modulators that maintain the effective anti-inflammatory properties but lack the GR-dependent transcriptional response as a safe alternative to traditional GCs. Many of these analogues or “dissociative” compounds show potential promise in in vitro studies but fail to reach human clinical trials. In this review, we discuss molecular effects of currently prescribed GCs on skeletal muscle and also discuss the current state of development of GC analogues as alternative therapeutics for inflammatory muscle diseases.