|
E-Pub Ahead of Schedule: Bentham Science
Publishers are pleased to offer electronic publication of
accepted papers prior to scheduled publication. These peer-reviewed
papers can be cited using the date of access and the unique
DOI number. Any final changes in manuscripts will be made
at the time of print publication and will be reflected in
the final electronic version of the issue. Articles ahead
of schedule may be ordered by pay-per-view at the relevant
links below, or alternatively if not available at the time,
be requested by completing the available inquiry form.
Disclaimer: Articles appearing in E-Pub Ahead-of-Schedule
sections have been peer-reviewed and accepted for publication
in this journal and posted online before scheduled publication.
Articles appearing here may contain statements, opinions,
and information that have errors in facts, figures, or interpretation.
Accordingly, Bentham Science Publishers, the editors and authors
and their respective employees are not responsible or liable
for the use of any such inaccurate or misleading data, opinion
or information contained of articles in the E-Pub Ahead-of-Schedule.
The tight relationship between osteoclasts and the immune system
Andrea Del Fattore and Anna Teti
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00052]
Inflammation-associated changes in bone homeostasis
Carina Scholtysek, Gerhard Krönke and Georg Schett
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00053]
Regulatory cross talks of bone cells, hematopoietic stem cells and the nervous system maintain hematopoiesis
Orit Kollet, Jonathan Canaani, Alexander Kalinkovich and Tsvee Lapidot
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00054]
Osteoblast and osteoclast crosstalks: from OAF to Ephrin
Roberto Tamma and Alberta Zallone
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00055]
Detection of abacavir hypersensitivity by ELISpot method
Stefan Esser, Robert Jablonka, Falko M. Heinemann, Stefan Reuter, Hans Jaeger, Ariane von Krosigk, Pia Schenk-Westkamp, Dirk Schadendorf, Peter A. Horn and Monika Lindemann
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00056]
Inhaled KMUP-1 prevents allergic pulmonary vascular inflammation and remodeling via NO and suppressed MMP-9 and ICAM-1/VCAM-1
Chung-Pin Liu, Chung-Han Hsieh, Bin-Nan Wu, Jwu-Lai Yeh, Zen-Kong Dai, Chee-Yin Chai and Ing-Jun Chen
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00057]
Proinflammatory activities of leptin in non-autoimmune conditions
Antonio La Cava
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00058]
Interstitial lung disease in systemic sclerosis: Pathophysiology, current and new advances in therapy
Snigdha Jain, Anupama Shahane and Chris T. Derk
[Abstract] [Purchase Article] [BSP/IA-DT/E-Pub/00059]
Effects of sublingual immunotherapy on allergic inflammation: an update
Mona-Rita Yacoub, Giselda Colombo, Francesco Marcucci, Marco Caminati, Laura Sensi, Giuseppe Di Cara, Franco Frati and Cristoforo Incorvaia
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00060]
A Review of Animal and Human Studies for Management of Benign Prostatic Hyperplasia with Natural Products; Perspective of new Pharmacological Agents
Hanieh Azimi, Ali-Asghar Khakshur, Iman Aghdasi, Mehrnaz Fallah-Tafti and Mohammad Abdollahi
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00061]
Editorial: Bone And Immune System Cross-Talk
Nadia Rucci and Hiroshi Takayanagi
[BSP/IA-DT/E-Pub/00062]
Efficacy of montelukast as added therapy in patients with chronic idiopathic urticaria
Sujoy Khan and N. Lynch
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00063]
Antagonizing IL-6 in Ankylosing Spondylitis: A Short Review
Sakthiswary Rajalingham and Srijit Das
[Abstract] [Purchase Article] [BSP/IA-DT/E-Pub/00064]
Probiotic multistrain treatment may eradicate Helicobacter pylori from the stomach of dyspeptics: a placebo-controlled pilot study
Rosa Rosania, Maria Filomena Minenna, Floriana Giorgio, Antonio Facciorusso, Vincenzo De Francesco, Cesare Hassan, Carmine Panella and Enzo Ierardi
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00065]
Inhaled KMUP-1 prevents allergic pulmonary vascular inflammation and remodeling via NO and suppressed MMP-9 and ICAM-1/VCAM-1
Chung-Pin Liu, Chung-Han Hsieh, Bin-Nan Wu, Jwu-Lai Yeh, Zen-Kong Dai, Chee-Yin Chai and Ing-Jun Chen
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00066]
Treatment of Guillain-Barré syndrome: a review
Yusuf A. Rajabally
[Abstract] [Purchase Article] [BSP/IA-DT/E-Pub/00067]
Bone marrow niches for hematopoietic stem cells and immune cells
Tatsuki Sugiyama and Takashi Nagasawa
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00068]
Apoptosis modulated by oxidative stress and inflammation during obstructive nephropathy
Walter Manucha and Patricia G Vallés
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00069]
Interleukin-21 in Immune and Allergic Diseases
Massimiliano Sarra, Maria Laura Cupi, Francesco Pallone and Giovanni Monteleone
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00070]
Nonstandard Drugs and Feasible New Interventions for Autoimmune Hepatitis. Part- I
Albert J. Czaja
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00071]
Nonstandard Drugs and Feasible New Interventions for Autoimmune Hepatitis. Part-II
Albert J. Czaja
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00072]
Allergen-Specific Responses of CD19high and CD19low B Cells in Non-IgE-mediated Food Allergy of Late Eczematous Reactions in Atopic Dermatitis: Presence of IL-17- and IL-32-producing Regulatory B Cells (Br17 & Br32)
Joonyong Noh and Geunwoong Noh
[Abstract] [FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00073]
Abstracts
The tight relationship between osteoclasts and the immune system
Andrea Del Fattore and Anna Teti
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00052]
Osteoimmunology is an interdisciplinary field addressing the interplay between the skeletal and the immune system. A substantial body of evidence demonstrated the existence of two-way regulatory mechanisms that affect both systems, placing them in much closer association to each other than one could ever predict. Inflammatory diseases have long been known to induce alterations in bone metabolism, and inflammatory cytokines play prominent roles in the control of bone resorption, representing communication pathways bridging the two systems. Osteoclasts are particularly linked to the immune cells because they belong to the monocyte/macrophage family, have tight relationships with B and T cells, and differentiate in response to RANKL which is also produced by lymphocytes and regulates lymphopoiesis. Osteoclasts are negatively regulated by cytokines and other factors known for their anti-inflammatory and immune regulatory activity. Finally, they express immune co-receptor typical of immune cells which are indispensable for their differentiation, thus leading to the hypothesis that osteoclasts are immune cells themselves. The underlying principle why an immune cell is required to resorb bone has not yet been elucidated. Data from early literature suggest that the bone matrix could trigger an innate immune response activating giant cells that could destroy large bone areas because of their unique property of resorbing bone extracellularly. Bone resorption could though be prevented by the physical barrier made by osteoblasts and lining cells, whose retraction would be required to give access to osteoclasts when specific pathways signal their precursors to differentiate and mature osteoclasts to reach the uncovered bone surface.
[Back to top]
Inflammation-associated changes in bone homeostasis
Carina Scholtysek, Gerhard Krönke and Georg Schett
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00053]
Bone is a dynamic tissue undergoing constant remodelling and repair. Its homeostasis is regulated by a coordinated process executed by bone forming and bone resorbing cells. Apart from being a major component of the locomotive system, bone provides protection for internal organs and represents a main mineral storage. Furthermore, it houses the haematopoietic system and is hence essential for the body’s immune response. In turn, the innate and adaptive immune system itself, critically affect bone homeostasis. This is most evident during chronic inflammatory diseases, such as Rheumatoid Arthritis, where bone mass is critically reduced. Recently the field of osteoimmunology, focusing on this crosstalk between the immune system and bone homeostasis, has gained increasing attention. This review will highlight cellular and molecular mechanisms linking the innate and adaptive immune response to bone biology and provide an overview about involved cytokines and cells. Moreover, chronic inflammation and its consequences for bone turnover are discussed.
[Back to top]
Regulatory cross talks of bone cells, hematopoietic stem cells and the nervous system maintain hematopoiesis
Orit Kollet, Jonathan Canaani, Alexander Kalinkovich and Tsvee Lapidot
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00054]
Adult hematopoietic stem cells (HSC) continuously replenish the blood with immune and blood cells with a finite life span, from the bone marrow (BM) reservoir of immature and maturing leukocytes. Regulation of HSC migration and development is essential for their function and blood cell production. These diverse and multiple states require a tight regulation to efficiently address host defense and repair requirements. Numerous recent studies disclose a central role for bone related cells in regulation of HSC and hematopoiesis. During ontogeny HSC home and seed the fetal BM in the last gestation period when the bone is already ossified. Ossification involves bone forming osteoblast- and bone degrading osteoclast activity and is considered essential for the formation of BM cavities and hematopoiesis. This synchronized association implies the need for active bone cells and bone turnover for HSC regulation. Osteoblastic cells and SDF-1+/nestin+ reticular adventitial and CAR cells are crucial for regulation of HSC lodgment, self-renewal and function. Bone resorbing osteoclasts regulate bone turnover and progenitor cell detachment and release from the BM. Sympathetic signals from the nervous system activated by circadian rhythms or stress conditions control both bone turnover and HSC migration and development. In this review we discuss pathways and mechanisms involved in this orchestrated regulatory network. A special focus is made on the pivotal role of the SDF-1/CXCR4 axis as a determinant of HSC fate. Inflammation, DNA damage, cytokine mobilization, microgravity and aging are discussed as specific physiologic and pathologic events entailing dysregulation of the tightly balanced Bone-Brain-Blood triad.
[Back to top]
Osteoblast and osteoclast crosstalks: from OAF to Ephrin
Roberto Tamma and Alberta Zallone
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00055]
The maintenance of bone homeostasis is tightly controlled, and largely dependent upon cellular communication between osteoclasts and osteoblasts, and the coupling of bone resorption to bone formation. This tight coupling is essential for the correct function and maintenance of the skeletal system, repairing microscopic skeletal damage and replacing aged bone. Cells in osteoclast and osteoblast lineages communicate with each other through diffusible paracrine factors, cell–cell contact, and cell–bone matrix interaction. Osteoclast–osteoblast communication occurs in a basic multicellular unit (BMU) at the initiation, transition and termination phases of bone remodeling. At the initiation phase, hematopoietic precursors are recruited to the BMU. These precursors differentiate into osteoclasts following interactions with osteoblasts, which express and/or secrete ligands as RANK-L and OPG. Subsequently, the transition from bone resorption to formation is mediated by osteoclast-derived ‘coupling factors’, which direct the differentiation and activation of osteoblasts in resorbed lacunae to refill it with new bone. Signals derived from molecules released from the resorbed bone matrix, as TGF-beta and bidirectional signaling generated by interaction between ephrinB2 on osteoclasts and EphB4 on osteoblast precursors facilitates the transition. At the termination phase, bone remodeling is completed by osteoblastic bone formation and mineralization of bone matrix. The research steps that brought to the present knowledge are summarized in this review.
[Back to top]
Detection of abacavir hypersensitivity by ELISpot method
Stefan Esser, Robert Jablonka, Falko M. Heinemann, Stefan Reuter, Hans Jaeger, Ariane von Krosigk, Pia Schenk-Westkamp, Dirk Schadendorf, Peter A. Horn and Monika Lindemann
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00056]
The antiretroviral agent abacavir can cause hypersensitivity reaction (HSR) and the presence of HLA-B*57:01 is predictive of abacavir-HSR in Caucasian HIV-infected patients. However, abacavir-HSR also occurs in HLA-B*57:01 negative patients. In these patients, a safe diagnostic tool to dissect clinically suspected HSR against abacavir from adverse reactions against co-administered drugs is mandatory, and abacavir-ELISpot was evaluated. Peripheral blood mononuclear cells from 87 HIV patients were stimulated by abacavir and the production of interferon-γ to the ELISpot was determined. Abacavir treated patients with HSR [confirmed (n=5) or suspected (n=12)] vs. without HSR (n=42) displayed significantly higher numbers of abacavir-specific cells (82.3±23.0 or 10.5±4.5 vs. -0.5±1.0 spot forming cells per million PBMC, p<.005 each). In conclusion, we established the first abacavir-specific ELISpot. According to our preliminary data, a negative abacavir-ELISpot nearly excludes HSR against abacavir. Thereby the ELISpot may facilitate the decision to continue or withdraw abacavir treatment.
[Back to top]
Inhaled KMUP-1 prevents allergic pulmonary vascular inflammation and remodeling via NO and suppressed MMP-9 and ICAM-1/VCAM-1
Chung-Pin Liu, Chung-Han Hsieh, Bin-Nan Wu, Jwu-Lai Yeh, Zen-Kong Dai, Chee-Yin Chai and Ing-Jun Chen
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00057]
Aims: This study determines whether KMUP-1 inhalation suppresses ovalbumine (OVA)-sensitized and -challenged peri-bronchial vascular inflammation and remodeling in mice. Methods and Results: After short-term KMUP-1 (1-5 mM, 30 min)-nebulization and L-NAME (12 mM, 15 min)-pretreatment, endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases- 9 (MMP-9) expression in lung were measured by Western blotting analysis. In 28-days experiment, mice were sensitized with intra-peritoneal OVA on day 1 and day 8, challenged with OVA nebulization and treatedwith KMUP-1 nebulization (5 mM, 30 mins) on day 21-27. Expression of eNOS, inducible nitric oxide synthase (iNOS), soluble guanylyl cyclase (sGC), protein kinase G (PKG), MMP-9, VCAM-1 and ICAM-1 were measured by Western blotting analysis. eNOS- and MMP-9-immunostaining were used for peri-vascular or peri-bronchial localization. Hematoxylin and eosin staining was used to show the vascular and bronchial wall thickness and infiltration of inflammatory cells. Cell counting and measurement of NO metabolite (NOx) in bronchoalveolar lavage fluid (BALF) were used to examine the NO production. KMUP-1 increased eNOS and decreased MMP-9 expression. L-NAME-pretreatment reversed these changes. KMUP-1 reduced OVA-sensitized vascular and bronchial wall thickening, eNOS-immunostaining at the alveolar septa, MMP-9-immunostaining in the bronchioles and infiltrated inflammatory cells in the peri-vascular and peri-bronchiolar region. The OVA-sensitized decrease of sGC and PKG and increase of iNOS, ICAM-1/VCAM-1 and plasma cytokines IL-5/IL-13 were reversed; cell count, NOx and MMP-9-activity in BALF were decreased by KMUP-1. Conclusions: Inhaled KMUP-1, preventing allergic pulmonary vascular inflammation and remodeling, would be useful for the treatment of asthma and respiratory obstruction disease.
[Back to top]
Proinflammatory activities of leptin in non-autoimmune conditions
Antonio La Cava
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00058]
Leptin is an adipokine whose proinflammatory properties contribute to the pathogenesis of several autoimmune diseases but also to the development and progression of inflammation in several non-autoimmune inflammatory conditions of the kidney, liver, lung, endometrium, blood vessels and endothelia. Here we review the influences of leptin in those conditions and the pertinent experimental work that has defined some mechanisms of action and/or suggested a therapeutic potential for leptin-based modulation of inflammation in non-autoimmune conditions.
[Back to top]
Interstitial lung disease in systemic sclerosis: Pathophysiology, current and new advances in therapy
Snigdha Jain, Anupama Shahane and Chris T. Derk
[Purchase Article] [BSP/IA-DT/E-Pub/00059]
Systemic sclerosis is an autoimmune connective tissue disorder characterized by fibrosis of the skin and visceral organs. Interstitial lung disease (ILD) is a major complication of this disease and along with pulmonary arterial hypertension is the leading cause of mortality in scleroderma patients. The pathogenesis of pulmonary fibrosis is characterized by epithelial cell injury, activation of the coagulation pathway and inflammation, which create a profibrogenic environment in the lung in the setting of autoimmunity. The current standard of treatment for ILD in systemic sclerosis is cyclophosphamide. In view of the modest benefits in pulmonary function seen with cyclophosphamide in two recent trials and its significant toxicity, the search for alternative treatments is ongoing. With the advances in our understanding of the pathogenic mechanisms of pulmonary fibrosis, many promising therapeutic agents have come into view, but their efficacy needs to be evaluated before they can be recommended clinically. This review discusses the pathogenesis of pulmonary fibrosis with a focus on the potential target pathways, the current treatment options and recent advances in the treatment of ILD in systemic sclerosis.
[Back to top]
Effects of sublingual immunotherapy on allergic inflammation: an update
Mona-Rita Yacoub, Giselda Colombo, Francesco Marcucci, Marco Caminati, Laura Sensi, Giuseppe Di Cara, Franco Frati and Cristoforo Incorvaia
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00060]
The most common allergic diseases, and especially the respiratory disorders such as rhinitis and asthma, are closely related to the allergic inflammation elicited by the causative allergen. This makes inflammation the main target of anti-allergic therapies. Among the available treatments, allergen specific immunotherapy (AIT) has a patent effect on allergic inflammation, which persists also after its discontinuation, and is the only therapy able to modify the natural history of allergy. The traditional, subcutaneous route of administration was demonstrated to modify the allergen presentation by dendritic cells (DCs) that in turn correct the phenotype of allergen-specific T cells, switching from the Th2-type response, typical of allergic inflammation and characterized by the production of IL-4, IL-5, IL-13, IL-17, and IL-32 cytokines to a Th1-type response. This immune deviation is related to an increased IFN-gamma and IL-2 production as well as to the anergy of Th2 or to tolerance, the latter being related to the generation of allergen-specific T regulatory (Treg) cells, which produce cytokines such as IL-10 and TGF-beta. Anti-inflammatory mechanisms observed during sublingual AIT with high allergen doses proved to be similar to subcutaneous immunotherapy. Data obtained from biopsies clearly indicate that the pathophysiology of the oral mucosa, with particular importance for mucosal DCs, plays a crucial role in inducing tolerance to the administered allergen.
[Back to top]
A Review of Animal and Human Studies for Management of Benign Prostatic Hyperplasia with Natural Products; Perspective of new Pharmacological Agents
Hanieh Azimi, Ali-Asghar Khakshur, Iman Aghdasi, Mehrnaz Fallah-Tafti and Mohammad Abdollahi
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00061]
Objective: In this paper, we reviewed plants being effective in treatment of BPH for the purpose of finding new sources of pharmaceutical agents.
Methods: All pertinent literature databases were searched. The search keywords were plant, herb, herbal therapy, phytotherapy, benign prostatic hyperplasia, BPH, and prostate. All of the human, animal and in vitro studies were evaluated.
Results: According to the studies, some of the substantial effective constituents of the plants in treatment of BPH are oenothein B, icaritin, xanthohumol, diarylheptanoid, 2,6,4'-trihydroxy-4-methoxybenzophenone, emodin, fatty acids, atraric acid, n-butylbenzene-sulfonamide, curbicin, theaflavin-3,30-digallate, penta-O-galloyl-b-D-glucose, lycopene, sinalbin, β-sitosterol, secoisolariciresinol diglucoside, genistein, apigenin, baicalein, and daidzein. Besides, Serenoa repens, Pygeum africanum, Curcubita pepo, and Urtica dioica as the most prevalent plants used to treat BPH. S. repens in human studies showed equivalent effectiveness to tamsulosin and in combination to U. dioica revealed equal effects to finastride with less side effects.
Conclusion: There are numerous plants that have beneficial influence on BPH although the mechanisms of action in some plants are not well understood yet. Active ingredients of some of these plants are known and can be used as lead components for development of new effective and safe drugs.
[Back to top]
Editorial: Bone And Immune System Cross-Talk
Nadia Rucci and Hiroshi Takayanagi
[BSP/IA-DT/E-Pub/00062]
Increasing evidence over the years has clearly shown two peculiarities of the bone tissue: - The dynamic nature, since during the life of an individual the bone is continuously renewed through a physiological process known as bone remodelling, whose fine tune regulation is mandatory to assure a correct bone mass; - The centrality of the bone tissue, which is able to interact with other organs of the body, thus regulating their functions and vice versa.
The latter aspect is very intriguing, since it has become evident that, besides the classical functions accomplished by bone such as locomotion, organ protection and calcium/phosphate homeostasis, there is a reciprocal regulation among the bone and tissues such as liver, kidney, gut and bone marrow.
What we would like to highlight in this special issue is the close relationship existing between bone and immune system, leading to a new branch of research, that is the osteoimmunology.
A paradigm of this cross-talk comes from recent finding on the mechanisms underlying the development of rheumatoid arthritis, which demonstrated the central role of a subset of T lymphocytes in the induction of an exaggerated osteoclast activity, thus leading to bone erosion in the affected joints. These studies shed light on the crucial role of the interleukin-17, a cytokine produced by T-helper cells, which induces the expression of receptor activator of nuclear factor kappaB ligand (RANKL) in synovial cells, thus contributing to the differentiation and activation of bone-resorbing osteoclasts. Among the other pro-inflammatory cytokines able to regulate osteoclast behavior there is TNFα, which stimulates osteoclast formation by increasing the production of stromal cell-derived RANKL and M-CSF (macrophage-colony stimulating factors). TNFα proved to be an important pro-resorptive regulator of bone remodelling also by increasing osteoclast activity and at the same time decreasing osteoblastogenesis. Similar effects were observed for other inflammatory cytokines, including IL-1β, IL-6 and IL-18.
Bone researchers and immunologists agree to state that an important pathway shared by bone and immune system is RANKL/RANK, which is essential for osteoclastogenesis but is also needed for differentiation of lymphocytes, so that diseases due to inactivating mutations of RANKL or RANK, such as osteopetrosis, manifest with immunological defects besides a bone phenotype. Although crucial for bone metabolism, RANKL, also known as TNF-Related Activation-induced Cytokine (TRANCE) according to the nomenclature of the immune system, and its receptor RANK, born in an immunological contest. Indeed they were first described as molecules expressed by T cells and dendritic cells, and their physical interaction increased the ability of dendritic cells to stimulate naive T cell proliferation as well as dendritic cell survival. Independent parallel studies performed by bone researchers identified the so called Osteoclast Differentiation Factor (ODF), expressed by the osteoblasts, which increased osteoclast formation, and OPG (osteoproteregin), an osteoblast secreted member of the TNF receptor family very similar in structure to RANK that, as suggested by the given name, inhibited osteoclast development and bone resorption acting as a decoy receptor. The molecule able to interact with OPG was then identified and named OPG-Ligand (OPGL). Finally, bone researchers and immunologists came to the conclusion that RANKL/TRANCE, ODF and OPGL were the same molecule, and that RANKL-expressing T cells could also activate osteoclasts, thus mimicking the effect of osteoblasts.
As widely described in the articles proposed, in addition to cellular interactions via cytokines, the immune and skeletal systems share further molecules, including transcription factors, signaling molecules and membrane receptors, which are crucial for a correct bone/immune system homeostasis.
In conclusions, we hope that the contributions of the authors of this special issue, who exhaustively delineate the state of the art of the cross-talk between bone and immune system, could encourage researchers to more deeply investigate this field, with the final aim of translating the new findings in the identification of new therapeutic strategies for the treatment of bone and immune diseases.
Corresponding Author:
Nadia Rucci
Department of Experimental Medicine
University of L’Aquila
Italy
E-mail: rucci@univaq.it
[Back to top]
Efficacy of montelukast as added therapy in patients with chronic idiopathic urticaria
Sujoy Khan and N. Lynch
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00063]
Chronic idiopathic urticaria is a common skin disorder characterized by recurrent appearance of wheals and/or angioedema for more than 6 weeks without an identifiable cause. Consensus guidelines suggest use of leukotriene receptor antagonists (montelukast or zafirlukast) in patients whose urticaria is resistant to antihistamines. Our objectives were (1) document the efficacy of montelukast in our patients, and (2) evaluate whether any clinical features or available laboratory investigations were associated with a response to montelukast.
Patients who received montelukast between the years 2008-2011 (4-year period) were retrospectively identified from clinic letters. Clinical features and laboratory investigations were collected and analyzed. The primary end point was adequate control of disease without the need for systemic steroid therapy.
25 patients (10 males and 15 females; median age, 33 years; age range, 13-66 years) with an average duration of urticaria at 3.8 years received montelukast 10mg daily. 12 patients (48%) were better on montelukast with combined anti-H1 and anti-H2 therapy, with no statistical significance between median age and duration of urticaria between males and females. In 11 patients, montelukast had no effect and in 2 patients the urticaria worsened after montelukast was started. 15 patients had peripheral blood basopenia of which 5 patients responded to montelukast. Two patients had positive antinuclear antibody, 3 thyroid peroxidase antibodies and 4 with positive basophil histamine release. All 20 patients who had complement C3 and C4 levels done were within normal limits. Four of 6 patients (67%) with positive specific IgE responded to montelukast and combined anti-H1/H2 therapy.
Almost half of our patients with chronic urticaria responded to montelukast and combined anti-H1 and anti-H2 therapy. We were unable to identify any clinical features or laboratory markers that were associated with a response to montelukast. Further studies are required to understand the failure of response of leukotriene inhibition in urticaria.
[Back to top]
Antagonizing IL-6 in Ankylosing Spondylitis: A Short Review
Sakthiswary Rajalingham and Srijit Das
[Purchase Article] [BSP/IA-DT/E-Pub/00064]
Ankylosing spondylitis (AS) is a chronic inflammatory disorder with predilection for the axial skeleton, leading to progressive restricted mobility and deformity of the spine. The fundamental mechanism involves autoimmunity orchestrated by T cells. Similar to other rheumatic diseases, the complex interplay of cytokines such as tumour necrosis factor alpha, interleukin-6 (IL 6) and interleukin-10 (IL 10) have been implicated in the pathogenesis of the disease. Despite extensive research over the past decades, the treatment options for AS, are limited. Non steroidal anti-inflammatory drugs are the first line of therapy, whereas anti TNF drugs are administered for refractory cases which fail to respond to the treatment. There have been conflicting views on the correlation of IL 6 with disease activity in AS. As such, the debate on the role of anti IL6 in AS is still ongoing. Anti IL 6 such as tocilizumab and siltuximab have proven efficacy based on the large randomized controlled trials. The Food and Drug Administration (FDA) has approved these drugs for treating rheumatoid arthritis and systemic juvenile idiopathic arthritis. Researchers have adventurously experimented anti IL 6 therapy in AS but the conclusions made were not consolidated into international guidelines or consensus statement for clinical practice. In the present review, we explore the role of anti IL6 in the treatment of AS based on the cumulative evidence over recent years.
[Back to top]
Probiotic multistrain treatment may eradicate Helicobacter pylori from the stomach of dyspeptics: a placebo-controlled pilot study
Rosa Rosania, Maria Filomena Minenna, Floriana Giorgio, Antonio Facciorusso, Vincenzo De Francesco, Cesare Hassan, Carmine Panella and Enzo Ierardi
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00065]
Probiotics survive in gastric environment competing with H. pylori. We studied probiotic “multistrain” administration in dyspeptics with H. pylori (placebo-controlled study).
Forty patients with H. pylori (urea breath test – UBT - and IgG) were treated for 10 days with a mixture of 8 species of probiotics. Control group of represented by 40 positive subjects received placebo. A second UBT and H. pylori stool antigen (HpSA) detection were performed after 1 month. Still positive Ppatients who remained infected were treated with triple therapy undergoing another UBT after 30 days. A second line therapy was administered in remaining positive patients. Statistics: Fisher’s exact probability and Student’s t tests.
Thirteen out 40 patients using probiotics became negative, while controls remained positive, irrespectively of independently by the initial UBT delta value. Triple therapy did not show No different difference in the eradication rates between the two groups was found (68%-71%). After second line therapy two patients remained positive.
An adequate supplementation with probiotics might eradicate H. pylori.
[Back to top]
Inhaled KMUP-1 prevents allergic pulmonary vascular inflammation and remodeling via NO and suppressed MMP-9 and ICAM-1/VCAM-1
Chung-Pin Liu, Chung-Han Hsieh, Bin-Nan Wu, Jwu-Lai Yeh, Zen-Kong Dai, Chee-Yin Chai and Ing-Jun Chen
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00066]
Aims: This study determines whether KMUP-1 inhalation suppresses ovalbumine (OVA)-sensitized and -challenged peri-bronchial vascular inflammation and remodeling in mice. Methods and Results: After short-term KMUP-1 (1-5 mM, 30 min)-nebulization and L-NAME (12 mM, 15 min)-pretreatment, endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases- 9 (MMP-9) expression in lung were measured by Western blotting analysis. In 28-days experiment, mice were sensitized with intra-peritoneal OVA on day 1 and day 8, challenged with OVA nebulization and treatedwith KMUP-1 nebulization (5 mM, 30 mins) on day 21-27. Expression of eNOS, inducible nitric oxide synthase (iNOS), soluble guanylyl cyclase (sGC), protein kinase G (PKG), MMP-9, VCAM-1 and ICAM-1 were measured by Western blotting analysis. eNOS- and MMP-9-immunostaining were used for peri-vascular or peri-bronchial localization. Hematoxylin and eosin staining was used to show the vascular and bronchial wall thickness and infiltration of inflammatory cells. Cell counting and measurement of NO metabolite (NOx) in bronchoalveolar lavage fluid (BALF) were used to examine the NO production. KMUP-1 increased eNOS and decreased MMP-9 expression. L-NAME-pretreatment reversed these changes. KMUP-1 reduced OVA-sensitized vascular and bronchial wall thickening, eNOS-immunostaining at the alveolar septa, MMP-9-immunostaining in the bronchioles and infiltrated inflammatory cells in the peri-vascular and peri-bronchiolar region. The OVA-sensitized decrease of sGC and PKG and increase of iNOS, ICAM-1/VCAM-1 and plasma cytokines IL-5/IL-13 were reversed; cell count, NOx and MMP-9-activity in BALF were decreased by KMUP-1. Conclusions: Inhaled KMUP-1, preventing allergic pulmonary vascular inflammation and remodeling, would be useful for the treatment of asthma and respiratory obstruction disease.
[Back to top]
Treatment of Guillain-Barré syndrome: a review
Yusuf A. Rajabally
[Purchase Article] [BSP/IA-DT/E-Pub/00067]
Guillain-Barré syndrome is a frequently post-infectious, autoimmune acute inflammatory polyradiculoneuropathy affecting all age groups. It typically results in rapid-onset weakness symmetrically affecting proximal and distal muscles. Cranial muscles are not infrequently affected and respiratory muscle weakness requiring mechanical ventilation occurs in 25% of cases. The incidence is around 1-2 per 100,000/year. Various clinical, electrophysiological and immunological subtypes are described. Plasma exchanges (PE) and intravenous immunoglobulins (IVIg) represent the main treatment options. PE were shown to be effective on rate of recovery in randomized trials. Subsequently further trials have demonstrated the equivalence of IVIg. IVIg are frequently the preferred option for practical reasons. Treatment can result in reversible clinical fluctuations which need to be readily recognized. Although number of PE appears to be optimally of 4, except in mildly affected patients where only 2 may suffice, the dosage of IVIg conventionally administered (2 g/kg) may be sub-optimal in some patients. This may relate to a relationship between IVIg pharmacokinetics and clinical outcome. Studies are under way to evaluate the usefulness of a second IVIg course in severely-affected GBS patients. There is no evidence for use of corticosteroids in GBS. Both IVIg and PE are costly and despite their use and established effectiveness, there is still a need for new treatments to lessen disability. Further research is warranted in optimizing currently available therapies as well as finding others to effectively improve the management of this potentially devastating condition.
[Back to top]
Bone marrow niches for hematopoietic stem cells and immune cells
Tatsuki Sugiyama and Takashi Nagasawa
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00068]
In mammals, hematopoietic stem cells (HSCs), which give rise to all blood cells, and their progenies, including immune cells are controled by special microenvironments, termed niches in the bone marrow during homeostasis and infection. However, the identity, nature and function of these niches remains unclear. It has been reported that HSCs are in contact with osteoblasts lining the bone surface and osteoblasts act as niches for HSCs (termed endosteal niche). However, recent studies suggest that only a small number of HSCs reside in the endosteal niche. In contrast, many HSCs are shown to be in contact with endothelial cells in the marrow. In addition, recent studies suggest that primitive mesenchymal cells, including CXCL12-abundant reticular (CAR) cells and Nestin-expressing cells, which have ability to differentiate into adipocytes as well as osteoblasts act as niches for HSCs. Here we review candidate niches for HSCs in the bone marrow controling hematopoiesis and chronic inflammation.
[Back to top]
Apoptosis modulated by oxidative stress and inflammation during obstructive nephropathy
Walter Manucha and Patricia G Vallés
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00069]
Kidney apoptosis and fibrosis are an inevitable outcome of all kinds of progressive chronic kidney disease where congenital obstructive nephropathy is the primary cause of end-stage renal disease in children, and is also a major cause of renal failure in adults. The injured tubular cells linked to interstitial macrophages, and myofibroblasts produce cytokines and growth factors that promote an inflammatory state in the kidney, induce tubular cell apoptosis, and facilitate the accumulation of extracellular matrix. Angiotensin II plays a central role in the renal fibrogenesis at a very early stage leading to a rapid progression in chronic kidney disease. The increasing levels of angiotensin II induce pro-inflammatory cytokines, NF-κB activation, adhesion molecules, chemokines, growth factors, and oxidative stress. Furthermore, growing evidences report that angiotensin II (a pro-inflammatory hormone) increases mitochondrial oxidative stress regulating apoptosis induction. In addition, direct and indirect renin-angiotensin system blockade produce similar changes on these oxidative inflammatory disorders. Finally, this review summarizes our understanding about possible mechanisms that contribute with apoptosis modulated by inflammation and/or oxidative stress during obstructive nephropathy. The new concept of anti-inflammatory tools regulating mitochondrial oxidative stress will directly affect the inflammatory process and apoptosis. This idea could have attractive consequences in the treatment of renal and other inflammatory pathologies.
[Back to top]
Interleukin-21 in Immune and Allergic Diseases
Massimiliano Sarra, Maria Laura Cupi, Francesco Pallone and Giovanni Monteleone
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00070]
Interleukin-21 (IL-21), a cytokine produced by various subsets of activated CD4+ T cells, plays a major role in the control of innate and adaptive immune responses. IL-21 biological activity is mediated by binding of the cytokine to a heterodimeric receptor, composed of a specific subunit, termed IL-21 receptor (IL-21R), and the common γ-chain, that is shared with IL-2, IL-4, IL-7, IL-9 and IL-15 receptors. IL-21 stimulates the proliferation of CD4+ and CD8+ T lymphocytes and regulates the profile of cytokines secreted by these cells, drives the differentiation of B cells into memory cells and Ig-secreting plasma cells, and enhances the activity of natural killer cells. IL-21 controls also the activity of non-immune cells, such as epithelial cells and stromal cells. The demonstration that IL-21 is involved in the immune responses occurring in chronic inflammatory and allergic diseases suggests that either disrupting or enhancing IL-21 signalling may be useful in specific clinical settings.
[Back to top]
Nonstandard Drugs and Feasible New Interventions for Autoimmune Hepatitis. Part- I
Albert J. Czaja
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00071]
Nonstandard drugs that target critical pathogenic pathways or immune regulatory mechanisms constitute the next generation of treatments for autoimmune hepatitis. Mycophenolate mofetil impairs the proliferation of lymphocytes, decreases autoantibody production, and induces apoptosis of activated immunocytes. Patients treated for azathioprine intolerance improve more frequently than patients treated for refractory liver disease (54% versus 10%), and mycophenolate mofetil is emerging as a rescue therapy for this population. Complete corticosteroid withdrawal is possible in 40% of patients treated with mycophenolate mofetil, and the frequency of side effects ranges from 3-34%. Budesonide in combination with azathioprine has normalized liver tests more frequently (47% versus 18%) and with fewer side effects (28% versus 53%) than standard therapy after 6 months. Budesonide is emerging as a frontline treatment in non-cirrhotic patients with uncomplicated disease or contraindications to conventional corticosteroids. Cyclosporine and tacrolimus are effective salvage agents for steroid-refractory disease, but side effects have been common and occasionally serious. The 6-thioguanine nucleotides and rapamycin are feasible treatments for autoimmune hepatitis, but 6-thioguanine has major obstacles to overcome, especially the risk of liver toxicity or nodular regenerative hyperplasia. The nonstandard drug therapies emerging for autoimmune hepatitis are reflective of the need to supplement or supplant current treatment regimens. None has been licensed for use in autoimmune hepatitis, and their applications have been based on results from small single-center experiences.
[Back to top]
Nonstandard Drugs and Feasible New Interventions for Autoimmune Hepatitis. Part-II
Albert J. Czaja
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00072]
Molecular, cellular, and genetic interventions are now feasible for autoimmune hepatitis because of improved understanding of pathogenic mechanisms, advances in recombinant technology, and previous successes in animal models and humans with other immune-mediated inflammatory diseases. Non-mitogenic monoclonal antibodies to CD3 promote apoptosis of cytotoxic T lymphocytes, inhibit production of pro-inflammatory cytokines, improve the function of regulatory T cells, and induce a durable remission in mouse models and humans with autoimmune diabetes. Monoclonal antibodies to CD20 deplete B lymphocytes, modify antibody-dependent and cell-mediated cytotoxic pathways, enhance regulatory T cell function, and improve isolated cases of autoimmune hepatitis with B-cell disorders. Recombinant cytotoxic T lymphocyte-4 fused with immunoglobulin can block the second co-stimulatory signal required for lymphocyte activation, and it has been licensed for use in rheumatoid arthritis but not tried in autoimmune hepatitis. Other considerations on the distant horizon are monoclonal antibodies against inhibitory receptors on regulatory T cells, adoptive transfer of fresh regulatory T cells, tailored glycolipids that strengthen the immunosuppressive activity of natural killer T cells, small inhibitory ribonucleic acid molecules that silence promoter genes supporting disease activity, and mesenchymal stem cell transplantation to re-constitute immune homeostasis and support the damaged liver. Development of these feasible new interventions for autoimmune hepatitis requires therapeutic animal models, societal support, and a collaborative network of investigators to conduct rigorous clinical trials.
[Back to top]
Allergen-Specific Responses of CD19high and CD19low B Cells in Non-IgE-mediated Food Allergy of Late Eczematous Reactions in Atopic Dermatitis: Presence of IL-17- and IL-32-producing Regulatory B Cells (Br17 & Br32)
Joonyong Noh and Geunwoong Noh
[FULL-TEXT INQUIRY] [BSP/IA-DT/E-Pub/00073]
Background: Food allergies are important etiologic factors in atopic dermatitis. CD19 is a B-cell-specific cell-surface molecule, with a critical role in B-cell activation. Recently, B cells showed independent two subpopulations as CD19hi and CD19low. The allergen-specific responses of the CD19high and CD19low B-cell subpopulations were investigated in patients with non-IgE-mediated food allergy.
Methods: Five milk-allergic subjects and eight milk-tolerant subjects were selected by a double-blind placebo-controlled food challenge. Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with casein or ovalbumin and stained with monoclonal antibodies to distinguish the B-cell subsets.
Results: After allergen stimulation, CD19high B cells increased in the number and the fraction in PBMCs in the milk-tolerant group, whereas theose remained unchanged in the milk-allergic group. These responses were constant, regardless of the kind of food allergen (milk or egg). The resulting CD19high/CD19low B-cell ratio increased markedly in the milk-tolerant group after allergen stimulation, but was unchanged in the milk-allergic group. IL-10, IL-17, IL-32 and TGF-β-producing regulatory B cells and Foxp3-expressing regulatory B cells were identified predominantly on CD19 low and CD5(+) B cells.
Conclusions: The response of the CD19high B-cell subpopulation to allergen stimulation is decisive for immune tolerance of non-IgE-mediated food allergy in atopic dermatitis. CD19 high and CD5(+) B cells dominantly produce cytokines and express Foxp3. Especially, IL-17 and IL-32 expressing B cells (Br17 & Br32) are present. The exact immunological role of CD19 and cytokines including IL-17 and IL-32 around B cells in immune tolerance requires further investigation.
[Back to top]
|
