Current Pharmaceutical Design - Volume 18, Issue 16, 2012

In this special issue, current insights in the pathomechanisms of inflammatory diseases are reviewed by experts in the field. The involvement of mast cells in allergic and inflammatory diseases is discussed by Theoharides and coauthors [1]. Mast cells are known for their key effector role in allergic diseases, but evidence for their contribution to chronic inflammatory, neurologic and autoimmune diseases is emerging. In the review, the potential role of mast cells as therapeutic targets in cardiovascular diseases and obesity is discussed. Mast cells can be activated by numerous antigen-specific and aspecific stimuli. A novel mechanism of antigen-specific activation of mast cells is discussed by Groot Kormelink et al. [2]. Immunoglobulin free light chains can activate mast cells in an antigen-specific -but IgEindependent- manner. Free light chains are found increased under many inflammatory conditions. The possible contribution of this mechanism to the pathogenesis of upper and lower airway disease, food allergy, inflammatory bowel disease and rheumatoid arthritis is discussed. Allergic sensitization and effector responses can be modulated at various stages. Paul Forsythe discusses the role of the nervous system as a critical regulator of immune responses underlying allergy [3]. Sympathetic nerve fibers innervate primary and secondary lymphoid organs extensively and can influence B and T cell activation and regulate antigen presenting cells. Bidirectional neuroimmune signaling systems may contribute to the etiology and pathophysiology of immune disorders and this review provides an overview of major aspects of the interaction between the immune and nervous system and the implications of this relationship to health and disease with particular reference to allergy. Two reviews deal with the mechanism of adjuvant-mediated immune stimulation. Adjuvants are widely used to improve the adaptive immune responses to e.g. vaccinations. Different molecular mechanisms are involved depending on the nature of the adjuvant used. Those containing microbial components stimulate pattern recognition receptors, while aluminum-based adjuvants stimulate the innate arm of the immune system via an endogenous danger signal. Fierens and Kool [4] describe the cellular and molecular mode of action of such adjuvants. Gilles et al. [5] discuss the importance of non-allergenic, adjuvant substances released from pollen. Many compounds and enzymes (NAPDH oxidases, proteases, adenosine, lipid mediators) are associated with pollen and may have an important contribution to the allergenicity of the pollen. The authors propose that systematic comparative studies on non-allergenic, adjuvant substances in different pollens might help to deduce the relevance of such substances for pollen allergenicity and could help to predict possible susceptibility to develop specific pollen allergies by individuals....

Mast cells are important in the development of allergic and anaphylactic reactions, but also in acquired and innate immunity. There is also increasing evidence that mast cells participate in inflammatory diseases, where they can be activated by non-allergic triggers, such as neuropeptides and cytokines, often having synergistic effects as in the case of substance P (SP) and IL-33. Secretion of vasoactive mediators, cytokines and proteinases contribute to the development of coronary artery disease (CAD), as well as to dietinduced obesity and the metabolic syndrome. Mast cells may be able to orchestrate such different biological processes through their ability to release pro-inflammatory mediators selectively without the degranulation typical of allergic reactions. Recent evidence suggests that mitochondrial uncoupling protein 2 (UCP2) and mitochondrial translocation regulate mast cell degranulation, but not selective mediator release. Better understanding of these two processes and how mast cells exert both immunostimulatory and immunosuppressive actions could lead to the development of inhibitors of release of specific mediators with novel therapeutic applications.

Mast cells are increasingly recognized as critical players in elicitation and maintenance of different inflammatory related disorders, like allergy, autoimmne diseases and cancer. Mast cells maturate within the tissue and are able to adapt to microenvironmental changes. Together with the ability to produce multiple pro- and anti-inflammatory mediators upon activation, mast cells are highly capable of exerting immunomodulatory functions. Cross-linking of receptor bound IgE is the best known mechanism of antigen-specific mast cell activation. In this review we focus on a different route of activation, via immunoglobulin free light chains (FLCs). Here, we describe current knowledge and concepts on FLCs based on preclinical models and data on human subjects, after briefly recapitulating early research findings on FLCs. Furthermore, because FLC research mainly focuses on mast cells, several mast cell mediated pathologies and mouse models for mast cell research will be discussed. Whether targeting of mast cells is beneficial for the treatment of specific disorders has to be addressed in future studies. Specific inhibition of FLC-mediated mast cell activation may be an interesting avenue to treat chronic inflammatory diseases.

The nervous and immune systems collaborate in the control of homeostasis and host defence. All divisions of the nervous system, sympathetic, parasympathetic and sensory, act to regulate immune cell function. Processes under neuronal control include antigen processing and presentation, Th1/Th2 balance, immunoglobulin production and antigen specific responses, while involvement of the central nervous system allows for behavioral changes leading to avoidance of antigen or noxious stimuli. It therefore follows that dysregulation of these complex bidirectional neuroimmune signaling systems may contribute to the aetiology and pathophysiology of immune disorders including atopic disease. A greater understanding on how the brain perceives, processes and responds to immune challenges and how multiple neurotransmitters interact to maintain or skew the balance between tolerance and immunity will undoubtedly provide opportunities for the development of novel therapeutics. Furthermore, the implications for atopic disease of relatively recent developments such as the cholinergic antiinflammatory pathway and the potential direct antigen-specific activation of the nervous system require further exploration.

Vaccinations have been given to people for at least 100 years of which 80 years formulated in adjuvants. Currently, aluminium- containing formulas and the oil-based substance called MF59 are the two adjuvants licensed for clinical use. Despite the massive use of aluminium adjuvant, its mechanism of action has been only recently addressed. In this review, we will discuss both the cellular and molecular mode of action of aluminium-containing adjuvants.

The question what makes an allergen an allergen puzzled generations of researchers. Pollen grains of anemophilous plants are the most important allergen carriers in ambient air, and pollinosis is a highly prevalent multi-organ disease in civilized countries. In the past, research on the allergenicity of pollen has mainly focused on elucidating genetic predisposing factors and on defining certain structural characteristics of pollen derived allergens. Recently, studies extended to the analysis of non-allergenic, adjuvant mediators coreleased from pollen. Besides active proteases and oxidases, extracts of pollen contain low molecular weight molecules like pollenassociated lipid mediators or adenosine exhibiting a potential to stimulate and modulate cultured human immune cells. This article reviews our current knowledge on non-allergenic, protein and non-protein compounds from pollen and their in vitro and in vivo effects on the allergic immune response. To ultimately judge the physiological relevance of these compounds, a systematic approach will be needed comparing their releasability, content and activity in different, allergenic and non-allergenic, pollen species. System biology such as proteome and metabolome analysis will be a useful future approach to better understand pollen biology.

Asthma and Chronic Obstructive Pulmonary Disease (COPD) are two important lung and airways diseases which affect the lives of ∼500 million people worldwide. Asthma is a heterogeneous disease that is broadly defined as a clinical syndrome characterized by altered lung function, mucus hypersecretion, peribronchial inflammation and hyperresponsiveness In contrast, the effect of inhalation of toxic particles and gases on the innate and adaptive inflammatory immune systems underlie the pathogenesis of COPD. In the last decade, knowledge concerning the pathophysiologic mechanisms underlying asthma and COPD has risen tremendously and current dogma suggests that the pathogenesis of both diseases is driven by the chronic inflammation present in the airways of these patients. Thus, understanding the mechanisms for the persistence of inflammation may lead to new therapeutic approaches. In this review, we provide an overview of the main signal transduction pathways implicated in asthma and COPD pathophysiology focusing on inflammasome signaling in various cells types which result in altered inflammatory mediator expression.

COPD (Chronic Obstructive Pulmonary Disease) is an important lung and airway disease which affects the lives of around 200 million people worldwide with an increasing incidence particularly in developing countries. The pathogenesis of COPD is based on the innate and adaptive inflammatory immune response to the inhalation of toxic particles and gases. Although cigarette smoking is the primary cause of this inflammation, many other environmental and occupational exposures contribute to the pathology of COPD. The immune inflammatory changes associated with COPD are linked to a tissue repair and remodeling process that increases mucus production and causes emphysematous destruction of the gas-exchanging surface of the lung. The inflamed airways of COPD patients contain several inflammatory cells including neutrophils, macrophages, T lymphocytes, and dendritic cells (DCs). Little is known about the relative contribution of DCs in the pathogenesis of COPD. However the number of DCs is changed in smokers and COPD patients and cigarette smoke (CS) induces the release of chemokines from DCs that play a role in the pathogenesis of COPD. In this review paper, an overview is presented on the role of DCs and their mediators in the pathogenesis of COPD. The activation of DCs and their signaling in response to CS will also be highlighted and discussed.

Chronic Rhinosinusitis (CRS), a chronic upper airway inflammation, is an inflammation of the nose and the paranasal cavities and is highly prevalent. Chronic rhinosinusitis is currently classified as CRS with nasal polyps or CRS without nasal polyps. This review highlights the pathophysiological differences in CRS on remodeling and on T-cell patterns. Nasal polyps have a high co-morbidity with the lower airway inflammatory disease, asthma. Evidence is accumulating for the role of superantigens, Staphylococcus aureus enterotoxins, in CRS with nasal polyps and asthma, both T helper 2 –biased diseases. Until today there are no biomarkers involved in the diagnosis of CRS or the treatment follow-up. Further differentiation of the phenotype of the disease is needed, which will reflect in the development of new biomarkers and in new innovative treatment options. Defining and predicting response to therapy in individual CRS patients is a challenge for future research.

IL-7, expressed by stromal cells in primary lymphoid organs, is known for its critical role in the development and homeostatic expansion of T cells in humans and mice. IL-7 is equally important for B cell development in human and mice, but only in mice seems critical for B cell development and expansion. Recent studies demonstrate that this potent immunostimulatory cytokine is overexpressed in inflamed tissues of patients with (rheumatic) autoimmune diseases and that expression levels correlate with clinical parameters of disease. In inflamed tissues several cell types, including macrophages, dendritic cells, and fibroblasts produce IL-7. IL-7 primarily acts on T cells that abundantly express the IL-7 receptor and that are increased at the inflammatory sites, and predominantly induces Th1 and Th17-associated cytokine secretion. IL-7-mediated T cell-dependent activation of macrophages, dendritic cells and B cells is accompanied by up regulation of T cell differentiating factors, chemokines, adhesion/co-stimulatory molecules and catabolic cytokines and enzymes. Moreover, overexpression of IL-7 is associated with ectopic lymphoid aggregate formation, corresponding with the capacity of IL-7 to induce LTβ and TNFα and to activate innate lymphoid tissue inducer cells. Additionally, IL-7 promotes T cell-driven osteoclastogenesis and fibroblast activation, processes involved in tissue destruction in chronic inflammation. Altogether this suggests that IL-7 is an important proinflammatory mediator in several chronic (rheumatic) inflammatory autoimmune diseases. The substantial amelioration of inflammation and immunopathology in experimental animal models for these diseases by blocking IL-7(receptor) supports this role of IL-7 and demonstrates that IL-7 and its receptor represent novel targets for immunotherapy.

Most cell types can release vesicles. Cell-derived vesicles are increasingly recognized as an evolutionary wide-spread mechanism of intercellular communication. The paracrine and long range activity of vesicles and their regulated cargo-composition endows these vesicles with regulatory properties beyond that of the parental cell. The release and biogenesis of cell-derived vesicles is a dynamic and tightly controlled process. In the past years it has become clear that these vesicles exert a plethora of biological effects. This has sparked the intense interest in these vesicles in relation to (patho)physiological processes. This review focuses on the role of cell-derived vesicles in inflammation, with emphasis on the immune modulating capacity of immune cell-derived vesicles. The biological activity of different leukocyte-derived vesicles is compared, and potential explanations for the strong biological effects exhibited by vesicles are provided. The role of cell-derived vesicles in inflammatory processes is discussed by speculating how these vesicles can contribute to allergic inflammation.

The so-called hygiene hypothesis is, at least in part, accountable for the increase in allergic diseases in the developed countries. Although there is support for one of its primary predictions that host-microbe interactions in early life have longterm effects on the development of disease across populations, the theory has already proven to be imperfect as many more recent increases in certain diseases cannot be explained by the hygiene hypothesis. Nevertheless, many research groups are interested in the host-microbe interactions and are exploring the use of “live micro-organisms which, when administered in adequate amounts, confer a health benefit to the host” (probiotics) and “selectively fermented ingredients that result in specific changes, in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health” (prebiotics) to reduce the allergic disease onset or clinical outcomes. As the definitions of pre- and probiotics by itself were already adapted after their original dictation, it is not surprising that producing generalistic conclusions on the effectiveness of pre-, pro and synbiotic intervention in allergic diseases is very challenging as large differences exist in used species, methodologies, prebiotic(s) (mixtures) and probiotic strains. In this review we elucidate on the hurdles in describing prebiotics, probiotics and the combination being synbiotics in allergic manifestations.

The diet is considered to have a major impact on human health. Dietary lipids including long chain polyunsaturated fatty acids (LCPUFA) possess potent immunomodulatory activities. Over the last decades the incidence of inflammatory disorders including allergic and cardiovascular diseases (CVD) has been rising. This phenomenon is associated with deficiencies in N-3 LCPUFA, found in fatty fish, and increased content of N-6 LCPUFA in the Western diet. LCPUFA act via different mechanisms including membrane fluidity, raft composition, lipid mediator formation, signaling pathways and transmembrane receptors. N-3 LCPUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can reduce the development of allergic disease by affecting both the innate and adaptive immune system involved in the initiation and persistence of allergic disease. Fish oil has been shown to be effective in the primary prevention of allergic disease in infants at risk when supplemented during pregnancy and lactation. Subtle effects of N-3 LCPUFA on the outcome of the immune response may underlie these protective effects. This review describes the currently reported effects of LCPUFA on dendritic cells, T cells, B cells and mast cells. Also CVD are positively affected by N-3 LCPUFA. Populations consuming high amounts of oily fish are protected against CVD. Moreover N-3 LCPUFA are effective in the secondary prevention of cardiovascular events. Amongst other effects, EPA and DHA have been shown to suppress endothelial cell activation hereby reducing adhesion molecule expression and endothelial cell – leukocyte interactions. This review describes the mechanistic basis of the preventive role for N-3 LCPUFA in allergic disease and CVD.