The role of IL-13 in established allergic airway disease

The effectiveness of targeting IL-13 in models where airway hyperresponsiveness (AHR) and airway inflammation have already been established is not well-described. We investigated the effects of blocking IL-13 on the early and late phase airway responses and the development of AHR in previously sensitized and challenged mice. BALB/cByJ mice were sensitized (days 1 and 14) and challenged (days 28-30) with OVA. Six weeks later (day 72), previously sensitized/challenged mice were challenged with a single OVA aerosol and the early and late phase response and development of AHR were determined. Specific in vivo blockade of IL-13 was attained after i.p. injection of a soluble IL-13Ralpha2-IgG fusion protein (sIL-13Ralpha2Fc) on days 71-72 for the early and late responses and on days 71-73 for the development of AHR. sIL-13Ralpha2Fc administration inhibited the late, but not early, phase response and the OVA challenge-induced changes in lung resistance and dynamic compliance; as well, sIL-13Ralpha2Fc administration decreased bronchoalveolar lavage eosinophilia and mucus hypersecretion following the secondary challenge protocols. These results demonstrate that targeting IL-13 alone regulates airway responses when administrated to mice with established allergic airway disease. These data identify the importance of IL-13 in the development of allergen-induced altered airway responsiveness following airway challenge, even when administered before rechallenge of mice in which allergic disease had been previously established.     

The role of fibrocytes in sickle cell lung disease

Background

Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease.

Methodology/Principal Findings

Fibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology.

Conclusions

These data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease.     

The role of chemokines in cutaneous allergic inflammation.

Eosinophils are the major effector cells that kill helminthic parasites and are - for unknown reasons present in the dermal part of atopic skin. This review summarizes our knowledge on the chemotactic factors involved in eosinophil tissue recruitment, focusing on the role of eosinophil-chemotactic chemokines. It is the current view that the chemokines RANTES and eotaxin represent the most important eosinophil-attracting chemokines. The inducibility of eotaxin in dermal fibroblasts only upon stimulation with Th2-cytokines IL-4 and IL-13 may explain why eosinophils appear only in the dermis and why the presence of Th2-cytokines is always linked with tissue eosinophilia.     

The role of the mast cell in allergic bronchospasm

In allergic bronchospasm inhaled allergen interacts with specific IgE antibody on the surface of mast cells, inducing the release of mediators, particularly histamine and leukotrienes, which induce bronchoconstriction. Disodium cromoglycate, previously considered to be predominantly a mast cell stabilizing agent, is effective prophylactically in inhibition of early and late phase asthmatic reactions. However, the microenvironment of the airways contains many cell types and the precise role of mast cells is not clear. Lymphocytes, alveolar macrophages, eosinophils, platelets, and neutrophils possess low affinity surface receptors for IgE and can respond to allergen, releasing mediators that have diverse functions. These observations compound the problem of which mediator(s) is most important in pathogenesis of asthma. Moreover, mast cell products modulate the functions of many cells, and thus whether mast cells act directly or indirectly on bronchial smooth muscle requires clarification. Neuropeptides activate or modulate mast cells, and together with evidence of the close association of mast cells and nerves, these observations provide exciting new directions for investigation. Evidence that mast cells from different sites are heterogeneous in their response to stimuli and antiallergic drugs and differ in mediator production and function amplifies the problems identified above. In summary, the role of mast cells in bronchoconstriction is complex and systematic analysis of interactions between mast cells and other cells of the airways is essential.     

Regulatory role of B cells in a murine model of allergic airway disease

Mice sensitized to OVA and subjected to acute OVA aerosol exposures develop allergic airway disease (AAD). However, chronic continuous Ag exposure results in resolution of AAD and the development of local inhalational tolerance (LIT). Because we have previously observed the persistence of B cells in the bronchoalveolar lavage (BAL) and hilar lymph nodes (HLN) at the resolution stage of this model, we investigated the role of B cells in the modulation of AAD. Although B cell-deficient mice developed LIT, adoptive transfer of HLN B cells from LIT mice to OVA-sensitized recipients resulted in attenuated AAD following subsequent OVA aerosol exposure, as determined by reduced BAL leukocytosis and eosinophilia, decreased tissue inflammation, and absent methacholine hyper-responsiveness. In similar adoptive transfer studies, HLN B cells from AAD mice were without effect. The protection transferred by LIT HLN B cells was Ag specific and was associated with accumulation of Foxp3(+) T regulatory cells regionally in BAL and HLN, but not systemically in the spleen. Fluorescent labeling of LIT HLN B cells before adoptive transfer demonstrated that these cells had the capacity to migrate to local inflammatory sites. In vitro assessment demonstrated that the LIT HLN B cells exerted this regulatory effect via TGF-beta induced conversion of CD4(+)CD25(-) T effector cells into functionally suppressive CD4(+)CD25(+)Foxp3(+) T regulatory cells. These findings illustrated a novel regulatory role for regional B cells in AAD and suggested a possible contributory role of B cells, along with other cell types, in the establishment of LIT.     

The role of protein ubiquitination in neurodegenerative disease.

Ubiquitin immunocytochemistry with an antiserum which reacts with ubiquitin-protein conjugates demonstrates the presence of ubiquitinated proteins in filamentous inclusions found in neurones in the major human neurodegenerative diseases, i.e. Alzheimer's disease, diffuse Lewy body disease, motor neurone disease. Ubiquitin immunohistochemistry has revolutionized the neuropathological diagnosis of dementia showing that diffuse Lewy body disease is not, as previously supposed, a rare cause of dementia. The filamentous inclusions in neurones in the human neurodegenerative diseases can be divided into at least two types based on recent immunocytochemical studies. We have shown that a ubiquitin-carboxyl terminal hydrolase is present in Lewy bodies but not in neurofibrillary tangles in Alzheimer's disease. This observation is significant since it indicates that molecular pathological mechanisms in neurones in diffuse Lewy body disease are fundamentally different to Alzheimer's disease. Ubiquitin-protein conjugates are also found in vacuoles in areas of granulovacuolar degeneration in hippocampal neurones in Alzheimer's disease and in granulovacuoles in neurones of scrapie infected mouse brain. These locations suggest that ubiquitinated protein are present in the lysosome-related system of neurones. We have recently shown that ubiquitin-protein conjugates are indeed enriched some 12-fold in the lysosomes of normal fibroblasts and lymphocytes.     

Eosinophils promote allergic disease of the lung by regulating CD4(+) Th2 lymphocyte function.

Eosinophils are primarily thought of as terminal effectors of allergic responses and of parasite elimination. However, limited studies suggest a more discrete immunomodulatory role for this leukocyte during these inflammatory responses. In this investigation, we highlight the potential of eosinophils to act as APCs and thus modulators of allergic responses by influencing Th2 cell function. In response to Ag provocation of the allergic lung, eosinophils rapidly trafficked to sites of Ag deposition (airways lumen) and presentation (lung-associated lymph nodes and T cell-rich paracortical zones). Eosinophils from the allergic lung expressed class II MHC peptides, T cell costimulatory molecules (CD80 and CD86), and rapidly internalized and processed Ag that was sampled from within the airway lumen. Ag-loaded eosinophils promoted the production of IL-4, IL-5, and IL-13 in cocultures with in vitro-polarized Th2 cells and induced IL-5 production in a dose-dependent manner from Ag-specific CD4(+) T cells isolated from allergic mice. In addition, Ag-loaded eosinophils primed for Th2 cell-driven allergic disease of the lung when transferred to naive mice. Thus, eosinophils have the potential to not only activate Th2 cells to release disease-modulating cytokines but also to assist in priming the immune system for allergic responses. This investigation highlights the potential of eosinophils to not only act as terminal effector cells but also to actively modulate allergic inflammation by amplifying Th2 cell responses.     

The role of interferon-gamma on immune and allergic responses

Allergic diseases have been closely related to Th2 immune responses, which are characterized by high levels of interleukin (IL) IL-4, IL-5, IL-9 and IL-13. These cytokines orchestrate the recruitment and activation of different effector cells, such as eosinophils and mast cells. These cells along with Th2 cytokines are key players on the development of chronic allergic inflammatory disorders, usually characterized by airway hyperresponsiveness, reversible airway obstruction, and airway inflammation. Accumulating evidences have shown that altering cytokine-producing profile of Th2 cells by inducing Th1 responses may be protective against Th2-related diseases such as asthma and allergy. Interferon-gamma (IFN-gamma), the principal Th1 effector cytokine, has shown to be crucial for the resolution of allergic-related immunopathologies. In fact, reduced production of this cytokine has been correlated with severe asthma. In this review, we will discuss the role of IFN-gamma during the generation of immune responses and its influence on allergic inflammation models, emphasizing its biologic properties during the different aspects of allergic responses.     

The role of nicotinic acetylcholine receptors in Alzheimer's disease.

The two hallmark lesions of Alzheimer's disease (AD) are extracellular amyloid plaques, mainly formed by a small peptide called amyloid-beta (Abeta), and neurofibrillary tangles, which are intracellular inclusions formed by aggregates of hyperphosphorylated tau protein. One of the major neurochemical features of AD is the marked reduction of nicotinic acetylcholine receptors in disease-relevant brain regions such as the cerebral cortex and hippocampus. This loss is further compounded by the loss of cholinergic cells, which contributes to the cognitive dysfunction. This observation has had a major impact on therapeutic treatments, as efforts to restore cholinergic function such as the administration of acetylcholinesterase inhibitors have been, until recently, the major treatment options available for AD. Understanding the relationship of these hallmark lesions with the plethora of other changes that occur in the AD brain has proven to be a difficult challenge to resolve. The utilization of transgenic mouse models, that recapitulate one or more neuropathological and neurochemical features of the AD brain is providing some inroads, as they offer a means to gain mechanistic insights into the disease process in an in vivo setting. In this review, we consider the role of nicotinic acetylcholine receptors in transgenic models and in AD.     

Budgerigar-fancier's lung: the commonest variety of allergic alveolitis in Britain.

A questionnaire survey of 1005 consecutive attenders at four outpatient clinics yielded 117 (12%) budgerigar fanciers (exposed to budgerigars- known in North America as parakeets-for at least three months) and 296 (29%) former fanciers. Twnety had precipitins to budgerigar serum or droppings or both, and 10 of these together with 39 precipitin-negative patients reported undue breathlessness on exertion during exposure to buderigars. These 59 patients were investigated further, seven completing a series of inhalation provocation tests with budgerigar antigens designed to confirm or exclude budgerigar-fancier''s lung (BrFL). Typical positive responses were obtained from four current and one former fancier. The prevalence of confirmed BrFL among the 11n current budgerigar fanciers was 3.4% (four cases). This was biased, however, by the inclusion of one patient whose attendance at the surveyed clinic was attributable to the disease. With the exclusion of this patient, confidence limits suggested that the true prevalence of BrFL among current budgerigar fanciers in the general population lies between 0.5% and 7.5%, which is similar to the prevalence of farmer''s lung in farm workers. In view of the enormous population at risk, however, this implies that BrFL rather than farmer''s lung is by far the commonest type of allergic alveolitis in Britain.