Small airway inflammation in asthma

Asthma was originally described as an inflammatory disease that predominantly involves the central airways. Pathological and physiological evidence reported during the past few years suggests that the inflammatory process extends beyond the central airways to the peripheral airways and the lung parenchyma. The small airways are capable of producing T-helper-2 cytokines, as well as chemokines, and they have recently been recognized as a predominant site of airflow obstruction in asthmatic persons. The inflammation at this distal site has been described as more severe than large airway inflammation. These findings are of great clinical significance, and highlight the need to consider the peripheral airways as a target in any therapeutic strategy for treatment of asthma

Vitamin D and Allergic Disease: Sunlight at the End of the Tunnel?

A role for vitamin D in the regulation of immune function was first proposed after the identification of Vitamin D Receptors in lymphocytes. It has since been recognized that the active form of vitamin D, 1α,25(OH)2D3, has direct affects on naïve and activated helper T cells, regulatory T cells, activated B cells and dendritic cells. There is a growing body of literature linking vitamin D (serum 25(OH)D, oral intake and surrogate indicators such as latitude) to various immune-related conditions, including allergy, although the nature of this relationship is still unclear. This review explores the findings of epidemiological, clinical and laboratory research, and the potential role of vitamin D in promoting the inappropriate immune responses which underpin the rise in a broad range of immune diseases

Melanogenesis is directly affected by metabolites of melatonin in human melanoma cells

Melatonin (N-acetyl-5-methoxytryptamine, MEL), its kynurenic ($N^{1}$-acetyl-$N^{2}$-formyl-5-methoxykynurenine, AFMK) and indolic derivatives (6-hydroxymelatonin, 6(OH)MEL and 5-methoxytryptamine, 5-MT) are endogenously produced in human epidermis. Melatonin, produced by the pineal gland, brain and peripheral organs, displays a diversity of physiological functions including anti-inflammatory, immunomodulatory, and anti-tumor capacities. Herein, we assessed their regulatory effect on melanogenesis using amelanotic (A375, Sk-Mel-28) and highly pigmented (MNT-1, melanotic) human melanoma cell lines. We discovered that subjected compounds decrease the downstream pathway of melanin synthesis by causing a significant drop of cyclic adenosine monophosphate (cAMP) level, the microphthalmia-associated transcription factor (MITF) and resultant collapse of tyrosinase (TYR) activity, and melanin content comparatively to N-phenylthiourea (PTU, a positive control). We observed a reduction in pigment in melanosomes visualized by the transmission electron microscopy. Finally, we assessed the role of G-protein-coupled seven-transmembrane-domain receptors. Obtained results revealed that nonselective MT1 and MT2 receptor antagonist (luzindole) or selective MT2 receptor antagonist (4-P-PDOT) did not affect dysregulation of the melanin pathway indicating a receptor-independent mechanism. Our findings, together with the current state of the art, provide a convenient experimental model to study the complex relationship between metabolites of melatonin and the control of pigmentation serving as a future and rationale strategy for targeted therapies of melanoma-affected patients

Genetic Variations in IL28B and Allergic Disease in Children

Environmental changes affecting the relationship between the developing immune system and microbial exposure have been implicated in the epidemic rise of allergic disease in developed countries. While early developmental differences in T cell function are well-recognised, there is now emerging evidence that this is related to developmental differences in innate immune function. In this study we sought to examine if differences associated with innate immunity contribute to the altered immune programming recognised in allergic children. Here, we describe for the first time, the association of carriage of the T allele of the tagging single nucleotide polymorphism rs12979860 3 kb upstream of IL28B, encoding the potent innate immune modulator type III interferon lambda (IFN-λ3), and allergy in children (p = 0.004; OR 4.56). Strikingly, the association between rs12979860 genotype and allergic disease is enhanced in girls. Furthermore, carriage of the T allele at rs12979860 correlates with differences in the pro-inflammatory profile during the first five years of life suggesting this contributes to the key differences in subsequent innate immune development in children who develop allergic disease. In the context of rising rates of disease, these immunologic differences already present at birth imply very early interaction between genetic predisposition and prenatal environmental influences

Airway Remodelling in Asthma: From Benchside to Clinical Practice

Airway remodelling refers to the structural changes that occur in both large and small airways relevant to miscellaneous diseases including asthma. In asthma, airway structural changes include subepithelial fibrosis, increased smooth muscle mass, gland enlargement, neovascularization and epithelial alterations. Although controversial, airway remodelling is commonly attributed to an underlying chronic inflammatory process. These remodelling changes contribute to thickening of airway walls and, consequently, lead to airway narrowing, bronchial hyper-responsiveness, airway edema and mucous hypersecretion. Airway remodelling is associated with poor clinical outcomes among asthmatic patients. Early diagnosis and prevention of airway remodelling has the potential to decrease disease severity, improve control and prevent disease expression. The relationship between structural changes and clinical and functional abnormalities clearly deserves further investigation. The present review briefly describes the characteristic features of airway remodelling observed in asthma, its clinical consequences and relevance for physicians, and its modulation by therapeutic approaches used in the treatment of asthmatic patients

Progress in Understanding Postnatal Immune Dysregulation in Allergic Disease

ABSTRACT: It is increasingly unlikely that allergic disease is the result of isolated immune defects, but rather the result of altered gene activation patterns in intricate immune networks. This appears to be driven by complex environmental changes, including microbial exposure, diet, and pollutants, which are known to modify immune development in early life, beginning in pregnancy. The first models showing possible epigenetic mechanisms for these effects are beginning to emerge. This review focuses on recent advances in our knowledge of the consequent effects on postnatal immune development, highlighting recognized differences in children with and without allergies. Although we characterized essential differences in longitudinal T-cell development more than 10 years ago, new technologies using whole genome microarrays are now being used to examine for differential gene expression in T cells from individuals with allergies. We have also recently performed the first comprehensive study of the longitudinal development of innate toll-like receptor responses in children with and without allergies during the first 5 years of life, identifying significant differences in these pathways as well. Finally, although there are preliminary differences in regulatory T-cell function at birth, longitudinal studies are limited by difficulties isolating these cells in sufficient numbers from young children for functional studies. Thymic tissue isolated during cardiac surgery is a rich source of regulatory T-cell function in children and may provide further avenues for assessing differences in maturation of these cells in individuals with allergies. To further understand the pathogenesis of these altered patterns of immune response, future research needs to encompass the complexity of gene-environmental interactions, which confer individual susceptibility to environmental exposures

Toll Like Receptors 4 and 2 Expression in the Bronchial Mucosa of Patients with Cystic Fibrosis

BACKGROUND: Cystic fibrosis (CF) is a lung disease characterized by chronic infection with Gram-negative bacteria Pseudomonas aeruginosa and Gram-positive bacteria Staphylococcus aureus. Recently, toll-like receptor (TLR) 4 has been shown to be responsible for the lipopolysaccharide (LPS)-mediated immune response. While TLR2 mediates responses driven by bacterial lipoproteins and peptidoglycans from Gram-positive bacteria, LPS derived from P aeruginosa may stimulate the immune response in the airways of patients with CF via activation of TLR4