Mechanism of Immune Reponses Related to Allergic Airway Diseases such as Asthma

Asthma is a chronic condition that adversely impacts the airway passages. This disease presents as episodic events typified by difficulty in breathing as a result of obstruction of the airways as well as inflammatory responses. This condition is provoked by response of the immune system to allergens. The inflammatory response manifests itself by the enhanced production of interleukin-4 (IL-4), increased activity of a particular subset of T helper lymphocytes (TH2) and serum immunoglobulins. A link has also been established between proteinases – enzymes that cleave proteins, the immune Toll-like receptor 4 (TLR4) and asthma. These proteinases that have been shown to initiate TH2-mediated allergic reactions are secreted by fungi, pollen and dust mite antigens.

 A full understanding of the underlying factors that trigger asthmatic episodes would, of course, be invaluable in developing therapeutic strategies to treat this illness. Dr. Valentine Ongeri Millien and colleagues from the Translational and Molecular Medicine Program at Baylor College of Medicine at Houston Texas have made some important discoveries in this light. The research efforts of this investigative team have established that airway- derived proteinases trigger allergic disease and innate immunity against fungal infection. Furthermore, they have shown that these particular outcomes were a direct result of the breakdown of fibrinogen, an essential clotting factor, by these proteinases. It is the products of this breakdown that bind to TLR4 on both epithelial cells that line the airways and to macrophages – a type of circulating cell of the immune system that has the role of ingesting invading infectious agents. From these results, it seems apparent that inflammation of the airways that is characteristic of asthma is a direct result of the immune antifungal defense strategy.

The Elucidation of this mechanism may prove to be invaluable in terms of developing therapeutic strategies for the treatment of allergen-induced pulmonary diseases such as asthma. In fact, this group when on to show that the use of hirudin, a drug that functions as a potent protease inhibitor, can lessen the severity of allergic lung disease. This may prove to be a very important finding.

The Role of Pathogens in Tumorigenesis

The Role of Pathogens in Tumorigenesis

A Long Noncoding RNA Involved in Activation and Repression of Immune Genes

The human body’s immune-based response to the presence of deleterious microbes engages a very intricate and complex system that has evolved over many millions of years.  In this regard, we share many aspects in common with the entire vertebrate world.   Immunity can be regarded as consisting of two categories of responses – innate and adaptive.  In the present discussion, we will focus our attention on the innate immune system.

   

The innate immune system has the extraordinary capability of recognizing a wide range of microbes and inducing the production of many proteins that become engaged in an elaborate defense against the invading organism and ultimately involve the adaptive response.  Over many years of concerted research efforts, it has been shown that the molecular basis of this recognition system involves a host of genetically determined pattern recognition receptors – an example being the so-called “Toll-like receptors” (TLRs).  It is the binding to these receptors that triggers a cascade of immune responses.

It has recently been discovered that long non-coding RNAs (lncRNAs) play a significant role in this process.  As a class of biologically active compounds, literally thousands of these lncRNAs have been discovered in mammalian genomes and they have been shown to regulate gene expression in a number of biological processes.   It is, therefore, of some interest to determine whether lncRNAs play a role in the innate immune system as well.

The work of Dr. Susan Carpenter and her colleagues at the Division of Infectious Diseases and Immunology in the Department of Medicine at the University of Massachusetts Medical School has helped answer this question.  The efficacy of the antimicrobial innate defense is wholly dependent upon the induction of inflammatory gene expression.   Implicated in this complex response is the activation of transcription factors, transcription co-regulators and other factors.

Carpenter and her associates have found that the activation of TLRs – as described previously – induce the expression of many lncRNAs and one of these – lincRNA-Cox2 – has been shown to be involved in the activation and repression of distinct groups of immune-related genes.  This finding is significant in that it helps to further elucidate the mechanism that underlies the innate immune response.

Hypercholesterolemia and Breast Cancer

It has been clearly established that obesity and the metabolic syndrome are risk factors for estrogen receptor (ER) positive breast cancer – a type of breast cancer in which the tumor cells bind the female hormone estrogen – in postmenopausal women.

This increased risk has been attributed to a number of factors including:

• Increased levels of insulin and insulin-like substances in the circulation
• Localized production of estrogen in adipose (fat) tissues
• The role of inflammatory substances like cytokines in enhancing tumor cell growth.

Recent studies have implicated hypercholesterolemia – high levels of cholesterol in the bloodstream – as a definitive risk factor in for estrogen receptor (ER) positive breast cancer in postmenopausal women.  Hypercholesterolemia correlates with obesity and together these conditions have been shown to increase morbidity.  In addition, it has been shown that disease-free survival is improved in those patients who were taking statins prior to diagnosis.  Statins are members of  a class of compounds designed to inhibit cholesterol production in the liver

Although it has been proposed that statins exert their effect by directly inhibiting tumor cell growth, the amount of circulating statins in individuals who use the drug at the typical dose level is far below the amount required to inhibit cancer cell growth as has been reported in–vitro  (in the laboratory).  Therefore, there must be some other explanation.  An understanding of the role of cholesterol in breast cancer pathology would be invaluable in regards to possible therapeutic approaches.  Dr. Eric R. Nelson and his colleagues from the Department of Pharmacology and Cancer Biology at the Duke Institute for Genome Sciences and Policy at Duke University in Durham, NC, have made a significant contribution in this regard.

Nelson and his group have shown that the actual substance that seems to be responsible for accelerating the growth of breast cancer tumors is a metabolite of cholesterol – 27-Hydoxycholesterol (27HC).  Furthermore, 27HC is a product of the action of the enzyme cytochrome P450 oxidase (CYP27A1).   The expressed level of CYP27A1 correlates well with tumor grade in breast cancer patients and inhibition of this enzyme had a positive impact on the suppression of tumor growth.

 

From this data, the authors conclude that lowering the level of circulating cholesterol or inhibiting its conversion to 27HC represent effective strategies in the treatment of estrogen receptor (ER) positive breast cancer in postmenopausal women.  This is, indeed, an important finding.

Carbon Dioxide Emissions from Areas of Tropical Deforestation

Although the levels in increased atmospheric carbon dioxide (CO²) as a direct outcome of the burning of fossil fuels have been extensively studied, the amount of CO² produced as a direct result of tropical deforestation has been inadequately examined.  In fact, emissions that are a direct result of anthropogenic land-use modifications represent the most ambiguous and under-studied of that set of human activities that impact the planetary carbon cycle.

.

There are many factors that make this avenue of investigation particularly challenging.  They include the following:

• An assessment of the rates of deforestation in relation to the amount of carbon contained within soils and vegetation
• The methodology used in clearing carbon and the fate of the cleared material
• The response of the soil-based carbon pool to the deforestation
• The longer term impact of the drastic modification of land cover that results from tropical deforestation.

In order to more effectively quantitate the carbon emissions that are a direct result of tropical deforestation, Dr. Nancy L. Harris and her colleagues at the Ecosystem Services Unit of Winrock International in Arlington Virginia used satellite observations of the loss of forest cover and mapped forest carbon stocks.  With these tools and methodologies, this group was able to estimate gross carbon emissions in targeted tropical regions between the years 2000 and 2005.

The result they obtained from this systematic approach was 0.81 petagrams of carbon emissions per year – a petagram is equivalent to 1000 trillion grams.  This value corresponds to ~ 1.8 trillion pounds of carbon emissions per year.  The authors of this study believe that their approach serves as a much more reliable model for estimating global progress on curbing CO² emissions from deforestation.   

A Gene Mutation Linked to Respiratory Infection and Airway Damage

Respiratory infections are known to be the most common illness experienced by individuals worldwide.  It has been shown that repeated respiratory infections can lead to a condition known as “bronchiectasis” that results from a dilation of the bronchi – specialized tubes that carry air from the trachea to the lungs.  Susceptibility to repeated respiratory infections and the resulting bronchiectasis may be due to an underlying primary immunodeficiency (PID).

There have been over 200 genes implicated in PIDs.  This expanded understanding of the role of genetic mutations in regards to susceptibility to respiratory infections among the world’s human population, is due in large part to the application of the advances made in genetic engineering and the fact that the human genome has been entirely deciphered.

To further elucidate the molecular biology of PID, Dr. Ivan Angulo and his colleagues in the Department of Medicine at the University of Cambridge, Cambridge UK, searched for the presence of genetic mutation(s) that might account for PIDs in thirty-five patients suffering from this syndrome.  These patients all suffered from repeated respiratory infections and a family history of susceptibility to these infections.   The fact that a family history was demonstrated, reinforced the assumption of a genetic predisposition.

In regards to the patients studied, the investigators were able to implicate a mutation in the PIK3CD gene that is responsible for the production of the catalytic subunit for the phosphoinositide 3-kinase δ enzyme.  The PID associated with this particular mutation is referred to as the activated PI3K- δ syndrome (APDS).  

An obvious question follows from these results as to the nature of the relationship between the phosphoinositide 3-kinase δ enzyme and the resulting disease state.  The investigators were able to show that the patient-derived immune-competent lymphocytes responsible for combating infection were prone to premature cell death, thereby increasing the likelihood of respiratory distress.  The application of these findings could eventually lead to therapeutic approaches to combat APDS.  

Hepatitis C Virus – the Core Structure of a Key Viral Protein

Hepatitis C virus (HCV) is a major cause of liver diseases such as hepatitis, cirrhosis of the liver and liver cancer.  This virus was discovered in 1989 and was identified as the causative agent of non-A, non-B hepatitis.  It has now been estimated that 2-3% of the entire world population – an estimated 170 million individuals - is infected with this viral agent.  This reality represents an extraordinary incidence of infection on a global scale.  Therefore, there is much interest in developing an effective vaccine.  This has proved problematic on account of the high variability of the genetic structure of this pathogen analogous to the difficulty in developing an effective vaccine against the human immunodeficiency virus 1 (HIV-1).

A virus, as a class of disease-producing organisms, is essentially dormant until it gains access to its cellular target.  Once it does so, it can subvert the cellular machinery of its host to produce proteins whose structure is dictated by the information found within the virus’ genetic material.  The end result of this process allows the virus to effectively make many copies of itself and eventually kill the host cell and spread the infection. 

Some of the problematic issues that face researchers are the fact that the virus has, as of yet, remained resistant to efforts to grow it in culture and that there is no suitable animal model for the disease.  HCV is a member of the hepacivirus genus.  HV is a so-called retrovirus – analogous to the HIV/AIDS virus.  Its infectious genetic material is RNA.  One of its disturbing features is its ability to produce chronic infection.  An unfortunate side effect of this capability is that of HCV infection can lead to liver cancer – hepatocellular carcinoma.  The development of a reliable vaccine is dependent on a fuller understanding of the particular mode of action of this virus.

In an effort to understand the mechanism of infection of HCV, Dr. Leopold Kong and his associates at the Department of Integrative Structural and Computational Biology at the Scripps Research Institute in La Jolla, California, have examined the molecular mechanism through which HCV gains entry into the target hepatic (liver) cell.  What they have discovered is of particular interest in regards to the eventual production of an effective vaccine.

It seems that at the surface of the virus there is a key glycoprotein (E2) that V H

combines with another glycoprotein, E1, on its surface – a glycoprotein is a kind of protein that is bonded to a sugar.  It is this E1/E2 complex that allows the virus to gain entry into the target cell by preferentially binding to a receptor protein on the cell membrane of liver cells – this receptor is referred to as CD81.  Interestingly, E2 is a target for the body’s natural immune response; however, due to the great variability in the structure of E2, this strategy is essentially ineffective.

 

These investigators were able to determine the three dimensional structure of E2 with a resolution of 2.65 angstroms using X-ray crystallography – an angstrom  is equivalent to one ten-billionth of a meter.  This level of detail may prove to be invaluable in future drug and vaccine design.