immune system – The Early Career Voice

How the Immune System Favors Females in Pulmonary Artery Hypertension? Another Regulatory T Cell Story.

August 21, 2018 Dalia Gaddis, PhD

While it is commonly thought that cardiovascular disease is a man’s disease, CVD is the number one killer of women with the same number of deaths per year as cancer, diabetes and respiratory disease combined (according to 2015 statistical data from AHA). In addition, women exhibit different and more silent symptoms of heart attacks. There is a lot of interest in the difference between how males and females respond to CVD. A lot of emphasis is put on hormonal differences, but the immune system also seems to play an important role in this disparity. Females have a more robust immune system and therefore respond faster to infections providing more protection than in males. However, a more responsive immune system also means a more reactive immune system that can result in increased incidence of autoimmune diseases, such as rheumatoid arthritis and lupus.

Part of the difference in the immune system response in females can be attributed to the fact that multiple immune-related genes are expressed on the X chromosome. Since females have two alleles of the X chromosomes and males have only one, it is evident that females express more genes that regulate immune system functions. One of these genes is Foxp3, the key transcription factor for regulatory T cells, an adaptive immune cell which I have discussed before in a previous post. Regulatory T cells play an important protective role in CVD, especially in atherosclerosis and hypertension.

Pulmonary artery hypertension (PAH) is a fatal cardio-pulmonary disorder where the pulmonary arterioles narrow leading to a right ventricular fibrosis, heart failure and death. Regulatory T cells play an important role in this disease as animal models that lack regulatory T cells are more susceptible to PAH. Adding regulatory T cells back prevents the development of PAH showing the protective power of these cells. A recent study published in the journal Circulation Research, shows that in the absence of regulatory T cells, females rats are more prone to PAH than male animals due to a lower levels of PGI2, a pulmonary vasodilator, and the lack of the enzyme COX-2 that regulated PGI2. The researchers conducting the study show that by transferring regulatory T cells into these rats, these immune cells were sufficient to restore the levels of COX-2 and PGI2, as well as other immune inhibitory molecules PDL1 and IL-10. The authors suggest that regulatory T cells have both a direct and indirect effects on the arteries. The direct effects are exerted on the endothelial cells directly via COX-2 and PGI2, and the indirect effect is through the release of inhibitory molecules such as IL-10 and TGF, both of which would result in immune suppression and preventing inflammation. The results from this report suggested that females are more reliant on regulatory T cells for protection against PAH.

These new findings highlight the subtlety of immune regulation between females and males and further proves that in addition to hormonal differences, immune regulation disparities between genders that can alter the outcome of cardiovascular diseases. By understanding more about gender differences in CVD and the immune system, and figuring out ways to manipulate these subtle differences, scientists hope to achieve a more personalized and effective therapies to women versus men to combat CVD.

Dalia Gaddis Headshot

Dalia Gaddis is a postdoctoral fellow at the La Jolla Institute for Allergy and Immunology. She has a Ph.D. in microbiology and immunology. She is currently working on understanding the interactions between the immune system and atherosclerosis development

Form over Abundance: The interesting case of how RNA isoforms in immune cells affect atherosclerosis.

June 19, 2018 Dalia Gaddis, PhD

The immune system plays a vital role in heart disease. In my last blog, I wrote about the role of complements in hypertension and lightly mentioned that it affected regulatory T cells. In this post, I would like to shine the spotlight on regulatory T cells, their function and their role in atherosclerosis, drawing attention to a recent publication that describes how the different forms of the RNA material in these cells correlates to cardiac incidents.

Regulatory T cells, or commonly known as Treg cells, belong to the T cell family, a part of the adaptive immune system. Treg cells play an important role in reducing inflammation and keeping the immune system in check. They are involved in multiple inflammatory diseases and their presence is crucial for controlling unnecessary immune activation that can lead to disease. Treg cells are protective in multiple heart conditions. Treg cells play a big role in controlling atherosclerosis progression and reducing the inflammation that occurs during plaque build up. Experiments, where researchers got rid of Treg cells, exacerbate atherosclerosis. Meanwhile transferring Treg cells into animals, reduce the severity of atherosclerosis. In addition to reducing inflammation, Treg cells also play a role in tissue repair as well as modulating lipoprotein metabolism. Reduction in Treg cells have been shown to correlate with increased risk for myocardial infarction and their numbers are either reduced or they switch to other inflammatory T cells in atherosclerotic lesions.

Treg cells function is dependent on their master transcription factor and regulator, Foxp3. Foxp3 is also the main molecule that defines these cells from other T cells. While only one form of transcribed Foxp3 mRNA is found in mouse cells, in humans, Foxp3 mRNA exists in more than one isoform. The two most dominant isoforms are the full length Foxp3 mRNA (foxp3fl) and a truncated form lacking exon 2 (foxp3Δ2). In a recent research article published in Circulation Research, a group of researchers from Karolinska Insitute in Sweden, examined the role of these two isoforms on Treg cells function and whether their presence correlated with disease incidents. The researchers first found that the activation of Treg cells resulted in more expression of the truncated isoform of foxp3. When they examined patients with atherosclerosis, the researchers found that patients who had unstable plaques; those defined as having one or more cardiac incidents; had lower expression of the truncated isoform of Foxp3 despite the fact that the total mRNA levels of Foxp3 was the same. This suggested that the Treg cells that express this truncated form are more protective against atherosclerosis.

This new research is very interesting and leads to many questions in the field. Does the same hold true with other cardiac disease like myocardial infarction? Can manipulating the Treg cells by expressing only the truncated isoform of Foxp3 reduce cardiac incidents? The researchers found that the truncated isoform of Foxp3 induced a specific glycoprotein that tethered TGFβ, an inhibitory cytokine, to the membrane of Treg cells. If this tethering were achieved differently, would it lead to the same results? There are still a lot more questions to be answered but the current research definitely points to the idea that it is all about form over abundance when it comes to the expression of Foxp3 in Treg cells.

Un-complementing The Immune System Improves Hypertension

May 17, 2018 Dalia Gaddis, PhD

Even though I have been studying immunology for 15 years, I am constantly fascinated by how elaborately involved the immune system is in different diseases and conditions. I have written previously about the intricate relationship between the immune system and heart disease. In this blog, I will be highlighting the role of the immune system in hypertension, focusing on a new study that examined the role of complements and regulatory T cells in hypertension.

According to the CDC, there are 75 million people – a third of the population – in the USA with hypertension. Another third of the population is at risk, being at a pre-hypertensive state. With the change in blood pressure guidelines that was announced at the end of 2017, it is expected that the number of people affected with hypertension will increase substantially. While half of the patients with hypertension have their high blood pressure under control, hypertension still contributes to more than 1,000 deaths per day in the US.

It is evident that the immune system is involved during hypertension. Activated immune cells can infiltrate target organs such as the perivascular tissue and the kidneys. Macrophages, an innate immune and phagocytic cell, contribute to hypertension by increasing inflammation and oxidative burst. T cells, a key adaptive immune cell, can also be found infiltrating aortas, perivascular tissue, vascular vessels as well as the kidneys, where they can produce inflammatory mediators. The lack of the above two cell types has been shown to reduce blood pressure in angiotensin II infusion mouse models.

A recent study in Circulation Research examined how the complement system affected regulatory T cells during hypertension. The authors show that two complement receptors, C3aR and C5aR, are increased on regulatory T cells, an anti-inflammatory T cells that protects against heart disease. The increase in complement receptors led to a reduction of the protective regulatory T cells in hypertensive mice. By deleting the two complement receptors, the authors show that there is a decrease in systolic and diastolic blood pressure and regulatory T cells were preserved in the angiotensin II treated mice. The authors also show that similar increase in C5aR is found in patients with hypertension.

Complements are a part of the immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells, having beneficial effects in immune defense. It is already known that ischemia is a potent activator of the complement system and the activated complement system play a role in tissue damage during myocardial infarction and contribute to atherosclerosis progression. There are studies to show that inhibition of the complement system can reduce myocardial infarction. Can the inhibition of the complement system assist in hypertension reduction in patients? Would scientists be able to design therapies that limit the activation of the complement system to benefit hypertensive patients without complete abrogation of the complements anti-microbial properties? There are still many uncertainties about how the scientific community can manipulate the complement system to benefit patients with hypertension, but I think the more advances we make in understanding how the different players in the immune system affect hypertension and other heart related conditions, the better we fair in getting closer to new therapies against heart disease.