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

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

 

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Metformin: A diabetes medication with cardiovascular protective effects

What if a diabetes medication can improve cardiovascular events? Since patients with type II diabetes are more prone to cardiac events, the use of diabetes medication to help reduce cardiovascular burden would definitely be beneficial. One of such medications is the drug, Metformin.

Metformin, also know with the trade name of Glucophage, is the first-line of treatment for type II diabetes. It is also often prescribed to patients with metabolic syndrome and patients with polycystic ovarian syndrome to control insulin resistance. Metformin works by increasing insulin sensitivity and decreasing glucose production by the liver. While its molecular mechanism of action is not completely understood, one way metformin exerts its effects is through regulating AMP-activated protein kinase (AMPK), an enzyme that plays an important role in insulin signaling and detecting cellular energy levels. By regulating AMPK, metformin also lowers inflammation and thus there is an emerging body of evidence suggesting that metformin regulates the immune system and reduces inflammation and can potentially protect against diseases such as inflammatory bowel disease and atherosclerosis. 

Until recently, there has been associations that metformin may protect against cardiovascular disease, although exactly how was never been directly studied. A recent study by a group of researchers in Columbia University in New York, published recently in the ATVB journal, looked at the role of metformin and how it may affect cardiovascular disease. The authors show that exposure of liver cells to metformin increased the expression of ABCG5 and ABCG8, two cholesterol transporter molecules responsible for the efflux of cholesterol. The authors also saw the same effect when they gave metformin to mice fed a western diet, also know as high cholesterol, high fat diet. This increase in expression of ABCG5 and ABCG8 was accompanied by an increase in cholesterol clearance from the plasma in these treated mice. This study provides first evidence of how metformin could have a direct cardiovascular disease protective effect.

Since metformin, through regulating AMPK, has an anti-inflammatory effect, this study shows that metformin may have a combined protective impact regarding cardiovascular disease; the first through increasing cholesterol clearance and the second through reducing immune mediated inflammation, overall resulting in lower cholesterol levels and less inflammatory mediators responsible for atherosclerosis progression and thus reducing cardiovascular disease risk. It would be interesting to see if patients who are taking metformin for diabetes treatment have a decrease in cardiovascular events in a controlled manner. Finally, this study highlights the potential of a drug like metformin, not only as a diabetes medication but as a cardiovascular protective drug as well.

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.

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

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.

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. 

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Un-complementing The Immune System Improves Hypertension

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.

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. 

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Apolipoprotein AI: A Promising New Therapy For Reducing Heart Disease.

Despite the advances made in the cardiovascular field, scientists are still looking for therapies that can lower the occurrence of cardiovascular events. In a previous post, I discussed the debate around the benefit of high levels of HDL – or “good cholesterol” – and how when it comes to HDL, quality over quantity matters most. A major way to measure HDL quality is by examining its capacity to remove lipids from lipid-laden cells also known as cholesterol efflux capacity – or CEC. In large clinical studies, CEC correlates better with predicting cardiovascular incidents than does HDL quantity.  In this month’s post, I would like to shed light on a particular component of the HDL molecule, Apolipoprotein AI – or ApoAI. The reason is two folds. First, ApoAI is the most functional component of the HDL molecule. Second, I have been studying the effect of ApoAI on the immune system and atherosclerosis for a few years now, and thus know about the therapeutic potential of this molecule.

ApoAI is a protein made in the liver that pairs up with phospholipids to form a lipid-poor molecule that allows for cholesterol efflux from macrophages. Due to this unique property, scientists and clinicians have been interested in understanding how to use ApoAI as a therapeutic agent to reduce cardiovascular incidents. In the past few months, three studies published in the ATVB journal have looked closely at ApoAI, its role in heart disease and correlation with CEC. The most recent of these studies – and perhaps, the most exciting due to its potential therapeutic application – was published in this month’s issue of the journal in the clinical and population studies section. In this study, atherosclerosis patients and healthy individuals were given an infusion of human ApoAI (or CSL112) and the researchers examined the patients’ serum capacity to efflux cholesterol. Because atherosclerosis patients show lower capacity to efflux cholesterol, the authors wanted to see how these patients faired after receiving ApoAI infusions. As one would hope, patients that received CSL112 showed an increase in CEC despite their health condition, showing promise of CSL112 as a therapeutic approach to reduce atherosclerosis and lower the risk of heart disease.

It is also important to note that ApoAI has non-cardiovascular properties, mainly anti-inflammatory ones. ApoAI can reduce the incident of rheumatoid arthritis, lupus and Alzheimer’s disease. ApoAI also is capable of affecting cells of the immune system suggesting that ApoAI effects can reach beyond heart disease to other inflammatory and immune conditions. As more clinical studies continue to investigate how ApoAI infusions work in patients, it will be interesting to see its impact not just on the cardiovascular system and its health but the immune system as well. Do patients that receive ApoAI develop less autoimmune disease or is the effect of ApoAI limited to cholesterol efflux?

One of the main concerns that remain to be addressed with ApoAI is its administration. So far, patients receiving ApoAI get it through an infusion every week. In the study mentioned above some patients were given two infusions per week for four weeks. Patient compliance and feasibility is a caveat in this setting and if ApoAI is to be used more broadly as a preventative therapy against cardiovascular disease, a more patient-friendly approach is needed. Is it possible to make a version of ApoAI that can be easily administered? One would only hope that because of its promise and as we discover more about what makes ApoAI so unique, that such a formula would soon become available.

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. 

 

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The Liver’s New Job: Making An Immune Response Towards Cholesterol!

If you think the liver’s only relationship with cholesterol is to control its metabolism and excretion, think again. It turns out the liver is also involved in the immune response towards cholesterol particularly in situations where cholesterol is increased, a recent study published in the Circulation Research journal shows.
 
In a previous post, I wrote about how complex the relationship between heart disease and the immune system is. While most studies that examine the role of the immune system in atherosclerosis focus on immune cells from the blood, lymphoid organs, or look at the immune cells in the aortic walls, there are very few studies that looked at the contribution of the immune system in the liver to atherosclerosis development.
 
As an immunological site, the liver plays an important role in preventing autoimmunity and defending against invaders. Being the largest solid organ in the body, with its rich blood flow and its proximity to the digestive system, the liver is a crucial organ in cholesterol metabolism. The liver is also filled with macrophages, an immune cell that, among its many jobs, specializes in getting rid of extra cholesterol. High cholesterol levels can destroy the liver’s ability to metabolize cholesterol and result in liver failure. However, not much is known about the role of the immune cells in the liver and how do they respond to high cholesterol levels. A research group from the Cardiovascular Medicine Unit in Karolinska Institute, Sweden, examined this exact question. Their study shows that in mouse models, T cells, a type of immune cell that is involved in adaptive immunity, increases in the liver as a result of high cholesterol levels. These liver T cells can travel to the aortic vessels were atherosclerosis occurs, providing first evidence that the liver immune cells may contribute to the immune response during atherosclerosis development.
 
As an immunologist who studies how the immune system affects atherosclerosis development, I am constantly fascinated by new findings in this area. The study made me think of whether the liver’s immune response is responding to the excess cholesterol in the circulation or to that accumulating in the liver. As there are different types of T cells, some that promote atherosclerosis while others reduce disease progression, the study also made me wonder if these different cells generated in the liver tipped the balance in favor or against a protective immune response. Does a similar immune response happen in the liver of people with high cholesterol levels? With these new findings, the door is now open to questions that will help our understanding of the complex relationship between cholesterol, the liver, the immune system and how it all ties together to influence atherosclerosis and heart disease.
 

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. 

 

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Weight Loss And Exercise: A Remedy For A Better Functioning HDL

We all know that weight loss and exercise are essential for a better health. A healthy life style reduces cardiovascular risk, obesity, and Type 2 Diabetes. In a previous post, I briefly touched upon the idea that weight loss and exercise make HDL, or our “good cholesterol,” better at reducing cholesterol circulating the bloodstream. In the latest issue of the ATVB journal, in the translational section, a new study from Baker Heart and Diabetes Institute in Melbourne, Australia looked at this specific idea. They asked how does weight loss and exercise affect HDL in patients. So I thought it would be interesting to share the results from this study.

The study examined 95 patients with metabolic syndrome and compared them to healthy individuals. Metabolic syndrome patients have characteristics that include obesity, high blood glucose levels, hypertension and/or dyslipidemia. These patients tend to have dysfunctional HDL, and its level fail to predict the possibility of future cardiovascular events. In the study, patients were divided into 3 groups. The first group had to reduce their caloric intake by 600 calories a day. The second group also reduced their caloric intake by 600 calories and, in addition, had to exercise for 3-4 sessions of about 30 minutes each. The third group kept their usual dietary and exercise patterns. The patients were monitored for 12 weeks and tested at the beginning and at the end of the study. Both groups resulted in similar weight loss. However, the researchers found evidence that the group of patients that followed both healthier diets and an exercise regimen had the most change in HDL capacity to excrete cholesterol.

Upon looking at the details of the study, the researchers first observed that metabolic syndrome patients had smaller HDL particles with different composition, and lesser ability to get rid of cholesterol easily. With diet and exercise, the size of HDL particles in those patients got bigger and their ability to function in cholesterol efflux assay improved making these particles overall better in excreting blood cholesterol.

Despite the small sample size of the study, these results are promising in providing a better understanding of how life style changes can impact HDL function and overall reduce risk for CVD and Type 2 Diabetes. For me personally, this study make me wonder if exercise alone would effect HDL function, since it has become apparent that while exercise is important, exercise alone without appropriate dietary changes are not sufficient to lead to weight loss. Can exercise alone improve HDL composition and function? While this study does not provide an answer to my question, I am sure more studies will come out to address this question specifically. So until we know more, keep those healthy salads and spinning classes coming.

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. 

 

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Can Increasing HDL Reduce Heart Disease? An Issue Of Constant Debate!

A couple of years ago I was fortunate to attend the HDL workshop that followed the ATVB council conference, which was held in San Francisco. The workshop’s main focus was to discuss and debate high-density lipoproteins (HDL), or what is commonly known as “the good cholesterol,” and how it influences heart disease.
 
You may ask, “HDL-cholesterol is good for your heart, so why dedicate two days to discuss what is already know?!” Here is where it gets interesting. While we look forward to lab results showing high HDL-cholesterol levels and low levels of LDL-cholesterol (bad cholesterol) as an indication of reduced risk for cardiovascular disease, the actual answer to the benefits of HDL for cardiovascular disease is far from a simple yes or no. Yes, having high HDL-cholesterol indeed reduces the risk of heart disease, but this does not hold true for patients with metabolic conditions like diabetes, or chronic inflammation like chronic kidney disease.  In fact, multiple clinical studies that aimed at increasing levels of HDL-cholesterol have failed to reduce cardiovascular events. It is now becoming evident that just increasing the quantity of HDL-cholesterol alone is not sufficient to ensure cardiovascular free events.
 
Scientists are discovering that there is more to HDL-cholesterol than its concentration. The size of these HDL molecules, their composition, and their ability to remove lipids from the blood stream for excretion are more indicative of HDL protective function.  In addition, scientists are also finding that HDL has other compelling properties that can lower cardiovascular risk indirectly. HDL can reduce inflammation, protects from cell death and promotes wound healing. HDL also had antithrombotic effects (prevents blood clots formation), all of which would decrease the possibility of a cardiovascular incident.
 
So why not measure for the functionality of HDL rather than its mere concentration to determine one’s risk for cardiovascular disease? This was a topic for discussion at the HDL workshop. The methods used to measure HDL functionality are far from being standardized for use in clinical settings. More work is needed to find techniques that can be used routinely and reliably across clinical laboratories.
 
It is worth to note that the increase in HDL-cholesterol levels that are triggered by life style changes: healthy diets and physical exercise, does in fact correlate with reduced risk of cardiovascular disease. Researchers think life style change does not only increase HDL-cholesterol but also has an effect on its function and on other metabolic parameters. So until science figures a more clinically feasible way to measure HDL functionality, it would still be a good practice to continue whatever healthy diet and exercise regimen you are on and to aim to keep those HDL-cholesterol numbers high and those LDL-cholesterol numbers low.

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. 

 

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A Vicious Cycle: Heart Disease And The Immune System

When I first started my career as a scientist, I had no idea how much impact the immune system has on cardiovascular disease. I was under this naïve idea that disease progression was dependent on blood cholesterol levels, stress or genetics only, never realizing how much the immune system influenced cardiovascular disease. Now that I have been studying the influence of heart disease on the immune system for a few years, I am still amazed by how intertwined these two systems are.
 
There is a lot of published research, both in patients as well as in experimental animal models, showing that the immune system plays a role in multiple heart conditions. Atherosclerosis is a prime example. The process of hardening of blood vessels due to cholesterol and lipid deposits is an immune system mediated disease. The inflammation triggered by the immune system is the root cause of the process of plaque formation and blood vessels blockage. Viral myocarditis, which can cause sudden death, occurs as a result of a hyper reactive immune response to viral infections. In congestive heart failure, the immune system contributes to disease by releasing inflammatory molecules that further increase the heart size. The influence of the immune system also extends to other disease that can trigger heart disease such as diabetes and obesity.
 
If you think the interaction between cardiovascular disease and the immune system stops there, think again. Recently, it has become evident that the cardiovascular and the immune systems live in this vicious cycle of constantly influencing each other to worsen disease outcome. For instance, the increase in lipids accumulated during coronary artery disease or obesity affects how the cells of the immune system consume fuel resources such as glucose and fats, a process known as immunometabolism. Changes in immunometabolism influence how immune cells respond to injury triggered by the increased lipids, further worsening disease. Not only that, but by virtue of overall changes in how immune cells function, heart and metabolic disease can affect how the immune system as a whole responds to other conditions such as infections and cancer.
 
This field of immunometabolism is still at its infancy. It will be interesting to see how much it will advance in the next few years and how much relationship scientists will find between immunometabolism and heart disease. If therapeutic approaches are found that can break this vicious cycle, patients with heart disease and other metabolic disease will gain tremendously. I would expect that the impact of such therapeutic approaches would extend to other ailments that hit those patients beyond the scope of cardiovascular disease.

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.