Medical Research

Research Update – Dr Eoghan M McCarthy

During the course of my project I investigated the role that different chemical messengers in the blood called cytokines play in driving the activity of disease in Irish Systemic Lupus Erythematosus patients. In particular my work focused on one such messenger, B Lymphocyte Stimulator or BLyS. This chemical can cause the body’s cells to produce antibodies that in turn attack its own tissues – thus causing the symptoms and organ damage associated with Lupus. This messenger is of particular importance as a new drug called Belimumab, which removes BLyS from the circulation, is approved for the treatment of SLE patients in both Europe andAmerica.

My research, conducted with the help of the rheumatologists in Beaumont andSt.JamesHospital, involved measuring the levels of BLyS in patients’ blood when they were seen in the rheumatology clinic and then following them over the next five years. We demonstrated that patients who had high levels of BLyS when they were seen in the clinic were more likely to have active disease at the time the blood sample was taken. These patients with high BLyS levels were also more likely to go on to develop organ damage from their lupus over the next five years. Furthermore we have seen that people with more severe subtypes of lupus have higher levels of BLyS. Whilst these results need to be verified in a larger group of patients they do have the potential to impact on patient care as it suggests that treating patients that present with high levels of BLyS on examination with Belimumab may reduce the activity of their disease and in turn prevent damage to organs and tissues.

Our results were supported by subsequent publication of analysis of the trials of anti-BLyS (Belimumab) suggesting that the drug would benefit some SLE patients. However both our own work and the data from these larger international studies showed that a significant number of patients failed to respond to treatment, highlighting a need for a better understanding of the cellular pathways that result in the high circulating BLyS levels seen in SLE patients. With the help of Lupus Group Ireland funding we also sought to investigate the effect of BLyS on a specific type of cell called “monocytes”. Monocytes play a key role in fighting infection in healthy people but can become overactive in some diseases. Whilst it has been known for a long time that monocytes are the main source of BLyS in both health and disease, no groups had previously studied what high levels of BLyS do to monocytes themselves in SLE patients despite the fact that they are the main producers of this chemical messenger.

Our results have demonstrated a previously unreported effect of BLyS on monocytes especially in SLE patients. Using the funds provided by LGI we were able to perform a series of experiments looking at signalling pathways inside the cell as well as markers of activity on the cell surface. These showed that in SLE patients BLyS promotes signals in monocytes that result in the excess production of harmful chemical messengers that are released into the periphery as well as causing increased activity on the cell surface which in turn causes other cells to start behaving abnormally. In addition we have been able to identify receptors on the surface of monocytes where BLyS interacts. This work has been well received when presented at both national and international rheumatology meetings including both the European and American College of Rheumatology and has such informed the practices of rheumatologists in the clinical setting.

Lupus Research Update – Dr Siobhán Smith

It has long been recognised that Lupus mainly affects women at a 9:1 ratio compared to males suggesting the female hormone oestrogen may be important in Lupus disease. My research in the Lupus Research Group of the Royal College of Surgeons in Ireland (RCSI), conducted with the help of the Rheumatology Departments in Beaumont and St. Vincent’s Hospital, Dublin is currently undertaking a project identifying the role that oestrogen plays in promoting Lupus in particular its role in driving the production of different chemical messengers in the blood called cytokines which drive symptoms. Previous work in the lab has highlighted a role for oestrogen in regulating the levels of other key molecules that control the immune response. This work has gone on to show that blocking the effect of oestrogen restores balance to the immune system in cells derived from Lupus patients and thus has potential in disease management. This work has recently been published in Arthritis and Rheumatology and I am hoping to continue this work assessing the effect of oestrogen regulation as a potential treatment of Lupus.

Donations received from Lupus Group Ireland will be used primarily to fund a research nurse for a year who will support/contribute to the Lupus research being conducted in the through Lupus patient recruitment, data collection and analysis. We strongly believe having the collated clinical patient information in combination with molecular signatures identified in the lab setting will result in the generation of much needed drugable targets for Lupus treatment. In addition funding from LGI will be used to allow us to carry out genetic sequencing to determine how oestrogen is affecting overall gene expression levels and the function of receptors that recognize and bind oestrogen itself, in order to better understand the role of oestrogen in this disease. The funding will also be used to facilitate training in top international labs in a number of cutting edge techniques as well as to allow me to talk of my findings in this exciting research both nationally and internationally. The funding from LGI will therefore have a maximum impact in the area of Lupus research and help advance our understanding into an area that has long confounded

Rheumatologists. It is hoped that this work will provide the background needed to support another look at the use of oestrogen modifying agents in the treatment of Lupus.

Research Blog - Dr Siobhan Smith

My main area of research in the lab concerns the role of oestrogen in SLE. It has long been recognised that there is a strong gender bias associated with this disease with females affected at a 9:1 ratio compared to males. This gender imbalance has suggested a role for hormones in particular oestrogen as being important in the development of SLE. My work aims to identify the role that oestrogen plays in promoting disease and trying to identify novel ways to control the effects oestrogen has on the cells of the immune system.

Recently the role for small regulatory genetic materialknown as microRNAs (miRNA) in SLE has become an area of interest. MicroRNAs work primarily to negatively regulate the expression of genes and when these microRNAs are perturbed many protectivepathways are lost or stimulatory pathways turned on. A number of these miRNA have been found to be regulated by oestrogen contributing to the altered immune balance observed in SLE. Thus strong links exist between oestrogen-regulated miRNAs and their altered levels in SLE therefore suggesting that understanding what pathways these microRNAs regulate will help our understanding of the role of oestrogen in SLE and identify microRNAs that may hold potential as therapeutic targets in SLE.

Preliminary studies in the lab have identified a panel of 87 novel miRNAs regulated by oestrogen in human immune cells. Whilst the targets for these miRNAs have not yet been identified, computational analysis suggests that these microRNAs target essential components of inflammatory signalling pathways important in the regulation of an appropriate immune balance, a balance altered in SLE. We therefore believe that alterations in oestrogen-regulated miRNAs in SLE patients may contribute to the uncontrolled inflammation observed in SLE through the regulation of key inflammatory pathways. The aim of my research for the upcoming two years is to elucidate the role oestrogen-regulated microRNAs and their gene targets play in disease. It is expected that the presence of certain oestrogen-regulated miRNAs will then be used as predictors of particular disease subtypes and related symptoms. If patients who will develop the more serious complications of the disease can be predicted based on molecular signatures driven by oestrogen, it may help clinicians to treat these patients more aggressively when they first present. Additionally identification of key oestrogen-regulated miRNAs associated with altered immune balance in SLE offers the potential to devise novel targeted therapeutics to alleviate disease inflammation.

Fundraising for Research Nurse

LGI are fundraising for a research nurse who will support/contribute to translational research being conducted in Lupus.

Please donate here towards our Research Nurse or if you would like to fundraise for this great project you can contact Aaron on a_o_bryan@hotmail.com for further info!!

Online Lupus Research Survey for Irish Psychology Dept – Take Part!!!

A research team from the University of Limerick in Ireland is seeking to conduct research into social support and quality of life in individuals with Systemic Lupus Erythematosus.

Specifically, this study is being conducted to examine how social support might be associated with quality of life in individuals with Systemic Lupus Erythematosus (Lupus). This study is being conducted by Dr. Ann-Marie Creaven (Lecturer in Psychology at the University of Limerick, Ireland) and Kirby Brennan (final year undergraduate student) in the Department of Psychology. As part of this research project, they have devised an online survey measuring social support and quality of life for individuals with Lupus over the age of 18. Responses to the survey are anonymous and confidential.

They hope this study will provide valuable information in regards to whether social support impacts on quality of life in individuals with Lupus. Another potential benefit is the contribution of knowledge that may provide insight into how to better the lives of individuals with SLE.

If you would like to help by completing the online study you can do so at http://ww2.unipark.de/uc/Lupus_SocialSupport_QualityofLife

**Please note this study is not being conducted on behalf of LGI and we have no affiliation with this project, we are simply advertising on behalf of Dr Ann Marie Creaven**

Lupus Research Update - Lupus and Oestrogen

Dr. Caroline Jefferies

Lupus is a disease where the immune system is overactivated and inappropriately recognizes the body’s own proteins and tissues causing inflammation and tissue destruction. It presents as a broad spectrum of symptoms and organ involvement and it is more and more evident that a wide variety of Lupus sub-types exist – ranging from disease that affects the kidneys to one that affects the skin and joints. Thus it is unlikely that one block-buster drug will be discovered that will treat all Lupus sub-types. Therefore it has become clear that a more personalized approach to treatment is required. To facilitate this, new diagnostic tools are required to aid the easy identification of specific sub-types of Lupus and thus aid disease management.

A well accepted feature of Lupus is that women are more likely to get the disease, suggesting that hormones such as oestrogen may be important drivers. Recent work in the lab of Prof. Jefferies at the Royal College of Surgeons in Ireland suggests that overactivation of the oestrogen system in lupus adversely affects the immune system and as a result contributes to the overall pathology of Lupus. The work of Prof. Jefferies and colleagues at RCSI shows oestrogen regulates the levels of key proteins that control the immune response. The result is overactivation of the immune response and hence the development of conditions such as lupus. Their work has gone on to show that blocking the effect of oestrogen restores balance to the immune system in cells derived from Lupus patients and thus has potential in disease management. This work has recently been published in Arthritis and Rheumatism and Prof. Jefferies' lab is hoping to continue this work assessing the effect of oestrogen regulation as a potential treatment of Lupus. In addition her group has unpublished findings that suggest that oestrogen may control changes in regulatory genetic material called microRNAs which are contributing to the abnormal immune response in Lupus. In addition Prof Jefferies and colleagues are gathering evidence that strongly indicates that different sub-types of Lupus are linked to alterations in molecular signatures that may be estrogen driven. Future avenues of investigation by the group aim to assess how this information can be used to aid patient stratification and a more personalized approach to patient care in Lupus.

Lupus Research Updates

Dr. Caroline Jefferies

Our immune system has evolved in order to fight infection from viruses and bacteria and anything else that might threaten our health. It’s an efficient network of cells that circulate in our blood and tissues ready to be activated once it meets an infectious agent or threat. Once a threat is detected, immune cells produce chemical messengers called cytokines that help drive the production of antibodies to aid clearance and prevent spread of the infectious agent. But what happens when our immune system becomes over-activated or fails to turn off once the threat has been cleared? The cells of the immune system continue to churn out cytokines and antibodies which when produced in excess or in the wrong context now target healthy tissues and cells – in other words we get autoimmunity.

Autoimmunity is when our immune system is tricked into thinking an infectious agent is present – and for lupus anti-viral immune defences are key in driving the disease. Researchers have identified a number of key chemical messengers or cytokines that are produced excessively in lupus – BlyS and IFN-alpha – and new therapies in lupus are aimed at reversing this excessive production or preventing the effects of these cytokines. For example antibodies that can bind and neutralize BLyS and IFN-alpha have been developed which have been shown to have beneficial effects in lupus patients in clinical trials. Indeed Bellimumab, which targets BLyS, was recently approved by the FDA for treatment of lupus patients – the first drug in over 50 years approved specifically for the treatment of lupus.

As we learn more and more about what is going wrong with the immune system, we can use this information to develop ways to try and restore its proper function. But lupus is a very diverse autoimmune disease and it is becoming clear that patients with different symptoms may require different treatments - in other words, we need a personalized approach to treatment. So as we approach this next exciting era in lupus research, the focus is on developing ways to aid patient diagnosis and determining which drug is best suited to individual patients and also on generating targeted therapies aimed at restoring the balance of the immune system.

Research Blog - Caroline Jeffries

The main research interest in the lab of Dr Caroline Jefferies is SLE. In particular her group are interested in the role that a particular white blood cell type called monocytes may play in the disease. These cells play a key role in keeping the body healthy by recognising foreign bodies and trying to eliminate them thus preventing infections etc. In SLE it is known that these cells play a role in causing the disease as they can start to recognise a person own cells as foreign and thus react against them. The work in Dr Jefferies group is aimed at better understanding how these cells work and how they recognise and talk to other cells in the immune system. In particular the group are interested in finding new ways to understand how these cells work with the ultimate aim of identifying how to control them and thus prevent disease in SLE.

In addition to trying to better understand the role of monocytes in SLE the group is also interested in the role of different chemical messengers that can attack tissues and organs in SLE patients causing damage. These chemical messengers called cytokines are of increasing interest in SLE as they are increasingly being targeted as a possible means of controlling the disease in patients who don’t respond to conventional therapy. This approach is highlighted by the fact that in the past two years the first drug specifically licensed for the treatment of lupus had been released in America and approved for use in Europe. Being better able to identify which patients would benefit from the addition of such treatment and when to give them would enhance care for patients.

The final area of research in the lab concerns the role of oestrogen in SLE. It has long been recognised that women are far more likely to develop the disease than men and many women develop the disease in their late 20’s/early 30’s. Much of this increased risk is due to the role of oestrogen and the group aims to once more identify the role that oestrogen plays in promoting disease and trying to identify novel ways to control the effects oestrogen has on the cells of the immune system. Over the coming weeks and months we will keep members posted on the progress of the research within the group.

Update on Irish Lupus Research

By Dr. Eoghan McCarthy

The focus of my research is looking at the role that different chemical messengers in the blood called cytokines play in driving the activity of disease in Irish Systemic Lupus Erythematosus patients. In addition we are investigating whether patients with different types of lupus have different levels of these messengers.

This research is important as patients from different genetic backgrounds get different types of lupus so a better understanding of what causes the disease in Irish patients may help in the development of treatments for patients. Furthermore if we can predict which patients will develop the more serious complications of the disease it may help us as doctors to treat these patients more aggressively when they first present.

To date we have focused on the role of a messenger called BLyS (B Lymphocyte Stimulator). This chemical can cause the body’s cells to produce antibodies that in turn attack its own tissues – thus causing the symptoms and organ damage associated with Lupus. We have focused on BLyS as in 2011 a new drug called Belimumab, which has been shown to lower the level of circulating BLyS in the body, was licensed for the treatment of lupus in both America and Europe. Unfortunately not all patients with lupus will respond to the treatment so we have attempted to identify patients that might respond best to therapy.

My research, conducted with the help of the rheumatologists in Beaumont and St. James Hospital, involved measuring the levels of BLyS in patients’ blood when they were seen in the rheumatology clinic and then following them over the next five years. We demonstrated that patients who had high levels of BLyS when they were seen in the clinic were more likely to have active disease at the time the blood sample was taken. These patients with high BLyS levels were also more likely to go on to develop organ damage from their lupus over the next five years. Furthermore we have seen that people with certain types of lupus have higher levels of BLyS. Whilst these results need to be verified in a larger group of patients they do have the potential to impact on patient care as it suggests that treating patients that present with high levels of BLyS on examination with Belimumab may reduce the activity of their disease and in turn prevent damage to organs and tissues.

“Lupus Group Ireland plan to advocate and donate a percentage of funds raised through various fundraising campaigns to research such as Dr. McCarthy’s so that he can progress his research of Lupus in Ireland” – Jessica O’ Bryan, Chairperson, Lupus Group Ireland