This grant was awarded to an international team of scientists who will investigate heterogeneity in immune cell behavior and cognitive function in systemic lupus erythematosus patients in remission.
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Betty Diamond, MD |
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Dzifa Dey, MD |
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David Eidelberg, MD |
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Riëtte du Toit, MD, PhDStellenbosch University and Tygerberg Academic Hospital, South Africa |
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Jimmie Ye, PhD |
Patients with active systemic lupus erythematosus (SLE) are often treated with immunosuppressive medications – drugs that decrease the activity of an overactive immune system. However, lupus is a heterogeneous disease, whereby patients experience a wide range of symptoms and respond differently to treatments. This complicates attempts to study and learn whether a current or potential lupus treatment is effective.
To better understand patient heterogeneity and to personalize lupus treatments, Dr. Diamond and colleagues will compare the immune cells of SLE patients in drug-free remission – when their symptoms are less or inactive – to those from patients with active SLE as well as healthy individuals. Study participants will be from London, Mexico City, Los Angeles, and New York City to reflect the ethnic and racial diversity of the overall lupus population. The goal is to understand the features of the immune cells that are kept in check in patients in remission who are not receiving lupus treatments and how immune cells change when patients relapse. The team will also study the change in cognitive function among SLE patients who are in remission and relapse. The study will determine if patients in remission experience SLE-related activity in their brain. Moreover, the global team will test if there is an association between abnormal brain function and immune cell behavior and risk of relapse in SLE patients.
What this study means for people with lupus
The findings will improve our understanding of immune cell heterogeneity and brain function in people living with SLE to provide insight into whether immune cell abnormalities can cause cognitive complications in these patients.
To date, studies exploring the heterogeneity of SLE have been conducted in patients with a range of disease activity and are confounded by immunosuppressant use and variable inflammatory pathways. We now propose to study 150 SLE patients in drug free clinical remission (+/- hydroxychloroquine) from 5 established, geographically dispersed, ethnically and racially diverse cohorts to dissect patient heterogeneity without the confounding effects of medication and ongoing inflammatory cascades. Of these patients, it is predicted that 30 will relapse over 3 years. We propose to determine the spectrum of immunophenotypes. The definition of remission in SLE does not address some manifestations of neuropathology; in particular it does not address cognitive impairment which is frequent and disturbing to patients. We will therefore address the nature and spectrum of brain pathology in these individuals. It is our hypothesis that immunophenotype and neurophenotype will be linked and those who relapse will have persistent central nervous system abnormalities even when in clinical remission. We will examine the protein expression and transcriptional and pattern of chromatin accessibility at the single cell level in circulating immune cells. It is our hypothesis that we will observe, at a minimum, two immunophenotypes, one with subclinical myeloid activation and one with subclinical B cell activation. Knowing this intrinsic heterogeneity in activation pathways that exists in SLE patients would have major implications for both initial therapy and maintenance therapy. We hypothesize that the composition of cellular subsets in patients in remission will differ from that of healthy controls. For example, we hypothesize a greater number of exhausted CD8+ T cells and regulatory T cells in some patients in remission. This information will influence therapeutic strategies and the goals of therapy. We further hypothesize that the pattern of chromatin accessibility may predict those at risk to relapse over three years of the study. We now appreciate that up to 80% of SLE patients experience cognitive impairment and many do so without any prior episode of overt brain involvement. Thus, our definition of remission currently downplays a vital organ. We propose to use neuroimaging to assess quantitatively regional changes in cerebral metabolism, blood-brain-barrier integrity, and the local inflammatory response (microglial activation), all reversible metrics of brain injury, during remission. We will determine if brain pathology exists in patients in remission and correlates with immunophenotype.