Labs

The Cuda Lab focuses on uncovering mechanisms underlying neuropsychiatric manifestations of systemic lupus erythematosus (NP-SLE) via basic and translational methodologies. SLE is a chronic and multi-systemic autoimmune disease plaguing 1.5 million Americans. Among the many organ systems affected, symptoms associated with the nervous system may appear in up to 90% of SLE patients depending on the attribution model and be among the earliest signs of SLE. NP-SLE can manifest in seizures, strokes, movement disorders, mood disorder, anxiety disorder, acute confusional state, psychosis, acute encephalopathy and/or chronic neurocognitive dysfunction. Despite the devastating impact of NP-SLE on health-related quality-of-life, our understanding of causal mechanisms is limited.

Microglia, the resident innate immune cell of the brain, have recently been implicated in NP-SLE. Studies show histological evidence of microglia activation in NP-SLE patients and mouse models of disease. Microglia display regional, functional, and disease-associated heterogeneity; in particular, a disease-associated microglia (DAM) subset was recently identified in Alzheimer’s disease and aging. DAM co-localize with amyloid-b plaques, are enriched for genes involved in lysosomal, lipid metabolism and phagocytic pathways and may play a protective role in the early stages of AD by reducing amyloid-b plaque burden. However, very few studies have examined microglial heterogeneity or contributions to NP-SLE. Our group is the first to show that expression of a shared NP-SLE transcriptional signature and DAM-associated genes correlates with the severity of hippocampal- and cerebellar-associated behavioral deficits in microglia isolated from two NP-SLE models prior to overt systemic disease. We also find that restricted expression of the DAM transcriptional program in NP-SLE DAM corresponds to improved behavioral outcomes in NP-SLE-prone mice following treatment with fingolimod, a sphingosine-1-phosphate receptor modulator that reduces microglia activation and improves blood brain barrier integrity. These discoveries mark the first to implicate DAM as a potentially pathogenic microglia subset in NP-SLE, which is in contrast to their proposed protective role in early AD development.

We also find that increasing numbers of macrophages in the brain correlate with worsening severity of behavioral deficits early in life and have identified an expanded brain macrophage subset in end-stage disease via scRNA-seq analysis that is detectable at two months of age. Since a worse prognosis is suggested when NP-SLE accompanies lupus nephritis and infiltrating macrophages contribute to organ-specific SLE pathogenesis, we hypothesize that macrophage-specific mechanisms underlying systemic disease are conserved in kidney and brain and detectable in circulating monocytes prior to extravasation into the affected end-organ.

Further, we are translating our findings to human disease by evaluating cerebrospinal fluid (CSF)-resident microglia-like cells and macrophages as well as circulating monocyte subsets from NP-SLE patients via scRNA-seq to interrogate the penetrance of causative mechanisms. Thus, we are interrogating microglial and macrophage heterogeneity to dissect cell subset-specific contributions to disease with the ultimate goal of identifying critical populations and/or pathways that may serve to improve diagnostic and/or therapeutic strategies in NP-SLE.

For more information, visit the faculty profile of Dr. Cuda

Publications

View Dr. Cuda's publications at PubMed

Contact Us

Contact Dr. Cuda at 312-503-7320 or by email

Rheumatoid arthritis (RA), though incurable, can improve naturally during pregnancy in a substantial proportion (50-75%) of women, while it may worsen or remain unchanged in others. These observations cannot be explained by hormonal changes alone. Furthermore, there is often a predictable flare of RA by 3-6 months after childbirth. It is not known how pregnancy brings about a natural improvement of RA, why some women worsen during pregnancy and what leads to a flare after childbirth. In fact, little is known about biological changes that occur in the mother’s blood during and after pregnancy, compared to before pregnancy, even among healthy women. Over the last several years, Dr. Jawaheer led an international multi-disciplinary research team, establishing a unique prospective pregnancy cohort of RA and healthy women in Denmark. This is the first such cohort with a pre-pregnancy baseline and with samples available from the same women during and after pregnancy, for gene expression and epigenetic studies to specifically address these questions. Using this cohort, our lab already generated some preliminary results showing that: specific immune-related pathways in the maternal periphery are modulated progressively during pregnancy; gene expression signatures at the pre-pregnancy baseline may be predictive of subsequent improvement or worsening of RA during pregnancy; dysregulated expression of a set of immune-related genes is associated with the RA postpartum flare. Our ongoing research using state-of-the-art genomics and bioinformatics approaches to follow up on these initial results is novel in the context of both RA and healthy pregnancies. This research can potentially lead to the identification of novel targets for improved therapies to mimic the beneficial effects of pregnancy on RA, which will benefit the millions of men and women worldwide who live with this disease.

For more information, visit the faculty profile of Dr. Jawaheer

Publications

View Dr. Jawaheer's publications at PubMed

Contact Us

Contact Dr. Jawaheer by email

Macrophages have emerged as key players in the development of inflammation and fibrosis in central target organs including the synovium, kidney and lung during the pathogenesis and remission of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), respectively. Macrophages also contribute to the co-morbidities associated with these diseases including atherosclerosis and obesity. We observed marked heterogeneity in the macrophage population within diseased tissues that is dependent on their origin (embryonic vs. bone marrow derived), target organ and microenvironment. Moreover, these macrophages are extremely plastic and can alter their phenotype throughout the course of disease. Based on our data we developed a central hypothesis that during the initiation and early progression phase of disease tissue resident macrophages that normally function to maintain tolerance to local antigens, are overwhelmed by recruited pro-inflammatory or pro-fibrotic monocyte derived macrophages or pro-inflammatory dendritic cells depending on the target organ and environmental milieu. As the disease progresses to the chronic phase, however, the recruited macrophages acquire characteristics reminiscent of tissue resident macrophages while retaining a pro-inflammatory and pro-fibrotic phenotype, resulting in failed resolution of inflammation and progressive tissue destruction and fibrosis. The data anticipated from our projects would be the first to demonstrate a direct linkage of macrophage ontogeny and activation to disease activity and tissue damage. In addition, our studies allow us to explore commonalities in macrophage function between diseases that could lead to broad therapeutic interventions. In our state-of-the-art murine models we use cutting-edge technologies that we developed including micro-MRI, CT and SPECT to evaluate joint inflammation, bone destruction and lung fibrosis, Luminex-based gene arrays and multiparameter flow cytometry/sorting, whole population RNA seq and single cell RNA Seq and Chip-seq. We will cross-reference these data with those we will obtain through the AMP programs, which examine macrophage heterogeneity in the synovium and kidney from patients with rheumatic disease. This will allow us to rapidly move to functional analyses of relevant pathways and testing of new therapeutic strategies in the mouse models. I believe that our data has the potential to be paradigm shifting and transformative for the field of rheumatic disease.

Publications

View Dr. Perlman's publications at PubMed

For more information related to the Perlman Lab, or to connect with us, please see Harris R Perlman’s, PhD, profile.

Contact

Contact Dr. Perlman at 312-503-8003 or the Perlman Lab at 312-503-1933.

Research Description

The goal of the Winter Lab of Functional Genomics is to apply genomic approaches to study rheumatic disease. Led by Dr. Deborah Winter, a computational immunologist, we employ the latest technologies for assays, such as RNA-seq, ChIP-seq, ATAC-seq and single cell expression, to profile the transcriptional and epigenomic profiles of immune cells in health and disease. Our goal is to define the underlying regulatory networks and understanding how they respond to challenge, illness and injury. We are particularly interested in the role of macrophages in diseases such as scleroderma, rheumatoid arthritis and lupus. Previous research has addressed the impact of the tissue environment on resident macrophages and the role of microglia, CNS-resident macrophages, in brain development. Our research combines molecular and systems biology, biotechnology, clinical applications and computer science. We use both mouse models and patient samples to help us understand and test different systems. We are committed to high standards of analysis and are continually updating and training in innovative computational techniques. We are currently recruiting highly motivated individuals to join the lab.

For more information, visit the faculty profile of Dr. Winter.

Publications

View Dr. Winter's publications at PubMed

Contact Us

Contact Dr. Winter at  312-503-0535 or by email.