2021 Grant Awards
Researchers at NYU Langone’s Judith and Stewart Colton Center for Autoimmunity received grant awards for the following projects in 2021.
Validation of a New Ion Channel as a Critical Modulator of Inflammatory Macrophage Function in Rheumatoid Arthritis
Principal investigator: Stefan Feske, MD
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, affecting 0.5 to 1 percent of the population. The disease primarily involves the inflammation and destruction of joints but can frequently also cause inflammation and damage of internal organs such as lungs and blood vessels. RA starts with the inflammation of the synovium, the tissue lining the inner surface of joints, and then progresses by causing the destruction of cartilage, the rubber-like padding that covers and protects the ends of bones and that forms the joints, and progresses to erosion of bones themselves. The end stage of RA is the severe deformation and loss of function of joints, which results in significant disability.
Many components of the immune system are involved in the disease mechanisms causing RA. One of the most critical immune cells causing inflammation in RA is a white blood cell type called macrophage. These cells not only ingest pathogens and cell debris, they also secrete messenger molecules, called cytokines, that recruit and activate other immune cells and cells in tissues including the joints. In RA, an increase in the number of macrophages in affected joints is an early mark of disease, and the degree of macrophage infiltration correlates with the degree of joint damage. The important role of macrophages in the development of RA has been demonstrated using animal models of RA. Macrophages are the main producers of cytokines, which cause joint inflammation, and neutralization of these cytokines has revolutionized RA treatment in the past two decades. Although these drugs have dramatically improved treatment options for people with RA, many patients do not respond to or become resistant to therapy, necessitating new therapeutic approaches.
In this project, the Feske Lab is investigating how the function of macrophages and their ability to cause inflammation in RA is regulated by a new ion channel. Ion channels form pores that can be opened and closed in the membrane of cells. They transport inorganic ions such as sodium and calcium or small organic molecules into or out of cells. There are hundreds of different ion channels. Some of them have been intensively studied and are important drug targets for the treatment of neuropsychiatric or cardiovascular diseases.
We have observed that a so far little studied ion channel is highly and selectively enriched in inflammatory macrophages. Importantly, the channel is strongly upregulated in macrophages present in the joints of RA patients. In further experiments, we found that genetic deletion of the channel almost completely suppresses the proinflammatory function of macrophages.
The overall goal of our pilot project is to understand (1) if suppression of the function of this new ion channel ameliorates the severity of RA in animal models of the disease, and (2) how the channel regulates proinflammatory macrophage function, as well as joint inflammation and destruction. Because this channel, like many other ion channels, is present at the surface of cells and therefore accessible to drugs, the long-term goal of this project is to determine if the channel is a new drug target for the treatment of RA.
Targeting MPZL1 in Autoimmune Disease
Multiple sclerosis (MS) is caused by immune-mediated demyelination and inflammation in the central nervous system (CNS), which results in debilitating symptoms. Current therapies only partially inhibit disease progression, and patients with progressive MS have limited benefit. Patients with systemic lupus erythematosus (SLE) exhibit varying clinical presentations but frequently have damage to critical organs. Conventional SLE treatments (e.g., corticosteroids, cyclophosphamide) can have serious side effects, while biologics, such as abatacept, have limited efficacy.
New approaches to modify immune regulatory pathways are needed to improve patient outcomes in both of these multifactorial disorders. Immune cell activation is regulated by transmembrane immune inhibitory receptors, also known as checkpoint receptors, that contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs; consensus sequence S/I/V/LxYxxI/V/L). Myelin protein zero like 1 (MPZL1, a.k.a. PZR) is a single-pass transmembrane protein with two ITIMs.
The MPZL1 structure suggests a regulatory role, yet little is known about its physiological function or ligands. Preliminary data indicate that MPZL1 plays a role in regulating autoimmune responses. We hope to define the mechanism by which MPZL1 regulates immune responses and explore the therapeutic utility of biologic modulators of MPZL1 function in mouse MS and SLE models. Our results could yield novel insights into pathogenesis and yield new therapeutic options for these disorders.
Identification of Putative Autoantigen in Hidradenitis Suppurativa
Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease that occurs in human apocrine sweat gland-bearing skin regions, with an estimated prevalence of 1%. It is characterized by extremely painful nodules, odorous suppuration, ulceration, extensive formation sinus tracts, and permanent scarring. Current treatments, including antibiotics and TNF-α inhibitors, are not effective, with surgical excision being the last resort. Even after surgical excision, patients often develop painful nodules again and disease continues to affect neighboring skin regions, which severely and negatively impact on patients’ quality of life. Clinically, it is still extremely difficult to treat due to the lack of understanding of the disease pathogenesis and the molecular pathways driving disease progression. Thus, there is a high clinical need to better characterize the disease and to identify novel targets for efficacious therapeutics for HS.
Our preliminary data reveals massive B and plasma cell infiltration in the proximity of sweat glands and sinus tracts in HS lesional skin, suggesting a possibility that HS may be an autoimmune disease. We plan to use single-cell RNA sequencing and VDJ-sequencing to examine the clonality of the B cells and plasma cells, and to characterize the antibodies and their antigen(s). We also hope to expand our collection of HS patient samples to acquire a more comprehensive understanding of the role of plasma cells in HS pathogenesis and how these cells may lead to other autoimmune comorbidities.
Impact of Type I Interferons on Rheumatoid Arthritis Patient Monocytes, Monocyte-Derived Macrophages and Fibroblast-Like Synoviocytes Using a Novel Vascularized Pannus-on-a-Chip Model
Principle investigators: Theresa L. Wampler Muskardin, MD, and Weiqiang Chen, PhD
In rheumatoid arthritis (RA), monocytes from the blood invade joint tissue (synovium/pannus) and transform into inflammatory monocyte and macrophage populations. This is influenced by environmental cues in the tissue, including fibroblast-like synoviocytes (FLS). Our preliminary data suggest that circulating type I interferons affect monocyte activation. The relative contributions of blood versus tissue signals in the invasion and differentiation of monocytes to inflammatory monocytes and macrophages is not known.
We hypothesize that increased type I interferon signaling in monocytes alters monocyte invasion into the joint tissue and that interferon-stimulated FLS promote a pro-inflammatory macrophage phenotype. We plan to test this hypothesis using a novel vascularized pannus-on-a-chip model. This bioengineered perfusable organ-on-chip device is ideal for examining effects of type I interferons on infiltrating and tissue cells and can be further adapted to include additional cell types in the future.
The bioengineered human pannus-on-a-chip system allows longitudinal analysis of cells to understand how the joint tissue environment changes the way cells act during immunomodulation. Manipulation of the RA-chip environments and monitoring the effects by multimodal means provides a new way to interrogate and examine human RA pathobiology. In our work, we plan to test type I interferons in this system. We will then test tumor necrosis factor inhibitors.
Ultimately, this bioengineered human synovium-on-a-chip model has the potential to achieve a so-called "clinical trial on a chip" that could prescreen patients suitable for specific immunotherapies. This platform could be used in preclinical drug testing for RA to support early-stage drug discovery work at the Colton Center.