Colton Center Current Projects & Lead Investigators

At NYU Langone’s Judith and Stewart Colton Center, our researchers conduct pilot projects and collect data for biomedical research to better understand the immunological basis of autoimmune disorders.

We pioneer basic science and translational research that drive advances in the diagnosis, treatment, and prevention of autoimmune diseases, such as ankylosing spondylitis, antiphospholipid syndrome, arthritis, lupus, Sjögren’s syndrome, and type 1 diabetes.

Featured Projects

“The Examination of Microbiota-Triggered Adaptive Immune Responses in Autoimmune Disease”
Principal investigator: Dan R. Littman, MD, PhD

The central hypothesis of our studies is that an altered gastrointestinal microbiome, or dysbiosis, is an important initiating factor in the development of inflammatory arthritis in genetically susceptible individuals. Study findings may lead to novel treatment strategies to prevent or treat diseases such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.  

Working with Steven Abramson, MD, and Jose U. Scher, MD, our group previously reported a correlation of new-onset rheumatoid arthritis (NORA) with colonization of the fecal microbiota with Prevotella copri. Based on results in a mouse model that showed that colonization with the Th17 cell–inducing segmented filamentous bacteria spontaneously triggered arthritis, we are seeking to determine whether P. copri likewise triggers disease. We have cultured multiple strains of P. copri from NORA patients and healthy controls and have prepared sequencing libraries from 96 strains, which are currently being processed.

Our group is collaborating with rheumatology groups at the University of Oxford and University College London to sequence the microbiota of patients with rheumatoid arthritis, ankylosing spondylitis, and juvenile inflammatory arthritis.

“The Examination of Microbiota-Triggered Immune Responses in Systemic Lupus Erythematosus and Antiphospholipid Antibody Syndrome”
Principal investigator: Gregg Silverman, MD

The overarching goal of these studies is to investigate whether specific bacterial isolates in the intestines of people with systemic lupus erythematosus (SLE) contribute to their autoimmune pathogenesis and to disease flares.

Working with Jill Buyon, MD, our group has uncovered several important new findings in studies of whether specific bacterial isolates in the intestines of SLE patients contribute to their autoimmune pathogenesis and to disease flares. One such finding has led to a project invention for antimicrobial fecal immunoglobulin A as a diagnostic for SLE.

“The Role of DNase IL3 and Microparticle-Associated DNA in Human Systemic Lupus Erythematosus”
Principal investigators: Boris Reizis, PhD, and Jill P. Buyon, MD

Our group is investigating the role of DNase IL3 in SLE and has developed a new assay to measure DNase IL3 activity in human serum or plasma, as well as a new method to measure DNA concentration in circulating microparticles in plasma.

We have developed three novel readouts of anti-DNA reactivity in SLE, which may represent novel, pathogenetically relevant parameters of the disease and have diagnostic or prognostic potential (or both). Based on these findings, we have developed a provisional project invention for DNase IL3 as a therapeutic agent.

2017–18 Pilot Projects

“Microbiome and its Metabolites in Psoriatic Arthritis Pathogenesis”
Principal investigators: Jose U. Scher, MD, and Sergei B. Koralov, PhD

Our team examines how the intestinal and skin microbiomes and the metabolites these microbes produce contribute to the chronic inflammation that characterizes psoriatic arthritis (PsA). We study how these microbiomes and microbial metabolites differ between patients with PsA and healthy individuals and also changes in the microbiome and metabolites that take place during progression from psoriasis to PsA.

We also examine changes in circulating immune cells among patients with PsA and control cohorts to correlate the changes in microbiota and metabolites to functional changes in the immune compartment. We recently characterized a novel small animal model of PsA and are using this model to demonstrate and probe the causal link between changes in microbiota and the metabolites they produce and the chronic inflammatory response in the skin and joints of these animals.

Our hope is that these studies will produce novel insight into PsA pathogenesis and identify novel targets for new therapeutic approaches.

“Functional Genetics of Interferon Regulatory Factor 5 in Human Lupus”
Principal investigators: Timothy Niewold, MD, and Jef Boeke, PhD

We study the lupus risk gene interferon regulatory factor 5 (IRF5). In our previous work, we have shown that the risk variant of IRF5 is gain-of-function downstream of endosomal toll-like receptors. How IRF5 functions to cause SLE is not currently clear.

There are four common functional elements in the IRF5 gene, and the SLE-risk variant is a Neanderthal-derived haplotype that contains all four of these functional elements. These elements are in strong linkage disequilibrium with low haplotype diversity, so the contribution of each element cannot be determined individually.

This presents a major limitation of genetic epidemiology: because the variants are not observed in isolation on human chromosomes, the causal element(s) cannot be determined.

In our pilot project, we use a novel DNA synthesis method in collaboration with the Boeke Laboratory and NYU Langone’s Institute for Systems Genetics to solve this problem. We are creating synthetic IRF5 haplotypes, which are not found in nature, that contain each risk-associated variant in isolation as well as in novel combinations to elucidate the molecular function of each element and potential synergy or interaction.

This will allow us to determine how these elements change the transcriptional output of IRF5, leading to SLE. This knowledge is crucial to developing personalized medicine strategies that target IRF5.  

“Translational Regulation of Autoimmune Suppressive Regulatory T Cells”
Principal investigators: Robert Schneider, PhD, and Adam Mor, MD, PhD

Regulatory T cells (Tregs) suppress the activation of other immune cells by both contact-dependent and independent mechanisms, thereby maintaining immune system homeostasis, inhibiting effector T cells in the periphery, controlling excessive responses to foreign antigens, and preventing autoimmune disease. When Treg function is impaired, autoimmune diseases arise both in patients and in mouse models.

Although it is well established that Treg production increases when the enzyme mTOR is inhibited—in fact, mTOR inhibitor drugs are sometimes used in kidney transplant recipients to prevent organ rejection—there are still many questions about the exact nature of the connection between mTOR and Treg production.

Our research has helped us better understand this connection with data showing a novel translational reprogramming mechanism that promotes Treg development and differentiation. We have found that disrupting the metabolic processes of mTOR is the key to Treg development. This disruption promotes the messenger RNA that “tells” undifferentiated, or naïve, T cells to become Tregs, while inhibiting messenger RNA that tells undifferentiated T cells to become other types.

We seek to understand, and ultimately target with drugs, the crucial intracellular molecular translational control signals that are essential for promoting and impairing Treg development and function.

“Understanding the Role of Calcium Ion Signaling in the Pathogenesis of Sjögren’s Syndrome”
Principal investigators: Stefan Feske, MD, and Rodrigo S. Lacruz, MSc, PhD

In Sjögren’s syndrome, a condition that affects as many as 4 million people in the United States, the moisture-producing glands of the body are impaired, which leads to symptoms such as excessive dryness of the salivary and tear ducts, profound fatigue, chronic pain, major organ involvement, and neuropathies and lymphomas. Approximately 50 percent of patients develop complications, including non-Hodgkin’s B-cell lymphoma.

Although Sjögren’s syndrome is considered an autoimmune disease, the reason why autoimmunity develops—for instance, in response to a viral infection—is not understood. However, recent discoveries indicate that genetic and environmental factors precipitate Sjögren’s syndrome and that subsequent activation of the adaptive immune system starts the cycle of inflammation and gland destruction.
In preliminary data, we found an unexpected link between the onset of Sjögren’s syndrome and the way that T cells process calcium signals. Calcium ions are crucial to the biological processes of all cell types. In T cells, calcium ions flow into the cell through a channel that is regulated by several proteins: ORAI1, STIM1, and STIM2.

When any of these proteins is deleted, T cells cannot properly process calcium ions, which leads to the autoimmune inflammation of the salivary glands that characterizes Sjögren’s syndrome.

2016–17 Pilot Projects

“The Microbiome and Its Metabolites in Psoriatic Arthritis Pathogenesis”
Principal investigators: Jose U. Scher, MD, and Sergei Koralov, PhD

Our team investigates the microbiome and its metabolites in psoriatic arthritis pathogenesis. We have demonstrated in mice a possible role for medium-chain fatty acidsupplementation in the progression of autoimmune disease.

We are conducting early intervention, proof-of-principle trials in healthy humans to assess the potential translational implications of these findings.

“Protein Engineering of a Nuclease for the Rational Immunotherapy of Systemic Lupus Erythematosus”
Primary investigators: Boris Reizis, PhD, and Timothy J. Cardozo, MD, PhD

A collaboration between the Boris Reizis Laboratory, which specializes in experimental immunology, and the Cardozo Lab, which focuses on protein engineering, our project focuses on DNase IL3, a unique secreted deoxyribonuclease associated with rare familial cases of human SLE.

With a model of the DNASE IL3 structure generated by the Cardozo lab, our team has characterized unique properties and endogenous DNA substrate of DNASE IL3. We have created a proof of principle for the delivery of exogenous DNASE IL3 to ameliorate anti–double-stranded DNA response. Because DNASE IL3 is an endogenous human serum protein, we hypothesize that its delivery as a biologic would be a safe and specific therapeutic strategy in SLE.

“Isolation of Novel Members of the Gut Microbiota that Mediate Resistance to Autoimmunity”
Primary investigators: Ken H. Cadwell, PhD, and P’ng Loke, PhD

Our team is investigating the hypothesis that an increase in the incidence of autoimmune diseases is associated with changes in the environment, such as decreased exposure to helminths and alterations to the gut microbiota.

Previously, we found that infecting mice that have NOD2 mutations with helminths induces expansion of Clostridiales species, which reverse intestinal disease by inhibiting Bacteroides vulgatus colonization. Helminth infections in the indigenous people of Malaysia have been associated with similar alterations in gut microbiota and suggest an antagonistic relationship between Clostridiales and inflammatory bacteria in humans.

Our research will isolate novel Clostridiales strains from a cohort of individuals with helminth infection and test their ability to suppress inflammation. This information may reveal strategies to improve the safety and efficacy of ongoing efforts to therapeutically target the microbiota in patients with autoimmune diseases.

“Epigenetics of Antibiotic-Induced Type 1 Diabetes in a Nonobese Diabetic Mouse Model”
Primary investigator: Martin Blaser, MD

Type 1 diabetes is a classic autoimmune disease that usually develops in early life. The substantial increase in the disease’s prevalence since World War II indicates the importance of exogenous influences. We are exploring the hypothesis that changes in human microbiome have significant immunological effects.

Our team has established a model that accelerates type 1 diabetes and has developed insights regarding possible mechanisms of disease. We now seek to extend these observations to better understand and ultimately prevent type 1 diabetes, as well as to obtain general information about the microbiota and immune interactions that drive autoimmunity.

Nonobese diabetic mice spontaneously develop type 1 diabetes, and we have shown previously that we can accelerate the incidence with exposure to antibiotics in early life. We are now examining the cells of the intestinal wall to determine whether changes to them can be explained by interactions between the microbes altered by antibiotic exposure and the immune system. Such epigenetic changes might be crucial in the microbe–host interface and might possibly be blocked to delay or prevent the development of type 1 diabetes.