Colton Center Current Projects & Lead Investigators

Project One: The examination of microbiota-triggered adaptive immune responses in autoimmune disease

Dan Littman
PI: Dan Littman, MD, PhD

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

Working with Dr. Steven Abramson and Dr. Jose Scher, the 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 of spontaneous arthritis, which was triggered by colonization with the Th17 cell-inducing segmented filamentous bacteria (SFB), we are seeking to determine if 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 that are currently being processed.

Dr. Littman’s group has also initiated collaboration with rheumatology groups at the University of Oxford and University College, London to sequence the microbiota of patients with RA, ankylosing spondylitis, and juvenile inflammatory arthritis.

References:

Scher, Jose U; Sczesnak, Andrew; Longman, Randy S; Segata, Nicola; Ubeda, Carles; Bielski, Craig; Rostron, Tim; Cerundolo, Vincenzo; Pamer, Eric G; Abramson, Steven B; Huttenhower, Curtis; Littman, Dan R. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife. 2013:2:e01202-e01202. DOI: 10.7554/eLife.01202

Scher, Jose U; Littman, Dan R; Abramson, Steven B. Microbiome in Inflammatory Arthritis and Human Rheumatic Diseases. Arthritis & rheumatology. 2016:68(1):35-45. DOI: 10.1002/art.39259

Project Two: The examination of microbiota-triggered immune responses in SLE and APS

Gregg Silverman
PI: Gregg Silverman, MD

The overarching goal is to investigate whether specific bacterial isolates in the intestines of people with systemic erythematosus lupus (SLE) contribute to their autoimmune pathogenesis and to disease flares. Working with Dr. Jill Buyon, Dr. Silverman has uncovered several important new findings in his group’s 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 IgA as a diagnostic for SLE.

References:

Gregg J. Silverman, Lelise Getu, Haitao Niu, Hanane El Bannoudi, Adriana Heguy, Alexander Alekseyenko, Jill P. Buyon, and Doua Azzouz. American College of Rheumatology 2015 (accepted as an oral presentation); “Does Dysbiosis within the Intestinal Microbiome Contribute to SLE Pathogenesis?” Arth. Rheum. (abstract), 2015.

Project Three: The role of DNASE1L3 and microparticle-associated DNA in human SLE

Jill Buyon
PIs: Jill Buyon, MD
Boris Reizis
Boris Reizis, PhD

Drs. Buyon and Reizis, who are investigating the role of DNASE1L3 in systemic lupus erythematosus (SLE), developed a new assay to measure DNASE1L3 activity in human serum or plasma, as well as a new method to measure DNA concentration in circulating microparticles in human plasma. Their study has developed three novel readouts of anti-DNA reactivity in SLE, which may represent novel, pathogenetically relevant parameters of the disease and have diagnostic and/or prognostic potential. These findings have led to a provisional project invention under preparation for DNASE1L3 as a therapeutic agent.

References:

V. Sisirak, B. Sally, V. D’Agati, W. Martinez-Ortiz, Z. B. Özçakar, J. David, A. Rashidfarrokhi, A. Yeste, C. Panea, M. Bogunovic, I. I. Ivanov, F. J. Quintana, I. Sanz, K. B. Elkon, M. Tekin, F. Yalçınkaya, T. J. Cardozo, R. M. Clancy, J. P. Buyon and B. Reizis. DNASE1L3 enforces tolerance to self-DNA by digesting microparticle associated chromatin from apoptotic cells. Cell (in press).

Project Four: Microbiome and its metabolites in psoriatic arthritis pathogenesis

Jose Sher
PIs: Jose Scher, MD
Sergei Koralov
Sergei Koralov, PhD

Dr. Scher and Dr. Koralov are investigating microbiome and its metabolites in psoriatic arthritis pathogenesis. They have demonstrated in mice a possible role for medium-chain fatty acid (MCFA) supplementation in the progression of autoimmune disease. Early intervention, proof-of-principle trials are being conducted in healthy humans to address the potential for translational implications of these findings.

References:

Abdollahi-Roodsaz, Shahla; Abramson, Steven B; Scher, Jose U. The metabolic role of the gut microbiota in health and rheumatic disease: mechanisms and interventions. Nature reviews. Rheumatology. 2016, June 3.

Scher, Jose U; Ubeda, Carles; Artacho, Alejandro; Attur, Mukundan; Isaac, Sandrine; Reddy, Soumya M; Marmon, Shoshana; Neimann, Andrea; Brusca, Samuel; Patel, Tejas; Manasson, Julia; Pamer, Eric G; Littman, Dan R; Abramson, Steven B.  Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis & rheumatology. 2015:67(1):128-139.DOI: 10.1002/art.38892

New Projects 2016-2017

Three new projects have been added to current research at the Colton Center.

Project Five: Protein engineering of a nuclease for the rational immunotherapy of SLE

PIs: Boris Reizis, PhD, and Timothy Cardozo, MD, PhD

The proposed work represents a collaboration between the labs specializing in experimental immunology (Reizis) and in protein engineering (Cardozo). Our recent collaborative work focused on DNASE1L3, a unique secreted DNase that is associated with rare familial cases of human systemic lupus erythematosus (SLE). Helped by a model of DNASE1L3 structure generated by the Cardozo lab, Drs. Cardozo and Reizis have characterized the unique properties and endogenous DNA substrate of DNASE1L3. They also provided a proof of principle for the delivery of exogenous DNASE1L3 to ameliorate anti-dsDNA response. Because DNASE1L3 is an endogenous human serum protein, they hypothesize that its delivery as a biologic would be a safe and specific therapeutic strategy in SLE.

Project Six: Isolation of novel members of the gut microbiota that mediate resistance to autoimmunity

PIs: Ken Cadwell, PhD, and P’ng Loke, PhD

This proposal will investigate a 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. Drs. Cadwell and Loke recently found that infecting Nod2 mutant mice with helminths induces expansion of Clostridiales species that reverse intestinal disease by inhibiting B. vulgatus colonization. Additionally, they demonstrated that helminth infections in indigenous people of Malaysia are associated with similar alterations in their gut microbiota, and that the antagonistic relationship between Clostrdiales and inflammatory bacteria is conserved in humans. In these new studies they will isolate novel Clostridiales strains from this unique cohort of helminth-infected individuals, 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.

Project Seven: Epigenetics of antibiotic-induced type 1 diabetes in the NOD mouse model

PI: Martin Blaser, MD

Type 1 diabetes (T1D) is a classic autoimmune disease, usually expressing in early life. The substantial increase in prevalence since World War II indicates the importance of environmental influences. Immunological effects due to changing populations of the microbes that live in and on us (the human microbiome) is a relevant hypothesis. We have established a model in which we can accelerate T1D, and already have insights about mechanisms. We now seek to extend the observations, which will help us understand and ultimately prevent T1D, and learn general lessons about microbiota/immune interactions that drive autoimmunity. Non-obese diabetic (NOD) mice spontaneously develop T1D, and our prior work has shown that we can accelerate this with exposure to antibiotics in early life. We will now examine cells of the intestinal wall to determine if there are changes that can explain how the altered microbes are interacting with the immune system. Such epigenetic changes might be critical in the microbial-host interface, and potentially could be blocked to delay or prevent the development of T1D.