Franck Barrat, PhD

Two new studies led by researchers at Hospital for Special Surgery (HSS) have uncovered key biological mechanisms driving systemic sclerosis (SSc), or scleroderma – a rare and often devastating autoimmune disease that causes fibrosis (tissue hardening) and inflammation. The research, published in the March issue of the Journal of Experimental Medicine, helps explain why the disease disproportionately affects women and reveals potential treatment targets, some of which are already in development. 

Scleroderma affects approximately 300,000 people in the U.S., with about one-third developing systemic disease, which can affect major organs such as the lungs, kidneys or heart. Women are four times more likely than men to be diagnosed with the disease, but until now, the underlying reason for this gender disparity had remained elusive. 

In one study, a team of researchers led by Franck Barrat, PhD, found that two genetic receptors called TLR7 and TLR8, which are present on the X chromosome, are important drivers for the activation of plasmacytoid dendritic cells (pDCs), fueling chronic fibrosis. pDCs are immune cells found in fibrotic skin but not in healthy skin and have previously been shown to contribute to scleroderma. 

In healthy cells, one X chromosome is typically deactivated, however, the study revealed that in patients with scleroderma, this process is disrupted due to the ability of TLR7 and TLR8 to escape X chromosome deactivation in pDCs. 
"The magnitude of this escape was striking," says Dr. Barrat. 

In healthy individuals, 10 to 15 percent of cells can evade the deactivation process. But in scleroderma patients, the escape occurred in more than 35 percent of the pDCs. This was a significant and unexpected difference. 

“The expression of two copies of the TLR7 and TLR8 in such a large number of cells can very well explain the chronic activation of these immune cells and why this disease is so prevalent in female patients,” concludes Dr. Barrat. 

In a separate study, armed with insights about the role of pDCs in driving fibrosis, Dr. Barrat and colleagues set out to understand why the body’s natural mechanisms fail to shut down inflammation in scleroderma patients. Normally, following a wound in the skin, immune cells infiltrate the skin and trigger an inflammatory response until the scarring process begins. A pause signal is then delivered to the immune cells to resolve the inflammation. But in scleroderma patients, this process stalls. 

The culprit? A cytokine (a type of protein that helps control inflammation in the body) called CXCL4, which researchers found to be highly expressed in the skin of scleroderma patients. Instead of allowing inflammation to subside, CXCL4 prevents immune suppression, keeping pDCs in a state of chronic activation and promoting skin fibrosis. 

“We show that CXCL4 prevents the normal termination of the immune response in the skin,” explains Dr. Barrat. “Basically, the pDCs are attracted by the fibrosis, but instead of being suppressed as they should be, CXCL4 keeps them active, in turn contributing to the cycle of fibrosis in these patients.” 

While there is currently no cure for scleroderma, the research highlights the potential of several therapeutic strategies. 
“This body of research makes a very strong case for exploring drugs that target and interfere with pDCs. There are already drugs in development that we can try,” says Dr. Barrat, noting that several therapies in clinical trials have shown promise in blocking pDCs and preventing skin lesions in patients with lupus. 

Both new studies were a collaborative work. Co-authors from the first study include Dr. Jean-Charles Guéry, PhD, of the University of Toulouse, as well as clinicians from the Scleroderma, Vasculitis & Miositis Center of Excellence at HSS and investigators from the HSS Research Institute. Co-authors from the second study include investigators from the HSS Research Institute; the Scleroderma, Vasculitis & Miositis Center of Excellence at HSS; Institut Toulousain des Maladies Infectieuses et Inflammatoires, Université de Toulouse, INSERM, France; Institut Cochin, Université Paris Cité, INSERM, France; and ImmunoConcEpt, CNRS, UMR 5164, University of Bordeaux, France. 

Lionel B. Ivashkiv, MD

A new study by HSS Research Institute scientists identifies a mechanism by which SARS-CoV-2 induces the inflammatory response in COVID-19 patient lungs, so-called “cytokine storm”, that can lead to lasting tissue damage and poor patient outcomes. The Lead Investigator Dr. Franck J. Barrat and Dr. Lionel B. Ivashkiv at Hospital for Special Surgery worked in collaboration with Drs. Olivier Elemento and Robert E. Schwartz at Weill Cornell Medicine (WCM) on this study, looking at lung tissue samples and bronchoalveolar lavage from COVID-19 patients. 

In a study published September 9 in Science Immunology, the investigators outline what controls the cytokine storm by lung-infiltrating macrophages, as these cells are not efficiently infected by SARS-CoV-2.

Researchers found that an immune cell type, called plasmacytoid dendritic cells (pDCs), are infected by SARS-CoV-2 and produce interferons that can provoke epigenetic changes in the nearby macrophages in the lungs of patients. Hence, this priming of macrophages by interferons leads to their exacerbated response to environmental stimuli, inducing the cytokine storm in the lungs of COVID-19 patients.

This is surprising as interferons and pDCs have been demonstrated to protect patients infected by SARS-CoV-2 – but this new research uncovers that they can also provoke damaging cytokine storms.

“There is still a lot we don’t know about the pathogenesis of COVID-19, and why macrophages can produce these cytokine storms that can have such dramatic consequences for patients. We hope that this research will bring us closer to that understanding and will lead to better treatment options for patients with severe COVID-19,” said Dr. Franck J. Barrat (Michael R. Bloomberg Chair, Hospital for Special Surgery; Professor of Microbiology and Immunology, Weill Cornell Medicine).

This work was supported by a grant from the HSS Research Institute to study the role of pDCs in SARS-CoV-2 pathogenesis as well as grants from the National Institute of Health, the Scleroderma Research Foundation, the Scleroderma Foundation, the Starr Cancer Consortium, the Irma Hirschl Trust Research Award and The Tow Foundation.

IpiNovyx Bio featuring Franck Barrat, PhD

Thanks to the generous support of donors, Hospital for Special Surgery (HSS) has announced the funding of nine grants for projects related to the study of COVID-19. These projects reflect the institution’s expertise in basic, translational and clinical research, and clinical care. Over $500,000 has been awarded so far.

HSS is the world’s largest academic medical center specialized in musculoskeletal health, spanning orthopedics, rheumatology and related disciplines. The HSS Research Institute maintains 20 laboratories dedicated to solving debilitating orthopedic and rheumatic conditions such as arthritis, bone and soft tissue injuries, autoimmune diseases, and musculoskeletal pain and deformities. There, more than 300 dedicated personnel focus on tissue repair, improving surgical outcomes, autoimmunity and inflammation, genomics, new treatments, and precision medicine.

“HSS has a long history of contributing to the collective base of clinical and basic science knowledge and finding healthcare solutions for complex conditions,” said Louis A. Shapiro, President and CEO, HSS. “We’re proud that through the joint efforts of our institution and philanthropic support, we will have the ability to make a strong impact on this growing and vital area of research.”

“As experts in inflammatory disorders and in the development of interventions for overactive immune responses, the clinicians and researchers at HSS are well-positioned to investigate many of the adverse effects of COVID-19,” says Lionel B. Ivashkiv, MD, Chief Scientific Officer at the HSS Research Institute. “This includes studying the causes of these adverse effects as well as how to prevent and treat them.”What follows are descriptions of the first group of funded projects in basic/translational research:

Activation of pDCs by SARS-CoV-2 and Its Impact on Macrophage Response

Principal Investigator: Franck Barrat, PhD

Co-Investigator: Marie-Dominique Ah Kioon, PhD

This project will study cell types that are responsible for cytokine storm syndrome — the hyperactive immune response seen in people with COVID-19 — by looking at how certain immune cells are activated by SARS-CoV-2. Research in mice infected with SARS-CoV, a coronavirus similar to the one that causes COVID-19, has suggested that plasmacytoid dendritic cell precursors (pDCs) are key to the immune response to infection. These pDCs activate macrophages, which in turn secrete cytokines. In the SARS-CoV research, depletion of pDCs appeared to protect the mice from lethal lung injury. Using blood samples from donors, the investigators will study the pathway by which pDCs activate macrophages and look at ways to therapeutically block that process.

Inhibiting RNA Polymerase II Transcription Complexes in Macrophages to Target COVID-19–Associated Cytokine Storm

Principal Investigator: Inez Rogatsky, PhD

Co-Investigators: Steven Josefowicz, PhD, and Robert P. Fisher, MD, PhD

This pilot project will dissect the role of macrophages in SARS-CoV-2-induced acute respiratory distress syndrome (ARDS), the main driver of COVID-19-associated mortality. We will test small-molecule inhibitors of RNA Polymerase II (Pol II) transcription complexes for their ability to modulate type I interferon and inflammatory pathways in monocytes/macrophages. This research will be done using cultured macrophages as well as donor blood and blood from COVID-19 patients.

Mechanisms of Cytokine Storm in Patients with COVID-19

Principal Investigator: Mary K. Crow, MD

Co-Investigators: Mikhail Olferiev, MD, and Lionel B. Ivashkiv, MD

The objectives of this study are to describe the process of the cytokine storm in people with COVID-19 and to identify biologic predictors of a favorable outcome in patients with severe cases of the disease. The project aims to characterize immune cell populations seen in COVID-19 patients who experience cytokine storm and compare them to those patients who do not, to compare the immune response before and after patients are given the anti-inflammatory drug anakinra, and to identify measures that suggest patients are more likely to decline and eventually require mechanical ventilation. The research will employ blood samples from HSS patients who are being treated for COVID-19 at New York–Presbyterian Hospital and who meet certain other qualifications.

What follows are descriptions of the first group of funded projects in the areas of clinical and health outcomes research:

Response to and Recovery from TKA in Patients with Antibodies to SARS-CoV-2

Principal Investigator: Miguel Otero, PhD

Co-Investigators: Meghan Kirksey, MD, PhD, and Peter K. Sculco, MD

It is unknown if people who have been exposed to COVID-19 may be at higher risk of experiencing an abnormal immune response following surgery, resulting in poor outcomes. This study will evaluate the response to and recovery from total knee arthroplasty (TKA) in people who have antibodies to COVID-19 — a marker of exposure. This study will include both patients who have COVID-19 antibodies and those who don’t, to act as controls. Patients will be followed for six weeks after surgery and evaluated for the presence of certain immune markers in the blood, as well as symptoms of inflammation including pain and stiffness in the joint.

SARS-CoV-2 Exposure and the Role of Vitamin D Among Hospital Employees

Principal Investigator: Emily M. Stein, MD, MS

Co-Investigators: Theresa T. Lu, MD, PhD; Andy O. Miller, MD; Jeri Nieves, PhD; and Alana Serota, MD

It is unknown if people with vitamin D deficiency may be more likely to become infected with COVID-19. This study will investigate vitamin D status and associated immune markers as risk factors for COVID-19 infection in a cohort of healthcare workers. Healthcare workers are at higher risk of contracting COVID-19 than the general population, making them a good group to study. Vitamin D is critical for immune function and is known to be protective against respiratory-tract infection and tuberculosis. This prospective, observational study will follow healthcare workers at HSS and at other healthcare facilities for one year, to determine whether levels of vitamin D and certain immune cells in the blood make someone more susceptible to COVID-19 infection.

Association of Immunomodulatory Medication Use and Social Determinants of Health with COVID-19 Infection in Systemic Rheumatic Disease Patients in New York City

Principal Investigator: Medha Barbhaiya, MD, MPH

Co-Investigators from HSS: Lisa Mandl, MD, MPH; Catherine MacLean, MD, PhD; Vinicius Antao, MD, PhD; Jane Salmon, MD; and Mayu Sasaki, MPH

Other Co-Investigators: Candace Feldman, MD, MPH (of Brigham and Women’s Hospital); Debra D’Angelo, MS (of Weill Cornell Medicine)

Using data from the INSIGHT Clinical Research Network, a central repository containing longitudinal electronic health data for residents of New York City, investigators will assemble a cohort of patients being treated with immunomodulatory medications for rheumatic disease. This patient population will then be used to study the effect of these medications on COVID-19 incidence and outcomes. Retrospective data will be used to evaluate the incidence and severity of COVID-19 in these patients. Patients will also be studied prospectively to determine whether there’s a relationship between COVID-19 infection and future rheumatic disease as well as to study connections between infection and future psycho-social issues.

Assessment of Surgical Outcomes in the COVID-19 Pandemic Era

Principal Investigator: Andy O. Miller, MD

Co-Investigators: Scott A. Rodeo, MD, and Mark Fontana, PhD

Investigators will implement a patient registry to evaluate how COVID-19 affects outcomes and complication rates after orthopedic surgery. This registry, along with COVID-19 screening procedures, will provide the tools to address specific research questions. Among these questions are determining the incidence of current and prior infection among the HSS surgical population, the clinical features associated with current and prior infections in this patient population, and whether COVID-19 status affects short-term complication rates.

What follows is a description of an integrated multidisciplinary study being undertaken jointly by the Adult Reconstruction and Joint Replacement (ARJR) Perioperative Research Group, Anesthesiology and Rheumatology:

Prediction and Prevention of Postoperative Blood Clots in COVID-19 Patients

Principal Investigators: Friedrich Boettner, MD; Kethy M. Jules-Elysee, MD; Lisa A. Mandl, MD, MPH

Co-Investigators: ARJR surgeons: Alejandro Gonzalez Della Valle, MD; Jason Blevins, MD; David J. Mayman, MD; Peter K. Sculco, MD; Geoffrey H. Westrich, MD and Thomas P. Sculco, MD

Medicine/Rheumatology: Medha Barbhaiya, MD, MPH; Doruk Erkan, MD, MPH; Deanna Jannat-Khah, DrPH

Pathology: Thomas W. Bauer, MD, PhD

Anesthesiology: Stavros G. Memtsoudis, MD, PhD, MBA; Alexandra Sideris, PhD

ARJR: Amethia Joseph, MHA; Ethan Krell, MS

Weill Cornell Medicine: Raymond David Pastore, MD

Recent literature suggests that one of the major complications seen in people with COVID-19 is thrombosis (the formation of blood clots) due to endothelial dysfunction, persistent inflammation and potentially antiphospholipid antibodies. As elective surgeries resume, those with prior exposure to SARS-CoV-2 will inevitably present for treatment, and some may have perioperative management considerations related to their risk of deep-vein thrombosis. This project will use, a noninvasive device that can determine clotting risks, to investigate whether people who have had COVID-19 have a more dysfunctional endothelium preoperatively and at 24 hours after surgery. The investigators will measure antiphospholipid antibodies and inflammatory markers, and evaluate the prevalence of asymptomatic post-operative deep-vein thrombosis in people who undergo TKR and have SARS-CoV-2 antibodies.

COVID-19 Translational Research Core at HSS

Principal Investigator: Theresa Lu, MD, PhD

Co-Investigators: Jessica Andrés-Bergós, PhD; Miguel Otero, PhD and Emily M. Stein, MD, MS

The COVID-19 Translational Research Core (TRC) was designed to fill critical gaps in the resources needed to promote the broad range of COVID-19–related clinical and translational research at HSS. The TRC will provide consultation on the design and implementation of COVID-19 research in the areas of orthopedics, rheumatology and metabolic bone disease; support for a COVID-19 biobank; and technical expertise and facilities required for clinical and translational researchers working on COVID-19–related projects. The TRC staff will help to acquire, house, and track biospecimens from investigator-initiated COVID-19–related research studies.

Scleroderma is a terribly debilitating disease with no effective treatments and the mortality rates are still upwards of 20%-50%, the highest of any rheumatic disease.

This disabling autoimmune disorder results in inflammation and fibrosis leading to the thickening of the body’s connective tissue, including the skin; and for decades its treatment has been symptomatic and, at best, inconsistently effective. But new research by a team from Hospital for Special Surgery (HSS) in New York City may signal hope for patients suffering from the condition.

The mechanism behind systemic sclerosis is not well understood. However, new research published today in Science Translational Medicine reveals a potential breakthrough into the cause of this disease, and also provides a possible treatment lead. Led by HSS researcher Dr. Franck Barrat -- the Michael Bloomberg Chair and Senior Scientist at HSS – along with clinicians of the Scleroderma center of HSS, the work implicates what are called plasmacytoid dendritic cells (pDCs) in contributing to scleroderma.

Normally pDCs secrete a compound called interferon to help fight off infections. However, as Dr. Barrat’s study revealed, in scleroderma patients these cells are chronically activated and infiltrate the skin causing fibrosis and inflammation.

"Plasmacytoid dendritic cells are known to be activated in many other rheumatic conditions, including lupus," explains Dr. Barrat. "But our findings suggest that they participate in both establishing and maintaining fibrosis in the skin as well. This is a very interesting finding as it opens new ways to tackle this condition."

Dr. Barrat found that depleting pDCs in an animal model of scleroderma prevented the disease from forming, while also reversing already existing fibrosis.

The new research also revealed that a receptor on the surface of pDCs called TLR8 is responsible for their increased activity.

Dr. Barrat fully acknowledges the limitations of the new study in particular the part where the research used animal models of scleroderma, which only partially reflect the complexity of the disease in humans. But he’s hopeful that not only will the new findings help illuminate the pathology of a puzzling disease, they may also represent potential novel approaches to treatment.

Strategies to eliminate pDCs are currently being evaluated by drug companies in diseases other than scleroderma. And though these potential treatments are still years away from being available, Dr. Barrat hopes that "a better understanding of the role pDCs play in fibrosis will open up the possibility of repurposing existing drugs to treat patients with scleroderma".