Lymphatic vessels act as communication highways, carrying signals from tissues to the immune system to alert it to infection, injury, or disease. When this system does not function properly, the body may struggle to fight infections, respond to vaccines, repair tissue, or control inflammation.

The new findings show that Langerhans cells play a key role during early life by helping lymphatic vessels grow and develop properly in the skin. This early “setup” has long-term consequences, influencing how well the immune system functions later in life.

“Our study shows that immune cells in the skin do much more than respond to threats—they help build the infrastructure the immune system depends on,” said senior author Theresa T. Lu, MD, PhD, who holds the St. Giles Chair for Research in the HSS Research Institute and is a member of Pediatric Rheumatology at HSS. “If this process is disrupted early in life, it can have lasting effects on immune health. Our results also underscore the critical role of skin health in regulating lymphatic vessel development and immune system function in health and disease.”

“These findings advance our understanding of how early-life biological processes influence long-term immune function,” explained JiHyun Sim, PhD, first author and Postdoctoral Fellow at HSS. “We are hoping to further understand if this physiologic process is disrupted to contribute to autoimmune disease.”

Key Findings

• Early-life development matters: Proper formation of lymphatic vessels in childhood is essential for strong immune responses in adulthood.
• New role for Langerhans cells: Beyond their known immune functions, these cells help guide the growth and programming of lymphatic vessels.
• Long-term impact: When Langerhans cells are reduced or impaired early in life, the immune system may be less effective later on.

Implications for Patients and Providers

The research suggests that conditions affecting skin health in early life—such as severe sunburn, burns, or certain autoimmune diseases like lupus—could interfere with Langerhans cells and, in turn, disrupt lymphatic development. This may contribute to weaker immune responses later in life, including reduced effectiveness of vaccines, increased susceptibility to infections, impaired healing, and potential autoimmune complications.

“These findings highlight the importance of protecting skin health early in life,” said Dr. Lu. “They also open the door to new approaches that could strengthen immune function by targeting the lymphatic system.”

A New Way of Thinking About Immune Health

The study adds to a growing body of evidence showing that early-life health and environmental factors can shape disease risk in adulthood. It also identifies a previously unknown mechanism by which immune cells influence tissue development—not just immune activation.

By uncovering how Langerhans cells regulate lymphatic vessel growth, researchers hope to pave the way for future strategies to improve immune responses and prevent disease across the lifespan.

Authors: JiHyun Sim, PhD, Richard Bell, PhD, Yurii Chinenov, PhD, Zhonghui Feng, PhD, Susan Chyou, BA, William D. Shipman, MD, PhD, Lionel Ivashkiv, MD, Theresa T. Lu, MD, PhD

By partnering program scholars with HSS’s world-class researchers as mentors, students are able to experience biomedical research and understand that this is also a career option for them. “While many students beginning college are understandably excited about becoming a doctor and helping patients, fewer understand that you can also make a difference through a career in biomedical research,” said Dr. Theresa Lu, scientific director of the HSS Macaulay Scholars Program. “It’s our privilege to open the doors of discovery to these exceptional students and we hope to ignite a lifelong commitment to advancing musculoskeletal health and biomedical science.”

HSS's unparalleled expertise in the field of musculoskeletal health provide students the opportunity to explore the intersection of medicine and science in a cutting edge environment, and scholars could witness firsthand how research drives advancements across a spectrum of medicine.

The selected students, from the prestigious Macaulay Honors College, were each paired with an established investigator and their group members to serve as their research mentors. Additionally, each student was provided with a stipend to support them throughout this eight-week program. The organizing committee was comprised of Dr. Lu along with HSS CSO Dr. Lionel Ivashkiv, Vice President of Research Rosemarie Gagliardi, Director of Research Institute Operations Nicole Seate-Martin, faculty member Dr. Alexis Sideris, Tri-Institutional MD-PhD student Stephanie Azzopardi, and Weill Cornell medical student Branden Sosa. Dr. Sideris and Stephanie Azzopardi are former Macaulay Honors College students themselves, and Branden Sosa graduated from CUNY’s Hunter College.

HSS remains committed to fostering lasting connections with these gifted scholars and they look forward to witnessing their development as scientists. The next Macaulay Scholars Program is slated to begin this upcoming academic year. Prospective scholars are encouraged to apply.

The Department of Defense has granted a three-year grant to study the proteins emitted from the skin that affect lymph nodes, the downstream immune tissues, while a two-year grant from the NIH will aid the investigation into non-protein molecules and changes of fibroblasts in lymph nodes. The team will do this by examining skin components including interstitial fluid.

“My lab is focused on understanding the pathogenesis of lupus. Lupus skin rashes affect the quality of life of patients and can be connected to systemic disease that can be life-threatening. Therapeutic options in lupus are limited, and it is important that we understand pathologic mechanisms so that we can develop better therapeutic options,” said lead investigator Theresa T. Lu, MD, PhD, from HSS Research Institute.

The grants and research will be executed at HSS Research Institute, the largest musculoskeletal research facility in the world.

About HSS Research Institute

HSS Research Institute is the largest musculoskeletal research facility in the world. With over 300 dedicated researchers and 20 laboratories, HSS Research Institute has been a leader in research aimed at improving the lives of patients suffering from debilitating orthopedic and rheumatic conditions such as arthritis, bone and soft tissue injuries, autoimmune diseases, and musculoskeletal pain and deformities.

In a new study being presented at ACR Convergence 2022, the annual meeting of the American College of Rheumatology, researchers from Hospital for Special Surgery (HSS) report that they have found an underlying mechanism that explains this association: decreased lymphatic drainage, which contributes to both photosensitivity and an immune response in the lymph nodes. The research also suggests that boosting lymphatic drainage may be an effective treatment for lupus photosensitivity and autoimmunity.

“When people with lupus have a systemic flare of their disease, it can affect any organ that is part of their disease,” says senior author Theresa T. Lu, MD, PhD, who holds the St. Giles Chair for Research in the HSS Research Institute, is a faculty member in Pediatric Rheumatology and in Rheumatology at HSS and is a professor of microbiology and immunology and of pediatrics at Weill Cornell Medicine. “We wanted to look at why sun exposure at the level of the skin affects internal organs like the kidneys, heart and lungs.”

“This study sheds some light on how sun exposure and UV light cause people with lupus to have more autoantibodies in their blood,” adds first author William Ambler, MD, a former fellow at HSS in Dr. Lu’s lab who is now Metzger Scholar in Translational Medicine at the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health.

The skin communicates with the immune system by sending cells and molecular signals via the lymphatic vessels to the lymph nodes, where immune responses begin. The signals that the skin sends to the lymph nodes control the type of immune responses that occur. Lymphatic vessels also serve the function of removing fluid and cells from the skin. If lymphatic vessels do not work properly to bring signals from skin to lymph nodes, there can be delayed resolution of skin inflammation, leading to faulty signals being sent to the lymph nodes.

Research in the Lu lab suggests that lymphatic flow from the skin to the draining lymph nodes is reduced in people with lupus. The investigators hypothesize that this decreased flow alters lymph node immune responses, making them more pathogenic. They decided to look more closely at this communication and how it impacts immune function. The current research employed both patient samples and mouse models of SLE.

The investigators studied skin biopsies from lupus patients as well as from healthy volunteers who served as controls. When they looked at the samples from the lupus patients, they found these more dilated lymphatic vessels compared with the healthy controls. This provided evidence that people with lupus have poor lymphatic flow.

They then studied mouse models of SLE, using a dye injected into the skin to visualize the flow of lymphatic fluid. They found that when lupus mice were exposed to UV radiation, more dye remained in the skin. This provided evidence that the lymphatics were not clearing the fluid as well as they should.

Importantly, the researchers then looked to see if they could improve certain hallmarks of disease in the mice by using manual lymphatic drainage techniques to manipulate the flow of lymph fluid. This type of therapy is used in people with certain types of cancer, especially breast cancer, to prevent lymphedema (fluid accumulation and swelling) after the surgical removal of lymph nodes. They found that performing lymphatic drainage in the mice reduced the numbers of plasmablasts and germinal center B cells, types of cells that are known to be important players in lupus.

Drs. Ambler and Lu are optimistic that manual lymphatic drainage may benefit lupus patients but emphasize that clinical trials in patients are needed to confirm it would be safe and effective.

The investigators note that this research is also important because it advances the broader field of understanding how skin and organs communicate through the lymph nodes and the immune system. 

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.

According to the article, Dr. Lu and her researchers found that a malfunction of Langerhans cells meant to protect the skin from UV damage, could be causing photosensitivity.

Additionally, findings indicated that skin samples from lupus patients also had decreased numbers of Langerhans cells.

Read the full article at European-biotechnology.com.

Additional Coverage:

• Lupus News Today: Langerhans Cells Protect Skin Against Photosensitivity in Lupus, Researchers Find

HSS rheumatologist Michael D. Lockshin, MD, and director of the Center, shared his conversations with patient Barbara Volcker, wife of former U.S. Federal Reserve Chairman Paul Volcker. According to the article, Mrs. Volcker met Dr. Lockshin in the 1970s to treat her rheumatoid arthritis.

"She was the type of patient that I really enjoyed taking care of because she challenged me on everything. She would say, 'But that answer doesn't make sense. Give me the information behind it. Convince me.' She drove me to question my own assumptions to respond to her," said Dr. Lockshin.

In the late 1990s, Mrs. Volcker's health worsened, and the Volckers offered to establish a center at HSS to honor her. Dr. Steven Paget, who was physician in chief at HSS, and Dr. Charles Christian, who was the emeritus physician in chief, invited Dr. Lockshin, then acting director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), to discuss the center's mission, and he was ultimately offered the job as director, a position he still holds.

The Center was established in 1997. Mrs. Volcker passed away the following year at the age of 68.

"Her questions are the core of the Center that bears her name," noted Dr. Lockshin.

The Center convened a conference on the biology of sex differences in autoimmune illness—the first of its kind—within a year of opening its doors, notes Dr. Lockshin. The topic later gained national attention for all human health when the Institute of Medicine (later renamed the National Academy of Medicine) convened a committee to address the same question and published a report in 2001, according to Dr. Lockshin, who served on the committee. Doruk Erkan, MD, MPH, a rheumatologist at HSS whose early research focused on antiphospholipid syndrome, joined the Center in 2005 as physician-scientist.

Today, the Center is marking 20 years of research and clinical work devoted to women with various rheumatic conditions. According to Dr. Lockshin, physicians at the Center see more than 3,000 individual patients for issues of pregnancy and contraception, antiphospholipid syndrome, and other rheumatic illnesses.

As part of the Center's research, HSS rheumatologists Jane E. Salmon, MD and Lisa R. Sammaritano, MD are co-investigators of a study on hormone treatment in lupus as well as pregnancy in lupus patients.

Additionally, HSS research associate Mikhail Olferiev, MD received a grant from the center to study the expression of genes across health donors and patients with lupus. "I hope that my study will contribute to a better understanding of an autoimmune disease and possibly identify new therapeutic targets," Dr. Olferiev said.

HSS scientist Theresa T. Lu, MD, PhD also received a grant to study whether fat tissue might influence stromal cells in lymph nodes to contribute to sex differences in rheumatic diseases.

Dr. Lockshin explained that concepts and ideas about pregnancy and issues related to women with rheumatic diseases have changed over time in part because of research discoveries coming out of HSS.

Additionally, the Center recently welcomed a new member, HSS rheumatologist Medha Barbhaiya, MD, MPH. Dr. Barbhaiya explained that she joined HSS because of the Center's strong emphasis on clinical care and clinical research related to lupus, antiphospholipid syndrome, and pregnancy in rheumatic diseases.

Several of its members hold leadership positions associated with the Center's mission, according to Dr. Lockshin. For example, Dr. Erkan chairs both the Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking, headquartered at the Center, and the 15th International Congress on Antiphospholipid Antibodies. Kyriakos Kirou, MD, conducts lupus nephritis clinical trials, and Dr. Sammaritano chairs the ACR Reproductive Health Guideline Project. With a background in environmental causes of autoimmune illnesses, Dr. Barbhaiya is involved with the ACR. In addition, Dr. Lockshin served on committees with a focus on pregnancy, sex differences, and other aspects of autoimmune illness and he is past editor in chief of Arthritis & Rheumatism (now Arthritis & Rheumatology).

In a phone interview, Mr. Volcker said that he is delighted with the Center's accomplishments over the years. Furthermore, he said he is sure if Mrs. Volcker were alive she would be "very pleased and happy that her name was attached to it, no doubt in my mind".

Read the full article at the-rheumatologist.org. This also appeared in the January 2018 print issue.