For centuries, scleroderma has evaded detection and, in large part, definition. As recently as the 1930s, patients with the autoimmune disease were described in lay accounts as turning to leather or stone, an aptly mythological descriptor for a diagnosis that is so little understood. Decades of careful study, pioneered by Italian physicians, established a more sophisticated understanding of the systemic condition’s impact and fatal progression. But, like all autoimmune diseases, its origins—and how to stop it—remain elusive.

At Cedars-Sinai’s Kao Autoimmunity Institute, tremendous advances in single-cell sequencing and computational techniques offer an opportunity to examine autoimmune patients and disease models on both a deeper and broader level than ever before. To best leverage new approaches and artificial intelligence tools, a trifecta of master clinicians, their enthusiastic patients, and brilliant computational and experimental biologists are embedded in the institute. Patients graciously give of themselves so that physicians can generate hypotheses, and biologists provide a novel opportunity to develop disease markers and metrics.

Nunzio Bottini, MD, PhD, the inaugural director of the institute, and Francesco Boin, MD, the director of both the institute’s Kao Multispecialty Scleroderma Program and the Division of Rheumatology, are developing a translational infrastructure that promises to deconstruct the disadvantages long faced by the field. The molecular study of blood and tissue, paired with longitudinal clinical observation, optimizes their chances to unravel the cellular mechanisms driving autoimmune diseases.

Ultimately, Kao Autoimmunity Institute leaders hope their strong collaboration with experts at the cusp of technological evolution will empower them to advance care by offering disease-modifying drugs that prevent progression.

"Technology can give us new information, but for it to benefit the patient, it requires an extraordinary marriage between specialized clinical experts and laboratories, which is exactly what is happening here: a unique structure without barriers," Bottini said.

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The Kao Autoimmunity Institute was founded in 2022 within the Cedars-Sinai Department of Medicine to build a robust research enterprise in partnership with the Rheumatology division. Boin and Bottini were each recruited for their major contributions to the field. Together, the two have increased the number of patients who join research cohorts and participate in clinical trials, and they have established a biorepository they hope will generate clinical trials based on their observations.

Bottini, who has been continuously funded by the National Institutes of Health for autoimmune disease research since 2007, said he was drawn to Cedars-Sinai’s collaborative and interdisciplinary culture and its investment in technology and computational infrastructure.

"Throughout my clinical and research career, I have become convinced that autoimmune diseases require scientists and highly specialized experts to work together to address the most relevant questions," Bottini said. "This is a rare opportunity to build an institute with a unique combination of research laboratories, facilities to handle precious patient specimens and specialized disease-focused programs."

More than 80 autoimmune diseases affect about 24 million people in the U.S. Each of these complex, heterogenous, multisystem disorders of varying severity is chronic, incurable and difficult to treat. The disabling disease process likely initiates years before symptoms arise, stealthily inflicting irreparable harm. In most conditions, the damage differs by patient, so clinicians lack targeted, effective treatments and accurate ways to measure disease activity.

Immunosuppressant drugs often prescribed to control excessive immune activation can also cause harm. For example, disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis make patients more prone to infection. Often, patients stop responding to the drugs. In response, clinicians try other treatments that can introduce new side effects and toxicity.

"It’s really basic trial and error," said Richard Ainsworth, PhD, a research scientist at the Kao Autoimmunity Institute and the Department of Computational Biomedicine who studies gene regulation. "Current drugs and treatment strategies are blunt tools that merely improve symptoms. We’re in the early stages of stratifying patients and having a deeper understanding of why they respond to different regimens."

Scleroderma still lacks clear targets for therapeutic interventions. Without therapies to modulate the immune system, the disease often causes interstitial lung disease and cardiac failure.

"We're still chasing different aspects of the disease and waiting to see some response,” said Boin, who holds the Cedars-Sinai Chair in Rheumatology. "We now hope to discover the fundamental mechanisms that drive and initiate the disease so we can intervene earlier with more targeted interventions that minimize collateral damage."

New computational approaches pioneered at Cedars-Sinai enable Ainsworth and other Kao Autoimmunity Institute researchers to better search for such mechanisms. Tools to assess large numbers of genes at the single-cell level allow investigators to discover new cell types and genetic mechanisms underlying disease development.

Using spatial transcriptomics—an enhanced method of measuring the location of cells and their relationship to each other—and advanced computer modeling of gene regulatory networks, they can better obtain functional analysis of cells in the context of the diseased tissue and organs. The cutting-edge methods, combined with close assessment and monitoring in the clinic, could help identify mediators of immune dysfunction and discover actionable targets.

Read: Scleroderma Awareness Month

Rheumatoid arthritis (RA), the most commonly diagnosed and well-treated autoimmune condition, originates from immune overactivity in the synovium, or the lining of the joints. RA leads to chronic inflammation that manifests in painful swelling of the joints and can ultimately damage the lungs, heart and other organs.

In a multilaboratory collaboration within the institute, Ainsworth is examining sophisticated models of RA to better understand dysregulation in regulatory T-cell populations. In inflamed RA tissue, some white blood cells transform from regulatory T-cells, which control excessive immune response, into helper T-cells that coordinate joint inflammation.

Using bulk and single-cell RNA sequencing, Ainsworth is analyzing gene regulatory changes in hopes of understanding what governs the switch and if certain subpopulations of T-cells are more prone to destabilizing. He applies an integrative systemics biology technique to integrate epigenetic and transcriptomic data to make predictions about how to stabilize regulatory T-cells.

The investigators’ goal is to find new targets for interventions to halt T-cell instability and restore cellular balance.

"By integrating with the strong genomics, proteomics and spatial biology programs at Cedars-Sinai, our investigators can characterize such immune cells at the single-cell level and correlate their features with clinical variables or progression of disease," Bottini said. "By studying those very specific changes that happen in immune cells in the joint, we hope to find targets that will stop the modification but won’t affect general immune processes against infections or cancer."

Scleroderma’s two dominant features are narrowing of the blood vessels, which causes progressive damage and is present in every patient, and fibrotic damage of the skin and internal organs. In 30% to 70% of scleroderma patients, scarring of the lungs can lead to pulmonary fibrosis.

Despite the disease’s varying paths, investigators hope to understand the common denominator across every patient, regardless their clinical differences. What happens first? When and how does the immune system drive an abnormal tissue repair?

“Our main goal is to define with greater precision the timing of scleroderma onset and to link it to the fundamental molecular mechanisms that drive tissue damage, organ dysfunction and disease manifestations,” Boin said. “It’s a critical moment for us to define the fundamental pathways causing scleroderma and to develop more targeted and precise therapies.”

Seeking to find signatures that relate to disease severity and progression, Ainsworth is performing single-cell analysis on blood donated by Boin’s scleroderma patients. In preliminary findings, he and Trinitee Oliver, a PhD student in the Department of Biomedical Sciences at Cedars-Sinai, have identified two novel clusters of white blood cells that express gene signatures associated with fibrosis in patients with severe interstitial lung disease.

In collaboration with other laboratories at the Kao Autoimmunity Institute and the Women’s Guild Lung Institute, they hope to characterize the cells with more granularity and validate the discovery in human lung specimens and animal models.

Ultimately, investigators hope the inquiries will lead to more precise interventions for patients based on their demographics and disease state.

"The physicians have this massive treasure chest of clinical information," Ainsworth said. "Using this data, we are training machine-learning models to predict disease progression and severity so we can get a better understanding of what is going on and eventually put a stop to it."