After 70 years of groundbreaking discoveries, researchers continue to unlock mysteries of lupus

In 1948, Philip Hench, MD, first demonstrated the remarkable therapeutic activity of Compound E (cortisone) for the treatment of lupus. The following year, a group of Dr. Hench’s colleagues at the Mayo Clinic provided the first description of the lupus erythematosus (LE) cell.

These breakthroughs more than 70 years ago set the stage for the many milestone discoveries over the ensuing years that continue to advance our understanding of the mechanisms and drivers of autoimmunity in lupus, according to Peggy Crow, MD, who delivered this year’s Philip Hench, MD Memorial Lecture, From LE Cell to Interferon: Deconstructing Lupus Pathogenesis, on Sunday, Nov. 7. Dr. Crow’s lecture can be viewed by registered meeting participants through March 11, 2022.

“As we look to the future, it’s important that we recognize all of those giants on whose shoulders we stand who have made such important contributions to lupus research over the decades,” said Dr. Crow, Physician-in-Chief at the Hospital for Special Surgery and the Joseph P. Routh Professor of Rheumatic Diseases in Medicine and Chief of the Rheumatology Division at Weill Cornell Medical College.

Within a few years of those groundbreaking discoveries at the Mayo Clinic, investigators at Johns Hopkins published observations on the relative specificity of the LE cell for lupus, documenting at the time that the LE cell was discovered in approximately 80% to 85% of lupus patients who were tested for it.

“Subsequent studies by a number of outstanding investigators followed up on this important observation and would demonstrate that the LE cell was not quite that specific for lupus, but still impressively so,” Dr. Crow said.

Those early observations provided key insights into the mechanisms that drive the pathogenesis of lupus and illustrate a principle — follow the autoantibody specificities — that Dr. Crow said has guided her own research.

It’s that mantra that led Dr. Crow and others in the early 2000s to observe that lupus is characterized by over-expression of type 1 interferon and to identify the interferon signature as an important biomarker for disease activity in lupus. That led to the subsequent discovery that self-nucleic acid acts as an adjuvant to induce type 1 interferon, with potential sources that include endogenous retroelements, mitochondria, and cell-derived nuclear debris.

Building on these discoveries, researchers today are focused on two categories of autoantibodies, defined by their specificities, that suggest distinct functions and potential for different therapeutic targets, Dr. Crow said.

“In the case of the anti-RNA binding protein antibodies, we’re trying to target long-lived plasma cells, and in the case of the anti-DNA antibodies, plasmablasts are the key target,” she said.

Looking to the future, Dr. Crow said that long-lived plasma cells, which produce autoantibodies specific for RNA-binding proteins, are attractive therapeutic targets.

“For the next 10 years, I think our goal is to characterize the molecular structure of these very important intracellular ribonucleoprotein particles, and how microbial infections might drive them to generate autoimmunity and break tolerance,” Dr. Crow said. “And then, develop therapeutic agents that are appropriately targeting the different components of these important pathogenic mechanisms.”