A potential biomarker has been found for a newly defined autoimmune disease associated with testicular cancer. Scientists at Chan Zuckerberg (CZ) Biohub, the Mayo Clinic, and University of California, San Francisco (UCSF) used the Mayo Clinic’s BioBank and a variation of programmable phage display technology to uncover the biomarker. The group’s phage display approach simultaneously screens more than 700,000 autoantibody targets across all human proteins. The study was published in The New England Journal of Medicine (NEJM).
The disease, called “testicular cancer-associated paraneoplastic encephalitis,” causes severe neurological symptoms in men. Patients progressively lose control of their limbs, eye movements, and, in some cases, speech. The testicular tumor seems to trigger symptoms by causing the immune system to attack the brain. Affected men are often misdiagnosed or undiagnosed and so may go without appropriate treatment.
Since this research was done, 37 more patients have been diagnosed with the disease based on the new biomarker test, and the scientists believe many more will follow. “This study is the tip of the iceberg,” said Joe DeRisi, Ph.D., co-president of CZ Biohub, who helped develop the adapted phage technology. “We know there are more paraneoplastic autoimmune diseases waiting to be discovered,” DeRisi said in a press release.
Paraneoplastic syndromes are caused by immune reactions against auto-antigens shared by cancer cells and the nervous system. They occur in less than 1% of cancer patients, but as this example shows, they can have devastating effects.
There have been clues about this newly named disease’s existence for a long time. The Mayo Clinic’s Neuroimmunology Laboratory screens about 150,000 patients annually for autoimmune neurological diseases by applying samples of patients’ serum or cerebrospinal fluid to brain tissue from mice. In some of these samples there are antibodies that bind to the brain tissue with a specific pattern of staining. About 20 years ago, Mayo scientists first identified a particular staining pattern with a sample from a male patient who had ataxia and turned out to also have testicular cancer. Over the years, the Mayo lab occasionally saw the same staining pattern in other samples, but the pattern was faint and easy to miss, so the autoantibody target remained elusive.
This current study began with one patient: a 37-year-old man with a history of testicular cancer and debilitating neurological symptoms, including vertigo, imbalance, and slurred speech.
A UCSF team led by DeRisi and Michael Wilson, M.D., a member of the UCSF Weill Institute for Neurosciences, developed a customized version of phage technology that identified Kelch-like protein 11 (KLHL11) in the patient’s cerebrospinal fluid sample. These results were correlated and validated on 12 samples from men with similar symptoms. All were positive with KLHL11 autoantibodies, suggesting this is a biomarker for the disease.
The enhanced phage technology builds on work pioneered in the laboratory of Stephen Elledge, Ph.D., at Harvard Medical School. Wilson and his colleagues hope to further expand that work’s applications. “For roughly half the patients with paraneoplastic or autoimmune causes of encephalitis, the protein being targeted has yet to be identified,” Wilson said. “Building on the Elledge lab’s work, we hope to tackle that problem head-on with this technology for finding antibodies, so we can potentially add to the number of diseases that are known, and help patients and families get diagnoses more quickly.”
This study “nicely demonstrates the power of phage display to identify the cause of an autoimmune disease,” wrote Susan Deutscher, Ph.D., in an accompanying NEJM editorial. Deutscher is with the Harry S. Truman Memorial Veterans’ Hospital Research Service and the department of biochemistry, University of Missouri.
“Mayo Clinic’s Neuroimmunology Laboratory has a long history of biomarker discovery, and this continues that tradition, bringing together Mayo Clinic’s bio bank, the largest repository of biospecimens in the world, with advanced technologies being devised and implemented at UCSF and CZ Biohub,” says Sean Pittock, M.D., a Mayo Clinic neurologist and corresponding author of the study. “By working together, our organizations have the potential to make biomarker discoveries much more rapidly.” Pittock is director of Mayo Clinic’s Neuroimmunology Laboratory and the Marilyn A. Park and Moon S. Park, M.D., Director of the Center for Multiple Sclerosis and Autoimmune Neurology.