Scientists find autoimmune disease related to testicular cancer

Forefront Magazine | Volume 8, Issue 4, December 2019

Summary

Scientists urge screening for paraneoplastic encephalitis autoimmune disease in patients with testicular cancer: Mayo Clinic Forefront cancer magazine.

Using advanced technology, scientists at Mayo Clinic, Chan Zuckerberg (CZ) Biohub and the University of California San Francisco (UCSF), have discovered an autoimmune disease that seems to affect men with testicular cancer.

The disease, testicular cancer-associated paraneoplastic encephalitis, causes severe neurological symptoms in men. The men progressively lose control of their limbs, eye movements and in some cases their speech. The disease begins with a testicular tumor, which appears to cause the immune system to attack the brain. Affected men often find themselves misdiagnosed or undiagnosed, and appropriate treatment is delayed.

In a study published July 4, 2019, in The New England Journal of Medicine, the team of scientists identified a highly specific and unique biomarker for the disease by using a variation of programmable phage display technology. Their refined version of this technology simultaneously screens more than 700,000 autoantibody targets across all human proteins.

Using this tool, the UCSF researchers evaluated cerebrospinal fluid from a 37-year-old man who had a history of testicular cancer and debilitating neurological signs and symptoms, including vertigo, imbalance and slurred speech. The enhanced phage technology identified autoantibodies targeting Kelch-like protein 11 (KLHL11), which is found in the testes and parts of the brain.

These results were correlated and validated with patient samples from Mayo Clinic. In addition to identifying the cause of this mysterious neurological disease, the results point the way to using this protein biomarker as a diagnostic test for men with testicular cancer-associated paraneoplastic encephalitis.

"Mayo Clinic's Neuroimmunology Laboratory has a long history of biomarker discovery, and this continues that tradition, bringing together the Mayo Clinic Biobank, the largest repository of biospecimens in the world, with advanced technologies being devised and implemented at UCSF and CZ Biohub," said Sean J. Pittock, M.D., a neurologist at Mayo Clinic in Rochester, Minnesota, and corresponding author of the published study. "By working together, our organizations have the potential to make biomarker discoveries much more rapidly."

Dr. Pittock is director of the Neuroimmunology Laboratory at Mayo Clinic and the Marilyn A. Park and Moon S. Park, M.D., director of the Center for Multiple Sclerosis and Autoimmune Neurology.

The Neuroimmunology Laboratory screens about 150,000 patients annually for autoimmune neurological diseases by applying their biospecimen samples — serum or cerebrospinal fluid — to thin slices of brain tissue from mice. Some patients with autoimmune neurological diseases harbor antibodies that bind to tissue with a specific pattern of staining.

About 20 years ago, Mayo Clinic scientists first identified a staining pattern that researchers dubbed sparkles because in a darkroom under a microscope, the patient's sample looked like stars shining dimly in the night sky. The male patient had ataxia — poor coordination, involuntary eye movements, changes in speech — and turned out to have testicular cancer. The sparkles pattern found when testing patients' biospecimen samples is related to autoantibodies targeting Kelch-like protein 11, which is found in the testes and parts of the brain.

Through the years, the Mayo Clinic lab occasionally identified the sparkles pattern, and the patients' clinical stories were the same: ataxia and testicular cancer. But the pattern was faint and easy to miss, and an autoantibody target remained elusive.

The collaborative effort reported in the new paper was spearheaded by co-first authors Caleigh Mandel-Brehm, Ph.D., a UCSF postdoctoral researcher, and Divyanshu (Div) Dubey, M.B.B.S., a neurologist and laboratory medicine physician at Mayo Clinic in Rochester, Minnesota. Analyses were conducted on biospecimens of 12 more men with similar medical histories. All were positive for autoantibodies targeting KLHL11.

Using this biomarker signature, 37 patients now have been diagnosed with testicular cancer-associated paraneoplastic encephalitis, and the scientists think many more will be diagnosed.

Physicians who suspect a patient might have this form of paraneoplastic encephalitis can work with Mayo Clinic to screen for KLHL11. "Early diagnosis is extremely important," Dr. Dubey said. "If we diagnose patients early, we can start them on immunosuppressive medications. The sooner we can prevent this damage from happening, the sooner we can stop the disease progression and the better chance we have for clinical improvement in the patient's life."


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