A new autoimmune disease has been discovered that is triggered by testicular cancer. Using a novel diagnostic tool, researchers discovered that testicular cancer can cause the immune system to attack the brain, resulting in a severe neurodegenerative disease that is often mis- or undiagnosed.
Kateryna Kon | Shutterstock
The neurodegenerative disease seen in patients with testicular cancer is called “testicular cancer-associated paraneoplastic encephalitis” and sees men lose control of their limbs, eye movement, and in some instances, their speech. Many men are misdiagnosed or left entirely undiagnosed, meaning appropriate treatment to limit the effects of the neurodegenerative disease often comes too late.
Until now, scientists have been unable to identify which specific antibody was causing a staining pattern only seen in patients with testicular cancer. But the new study, published in The New England Journal of Medicine, showed a unique biomarker responsible for the disease, which begins with a testicular tumor that acts as the trigger for the attack on the body’s immune system.
A staining pattern, dubbed “sparkles” for its resemblance to stars in a night sky under microscope observation, was identified 20 years ago. However, the antibody causing this staining pattern could not be identified, and the staining pattern itself was routinely missed.
The research team at Chan Zuckerberg (CZ) Biohub, Mayo Clinic and University of California, San Fransisco (UCSF), used a variation of “programmable phage display” technology, which simultaneously screens over 700,000 autoantibody targets across every human protein.
Diagnoses are rare but growing in number
Cerebrospinal fluid from a 37-year-old man with a history of testicular cancer and neurological symptoms was analyzed. The man’s symptoms included vertigo, imbalance, and slurred speech. The phage technology identified autoantibodies targeting Kelch-like protein 11 (KLHL11), found in the testes and in certain parts of the brain.
Using phage display, a further 12 biospecimens taken from men with similar neurological symptoms along with testicular cancer were analyzed. All of the samples were positive for autoantibodies targeting KLHL11.
But this man’s neurological symptoms seen alongside his testicular cancer were not unique, with the Mayo lab finding a number of other cases in which men were diagnosed with testicular cancer and showed signs of ataxia, a neurological disease characterized by involuntary eye movement, alterations in speech, and poor coordination.
37 patients have since been diagnosed with paraneoplastic encephalitis, and the researchers believe diagnoses will continue to grow in number.
Every year, Mayo Clinic’s Neuroimmunology Laboratory screens around 150,000 patients for autoimmune neurological diseases. A patient’s biospecimen samples, which can be serum or cerebrospinal fluid, are bound to brain tissue from mice. In some cases, patients with autoimmune neurological conditions possess antibodies that bind to tissues with specific staining patterns.
Mayo Clinic’s Neuroimmunology Laboratory has a long history of biomarker discovery, and this [new study] continues that tradition, bringing together Mayo Clinic’s biobank, the largest repository of biospecimens in the world, with advanced technologies being devised and implemented at UCSF and CZ Biohub. By working together, our organizations have the potential to make biomarker discoveries much more rapidly.”
Dr. Sean Pittock, Co-Author, Mayo Clinic
The study included an epidemiological assessment, which found that the prevalence of KLHL11 encephalitis in Olmsted County, Minnesota, was approximately three per 100,000 men. This makes KLHL11 one of the more common autoimmune encephalitis biomarkers in Olmsted County, suggesting this may be the case in other parts of the US and across other countries.
The current research is just 'the tip of the iceberg'
“This study is the tip of the iceberg,” biochemist Joe DeRisi, who worked on the new research, said. “We know there are more paraneoplastic autoimmune diseases waiting to be discovered and more people to help.”
DeRisi believes that this novel screening technology will aid in the discovery of unidentified autoimmune diseases. The short-term benefits of the research may be that a new diagnostic tool can be developed to test for this specific biomarker, which will be able to stop the neurodegeneration caused by the condition from progressing too rapidly in patients with testicular cancer.
“Early diagnosis is extremely important,” Divyanshu Dubey, co-first author on the research, 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.”
Dr. Wilson spoke further on the benefits of the advanced technology that allowed this important discovery to be made:
For roughly half the patients with paraneoplastic or autoimmune causes of encephalitis, the protein being targeted has yet to be identified. 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.”
Journal reference:
Mandel-Brehm, C., et al. (2019). Kelch-like Protein 11 Antibodies in Seminoma-Associated Paraneoplastic Encephalitis. N Engl J Med. DOI: 10.1056/NEJMoa1816721.