KLHL11 autoantibodies are associated with paraneoplastic encephalitis in patients with testicular cancer. The US researchers used phage display to identify this novel paraneoplastic autoantibody. The findings are published in The New England Journal of Medicine.
The study team first described a case of 37 years old patient with a history of seminoma who presented with vertigo, ataxia, and diplopia. He underwent surgery for a testicular seminoma and received chemotherapy 3 years before the onset of progressive brain-stem and cerebellar encephalitis, or rhombencephalitis. Conventional paraneoplastic autoantibodies, including Ma2 IgG, were not detected. By using a customised phage display system, the researchers identified antibodies to the human protein KLHL11 in cerebrospinal fluid.
Subsequently same antibody was detected in 12 other patients with similar neurologic features and testicular disease. Most of the patients in this series presented with a syndrome of vertigo, tinnitus, hearing loss, and ataxia, and 11 of 13 had an underlying seminoma; 2 had testicular microlithiasis. The neurologic syndrome preceded the detection of cancer or a premalignant condition in 8 of 13 patients.
The researchers estimated the age- and sex-adjusted prevalence of paraneoplastic anti-KLHL11 encephalitis in Olmsted County, Minnesota, on the basis of the Rochester Epidemiology Project database from the Mayo Clinic, which contains the medical records of more than 95% of persons who lived in Olmsted County from 1 January 1966 to 1 January 2014. This analysis resulted in an estimate of 1.4 cases per 100,000 population. The estimated age-adjusted prevalence among men was 2.79 cases per 100,000 population.
The authors commented that although KLHL11 IgG was rare in this series, the prevalence was higher than that of the other typical paraneoplastic antibodies associated with autoimmune encephalitis (e.g., ANNA2 IgG, 0.6 per 100,000 population; and collapsin response mediator protein 5 IgG, 0.7 per 100,000).
Although rhombencephalitis has been reported among patients with Ma2 IgG and testicular cancer, many Ma2 IgG–positive patients have clinical or imaging features that implicate the limbic system or diencephalon. Other paraneoplastic brain-stem syndromes include those associated with ANNA-2, which differ from KLHL11 encephalitis in that they have different associated tumours, mainly carcinoma of the lung and breast, and clinical features including opsoclonus–myoclonus, laryngospasm, and jaw-opening dystonia that were not observed in the patients with KLH11 encephalitis. Women with PCA-1 (anti-Yo)–associated paraneoplastic cerebellar degeneration can also present with a syndrome similar to KLHL11 encephalitis, but PCA-1 usually occurs with gynaecologic and breast cancers.
In this series, all patients received immunotherapy for treatment of the neurologic syndrome.
KLHL11 is one of 42 evolutionarily conserved proteins within the KLHL family that have in common a BTB and C-terminal kelch domain, implicating a role in ubiquitination. The intracellular localisation of KLHL11 protein probably precludes a direct role of KLHL11 IgG in neuronal cell death and injury.
KLHL11 IgG may serve as a surrogate marker of a cytotoxic T-cell–mediated injury directed through T-cell receptors recognising KLHL11 peptides. Such a KLHL11-specific T-cell response may be stimulated by the lineage of KLHL11 IgG–producing B cells.