Molecular disease mechanisms of human antineuronal monoclonal autoantibodies.

Autoantibodies targeting brain antigens can mediate a wide range of neurological symptoms ranging from epileptic seizures to psychosis to dementia. Although earlier experimental work indicated that autoantibodies can be directly pathogenic, detailed studies on disease mechanisms, biophysical autoantibody properties, and target interactions were hampered by the availability of human material and the paucity of monospecific disease-related autoantibodies. The emerging generation of patient-derived monoclonal autoantibodies (mAbs) provides a novel platform for the detailed characterization of immunobiology and autoantibody pathogenicity in vitro and in animal models. This Feature Review focuses on recent advances in mAb generation and discusses their potential as powerful scientific tools for high-resolution imaging, antigenic target identification, atomic-level structural analyses, and the development of antibody-selective immunotherapies.

Paraneoplastic Autoimmune Neurological Syndromes and the Role of Immune Checkpoint Inhibitors.

The introduction of immune checkpoint inhibitors (ICIs) in oncologic therapies has led to a paradigm shift in cancer treatment. ICIs have increased the overall survival in patients with malignant melanoma, small-cell lung cancer, and many other tumor entities. Despite their clinical benefits, these novel cancer immunotherapies can induce neurological immune-related adverse events (irAEs). Such immune-mediated complications can manifest within the spectrum of paraneoplastic neurological syndromes (PNSs). PNSs are rare immune-mediated complications of systemic cancers that can involve every aspect of the nervous system. The emergence of PNSs with ICI treatment opens further pathways to study the complex immunopathological interplay of cancer immunity, cross-reactive neurological autoimmune phenomena, and effects of ICIs on the immune system. ICI-induced PNSs comprise a diverse antibody repertoire and phenotypic spectrum with severe and life-threatening disease progression in some cases. Timely diagnosis and urgent interventions are pivotal for a favorable neurologic and oncologic outcome. This review focuses on the pathogenesis of cancer immunotherapy and the disruption of immune tolerance in PNSs and provides an overview of the most pertinent clinical manifestations and principles of diagnostic and therapeutic managements in light of the expected increase in PNSs due to the widespread use of ICIs in clinical practice. This review further discusses potential and evolving concepts of therapeutic monoclonal antibodies for the treatment of PNSs.

Neurotoxicities associated with immune checkpoint inhibitor therapy.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have emerged as a promising class of cancer immunotherapies. Neurotoxicities are uncommon, but often severe, and potentially fatal complications of ICIs, and clinical experience is limited. The aim of this study is to further define the clinical spectrum and outcome of ICI-mediated neurotoxicities. METHODS: Patients with ICI-associated neurotoxicities were identified from retrospective review of the quality control database at a single institution. Data regarding demographics, medical history, clinical presentation, diagnosis, management and outcome were recorded. RESULTS: We identified 18 patients with neurotoxicity following ICI therapy with pembrolizumab, nivolumab, atezolizumab, or ipilimumab for a diverse set of malignancies. Neurotoxicities comprised central demyelinating disorder (28%), autoimmune encephalitis predominantly affecting the grey matter (17%), aseptic meningitis (6%), myasthenia gravis (MG) (17%) with concurrent myositis (6%), sensorimotor polyneuropathy (11%) and hypophysitis (17%). Median time to onset of neurotoxicities was 5 weeks (range 1-72). All patients discontinued ICIs and received steroids with additional immunomodulation required in 9 patients, resulting in improvement for 16 of 18 patients. Grade 3-4 neurotoxicity developed in 14 patients, of whom 6 had died at database closure. Grade 3-4 severity negatively impacted overall survival (OS) (p = 0.046). CONCLUSIONS: ICI-mediated neurotoxicities present early, are rapidly progressive and include a diverse phenotype affecting the CNS, PNS and neuroendocrine system. A high level of vigilance is warranted, as early diagnosis and targeted treatment can substantially prevent morbidity and mortality. Prospective clinical trials are warranted to assess optimized management of ICI-induced neurotoxicities.

Decreased Polycystin 2 Levels Result in Non-Renal Cardiac Dysfunction with Aging.

Mutations in the gene for polycystin 2 (Pkd2) lead to polycystic kidney disease, however the main cause of mortality in humans is cardiac related. We previously showed that 5 month old Pkd2+/- mice have altered calcium-contractile activity in cardiomyocytes, but have preserved cardiac function. Here, we examined 1 and 9 month old Pkd2+/- mice to determine if decreased amounts of functional polycystin 2 leads to impaired cardiac function with aging. We observed changes in calcium handling proteins in 1 month old Pkd2+/- mice, and these changes were exacerbated in 9 month old Pkd2+/- mice. Anatomically, the 9 month old Pkd2+/- mice had thinner left ventricular walls, consistent with dilated cardiomyopathy, and the left ventricular ejection fraction was decreased. Intriguingly, in response to acute isoproterenol stimulation to examine ß-adrenergic responses, the 9 month old Pkd2+/- mice exhibited a stronger contractile response, which also coincided with preserved localization of the ß2 adrenergic receptor. Importantly, the Pkd2+/- mice did not have any renal impairment. We conclude that the cardiac-related impact of decreased polycystin 2 progresses over time towards cardiac dysfunction and altered adrenergic signaling. These results provide further evidence that polycystin 2 provides a critical function in the heart, independent of renal involvement.