Mutated cancer autoantigen implicated cause of paraneoplastic myasthenia gravis

Ζεκερίδου, Αναστασία; Griesmann, Guy E.; Lennon, Vanda A.

doi:10.1002/mus.26166

Cited by 12 publications

(16 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The neurological presentations are more diverse than traditionally recognized and can be misdiagnosed as neurodegenerative disorders or cancer progression. The profile of neural autoantibodies in a patient's serum reflects the onconeural antigens expressed by the tumor . It is not unusual for multiple autoantibodies and paraneoplastic disorders to co‐exist in one patient …”

Section: Introductionmentioning

confidence: 99%

Paraneoplastic autoimmunity and small‐cell lung cancer: Neurological and serological accompaniments

et al. 2019

Self Cite

View full text Add to dashboard Cite

Paraneoplastic neurological autoimmunity is often associated with small‐cell lung cancer (SCLC), a highly malignant neuroendocrine tumor. Paraneoplastic autoimmunity often correlates with longer survival. We describe the paraneoplastic neurological manifestations of patients with SCLC with and without SCLC‐predictive autoantibodies and the correlation between autoimmunity and survival. We reviewed the records of 116 patients (51% male) from the Mayo Clinic with histopathologically confirmed SCLC for whom stored serum was available for neural autoantibody testing. Cancer was limited stage in 41%; the median age at diagnosis was 64 years. Paraneoplastic neurological manifestations were recorded in 61% (decreasing frequency: peripheral neuropathy, dysautonomia, cognitive decline, cerebellar ataxia, neuromuscular junction disorder, seizures, cranial neuropathy, movement disorder, brainstem disorder, or myelopathy). Neural autoantibodies, some with pathogenic potential, were detected in the sera of SCLC patients with and without neurological autoimmunity. The most frequent among patients with neurological manifestations were: anti‐neuronal nuclear antibody‐type 1, voltage‐gated calcium channel (VGCC)‐N‐type, VGCC‐P/Q‐type, glutamic acid decarboxylase 65 (GAD65), SOX1, and muscle acetylcholine receptor (AChR); while the most common in patients without neurological manifestations were: GAD65, muscle‐AChR, and VGCC‐P/Q‐type. Neither cancer stage at diagnosis nor survival correlated with neurological manifestations or autoantibody‐positivity, except for shorter survival in patients with myelopathy. The only predictor of longer survival was limited‐stage disease at diagnosis.

show abstract

Section: Introductionmentioning

confidence: 99%

Paraneoplastic autoimmunity and small‐cell lung cancer: Neurological and serological accompaniments

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…14 In addition, multiple messenger RNA transcripts encoding potential mutated forms of the muscle acetylcholine receptor (AChR) a1 subunit polypeptides were found in a small cell lung carcinoma (SCLC) of a patient with paraneoplastic myasthenia gravis. 15 Neurologic Paraneoplastic Autoimmunity Organ-restricted autoimmune damage is mediated by IgG or by cytotoxic T lymphocytes. A major determinant of the pathophysiologic outcome is the autoantigen's subcellular location.…”

mentioning

confidence: 99%

Neurologic Autoimmunity in the Era of Checkpoint Inhibitor Cancer Immunotherapy

Ζεκερίδου

Lennon

2019

Mayo Clinic Proceedings

Self Cite

View full text Add to dashboard Cite

Neurologic autoimmune disorders in the context of systemic cancer reflect antitumor immune responses against onconeural proteins that are autoantigens in the nervous system. These responses observe basic principles of cancer immunity and are highly pertinent to oncological practice since the introduction of immune checkpoint inhibitor cancer therapy. The patient's autoantibody profile is consistent with the antigenic composition of the underlying malignancy. A major determinant of the pathogenic outcome is the anatomic and subcellular location of the autoantigen. IgGs targeting plasma membrane proteins (eg, muscle acetylcholine receptor -IgG in patients with paraneoplastic myasthenia gravis) have pathogenic potential. However, IgGs specific for intracellular antigens (eg, antineuronal nuclear antibody 1 [anti-Hu] associated with sensory neuronopathy and small cell lung cancer) are surrogate markers for CD8 þ T lymphocytes targeting peptides derived from nuclear or cytoplasmic proteins. In an inflammatory milieu, those peptides translocate to neural plasma membranes as major histocompatibility complex class I protein complexes. Paraneoplastic neurologic autoimmunity can affect any level of the neuraxis and may be mistaken for cancer progression. Importantly, these disorders generally respond favorably to early-initiated immunotherapy and cancer treatment. Small cell lung cancer and thymoma are commonly associated with neurologic autoimmunity, but in the context of checkpoint inhibitor therapy, other malignancy associations are increasingly recognized.

show abstract

“…2,20,21 The foci of PDE10A immunoreactivity in the renal cell adenocarcinoma of patient 4 supports a peripheral carcinoma being the initial immunogenic trigger for an autoimmune response. 22,23 A single control patient with renal cell adenocarcinoma had low PDE10A-IgG seropositivity by CBA alone, suggesting a possible onconeural antigen-specific antitumor immune response without the corresponding neurologic phenotype. 3,24 Neither this patient's renal cell carcinoma nor control renal cell carcinomas were tested for PDE10A expression in this study, but mRNA data suggest that PDE10A can be expressed in kidney tumors (proteinatlas.org).…”

Section: Discussionmentioning

confidence: 99%

“…The immunologic trigger for bypassing self-tolerance and development of antigen-specific autoimmunity remains unknown but expression of neoantigens by the tumors has been implicated. 22,23,25…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase 10A IgG

et al. 2019

Self Cite

View full text Add to dashboard Cite

ObjectiveTo describe a novel antibody biomarker of neurologic paraneoplastic autoimmunity specific for phosphodiesterase 10A (PDE10A), a striatum-enriched phosphodiesterase, and to characterize the clinical phenotype of patients with PDE10A immunoglobulin G (IgG).MethodsWe describe 7 patients with autoantibodies specific for PDE10A identified in the Mayo Clinic Neuroimmunology Laboratory. Patient specimens (sera, 7; CSF, 4) produced identical basal ganglia‐predominant synaptic staining of murine brain tissue by indirect immunofluorescence. The autoantigen was identified by immunoprecipitation and mass spectrometry as PDE10A, and confirmed by antigen-specific recombinant Western blot and cell-based assays, and immune absorption experiments.ResultsThe median patient age was 70 years (range 66–76); 4 were men. Four patients with clinical information available had movement disorders (hyperkinetic in 3 [chorea, ballismus, dystonia] and parkinsonism in 1). All patients but one had cancer (lung [adenocarcinoma 1, squamous cell carcinoma 1, poorly differentiated mesenchymal carcinoma 1], renal adenocarcinoma 2, and pancreatic adenocarcinoma 1). Two of the 7 patients developed hyperkinetic movement disorders during treatment with immune checkpoint inhibitors (nivolumab and pembrolizumab), though none of 26 cancer control patients treated with immune checkpoint inhibitors harbored PDE10A IgG in their serum. MRIs from those 2 patients with hyperkinetic movement disorders demonstrated fluid-attenuated inversion recovery/T2 basal ganglia hyperintensities, and their CSF harbored unique oligoclonal bands. One of those 2 patients had substantial improvement after corticosteroids. One patient's renal adenocarcinoma expressed PDE10A by immunohistochemistry.ConclusionsPDE10A IgG defines a novel rare neurologic autoimmune syndrome and expands the spectrum of diagnosable paraneoplastic CNS disorders. The intracellular location of PDE10A suggests a T-cell-mediated pathology targeting cells displaying MHC1-bound PDE10A peptides.

show abstract

Mutated cancer autoantigen implicated cause of paraneoplastic myasthenia gravis

Abstract: Our findings support onconeural protein products as pertinent immunogens initiating paraneoplastic neurological autoimmunity. Muscle Nerve 58: 600-604, 2018.

Cited by 12 publications

References 20 publications

Paraneoplastic autoimmunity and small‐cell lung cancer: Neurological and serological accompaniments

Paraneoplastic autoimmunity and small‐cell lung cancer: Neurological and serological accompaniments

Neurologic Autoimmunity in the Era of Checkpoint Inhibitor Cancer Immunotherapy

Phosphodiesterase 10A IgG

Contact Info

Product

Resources

About