Kryzer, Thomas J.

An autoantibody target on brain microvascular endothelial cells in patients with neuromyelitis optica may be exploited to manipulate blood-brain barrier permeability.

Significance Neuromyelitis optica (NMO) is a severe inflammatory central nervous system demyelinating disease (IDD). Detection of NMO-specific IgG in serum distinguishes NMO from other IDDs, enables rapid diagnosis, and expedites NMO-appropriate therapy. Binding of NMO-IgG to aquaporin-4 (AQP4), the astrocytic water channel antigen, initiates endocytosis of AQP4 and its coupled EAAT2 glutamate transporter. Sequelae potentially contributing to NMO lesions include reduced water fluxes, reduced extracellular glutamate clearance, activation of a proinflammatory astrocyte response, and complement activation. Our paper investigates early events following IgG–AQP4 interaction and demonstrates that AQP4 and EAAT2 internalization, but not astrocytic secretion of IL-6, requires astrocytic Fc receptor signaling. Selective attenuation of these signaling events offers an upstream therapeutic target.

ObjectiveTo report the identification of microtubule‐associated protein (MAP) 1B as the antigen of the previously described Purkinje cell cytoplasmic antibody type 2 (PCA‐2) antibody, its frequency, and clinical, oncological, and serological associations.MethodsArchival serum or cerebrospinal fluid (CSF) specimens were available from 96 of 118 consecutive PCA‐2‐IgG–seropositive patients identified during 1993–2016. The autoantigen, defined in mouse brain lysate by Western blot and mass spectrometry, was confirmed by dual immunohistochemical staining using commercial antibodies. The major antigenic region was defined by Western blot using recombinant protein fragments.ResultsIgG in 95 of 96 patients’ serum or CSF (but in none of 98 healthy or disease control subjects’ serum specimens) bound to recombinant MAP1B. A minority (17.5%) of patients’ IgG also bound to MAP1A. PCA‐2 was often accompanied by additional neural autoantibody markers of small‐cell carcinoma, including collapsin response‐mediated protein 5 (CRMP5) IgG (26%) or antineuronal nuclear antibody type 1 (ANNA‐1) IgG (also known as anti‐Hu; 13%). Neurological manifestations in 95 patients were (in decreasing frequency): peripheral neuropathy, 53%; cerebellar ataxia, dysmetria, or dysarthria, 38%; and encephalopathy, 27%. Cancer (majority small‐cell lung carcinoma [SCLC]) was detected in 66 of 84 evaluated patients (79%). The MAP1B (PCA‐2) autoantibody detection rate, among approximately 70,000 patients undergoing service neural autoantibody evaluation in 2015, was 0.024%, equaling amphiphysin IgG (0.026%) and more common than ANNA‐2 (also known as anti‐Ri; 0.016%) and PCA‐Tr (also known as delta/notch‐like epidermal growth factor‐related receptor [DNER]; 0.006%).InterpretationMAP1B, the PCA‐2 autoantigen, represents a novel target in paraneoplastic neurological disorders and has high predictive value for SCLC. Its relatively high prevalence, compared with other recognized paraneoplastic neural autoantibodies, justifies its testing in comprehensive paraneoplastic neural autoantibody evaluation. Ann Neurol 2017;81:266–277