Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome

Abstract

Objective: To report the metabotropic glutamate receptor 5 (mGluR5) as the autoantigen of antibodies from 2 patients with Hodgkin lymphoma (HL) and limbic encephalopathy (Ophelia syndrome).

Methods: Immunohistochemistry with brain tissue and cultures of rat hippocampal neurons were used to demonstrate antibodies. Immunoprecipitation, mass spectrometry, and mGluR5-null mice served to identify the antigen. HEK293 cells transfected with mGluR5 or mGluR1 were used to determine immunologic crossreactivity.

Results: Both patients developed symptoms consistent with limbic encephalopathy; one had MRI findings typical of this disorder and the other had more extensive radiologic involvement, including parietal and occipital cortex. Patients' sera had antibodies that predominantly reacted with the neuropil of hippocampus and cell surface of live hippocampal neurons. Immunoprecipitation from cultured neurons and mass spectrometry demonstrated that the antigen was mGluR5, a receptor involved in processes of learning and memory. The reactivity of patients' sera was abrogated in brain of mGluR5-null mice, further confirming the antibody specificity. Studies with a large number of controls including 2 patients with cerebellar ataxia and mGluR1 antibodies showed that mGluR5 was only identified by sera of the 2 patients with the Ophelia syndrome, and that despite the homology of this receptor with mGluR1 each autoantigen was specific for a distinct syndrome.

Conclusions: Antibodies to mGluR5 should be considered in patients with symptoms of limbic encephalitis and HL (Ophelia syndrome). Recognition of this disorder is important because it can affect young individuals and is reversible.

Figure 1. Patients' antibodies recognize metabotropic glutamate receptor 5 (mGluR5) in transfected cells and rodent brain

Left panels show HEK cells transfected to express mGluR5, reacted with a commercial antibody to mGluR5 (A, D, G), serum from a patient with the Ophelia syndrome (B), serum from a patient with cerebellar ataxia and mGluR1 antibodies (E), and serum from a normal individual (H). Merged reactivities are shown in the column of the right where the nuclei of the cells are labeled blue with DAPI (C, F, I). Note that mGluR5 is only recognized by serum of the patient with Ophelia syndrome. Scale is 10 μm. Right panels show that the serum of a patient with Ophelia syndrome and mGluR5 antibodies intensively reacts with wild-type mouse brain, especially the hippocampus (J), but the reactivity is abrogated in mGluR5-null mouse brain (L). In contrast, the serum of a patient with ataxia and mGluR1 antibodies intensively reacts with mGluR5-null mouse brain, mainly the cerebellum (N; an identical reactivity was noted with the wild-type brain, not shown). A predominant reactivity with the hippocampus of wild-type brain (K) is also demonstrated with a polyclonal rabbit antibody to mGluR5 (06–541, Milipore, Billerica, MA; 1:500). The reactivity of this antibody is abrogated in the brain of mGluR5-null mouse (M). Scale is 1 mm.