Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders

Abstract

The identification of antineuronal antibodies has facilitated the diagnosis of paraneoplastic neurological disorders and the early detection of the associated tumours. It has also led to the cloning of possibly important neuron-specific proteins. In this study we wanted to identify novel antineuronal antibodies in the sera of patients with paraneoplastic neurological disorders and to clone the corresponding antigens. Serological studies of 1705 sera from patients with suspected paraneoplastic neurological disorders resulted in the identification of four patients with antibodies that reacted with 37 and 40 kDa neuronal proteins (anti-Ma antibodies). Three patients had brainstem and cerebellar dysfunction, and one had dysphagia and motor weakness. Autopsy of two patients showed loss of Purkinje cells, Bergmann gliosis and deep cerebellar white matter inflammatory infiltrates. Extensive neuronal degeneration, gliosis and infiltrates mainly composed of CD8+ T cells were also found in the brainstem of one patient. In normal human and rat tissues, the anti-Ma antibodies reacted exclusively with neurons and with testicular germ cells; the reaction was mainly with subnuclear elements (including the nucleoli) and to a lesser degree the cytoplasm. Anti-Ma antibodies also reacted with the cancers (breast, colon and parotid) available from three anti-Ma patients, but not with 66 other tumours of varying histological types. Preincubation of tissues with any of the anti-Ma sera abrogated the reactivity of the other anti-Ma immunoglobulins. Probing of a human complementary DNA library with anti-Ma serum resulted in the cloning of a gene that encodes a novel 37 kDa protein (Mal). Recombinant Mal was specifically recognized by the four anti-Ma sera but not by 337 control sera, including those from 52 normal individuals, 179 cancer patients without paraneoplastic neurological symptoms, 96 patients with paraneoplastic syndromes and 10 patients with non-cancer-related neurological disorders. The expression of Mal mRNA is highly restricted to the brain and testis. Subsequent analysis suggested that Mal is likely to be a phosphoprotein. Our study demonstrates that some patients with paraneoplastic neurological disorders develop antibodies against Mal, a new member of an expanding family of 'brain/testis' proteins.

Encephalitis and AMPA receptor antibodies

“…Serum and CSF samples were tested for antibodies to intracellular and cell surface antigens using immunohistochemistry on rat brain as previously reported. 2,10 Samples showing specific tissue staining were further examined with in-house or immunoblot assays for antibodies to onconeuronal antigens (Hu, Yo, Ri, amphiphysin, Ma1/2, Tr), tumor-associated antigens (SOX1, ZIC4), and nontumor-associated antigens (GAD65, AK5, Homer3). 11,12 The identity of the target cell surface or synaptic autoantigens was determined with HEK293 cells expressing LGI1, CASPR2, NMDAR, AMPAR, and GABA(B)R, as reported.…”

“…In order to assess the significance of the presence of an underlying tumor or additional paraneoplastic antibodies in the clinical outcome (survival and relapse frequency), we reviewed the current data along with all previously reported oncologic or paraneoplastic cases of anti-AMPAR encephalitis. [1][2][3][4][5][6][7][8][9][10][11][12]. Two of these patients developed seizures (nos.…”

Recognizing Autoimmune-Mediated Encephalitis in the Differential Diagnosis of Limbic Disorders

“…21,22 This AME occurs mostly in association with testicular germinal cell tumors in younger male individuals; but, in older individuals, there may be an underlying nonsmall cell lung carcinoma or breast cancer. 23 Improvement with immunotherapy is more likely than in other forms of LE that involve antibodies against intracellular antigens.…”

What should you know about limbic encephalitis?

“…It occurs mostly in association with testicular germinal cell tumour in younger males, but in older individuals there may be an underlying non-small cell lung carcinoma or breast cancer 12 . Men with Ma2-antibody encephalitis in whom there is no detectable testicular tumour may have a microscopic tumour below the detection threshold of imaging techniques.…”