ABSTRACT
OBJECTIVE: To determine whether serum Zic4 antibodies associate with paraneoplastic neurologic disorders (PND) and small-cell lung cancer (SCLC), and the association of these antibodies with other onconeuronal immunities associated with SCLC. DESIGN/METHODS: The authors studied 498 patients (215 with PND and 283 without PND or without cancer). The presence of antibodies was tested with immunoblots of Zic4, HuD, and CRMP5 proteins. The tumor expression of these proteins was determined by immunohistochemistry. RESULTS: Zic4 antibodies were identified in 61 patients. Ninety-two percent of patients with Zic4 antibodies had SCLC; detection of these antibodies segregated with the presence of PND (p = 0.031). Intrathecal synthesis of Zic4 antibodies was demonstrated in 5/7 patients with PND. None of 175 control patients without PND or cancer had Zic4 antibodies. Because of the robust association between Zic autoimmunity and SCLC, all patients were tested for other SCLC-related antibodies; concurrent Zic4, Hu, or CRMP5 antibodies occurred in the serum or CSF of 27% of SCLC patients with PND. Patients with isolated Zic4 antibodies were more likely to develop predominant cerebellar dysfunction than patients with several immunities (p < 0.001). Tumors of patients with and without onconeuronal antibodies coexpressed Zic, Hu, and CRMP5 proteins, indicating that the tumor expression of these antigens is necessary, but not sufficient, for immunologic activation. CONCLUSIONS: In patients with neurologic symptoms of unknown cause detection of Zic4 antibodies predicts a neoplasm, usually a SCLC, and suggests that the neurologic disorder is paraneoplastic. Detection of Zic4 antibodies often associates with anti-Hu or CRMP5 antibodies. Patients with isolated Zic4 antibodies are more likely to develop cerebellar dysfunction than those with concurrent immunities.
Subject(s)
Antibodies, Neoplasm/blood , Antibodies, Neoplasm/cerebrospinal fluid , Carcinoma, Small Cell/immunology , Lung Neoplasms/immunology , Nerve Tissue Proteins/immunology , Paraneoplastic Polyneuropathy/immunology , Transcription Factors/immunology , Aged , Aged, 80 and over , Antibodies, Neoplasm/metabolism , Carcinoma, Small Cell/metabolism , ELAV Proteins , ELAV-Like Protein 4 , Female , Humans , Hydrolases , Immunoblotting , Immunohistochemistry , Lung Neoplasms/metabolism , Male , Microtubule-Associated Proteins , Middle Aged , Nerve Tissue Proteins/metabolism , Paraneoplastic Polyneuropathy/diagnosis , Paraneoplastic Polyneuropathy/metabolism , RNA-Binding Proteins/immunology , RNA-Binding Proteins/metabolism , Transcription Factors/metabolismABSTRACT
The serum of a patient with subacute cerebellar dysfunction was used to probe a cDNA expression library and isolate two genes: Zic1 (zinc-finger of the cerebellum) and Zic4. The patient had intrathecal synthesis of Zic antibodies, suggesting that the Zic proteins were autoantigens of the neurologic disorder. The Zic proteins are involved in cerebellar development and are reported as being preferentially expressed by medulloblastomas. It was found that the expression of Zic proteins is enriched in, but not limited to, medulloblastomas and primitive neuroectodermal tumors.
Subject(s)
Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Cerebellar Diseases/pathology , Cerebellum/pathology , Nerve Degeneration/pathology , Zinc Fingers/immunology , Aged , Autoantibodies/analysis , Autoantibodies/cerebrospinal fluid , Autoantibodies/immunology , Blotting, Western , Cerebellar Neoplasms/immunology , Cerebellar Neoplasms/pathology , DNA, Complementary/genetics , Humans , Immunohistochemistry , Magnetic Resonance Imaging , Male , Medulloblastoma/immunology , Medulloblastoma/pathology , Neuroectodermal Tumors/immunology , Neuroectodermal Tumors/pathologyABSTRACT
Antibodies to Ma1 and Ma2 proteins identify a paraneoplastic disorder that affects the limbic system, brain stem, and cerebellum. Preliminary studies suggested the existence of other Ma proteins and different patterns of immune response associated with distinct neurologic symptoms and cancers. In this study, our aim was to isolate the full-length sequence of Ma2 and new family members, identify the major autoantigen of the disorder, and extend the dinical-immunological analysis to 29 patients. Sera from selected patients were used to probe a brainstem cDNA library and isolate the entire Ma2 gene and a new family member, Ma3. Ma3 mRNA is ubiquitously expressed in brain, testis, and several systemic tissues. The variable cellular expression of Ma proteins and analysis of protein motifs suggest that these proteins play roles in the biogenesis of mRNA. Immunoblot studies identify Ma2 as the major autoantigen with unique epitopes recognized by all patients' sera. Eighteen patients had antibodies limited to Ma2: they developed limbic, hypothalamic, and brainstem encephalitis, and 78% had germ-cell tumors of the testis. Eleven patients had antibodies to Ma2 and additional antibodies to Ma1 and/or Ma3; they usually developed additional cerebellar symptoms and more intense brainstem dysfunction, and 82% of these patients had tumors other than germ-cell neoplasms. Overall, 17 of 24 patients (71%) with brain magnetic resonance imaging studies had abnormalities within or outside the temporal lobes, some as contrast-enhancing nodular lesions. A remarkable finding of immunity to Ma proteins is that neurologic symptoms may improve or resolve. This improvement segregated to a group of patients with antibodies limited to Ma2.
