Molecular and clinical diversity in paraneoplastic immunity to Ma proteins
ABSTRACT 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.
- SourceAvailable from: Slawomir Michalak[Show abstract] [Hide abstract]
ABSTRACT: Paraneoplastic neurological syndromes (PNS) are disorders of the nervous system that are associated with remote effects of malignancy. PNS are considered to have an autoimmune pathology. It has been suggested that immune antitumor responses are the origin of improved outcome in PNS. We describe cell-mediated immune responses in PNS and their potential contributions to antitumor reactions. Experimental and neuropathological studies have revealed infiltrates in nervous tissue and disturbances in lymphocyte populations in both cerebrospinal fluid and peripheral blood. A predominance of cytotoxic T lymphocytes (CTLs) over T helper cells has been observed. CTLs can be specifically aggressive against antigens shared by tumors and nervous tissue. Based on genetic studies, a common clonal origin of lymphocytes from blood, tumor, and nervous tissue is suggested. Suppressive regulatory T (Treg) lymphocytes are dysfunctional. Simultaneously, in tumor tissue, more intense cell-mediated immune responses are observed, which often coincide with a less aggressive course of neoplastic disease. An increased titer of onconeural antibodies is also related to better prognoses in patients without PNS. The evaluation of onconeural and neuronal surface antibodies was recommended in current guidelines. The link between PNS emergence and antitumor responses may result from more active CTLs and less functional Treg lymphocytes.Clinical and Developmental Immunology 12/2013; 2013:630602. DOI:10.1155/2013/630602 · 2.93 Impact Factor
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ABSTRACT: Paraneoplastic neurological syndromes (PNSs) cover a wide range of diseases and involve both the central nervous system (CNS) and peripheral nervous system. Paraneoplastic encephalitis comprises several diseases such as paraneoplastic cerebellar degeneration (PCD), limbic encephalitis (LE), paraneoplastic encephalomyelitis (PEM), brainstem encephalitis, opsomyoclonus syndrome, in addition to other even less frequently occurring entities. LE was the first historically identified CNS PNS, and similarities between other temporal lobe diseases such as herpes encephalitis have been elucidated. In the past few decades several autoantibodies have been described in association with LE. These encompass the classical 'onconeuronal' antibodies (abs) such as Hu, Yo, Ri and others, and now additionally abs towards either ion channels or surface antigens. The clinical core findings in LE are various mental changes such as amnesia or confusion, often associated with seizures. Careful characterization of psychiatric manifestations and/or associated neurological signs can help to characterize the syndrome and type of ab. The treatment options in LE depend on the aetiology. In LE caused by onconeuronal abs, the treatment options are poor. In two types of abs associated with LE, abs against ion channels and surface antigens (e.g. NMDA), immunomodulatory treatments seem effective, making these types of LE treatable conditions. However, LE can also occur without being associated with cancer, in which case only immunomodulation is required. Despite effective treatments, some patients' residual deficits remain, and recurrences have also been described.Therapeutic Advances in Neurological Disorders 07/2011; 4(4):237-48. DOI:10.1177/1756285611405395
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ABSTRACT: To understand the relationship between the structure and function of primate neocortical areas at a molecular level, we have been screening for genes differentially expressed across macaque neocortical areas by restriction landmark cDNA scanning (RLCS). Here, we report enriched expression of the paraneoplastic antigen-like 5 gene (PNMA5) in association areas but not in primary sensory areas, with the lowest expression level in primary visual cortex. In situ hybridization in the primary sensory areas revealed PNMA5 mRNA expression restricted to layer II. Along the ventral visual pathway, the expression gradually increased in the excitatory neurons from the primary to higher visual areas. This differential expression pattern was very similar to that of retinol-binding protein (RBP) mRNA, another association-area-enriched gene that we reported previously. Additional expression analysis for comparison of other genes in the PNMA gene family, PNMA1, PNMA2, PNMA3, and MOAP1 (PNMA4), showed that they were widely expressed across areas and layers but without the differentiated pattern of PNMA5. In mouse brains, PNMA1 was only faintly expressed and PNMA5 was not detected. Sequence analysis showed divergence of PNMA5 sequences among mammals. These findings suggest that PNMA5 acquired a certain specialized role in the association areas of the neocortex during primate evolution.Cerebral Cortex 05/2009; 19(12):2865-79. DOI:10.1093/cercor/bhp062 · 8.31 Impact Factor