Rosenfeld MR, Eichen JG, Wade DF, et al. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins

Department of Neurology, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
Annals of Neurology (Impact Factor: 9.98). 09/2001; 50(3):339-48. DOI: 10.1002/ana.1288.abs
Source: PubMed


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.

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    • "The plasma cells and B lymphocytes, however, have also been identified at an early stage of PNS to be related to anti-Ma2 antibodies [36] [37]. An increased population of macrophages (CD68 + ) has also been detected in paraneoplastic ganglionitis [38]. "
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    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.
    Full-text · Article · Dec 2013 · Clinical and Developmental Immunology
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    • "Two cases of PLE coexisting with HSE have also been reported. The first one with lung adenocarcinoma and antibodies to Ma2 that developed HSV encephalitis confirmed by CSF PCR after 6 weeks [10]. The second with antibodies to Hu (no identifiable neoplasm) that a HSV encephalitis was confirmed by postmortem immunocytochemistry and positive PCR performed on temporal tissue extracts [11]. "
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    ABSTRACT: Introduction. Paraneoplastic limbic encephalitis (PLE) is a rare disorder that typically follows a chronic or subacute course of personality changes, memory loss, seizures, and hallucinations. Early diagnosis is difficult and characteristic symptoms can be mimicked by a variety of conditions. We present a case of PLE, initially presenting as acute herpetic encephalitis. Case Presentation. A 56-year-old male was admitted for evaluation of acute onset headache, fever, and confusion. On neurological examination he was confused with MMSE score of 15/30. CSF analysis revealed marked lymphocytic pleocytosis. A possible diagnosis of acute herpetic encephalitis was rendered and patient was treated with acyclovir. CSF PCR was negative. Cranial MRI revealed bilateral hyperintense lesions in medial temporal lobes with contrast enhancement. Despite treatment with acyclovir patient was deteriorated; thus, a paraneoplastic syndrome was suspected. Chest CT showed a right paratracheal lymph node mass, while a biopsy revealed neuroendocrine lung cancer. Auto antibodies to Hu were also detected. The patient was treated with steroids and chemotherapy. Six months later, he had complete tumour remission and marked neurological improvement. Discussion. PLE can rarely invade acutely, being indistinguishable from herpetic encephalitis. Inclusion of PLE in the differential diagnosis of acute encephalitis is of great clinical significance.
    Full-text · Article · Nov 2013
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    • "A paraneoplastic Ma antigen (PNMA) family is another large family consisting of eutherian- and marsupial-specific genes (Schüller, 2005; Iwasaki et al., in preparation; Figure 3). PNMA-family genes (PNMA1–3) were first identified as genes encoding neuronal auto-antigens using sera from human patients with paraneoplastic neurological syndromes (Voltz et al., 1999; Rosenfeld et al., 2001). By comprehensive search of a protein database, Schüller (2005) identified additional human PNMA genes, MOAP1/PNMA4, PNMA5, and PNMA6, among which PNMA6 has no mouse ortholog. "
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    ABSTRACT: The acquisition of multiple genes from long terminal repeat (LTR) retrotransposons occurred in mammals. Genes belonging to a sushi-ichi-related retrotransposon homologs (SIRH) family emerged around the time of the establishment of two viviparous mammalian groups, marsupials and eutherians. These genes encode proteins that are homologous to a retrotransposon Gag capsid protein and sometimes also have a Pol-like region. We previously demonstrated that PEG10 (SIRH1) and PEG11/RTL1 (SIRH2) play essential but different roles in placental development. PEG10 is conserved in both the marsupials and the eutherians, while PEG11/RTL1 is a eutherian-specific gene, suggesting that these two domesticated genes were deeply involved in the evolution of mammals via the establishment of the viviparous reproduction system. In this review, we introduce the roles of PEG10 and PEG11/RTL1 in mammalian development and evolution, and summarize the other genes domesticated from LTR retrotransposons and endogenous retroviruses (ERVs) in mammals. We also point out the importance of DNA methylation in inactivating and neutralizing the integrated retrotransposons and ERVs in the process of domestication.
    Preview · Article · Jul 2012 · Frontiers in Microbiology
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