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B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice.

ABSTRACT: We studied the cellular basis of self tolerance of B cells specific for brain autoantigens using transgenic mice engineered to produce high titers of autoantibodies against the myelin oligodendrocyte glycoprotein (MOG), a surface component of central nervous system myelin. We generated "knock-in" mice by replacing the germline JH locus with the rearranged immunoglobulin (Ig) H chain variable (V) gene of a pathogenic MOG-specific monoclonal antibody. In the transgenic mice, conventional B cells reach normal numbers in bone marrow and periphery and express exclusively transgenic H chains, resulting in high titers of MOG-specific serum Igs. Additionally, about one third of transgenic B cells bind MOG, thus demonstrating the absence of active tolerization. Furthermore, peritoneal B-1 lymphocytes are strongly depleted. Upon immunization with MOG, the mature transgenic B cell population undergoes normal differentiation to plasma cells secreting MOG-specific IgG antibodies, during which both Ig isotype switching and somatic mutation occur. In naive transgenic mice, the presence of this substantial autoreactive B cell population is benign, and the mice fail to develop either spontaneous neurological disease or pathological evidence of demyelination. However, the presence of the transgene both accelerates and exacerbates experimental autoimmune encephalitis, irrespective of the identity of the initial autoimmune insult.

SUBMITTER: Litzenburger T

PROVIDER: S-EPMC2525547 | biostudies-literature | 1998 Jul

REPOSITORIES: biostudies-literature

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B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice.

Litzenburger T T Fässler R R Bauer J J Lassmann H H Linington C C Wekerle H H Iglesias A A

The Journal of experimental medicine 19980701 1

We studied the cellular basis of self tolerance of B cells specific for brain autoantigens using transgenic mice engineered to produce high titers of autoantibodies against the myelin oligodendrocyte glycoprotein (MOG), a surface component of central nervous system myelin. We generated "knock-in" mice by replacing the germline JH locus with the rearranged immunoglobulin (Ig) H chain variable (V) gene of a pathogenic MOG-specific monoclonal antibody. In the transgenic mice, conventional B cells r ...[more]

PMID: 9653093

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Project description:Background: Both Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are neurodegenerative and inflammatory demyelination disorders. Sporadic reports showed that the increased levels of thyroid function and autoantibodies are associated with GBS, CIDP, or both, but no systematic study has been reported. We assessed the differences of thyroid function and autoantibodies between GBS and CIDP in a Chinese cohort. Methods: A total of 256 patients were enrolled in this study. 175 clinically confirmed GBS and CIDP patients were selected. Meanwhile, 81 patients hospitalized for diseases other than GBS or CIDP with mild symptoms were enrolled as a control group. Relevant clinical data, including thyroid function, and autoantibody examinations, were collected for statistical analysis. Results: In the comparison of thyroid function and autoantibody parameters, the levels of total thyroxine (TT4), thyroid peroxidase antibody (TPO-Ab), and thyroglobulin antibody (TG-Ab) in the GBS group were all higher than those in the CIDP and Control groups (P < 0.01). The thyroid antibody positive rates in the GBS and CIDP groups were 70.10 and 14.10%, respectively (P < 0.01). In the receiver operating characteristic (ROC) curve analysis, TT4, TPO-Ab, and TG-Ab were higher in the GBS group and lower in the CIDP group (P < 0.01). To achieve a high specificity of 97-99%, the diagnostic cutoff value of TPO-Ab was higher than 133 IU/mL (Sensitivity: 11.34%) or lower than 0.01 IU/mL (Sensitivity: 9.09%), while the diagnostic cutoff value of TG-Ab was higher than 261.1 IU/mL (Sensitivity: 2.06%) or lower than 0.46 IU/mL (Sensitivity: 11.69%). Multivariate logistic regression analysis showed that the differences in TPO-Ab were statistically significant between GBS patients with TPO-Ab was higher than 133 IU/mL and CIDP patients (P < 0.01); the differences in TG-Ab were statistically significant between GBS patients with TG-Ab was higher than 261.1 IU/mL and CIDP patients (P < 0.05). Conclusion: The elevation of thyroid autoantibodies was associated with GBS. TPO-Ab higher than 133 IU/mL or lower than 0.01 IU/mL and TG-Ab higher than 261.1 IU/mL or lower than 0.46 IU/mL had high specificity for differentiating between GBS and CIDP; therefore, TPO-Ab and TG-Ab can be used as biomarkers for the differential diagnosis of GBS and CIDP.

Project description:Jatropha curcas L. is a potential biofuel plant and its seed oil is suitable for biodiesel production. Despite this promising application, jatropha seeds contain two major toxic components, namely phorbol esters and curcins. These compounds would reduce commercial value of seed cake and raise safety and environment concerns on jatropha plantation and processing. Curcins are Type I ribosome inactivating proteins. Several curcin genes have been identified in the jatropha genome. Among which, the Curcin 1 (C1) gene is identified to be specifically expressed in endosperm, whereas the Curcin 2A (C2A) is mainly expressed in young leaves.A marker-free RNAi construct carrying a ?-estradiol-regulated Cre/loxP system and a C1 promoter-driven RNAi cassette for C1 gene was made and used to generate marker-free transgenic RNAi plants to specifically silence the C1 gene in the endosperm of J. curcas. Plants of transgenic line L1, derived from T0-1, carry two copies of marker-free RNAi cassette, whereas plants of L35, derived from T0-35, harbored one copy of marker-free RNAi cassette and three copies of closely linked and yet truncated Hpt genes. The C1 protein content in endosperm of L1 and L35 seeds was greatly reduced or undetectable, while the C2A proteins in young leaves of T0-1 and T0-35 plants were unaffected. In addition, the C1 mRNA transcripts were undetectable in the endosperm of T3 seeds of L1 and L35. The results demonstrated that the expression of the C1 gene was specifically down-regulated or silenced by the double-stranded RNA-mediated RNA interference generated from the RNAi cassette.The C1 promoter-driven RNAi cassette for the C1 gene in transgenic plants was functional and heritable. Both C1 transcripts and C1 proteins were greatly down-regulated or silenced in the endosperm of transgenic J. curcas. The marker-free transgenic plants and curcin-deficient seeds developed in this study provided a solution for the toxicity of curcins in jatropha seeds and addressed the safety concerns of the marker genes in transgenic plants on the environments.

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B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice.

Publications

B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice.

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