Biomedical subjects

Erdem Tüzün

Publications and source records attributed to Erdem Tüzün.

15 recordsLinked to original sources

PubMed2006

Pros and cons of treating murine myasthenia gravis with anti-C1q antibody.

To test the feasibility of classical complement pathway manipulation in experimental autoimmune myasthenia gravis (EAMG) treatment, C57BL/6 (B6) and RIIIS/J mice with EAMG were treated with 10 microg or 100 microg of anti-C1q Ab or isotype Ab. Treatment with 10 microg anti-C1q Ab significantly reduced the clinical severity, decreased lymph node cell IL-6 production and T cell populations. Conversely, administration of 100 microg anti-C1q Ab caused harmful side effects such as increased serum anti-acetylcholine receptor antibody, immune complex, C3 and lymph node B cell levels and kidney C3 and IgG deposits, which reduced the treatment efficacy.

Animals↗

PubMed2006

Complement regulator CD59 deficiency fails to augment susceptibility to actively induced experimental autoimmune myasthenia gravis.

Complement deficient mice are resistant to experimental autoimmune myasthenia gravis (EAMG), suggesting a pivotal role for the membrane attack complex (MAC) in EAMG pathogenesis. To test the significance of MAC regulation in EAMG pathogenesis, CD59 KO and wild type mice were immunized with acetylcholine receptor (AChR). Interestingly, deletion of CD59, the regulator of MAC assembly, failed to augment EAMG susceptibility. The CD59 KO mice had reduced serum anti-AChR IgG1, IgG2b and complement levels. Their lymph node cell IL-2 production and lymphocyte proliferation response to AChR were reduced. The data challenge the current paradigm that CD59 is solely involved in MAC regulation and suggest a role for this molecule in antigen-driven T cell and B cell activation.

Animals↗

PubMed2006

Immunization of mice with T cell-dependent antigens promotes IL-6 and TNF-alpha production in muscle cells.

IL-6 and TNF-alpha are proinflammatory cytokines involved in various inflammatory or non-inflammatory disorders characterized by muscle wasting. While infiltrating leukocytes are known to be the major source of these cytokines, it is unclear whether muscle cells also contribute to local inflammation. In this study, we first showed that cultured muscle cells and naive mouse muscle tissue were capable of producing IL-6 and TNF-alpha. We demonstrated an increased expression of IL-6 and TNF-alpha on muscle sections of C57BL/6J mice immunized with acetylcholine receptor (AChR) in the complete Freund's adjuvant (CFA) or with CFA only. In the presence of IL-6 or TNF-alpha, cultured AChR-expressing mouse (G-8) and human (TE671) skeletal muscle cells showed significantly decreased alpha-bungarotoxin-binding sites as measured by cellular ELISA. Moreover, IL-6- or TNF-alpha-treated muscle cells displayed a considerable increase in apoptotic cell ratios. Collectively, this study suggests a direct role for these two cytokines in muscle cell destruction and a possibility of muscle cell damage via an autocrine fashion.

Animals↗

PubMed2006

Neuronal acetylcholine receptor alpha9-subunit: a possible central nervous system autoantigen.

Nicotinic acetylcholine receptor (AChR) is a membrane glycoprotein composed of five subunits. Muscle AChR is consist of two alpha1 and one each beta, delta, and epsilon subunits, whereas the neuronal AChR molecules are made up of various combinations of alpha (alpha2-alpha10) and beta (beta1-beta4) subunits. Myasthenia gravis (MG) develops as a result of an autoimmune attack against muscular AChR. While the prevailing symptom is muscle weakness, very rarely MG patients may develop additional central nervous system (CNS) symptoms. The majority of the anti-AChR antibodies responsible from disease induction is directed against alpha1 subunit of AChR. There is considerable identity between muscular alpha1 and neuronal alpha9 subunits. Preliminary studies showed antibodies reactive with the CNS antigens in the serum samples of mice with experimental autoimmune myasthenia gravis (EAMG). Also, alpha9 was present in the CNS in widespread locations and the binding pattern of anti-alpha9 antibody was reminiscent of that of serum samples of some of the mice with EAMG. Serum anti-AChR antibodies of myasthenic patients might be cross-reacting with CNS AChR subunits and thus inducing CNS symptoms. Neuronal AChR alpha9-subunit might be a major target antigen in this process.

Animals↗

PubMed2006

Genetic evidence for the involvement of Fcgamma receptor III in experimental autoimmune myasthenia gravis pathogenesis.

Immune complexes and classical complement pathway play vital roles in experimental autoimmune myasthenia gravis (EAMG). To analyze the role of immune complex receptors in EAMG, FcgammaRIII knockout (KO) mice were immunized with AChR and were found out to be resistant to EAMG induction. This was associated with reduced neuromuscular junction deposits, lymph node cell (LNC) IL-6 production and serum complement levels. EAMG resistance of anti-C1q Ab-administered mice was also associated with reduced LNC IL-6 production and neuromuscular junction deposits, indicating C1q involvement in EAMG resistance. The data provide the first direct genetic evidence for Fcgamma receptor involvement in EAMG pathogenesis.

Animals↗

PubMed2006

Predictive value of serum anti-C1q antibody levels in experimental autoimmune myasthenia gravis.

Components of the complement cascade and circulating immune complexes play important roles in both experimental autoimmune myasthenia gravis and myasthenia gravis in humans. Thus far, no serological factor has been identified to predict the clinical severity of either myasthenia gravis. Upon immunization with acetylcholine receptor, levels of complement factors C1q, C3 and CIC increase with time in sera from C57BL/6 (B6) mice. Both these and plasma samples from myasthenia gravis patients also contain anti-C1q antibodies. The serum levels of anti-C1q antibodies but not C1q, C3 and CIC are significantly correlated with the clinical severity in the experimental myasthenia mice. However, this correlation is not observed in myasthenia gravis patients.

Adult↗

PubMed2006

Autoimmune thyroid encephalopathy presenting with epilepsia partialis continua.

We report the first case of an autoimmune thyroid encephalopathy presenting with multifocal motor status epilepticus. A 37-year-old female patient was admitted with multifocal motor seizures intractable to intravenous status epilepticus treatments, asymmetrical quadriparesis, truncal ataxia and continuous semi-rhythmical jerks. Pathological signal alterations were detected in both precentral cortices in MRI examination. Autoimmune thyroiditis was diagnosed after radiological examinations of the thyroid gland and thyroid function tests. Seizures promptly ceased following intravenous steroid treatment. Immunohistochemistry studies showed mild to moderate neuronal staining with the plasma and CSF samples. Remarkably, autoimmune thyroiditis may present with migrating focal motor status epilepticus. We recommend anti-thyroid antibody screening for multifocal motor status epilepticus cases of unspecified cause.

Adult↗

PubMed2005

The cDNA of mouse skeletal muscle transcribe for both isoforms 1 and 2 of acetylcholine receptor alpha subunit.

The mRNA isolated from mouse ocular and limb muscle and human rabdomyosarcoma cell line TE671 was subjected to reverse transcriptase polymerase chain reaction (RT-PCR) using a specific primer pair for the extracellular domain of AChR-alpha subunit that transcribes both for P3A- (isoform 1) and P3A+ (isoform 2). The cDNA synthesized from mRNA by reverse transcription, transcribed both isoforms 1 and 2 from mRNA of mouse limb and ocular muscle and human rabdomyosarcoma cell line TE671 as evidenced by agarose gel electrophoresis of polymerase chain reaction products.

Animals↗

PubMed2005

IL-1 receptor antagonist-mediated therapeutic effect in murine myasthenia gravis is associated with suppressed serum proinflammatory cytokines, C3, and anti-acetylcholine receptor IgG1.

In myasthenia gravis (MG), TNF and IL-1beta polymorphisms and high serum levels of these proinflammatory cytokines have been observed. Likewise, TNF and IL-1beta are critical for the activation of acetylcholine receptor (AChR)-specific T and B cells and for the development of experimental autoimmune myasthenia gravis (EAMG) induced by AChR immunization. We tested the therapeutic effect of human recombinant IL-1 receptor antagonist (IL-1ra) in C57BL/6 mice with EAMG. Multiple daily injections of 0.01 mg of IL-1ra administered for 2 wk following two AChR immunizations decreased the incidence and severity of clinical EAMG. Furthermore, IL-1ra treatment of mice with ongoing clinical EAMG reduced the clinical symptoms of disease. The IL-1ra-mediated suppression of clinical disease was associated with suppressed serum IFN-gamma, TNF-alpha, IL-1beta, IL-2, IL-6, C3, and anti-AChR IgG1 without influencing total serum IgG. Therefore, IL-1ra could be used as a nonsteroidal drug for the treatment of MG.

Animals↗

PubMed2005

Myasthenia gravis patients with low plasma IL-6 and IFN-gamma benefit from etanercept treatment.

Steroid-dependent myasthenia gravis patients improved following treatment with etanercept (recombinant human TNF receptor:Fc) in a prospective pilot trial. While the plasma anti-acetylcholine receptor antibody levels remained unaffected, etanercept treatment increased plasma levels of C3, circulating immune complexes, IL-10 and IFN-gamma. There was a direct correlation between plasma IL-6, TNF-alpha and IFN-gamma levels and the post-treatment clinical scores of patients. Moreover, patients with lower pre-treatment plasma IL-6 and IFN-gamma levels attained better clinical improvement following etanercept treatment.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2004

Circulating immune complexes augment severity of antibody-mediated myasthenia gravis in hypogammaglobulinemic RIIIS/J mice.

Experimental autoimmune myasthenia gravis (EAMG) is severe in RIIIS/J mice, despite a significant B cell immunodeficiency and a massive TCR V beta gene deletion. Severity of EAMG in RIIIS/J mice is greater than MHC-identical (H-2(r)) B10.RIII mice, suggesting the influence of non-MHC genes as an EAMG-potentiating factor in this strain. To delineate the role of deleted TCR V beta genes in RIIIS/J mice, we obtained (RIIIS/J x B10.RIII)F(1) (V beta(b/c)) x RIIIS/J (V beta(c)) backcross mice using Mendelian genetic methods and immunized them with acetylcholine receptor. EAMG susceptibility was not elevated in mice with V beta(c) genotype having 70% V beta gene deletion. Next, we performed microarray analysis on 12,488 spleen cDNAs obtained from spleens of naive RIIIS/J and B10.RIII mice. In RIIIS/J mice, 263 cDNAs were overexpressed and 303 cDNAs were underexpressed greater than 2-fold, compared with B10.RIII mice. TCR gene expression was augmented, whereas NK receptor, C1q, and C3 gene expressions were diminished in RIIIS/J mice. RIIIS/J mice also had increased lymph node T cell counts, elevated serum anti-AChR Ab levels, and serum C3 and C1q-conjugated circulating immune complex levels. A direct correlation between increased serum C1q-conjugated circulating immune complex levels and disease severity was observed in RIIIS/J mice.

Adjuvants, Immunologic↗

PubMed2004

ICOS is essential for the development of experimental autoimmune myasthenia gravis.

Lymphocyte costimulation via the inducible costimulatory molecule (ICOS) is required for effective humoral immunity development. Following immunization with Torpedo acetylcholine receptor (AChR), ICOS gene knockout (KO) mice were highly resistant to clinical experimental autoimmune myasthenia gravis (EAMG) development, had less serum AChR-specific immunoglobulins (Igs), and exhibited a diminutive germinal center (GC) reaction in secondary lymphoid tissues. Lymphocyte proliferation and both Th1 and Th2 differentiation in response to AChR and the AChR dominant alpha146-162 peptide were inhibited by the ICOS gene deficiency. ICOS-mediated lymphocyte costimulation is thus vital to the induction of T cell-mediated humoral immunity to AChR and the development of clinical EAMG.

Animals↗

PubMed2003

Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis.

Abs to acetylcholine receptor (AChR) and complement are the major constituents of pathogenic events causing neuromuscular junction destruction in both myasthenia gravis (MG) and experimental autoimmune MG (EAMG). To analyze the differential roles of the classical vs alternative complement pathways in EAMG induction, we immunized C3(-/-), C4(-/-), C3(+/-), and C4(+/-) mice and their control littermates (C3(+/+) and C4(+/+) mice) with AChR in CFA. C3(-/-) and C4(-/-) mice were resistant to disease, whereas mice heterozygous for C3 or C4 displayed intermediate susceptibility. Although C3(-/-) and C4(-/-) mice had anti-AChR Abs in their sera, anti-AChR IgG production by C3(-/-) mice was significantly suppressed. Both C3(-/-) and C4(-/-) mice had reduced levels of B cells and increased expression of apoptotis inducers (Fas ligand, CD69) and apoptotic cells in lymph nodes. Immunofluorescence studies showed that the neuromuscular junction of C3(-/-) and C4(-/-) mice lacked C3 or membrane attack complex deposits, despite having IgG deposits, thus providing in vivo evidence for the incapacity of anti-AChR IgGs to induce full-blown EAMG without the aid of complements. The data provide the first direct genetic evidence for the classical complement pathway in the induction of EAMG induced by AChR immunization. Accordingly, severe MG and other Ab- and complement-mediated diseases could be effectively treated by inhibiting C4, thus leaving the alternative complement pathway intact.

Animals↗

PubMed2003

B7-1 costimulatory molecule is critical for the development of experimental autoimmune myasthenia gravis.

Following immunization with acetylcholine receptor (AChR), MHC class II-restricted, AChR-specific CD4 cell activation is critical for the development of experimental autoimmune myasthenia gravis (EAMG) in C57BL/6 mice. To study the contributions of B7-1 and B7-2 costimulatory molecules in EAMG, B7-1, B7-2, and B7-1/B7-2 gene knockout (KO) mice were immunized with Torpedo AChR in CFA. Compared with wild-type C57BL6 mice, B7-1 and B7-1/2 KO mice were resistant to EAMG development. B7-1 KO mice had reduced anti-AChR Ab compared with C57BL/6 mice. However, neither B7-1 nor B7-2 gene disruption impaired AChR-induced or dominant alpha(146-162) peptide-induced in vitro lymphoproliferative responses. Blocking of the B7-1 or B7-2 molecule by specific mAbs in vivo led to a reduction in the AChR-specific lymphocyte response, and the reduction was more pronounced in mice treated with anti-B7-2 Ab. The findings implicate B7-1 molecules as having a critical role in the induction of EAMG, and the resistance of B7-1 KO mice is associated with suppressed humoral, rather than suppressed AChR-specific, T cell responses. The data also point to B7-2 molecules as being the dominant costimulatory molecules required for AChR-induced lymphocyte proliferation.

Animals↗

PubMed2002

Resistance to experimental autoimmune myasthenia gravis in IL-6-deficient mice is associated with reduced germinal center formation and C3 production.

To provide direct genetic evidence for a role of IL-6 in experimental autoimmune myasthenia gravis (EAMG), IL-6 gene KO (IL-6(-/-)) mice in the C57BL/6 background were immunized with Torpedo californica acetylcholine receptor (AChR) and evaluated for EAMG. Only 25% of AChR-immunized IL-6(-/-) mice developed clinical EAMG compared to 83% of C57BL/6 (wild-type) mice. A significant reduction in the secondary anti-AChR Ab of IgG, IgG(2b), and IgG(2c), but not the primary or secondary IgM response was observed in AChR-immunized IL-6(-/-) mice, suggesting a possible defect in T cell help and class switching to anti-AChR IgG(2) isotype. The AChR-specific lymphocyte proliferative response, IFN-gamma, and IL-10 production were suppressed in AChR-immunized IL-6(-/-) mice. EAMG resistance in IL-6(-/-) mice was associated with a significant reduction in germinal center formation and decreased serum complement C3 levels. The data provide the first direct genetic evidence for a key role of IL-6 in the autoimmune response to AChR and in EAMG pathogenesis.

Animals↗