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Biomedical subjects

Mark A Myers

Publications and source records attributed to Mark A Myers.

5 recordsLinked to original sources
PubMed2006

The effects of repeated exposure to sub-toxic doses of plecomacrolide antibiotics on the endocrine pancreas.

The plecomacrolide vacuolar ATPase inhibitors bafilomycin and concanamycin contaminate tuberous vegetables and damage pancreatic islets in mice. The consequences of repeated exposure of adult mice to sub-toxic doses of bafilomycin A1 or concanamycin A was examined by injection of the plecomacrolides on each of five consecutive days. There was a significant reduction in islet size in female C57BL/6j mice (p<0.004 and p<0.0001 respectively). There were no significant differences in fasted insulin levels and beta cell mass between treated and control groups but oral glucose tolerance worsened with increasing age in BALB/c female mice injected with concanamycin A. Streptozotocin reduced glucose tolerance and islet number but not islet size in all strains and sexes. Chronic exposure of C57BL/6j mice to concanamycin A for 16 weeks caused a significant reduction in islet size in both sexes and a significant increase in the spleen weight of female mice (p<0.001). We conclude that repeated exposure to small quantities of vacuolar proton-translocating ATPase inhibitory plecomacrolides reduces islet size and can lead to glucose intolerance, possibly due to impaired maintenance of pancreatic islets. This may lead to earlier progression to beta cell failure and insulin deficiency in those at risk of diabetes.

Animals↗
PubMed2003

A diabetes-related epitope of GAD65: a major diabetes-related conformational epitope on GAD65.

The 65-kDa isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes, and most patients have serum antibodies reactive with conformational epitopes on the GAD65 molecule. The aims of this study were to prepare mutants of GAD65 to further localize the type 1 diabetes epitope in the region of the PEVKEK loop of GAD65 and to identify the particular amino acids within the epitope that are recognized by autoimmune diabetes sera.

Autoantibodies↗
PubMed2002

Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis compared with other diseases.

The molecule SOX13 was initially identified as an autoantigen (ICA12) in Type 1 diabetes. SOX13 is a member of the SOX family of transcriptional regulatory proteins that contain a high mobility group (HMG) motif with structural similarity to HMG proteins 1 and 2. Antibodies to HMG 1 and 2 occur in autoimmune diseases of the liver and in ulcerative colitis. We measured the occurrence and levels of anti-SOX13 by radioimmunoprecipitation in primary biliary cirrhosis (PBC) and other diseases, and compared frequencies with anti-HMG measured by ELISA. Anti-SOX13 was detected in 18% of patients with PBC, 13% with autoimmune hepatitis, 18% with Type 1 diabetes, at lower frequencies in other conditions including the multisystem autoimmune diseases, systemic lupus erythematosus and rheumatoid arthritis, and in 1% of normal sera. Anti-HMG1 and anti-HMG2 occurred at frequencies of 30% and 35% respectively in PBC. Serum levels of anti-SOX13 and anti-HMG correlated significantly for PBC although not for Type 1 diabetes. Anti-SOX13 in PBC may occur merely as an immune response to products of damage to parenchymal tissue, or may be illustrative of a general proclivity of transcriptional regulatory proteins to elicit autoimmune responses.

Antigens, Nuclear↗
PubMed2002

The PEVKEK region of the pyridoxal phosphate binding domain of GAD65 expresses a dominant B cell epitope for type 1 diabetes sera.

Molecular mimicry between the 65-kDa isoform of glutamic acid decarboxylase (GAD65) and the protein 2C (P2C) of Coxsackie B4 virus (CBV) may initiate human type 1 diabetes. GAD65 contains a motif that has a 6-amino acid identity with CBV-P2C (PEVKEK), whereas the weakly autoantigenic isoform, GAD67, contains PEVKTK. A human-derived monoclonal antibody (mAb) MICA3 reacts with a surface loop of GAD65 that includes PEVKEK, and mutagenic deletion of this loop was shown to reduce reactivity of GAD with the mAb by 70%. To establish that the PEVKEK motif on GAD65 contains a major epitope for diabetes sera and to identify the amino acids involved, mutants of nucleotides of GAD65 and GAD67 at sites in the PEVKEK motif were created and the expressed proteins used for radioimmunoprecipitation (RIP) tests with sera from patients with type 1 diabetes. A potent mouse mAb (GAD6) to GAD65, and a rabbit polyclonal antibody (AB108) to GAD67, were used to standardize the reactivity of the diabetes sera with the mutant molecules. Of 45 type 1 diabetes sera tested, 30 (67%) had an 80% or greater reduction of reactivity to GAD65(delta258-270) vs. intact GAD65. Various single-surface amino acids in the PEVKEK epitope region of GAD65 were mutated, but most molecules carrying these mutations reacted similarly to the parent molecule. However after point mutation of the equivalent motif of GAD67 (PEVKTK to PEVKEK), there was an increase in the reactivity of 12 of 49 (24%) type 1 diabetes sera tested; 7 of 8 sera reactive with GAD67 showed increased reactivity with GAD67(T273E), and 5 previously negative sera gained reactivity with GAD67(T273E). Thus, the PEVKEK motif on GAD65 contributes to serologic reactivity of type 1 diabetes sera. This favors the hypothesis that CBV infection causes type 1 diabetes by the process of viral mimicry with cross-reactivity to a critical epitope of GAD65.

Amino Acid Sequence↗