Cross-linking cellular prion protein induces neuronal type 2-like hypersensitivity

Background: Previous reports identified proteins associated with ‘apoptosis’ following cross-linking PrPC with motif-specific anti-PrP antibodies in vivo and in vitro. The molecular mechanisms underlying this IgG-mediated neurotoxicity and the role of the activated proteins in the apoptotic pathways leading to neuronal death has not been properly defined. Previous reports implicated a number of proteins, including apolipoprotein E, cytoplasmic phospholipase A2, prostaglandin and calpain with antiPrP antibody-mediated ‘apoptosis’, however, these proteins are also known to play an important role in allergy. In this study, we investigated whether cross-linking PrPC with anti-PrP antibodies stimulates a neuronal allergenic response. Methods: Initially, we predicted the allergenicity of the epitope sequences associated with ‘neurotoxic’ anti-PrP antibodies using allergenicity prediction servers. We then investigated whether anti-PrP antibody treatment of mouse primary neurons (MPN), neuroblastoma cells (N2a) and microglia (N11) cell lines lead to a neuronal allergenic response. Results: In-Silico studies showed that both tail- and globular-epitopes were allergenic. Specifically, binding regions that contain epitopes for previously reported ‘neurotoxic’ antibodies such as ICSM18 (146-159), ICSM35 (91-110), POM 1 (138-147) and POM 3 (95-100) lead to activation of allergenic related proteins. Following direct application of antiPrPC antibodies on N2a cells, we identified 4 neuronal allergenic-related proteins when compared with untreated cells. Furthermore, we identified 8 neuronal allergenic-related proteins following treatment of N11 cells with anti-PrPC antibodies prior to co-culture with N2a cells when compared with untreated cells. Antibody treatment of MPN or MPN co-cultured with antibody-treated N11 led to identifying 10 and 7 allergenic-related proteins when compared with untreated cells. However, comparison with 3F4 antibody treatment revealed 5 and 4 allergenic-related proteins respectively. Of importance, we showed that the allergenic effects triggered by the anti-PrP antibodies were more potent when antibody-treated microglia were co-cultured with the neuroblastoma cell line. Finally, co-culture of N2a or MPN with N11-treated with anti-PrP antibodies resulted in significant accumulation of NO and IL6 but not TNF-a in the cell culture media supernatant. Conclusions: This study showed for the first time that anti-PrP antibody binding to PrPC triggers a neuronal hypersensitivity response and highlights the important role of microglia in triggering an IgG-mediated neuronal hypersensitivity response. Moreover, this study provides an important impetus for including allergenic assessment of therapeutic antibodies for neurodegenerative disorders to derive safe and targeted biotherapeutics

Gastrointestinal stromal tumors: A multicenter study of 1160 Turkish cases

PubMed ID: 22798108Background/aims: The aim of this multicenter study was to determine the histopathological features and immunohistochemical profiles of gastrointestinal stromal tumors diagnosed in Turkish patients. Material and Methods: Twenty-eight participating centers registered their gastrointestinal stromal tumor cases on a nationwide database. The diagnosis of gastrointestinal stromal tumor relied upon hematoxylin & eosin features and the results of antibody panel including CD117, CD34, desmin, smooth muscle actin, S-100 protein, and Ki67. The database consisted of parameters including age, gender, location, and all other histopathological and immunohistochemical findings. Statistical analysis was performed using Pearson, Kruskal-Wallis, Mann-Whitney U, and Spearman tests. Results: From all of the gastrointestinal stromal tumors in the database, 1160 cases with a male to female ratio of 1.22 and a mean age of 56.75 years were included in the study. The most common location was the stomach (45.0%), followed by the small intestine, omentum-peritoneum, large intestine, and esophagus (32.0%, 12.6%, 9.3%, 1.1%, respectively). The risk groups were distributed as: 6.1% very low, 21.7% low, 19.3% intermediate, and 53% high-risk cases. Many histopathologic findings were correlated with risk groups. CD117 was positive in 95.3% of gastrointestinal stromal tumors, whereas CD34 was positive in 74.9%, smooth muscle actin in 45.9%, desmin in 9.2%, and S-100 in 19.1.%. Though no significant relation was found between CD117 expression and tumor location, CD34, smooth muscle actin and Ki67 expressions significantly varied in different locations (p=0.001) and risk groups. Conclusions: The results of this multicenter study demonstrated that features other than tumor size and mitosis and immune markers other than CD117 and Ki67 included in the antibody panel seem to be useful as predictive risk factors

Students with learning disabilities within the context of inclusive education: issues of identification and school management

This paper reports findings of a case study carried out in twoelementary mainstream schools in Turkey. The main aim of thestudy was to investigate the role of identification and schoolmanagement within the process of educating students withlearning disabilities in mainstream schools. Interviews withstakeholders, observations and documentary analysis yielded thefollowing broad themes: (a) referral and identification was oftencarried out with little consideration of preventive and holisticapproaches; (b) identification based on narrow assessment guidedthe educational content, influenced school climate and teacherpractices and (c) school management bodies assumed littleresponsibility to plan, coordinate and evaluate the educationprovided to students with learning disabilities. Outcomes of this study can guide good practice and policy regarding identification and school management in Turkey as well as other countries going through similar processes in terms of educating students with learning disabilities in mainstream schools