Identifikation und Analyse von Interaktionen Erreger-spezifischer Antikörper mit Proteinen des fötalen Gehirns
Eine immunologische Grundlage für die Entstehung schizophrener Erkrankungen?
von Aaron David Kleine
Datum der mündl. Prüfung:2023-07-11
Erschienen:2023-12-11
Betreuer:Prof. Dr. Bernhard Reuß
Gutachter:Prof. Dr. Bernhard Reuß
Gutachter:Prof. Dr. Abdul Rahman Asif
Dateien
Name:Dissertation_Kleine_eDiss.pdf
Size:3.40Mb
Format:PDF
Zusammenfassung
Englisch
Schizophrenic disorders affect approximately 1% of the global population and are associated with a significant impairment of mental and physical health. To date, similar to many other neuropsychiatric disorders, there is no clear etiology known. Indications suggest a disrupted fetal brain development, increasing vulnerability to schizophrenic disorders. Epidemiological and experimental studies also indicate an autoimmune basis for this disturbed brain development. Maternally produced antibodies, particularly of the IgG subtype, transferred to the fetus's blood, play a crucial role. Imbalanced maternal immune tolerance and a fragile fetal blood-brain barrier may lead to auto-reactive IgG antibodies coming into contact with fetal neural tissue. If fetal neural proteins structurally or sequentially resemble pathogen-specific epitopes based on molecular mimicry, it can result in auto-reactive interactions and disruption of fetal brain development. This study investigates interactions between pathogen-specific antibodies and fetal neural proteins. The antisera directed against Borrelia burgdorferi, Campylobacter jejuni, Helicobacter pylori, and Toxoplasma gondii were examined. For interaction identification, hEXselect Multiprotein Arrays presenting approximately 10,000 proteins of the prenatal fetal central nervous system in the first trimester were used. Incubating these arrays with pathogen-specific antisera identified 31 interaction partners for Borrelia burgdorferi antisera, including the receptor tyrosine kinase ERBB3 involved in cell proliferative processes. Campylobacter jejuni antisera revealed 107 interaction partners, with the synaptic protein SYT5 identified as a common partner for both Campylobacter jejuni and Helicobacter pylori antisera. Helicobacter pylori antisera showed interactions with 99 fetal proteins, including ASTN2, a neuronal surface protein involved in dendritic growth. 32 interaction partners were identified for Toxoplasma gondii antisera, including the synaptic protein CPLX2 and the neural structural protein SSPO. Interactions were confirmed for ASTN2, CPLX2, ERBB3, and SYT5 through Western blot and 2D gel electrophoresis. Functional tests were conducted using the mast cell line RBL-2H3, neuronal cell lines SiMa and SH-SY5Y, and the breast cancer cell line T-47D. SiMa cells treated with Helicobacter pylori antisera exhibited reduced dendritic growth. Reduced release of synaptic vesicles in SiMa cells treated with Campylobacter jejuni and Helicobacter pylori antisera was observed through FM1-43 and Fluo-3-AM assays. MTT assays demonstrated reduced mitochondrial performance in RBL-2H3 and SH-SY5Y cells treated with Toxoplasma gondii antisera. Post-stimulatory changes in nuclear-cytoplasmic ratio, decreased exocytosis performance, and altered intracellular CPLX2 fluorescence intensity were observed in RBL-2H3 cells under Toxoplasma gondii antisera treatment. Reduced cell proliferation was measured in SH-SY5Y cells treated with Borrelia burgdorferi antisera through KI-67 assay and mitotic figure rate. Using epitope mapping programs, amino acid sequence homology was found between the human protein ERBB3 and the Borrelia burgdorferi protein Erp family outer-surface lipoprotein. The results of this study provide an experimental foundation for deeper exploration of the etiology of neuropsychiatric disorders in the context of autoimmune reactions. The practical relevance of these findings, however, needs further confirmation through additional clinical and in vivo studies in the future.
Keywords: autoimmunity; schizophrenia; molecular mimicry; Borrelia burgdorferi; Campylobacter jejuni; Helicobacter pylori; Toxoplasma gondii
Schlagwörter: Autoimmunität; Schizophrenie; Molekulare Mimicry; Borrelia burgdorferi; Campylobacter jejuni; Helicobacter pylori; Toxoplasma gondii