THE RESULTS OF THE SEARCH FOR LABORATORY SIGNS OF AUTOIMMUNE REACTIONS TO CEREBRAL AND EXTRACEREBRAL AUTOANTIGENS IN CHILDREN WITH AUTISM SPECTRUM DISORDERS ASSOCIATED WITH GENETIC DEFICIENCY OF THE FOLATE CYCLE

Abstract

Relevance. The results of five meta-analyzes of randomized controlled clinical trials indicate an association between genetic deficiency of the folate cycle (GDFC) and autism spectrum disorders (ASD) in children. Autoimmune mechanisms play a special role in the pathogenesis of encephalopathy in children with ASD associated with GDFC. Objective: to study the structure of autoimmune reactions in children with ASD associated with GDFC, according to the accumulated evidence base and to identify associations of laboratory signs of autoimmunity and microorganisms to improve understanding of encephalopathy pathogenesis and diagnostic, monitoring and treatment algorithms. Materials and methods. The medical data of 225 children aged 2 to 9 years with GDFC, who had clinical manifestations of ASD (183 boys and 42 girls) were retrospectively analyzed. The diagnosis of ASD was made by child psychiatrists according to the criteria DSM-IV-TR (Diagnostic and Statistical Manual of mental disorders) and ICD-10 (The International Statistical Classification of Diseases and Related Health Problems) (study group; SG). The control group (CG) included 51 clinically healthy children (37 boys and 14 girls) of similar age and gender distribution who did not suffer from GDFC and ASD. Pathogenic polymorphic variants of folate cycle genes were determined by PCR with restriction (Sinevo, Ukraine). Autoantibodies to autoantigens of CNS subcortical ganglion neurons in blood serum were determined using a Cunningham panel (Moleculera Labs, Inc, USA). Serum autoantibodies to neurons of the mesolimbic system of the brain were identified by ELISA (MDI Limbach Berlin GmbH, Germany). Autoimmunization to myelin was assessed by serum autoantibody titer to basic myelin protein (ELISA) and signs of neutrophil and CD8+ T-lymphocyte sensitization to hemispheric white matter autoantigens (cell-based assay; department of neuroimmunology at the Neurosurgery Institute; Ukraine). Serum autoantibodies to nuclei of connective tissue cells and striated muscle proteins were determined by western blot analysis (Sinevo, Ukraine). To determine the significance of the differences between the indicators in the observation groups, we used the Student's parametric T-test with the confidence probability p and the nonparametric criterion – the number of signs Z according to Urbach Yu.V. The odds ratio (OR) and the 95% confidence interval (95% CI) were used to study the associations between the studied indicators. The study was performed as a fragment of research work commissioned by the Ministry of Health of Ukraine (№ state registration 0121U107940). Research. Positive results of the Cunningham panel occurred in 32%, laboratory signs of autoimmunization to neurons of the mesolimbic system – 36%, myelin of white matter of the hemispheres – 43%, nuclei autoantigens of connective tissue cells – 53%, proteins of striated muscles – 48% of cases among children SG (in general – 68% of cases; p < 0.05; Z < Z0.05). Serological signs of autoimmunization to autoantigens of the subcortical ganglia of the cerebral hemispheres were associated with Streptococcus pyogenes and Borrelia, to neurons of the mesolimbic system – EBV, HHV-6, HHV-7, Toxoplasma and TTV, to CNS myelin – EBV, HHV-6, HHV-7, Borrelia and TTV, to the nuclei of connective tissue cells and striated muscles – EBV, HHV-6, HHV-7, Borrelia and TTV. Conclusions. In children with ASD associated with GDFC laboratory sings of microbial-induced autoimmunity to a number of cerebral and extracerebral autoantigens has been evaluated, which affects the mental and physical health of patients and is a potential target for effective therapeutic interventions.