Complement System Dysregulation: A Contributing Factor for Autism Spectrum Disorder?

Poster Presentation
Friday, May 11, 2018: 5:30 PM-7:00 PM
Hall Grote Zaal (de Doelen ICC Rotterdam)
J. Magdalon1, J. S. de Souza1, K. Griesi-Oliveira1, A. L. Teles e Silva1, M. R. Passos-Bueno2 and A. L. Sertie1, (1)Centro de Pesquisa Experimental, Hospital Israelita Albert Einstein, Sao Paulo, Brazil, (2)Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, Sao Paulo, Brazil
Background: Accumulating evidence points toward an important role of the complement system, a critical arm of the innate immune response, in normal brain development and connectivity. Complement cascade components expressed by neuronal and glial cells, such as C1q and C3, have been implicated in developmental pruning of rodent central nervous system synapses. Also, complement C3 fragments and their receptors were shown to positively regulate neurogenesis and neuronal migration in mice models. There is some evidence to suggest that improper complement activation can contribute to Autism Spectrum Disorder (ASD). Association between C4B null alleles and ASD was reported. Increased levels of C1q, complement factor H related protein, C3 and C3 fragments, as well as enhanced activity of complement factor I were found in the plasma of ASD patients. However, the involvement of the complement system in human neurodevelopment and in ASD is still poorly explored and understood.

Objectives: To compare the gene expression patterns of the main components of classical, lectin and alternative complement pathways in neural progenitor cells (NPCs), neurons and astrocytes derived from ASD patients and controls.

Methods: We have generated iPSC-derived NPCs, neurons and astrocytes from 7 patients with idiopathic ASD and from 4 control individuals. The expression levels of lineage specific markers were analyzed by immunofluorescence and RT-qPCR (TaqMan assays). The gene expression levels of complement cascade components (C1QA, C1R, C1S, SERPING1, C3, C3AR1, C5, C5AR1, CD59, C7, C9, MBL2, MASP1, MASP2, CFB, CFD, CFH) were analyzed by RT-qPCR (TaqMan assays). The mRNA expression levels of the target genes were normalized to the expression of the housekeeping genes GAPDH, HMBS and HPRT1.

Results: We observed that: i) iPSCs were successfully differentiated into NPCs, neurons and astrocytes; ii) the gene expression levels of most complement components were higher in neurons than in NPCs and astrocytes; iii) ASD-derived NPCs showed significantly increased levels of C1R and C7, and significantly decreased levels of MASP2 compared to control NPCs; iv) ASD-derived neurons showed significantly increased levels of C3AR1 compared to control neurons; v) ASD-derived astrocytes showed significantly decreased levels of C4 compared to control astrocytes.

Conclusions: Our results suggest that iPSC-derived neuronal and astroglial cells express a complete set of major complement components and therefore, constitute an interesting model to investigate the roles of the complement system in human neurogenesis and in ASD. Also, although further characterization and mechanistic investigation are required, our results point to abnormal complement regulation in ASD.