Impact of cytokines/chemokines on epigenetic modifications in immune cells isolated from healthy Down syndrome individuals Restricted; Files Only

Abstract

Down syndrome (DS) is the most common genetic disorder, affecting individuals’ development, neurological function, and immune system. DS is caused by the trisomy of chromosome 21, which encodes 4/6 IFN receptors, causing over signaling of immune cells and thus chronic inflammation. It is proposed that epigenetic modifications of histones have an impact on the immune system signaling and cell functions. The circulating cytokines, immune cell frequencies, and histone modifications of H3K27Me3, H3K4Me3, and H3K9Ac were analyzed in a cohort of DS (n = 51) and non-down syndrome (n=59) individuals from São Paulo, Brazil. The cytokine analysis revealed that DS individuals had lower levels of TGF-β1 and TGF- β2, but higher levels of TGF- β3 and IL-10, and 9 out of the 38 chemokines were significantly elevated. The immune cell phenotypes (monocytes, natural killer cells, CD4⁺ and CD8⁺ lymphocytes, and B lymphocytes) were also found to be significantly different between the groups. All three histone modifications were upregulated in DS compared to non-DS individuals in four out of the six immune subsets analyzed. Finally, correlations between H3K27Me3, H3K4Me3, and H3K9Ac modifications to circulating levels of IL-10, FLT3 ligand, TGF-β1, and TGF- β2 were established. These findings suggest that DS has distinct immunological characteristics, which are modulated through cytokine/chemokine expression and epigenetics. The results have implications for understanding the immune dysregulation in DS individuals, which may lead to the development of novel therapeutic interventions.

Table of Contents

Introduction ............................................................................................................................................................... 1 

Down Syndrome ......................................................................................................................................................... 1 

Immune System Overview ........................................................................................................................................... 2 

Cytokine Profile ......................................................................................................................................................... 3 

Natural Killer Cells ..................................................................................................................................................... 5 

Dendritic Cells ........................................................................................................................................................... 6 

Monocytes ................................................................................................................................................................. 6 

CD4+ T Cells .............................................................................................................................................................. 7 

CD8+ T Cells .............................................................................................................................................................. 7 

B Cells ....................................................................................................................................................................... 8 

Epigenetics ................................................................................................................................................................ 9 

Objectives and Hypothesis ..........................................................................................................................................11 

Methods ....................................................................................................................................................................12 

Cohort and Sample Collection.....................................................................................................................................12 

Thawing of PBMC Samples .........................................................................................................................................12 

Immunofluorescent Cell Staining ................................................................................................................................13 

Flow Cytometer .........................................................................................................................................................13 

Cytokine Assay ..........................................................................................................................................................14 

Statistics ...................................................................................................................................................................15 

Results ......................................................................................................................................................................16 

Cytokine Profile .........................................................................................................................................................16 

Immune Cell Populations ...........................................................................................................................................19 

Epigenetic Modifications ...........................................................................................................................................24 

Cytokine/Chemokine Association with Epigenetic Modifications ...................................................................................26 

Feature Selection ......................................................................................................................................................28 

Discussion ................................................................................................................................................................29 

Cytokine Profile ........................................................................................................................................................29 

Immune Cell Populations ..........................................................................................................................................31 

Epigenetic Modifications...........................................................................................................................................32 

Cytokine/chemokines Influences of Epigenetic Modifications ......................................................................................32 

Limitations and Future Directions .............................................................................................................................34 

Conclusion...............................................................................................................................................................36 

Supplemental Information.........................................................................................................................................37 

References ................................................................................................................................................................42 

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Cell
Palabra Clave	Immunology Biology Histone modifications Epigenetics Down Syndrome
Committee Chair / Thesis Advisor	Susan Pereira Ribeiro, Emory University
Committee Members	Arri Eisen, Emory University Christina Gavegnano, Emory University

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