Rewiring of Th-memory-associated gene co-expression networks underlie immunotherapy-induced changes in symptom expression in mite-sensitised atopics [article]

Anya C Jones, Denise Anderson, Niamh M Troy, Dominic Mallon, Rochelle Hartmann, Michael Serralha, Barbara J Holt, Anthony Bosco, Patrick G Holt
2018 bioRxiv   pre-print
Multiple regulatory mechanisms have been identified employing conventional hypothesis-driven approaches as contributing to allergen-specific immunotherapy outcomes, but understanding of how these integrate to maintain immunological homeostasis is incomplete. Objective: To explore the potential for unbiased systems-level gene co-expression network analysis to advance understanding of immunotherapy mechanisms. Methods: We profiled genome-wide allergen-specific Th-memory responses prospectively
more » ... oss 24mths of subcutaneous immunotherapy (SCIT) in 25 rhinitics, documenting changes in immunoinflammatory pathways and associated co-expression networks and their relationships to symptom scores to 36mths. Results: Prior to immunotherapy, mite-specific Th-memory response networks involved multiple discrete co-expression modules including those related to Th2-, Type1-IFN-, Inflammation-, and FOXP3/IL2-associated signalling. A signature comprising 109 genes correlated with symptom scores, and these mapped to cytokine signalling/T-cell activation-associated pathways, with upstream drivers including hallmark Th1/Th2- and inflammation-associated genes. Reanalysis after 3.5mths SCIT updosing detected minimal changes to pathway/upstream regulator profiles despite 32.5% reduction in symptoms, however network analysis revealed underlying merging of FOXP3/IL2- with Inflammation- and Th2-associated modules. By 12mths on SCIT, symptoms had reduced by 41% without further significant changes to pathway/upstream regulator or network profiles. Continuing SCIT to 24mths stabilised symptoms at 47% of baseline, accompanied by upregulation of the Type1-IFN-associated network module and its merging into the Th2/FOXP3/IL2/Inflammation module. Conclusions: SCIT stimulates progressive integration of Th-memory-associated Th2-,FOXP3/IL2-, Inflammation-, and Type1-IFN-signalling subnetworks, forming a single highly integrated co-expression network module, maximising potential for stable homeostatic control of allergen-specific Th2 responses via cross-regulation. Th2-anatogonistic Type1-IFN signalling may play a key role in stabilising clinical effects of SCIT.
doi:10.1101/473561 fatcat:ezs4rb2a2fak7ltwqoede7fgdy