Rewiring of gene networks underlying mite allergen‐induced CD4 + Th‐cell responses during immunotherapy

• DOI: 10.1111/all.14265
• Publication Date: 2020-03-17T13:31:57Z
• Authors: Anya C. Jones; Denise Anderson; Niamh M. Troy; Dominic Mallon; Rochelle Hartmann; Michael Serralha; Barbara Holt; Anthony Bosco; Patrick G. Holt
• Keywords: Allergen Immunotherapy

Multiple regulatory mechanisms have been identified employing conventional hypothesis-driven approaches as contributing to allergen-specific immunotherapy outcomes, but understanding of how these integrate maintain immunological homeostasis is incomplete.To explore the potential for unbiased systems-level gene co-expression network analysis advance mechanisms.We profiled genome-wide allergen-induced Th-cell responses prospectively during 24 months subcutaneous (SCIT) in 25 rhinitis, documenting changes immunoinflammatory pathways and associated networks their relationships symptom scores out 36 months.Prior immunotherapy, mite-induced response involved multiple discrete modules including those related Th2-, type1 IFN-, inflammation- FOXP3/IL2-associated signalling. A signature comprising 109 genes correlated with scores, mapped cytokine signalling/T-cell activation-associated pathways, upstream drivers hallmark Th1/Th2- inflammation-associated genes. Reanalysis after 3.5 SCIT updosing detected minimal pathway/upstream regulator profiles despite 32.5% reduction; however, revealed underlying merging FOXP3/IL2-with inflammation-and Th2-associated modules. By 12 SCIT, symptoms had reduced by 41% without further significant or profiles. Continuing stabilized at 47% baseline, accompanied upregulation IFN-associated module its into Th2/FOXP3/IL2/inflammation module.Subcutaneous stimulates progressive integration Th cell-associated FOXP3/IL2-, finally IFN-signalling subnetworks, forming a single highly integrated module, maximizing stable homeostatic control Th2 via cross-regulation. Th2-antagonistic IFN signalling may play key role stabilizing clinical effects SCIT.