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

BACKGROUND: 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-induced Th-cell responses prospectively during 24mths subcutaneous immunotherapy (SCIT) in 25 rhinitics, documenting changes in immunoinflammatory pathways and associated co-expression networks and their relationships to symptom scores out to 36mths. RESULTS: Prior to immunotherapy, mite-induced Th-cell 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% symptom reduction, however network analysis revealed underlying merging of FOXP3/IL2- with Inflammation- and Th2-associated modules. By 12mths 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 mite-induced Th-cell-associated Th2-, FOXP3/IL2-, Inflammation-, and finally Type1-IFN-signalling subnetworks, forming a single highly integrated co-expression network module, maximising potential for stable homeostatic control of allergen-induced Th2 responses via cross-regulation. Th2-antagonistic Type1-IFN signalling may play a key role in stabilising clinical effects of SCIT.