Premium
Rewiring of gene networks underlying mite allergen‐induced CD4 + Th‐cell responses during immunotherapy
Author(s) -
Jones Anya C.,
Anderson Denise,
Troy Niamh M.,
Mallon Dominic,
Hartmann Rochelle,
Serralha Michael,
Holt Barbara,
Bosco Anthony,
Holt Patrick G.
Publication year - 2020
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.14265
Subject(s) - foxp3 , immunotherapy , immunology , inflammation , house dust mite , medicine , t cell , regulator , allergy , biology , immune system , allergen , gene , genetics
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 24 months subcutaneous immunotherapy (SCIT) in 25 rhinitis, documenting changes in immunoinflammatory pathways and associated co‐expression networks and their relationships to symptom scores out to 36 months. 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 3.5 months 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 12 months SCIT, symptoms had reduced by 41% without further significant changes to pathway/upstream regulator or network profiles. Continuing SCIT to 24 months stabilized 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 Subcutaneous immunotherapy 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, maximizing potential for stable homeostatic control of allergen‐induced Th2 responses via cross‐regulation. Th2‐antagonistic type1 IFN signalling may play a key role in stabilizing clinical effects of SCIT.