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

Abstract

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.

Protection against severe infant lower respiratory tract infections by immune training: Mechanistic studies

“…Additionally, the study involved a high-risk cohort and needs to be repeated in an unselected population. Moreover, while there are an expanding number of precedents for suggesting a key role 49 in immune modulation for gene network rewiring in the absence of overt changes in differential expression profiles, [49][50][51] the contribution of different cell populations in such processes remains obscure. In this regard, animal model studies suggest that myeloid precursor cells may be key targets for OM85-mediated IT effects, 18,19 and this possibility merits follow-up that uses recently developed single-cell RNA sequencing technologies.…”

Advances and highlights in allergic rhinitis

“…63 Furthermore, as type 1 IFNs negatively control many of the downstream proinflammatory effects of Th2 cytokines, a fusion with an upregulated type 1 interferon signaling module may potentially stabilize Th2 response in the second year of SCIT. 63 A comprehensive longitudinal analysis of the systemic innate immune cell repertoire during the course of AIT has demonstrated a sustained decrease of group ILC2s and increase in group ILC1s after AIT, as well as a shift in monocytes from a proinflammatory (non-classical) to an anti-inflammatory (intermediate) phenotype, and up-regulation of plasmacytoid dendritic cells (pDCs) and CD141 + myeloid DCs in the first year of AIT. 64 However, overall evidence of the immunomodulatory properties of AIT on T cells, B cells, ILC2s, monocytes, and DCs, and the understanding of the collective effects of these immune cells in AIT are relatively scant.…”

“…Interestingly, SLIT has also been shown to induce differentiation of IL‐10–producing ILC2s from ILC2 precursors regulating the pathology of grass pollen‐induced allergy 62 . Unbiased systems‐level gene co‐expression network analysis has demonstrated that the reduction of early symptom in the early phase of SCIT is associated with initial merging of Th2‐effector and IL‐2/T‐regulatory network modules, without major quantitative changes in gene expression 63 . Furthermore, as type 1 IFNs negatively control many of the downstream proinflammatory effects of Th2 cytokines, a fusion with an upregulated type 1 interferon signaling module may potentially stabilize Th2 response in the second year of SCIT 63 .…”

“…Unbiased systems‐level gene co‐expression network analysis has demonstrated that the reduction of early symptom in the early phase of SCIT is associated with initial merging of Th2‐effector and IL‐2/T‐regulatory network modules, without major quantitative changes in gene expression 63 . Furthermore, as type 1 IFNs negatively control many of the downstream proinflammatory effects of Th2 cytokines, a fusion with an upregulated type 1 interferon signaling module may potentially stabilize Th2 response in the second year of SCIT 63 . A comprehensive longitudinal analysis of the systemic innate immune cell repertoire during the course of AIT has demonstrated a sustained decrease of group ILC2s and increase in group ILC1s after AIT, as well as a shift in monocytes from a proinflammatory (non‐classical) to an anti‐inflammatory (intermediate) phenotype, and up‐regulation of plasmacytoid dendritic cells (pDCs) and CD141 + myeloid DCs in the first year of AIT 64 .…”

Unlocking immune-mediated disease mechanisms with transcriptomics

“…By focusing on the correlation structure of the data, WGCNA can unveil mechanisms that are not detected through differential expression analysis. Jones et al [ 23 ] demonstrate this principle in a recent longitudinal study of CD4+ T-cell responses to house dust mite (HDM) during HDM-specific immunotherapy in allergic rhinitis patients. The authors reported that no differentially expressed genes were identified with respect to treatment effect during immunotherapy.…”