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IgG immunocomplexes sensitize human monocytes for inflammatory hyperactivity via transcriptomic and epigenetic reprogramming in Rheumatoid Arthritis

ABSTRACT: Prevalence of circulating immunocomplexes (ICs) strongly correlates with rheumatoid arthritis (RA) in humans. Deposits of IgG-ICs are abundant in affected joints of patients, yet molecular mechanisms for the pathogenic roles of such ICs are not fully understood. In this study, we present evidence that IgG-ICs precipitated from RA sera sensitized human monocytes for a long lasting inflammatory functional state, characterized by a strong TNF-a response to cellular proteins representing damage associated molecular patterns and microbe-derived pathogen-associated molecular patterns. Importantly, plate-coated human IgG (a mimic of deposited IC without Ag restriction) exhibited a similarly robust ability of monocyte sensitization in vitro. The plate-coated human IgG–induced functional programming is accompanied by transcriptomic and epigenetic modification of various inflammatory cytokines and negative regulator genes. Moreover, macrophages freshly isolated from synovia of patients with RA, but not sera-negative arthropathy, displayed a signature gene expression profile highly similar to that of IC-sensitized human monocytes, indicative of historical priming events by IgG-ICs in vivo. Thus, the ability of IgG-ICs to drive sustainable functional sensitization/reprogramming of monocytes and macrophages toward inflammation may render them key players in the of RA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE102728 | GEO | 2017/10/15

SECONDARY ACCESSION(S): PRJNA398510

REPOSITORIES: GEO

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Project description:Preschool children with recurrent wheezing are heterogeneous, with differing responses to respiratory viral infections. Although neutrophils are crucial for host defense, their function has not been studied in this population. We performed functional immunophenotyping on isolated blood neutrophils from 52 preschool children with recurrent wheezing (aeroallergen sensitization, n=16; no sensitization, n=36). Blood neutrophils were purified and cultured overnight with polyinosinic:polycytidylic acid (poly(I:C)) as a viral analog stimulus. Neutrophils underwent next-generation sequencing with Reactome pathway analysis and were analyzed for cytokine secretion, apoptosis, myeloperoxidase and extracellular DNA release. CD14+ monocytes were also exposed to neutrophil culture supernatant and analyzed for markers of M1 and M2 activation. 495 genes, related largely to the innate immune system and neutrophil degranulation, were differently expressed in children with versus without aeroallergen sensitization. Functional experiments identified more neutrophil degranulation and extracellular trap formation (i.e., more myeloperoxidase and extracellular DNA) and less neutrophil pro-inflammatory cytokine secretion in children with aeroallergen sensitization. Neutrophils also shifted CD14+ monocytes to a more anti-inflammatory (i.e., M2) phenotype in sensitized children and a more pro-inflammatory (i.e., M1) phenotype in non-sensitized children. Although both groups experienced viral exacerbations, annualized exacerbation rates prompting unscheduled healthcare were also higher in children without aeroallergen sensitization after enrollment. Systemic neutrophil responses to viral infection differ by allergic phenotype and may be less effective in preschool children without allergic inflammation. Further studies of neutrophil function are needed in this population, which often has less favorable therapeutic responses to inhaled corticosteroids and other therapies directed at T2-high inflammation.

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IgG immunocomplexes sensitize human monocytes for inflammatory hyperactivity via transcriptomic and epigenetic reprogramming in Rheumatoid Arthritis

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