Background/Purpose: Trisomy 8 mosaicism is associated with an inflammatory disease characterized by recurrent fever and oral, genital, and gastrointestinal ulcers, resembling Behçet’s disease. Little is known about the immunologic profile of children with trisomy 8 mosaicism and inflammatory pathways involved in pathogenesis.

Methods: High dimensional flow cytometry was used to characterize peripheral blood mononuclear cells (PBMCs) of 12 subjects with trisomy 8 mosaicism and inflammatory disease and 13 age-matched healthy controls using a Cytek Aurora. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) was used to assess surface markers, transcriptome, and T cell and B cell receptor sequences at the single cell level in PBMCs of 6 subjects with trisomy 8 mosaicism and 3 controls. Analyses were performed in R.

Results: With high dimensional flow cytometry, we found that subjects with trisomy 8 mosaicism had a higher proportion of CD14⁺⁺CD16^– classical monocytes, which also had elevated expression of Ki67, CD64, IL-1β, IL-12p40, and CD169, a type 1 interferon (IFN) stimulated protein. In addition, trisomy 8 subjects had a higher frequency of CD4⁺ T cells and lower frequency of CD8⁺ T cells; both memory CD4⁺ and CD8⁺ T cells had lower expression of HLA-DR, an activation marker. With CITE-seq, we found that trisomy 8 subjects had expansion of classical monocyte populations with prominent IL1B and IFN stimulated gene expression. Moreover, we differentiated trisomy and disomy cells in trisomy 8 subjects using expression levels of chromosome 8 genes. We found that monocytes had a high proportion of trisomy 8 cells, which had higher expression of type I IFN, type II IFN, and IL-1β signaling pathways compared to healthy controls. However, among lymphocytes, naïve T cells had high levels of trisomy 8 cells, while their effector/memory counterparts had low levels. Trisomy 8 memory CD8⁺ T cells had lower expression of cytotoxic genes compared to disomy cells and healthy controls. Significantly fewer trisomy 8 cells were noted among expanded CD8⁺ memory T clones compared to unexpanded clones.

Conclusion: Trisomy 8 mosaicism is associated with an autoinflammatory disease we propose calling trisomy 8-associated autoinflammatory disease or TRIAD. We found expansion and activation of classical monocytes in TRIAD with involvement of IL-1β, IL-12-IFNγ, and type I IFN signaling pathways, which can be treatment targets. However, memory CD8⁺ T cells are less tolerant to trisomy 8, which affects their cytotoxic and proliferative abilities and may affect adaptive immune responses in these subjects.

This research was supported in part by the Division of Intramural Research of NIAID and NHGRI, NIH.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/deep-immunologic-profiling-of-trisomy-8-associated-autoinflammatory-disease-triad/