Session Type: Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: The disease progression of patients (pts.) with type-I interferon (IFN)-mediated diseases undergoing treatment with JAK1 and JAK2 inhibitors is monitored in part by measuring the transcription of a 28 IFN response gene (IRG) signature in whole blood with Nanostring technology to calculate a 28-gene IFN score. We sought to determine the differences in 28-gene IFN scores and in the patterns of IRG signatures among peripheral blood mononuclear cells (PBMCs), monocytes, CD4 and CD8 T cells, B cells, NK cells, and neutrophils in the type-I IFN-mediated diseases CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures) and SAVI (STING-associated vasculopathy with onset in infancy).
Methods: All patients (pts.) were enrolled into an IRB-approved natural history protocol (NCT02974595). RNA was extracted from pts. and healthy control whole blood, PBMCs, monocytes, CD4 and CD8 T cells, B cells, NK cells, and neutrophils. Transcript counts for 28 IRGs and 4 additional genes were measured with a NanoString instrument and compared to expression in the same cells or tissues in a cohort of healthy controls (HCs).
Results: Both CANDLE (p=0.065) and SAVI pts. (p=0.004) had greater 28-gene standardized IFN scores in whole blood and PBMCs compared to HCs. Significantly higher IFN scores were seen in SAVI PBMCs as compared to SAVI whole blood (p=0.035) while CANDLE PBMC IFN scores were not significantly different compared to CANDLE whole blood. SAVI PBMCs expressed more IFNA2 and IFNB1 than PBMCs from CANDLE pts. (p=0.0023; p=0.0012) or HCs (p=0.0097; p=0.0004). One family of SAVI pts. with a novel STING missense variant was found to have elevated IFN scores in their PBMCs while their whole blood IFN scores were not elevated. In cell subsets isolated from PBMCs, CANDLE and SAVI pts. had elevated IFN scores in monocytes and T cells, but the IFN scores in B cells and NK cells were not significantly different from HCs. SAVI pts. had significantly high IFN scores than CANDLE patients in the monocyte (p=0.02) and CD4 T cell (p=0.002) subsets. Within the 28 IRGs of the IFN score, SAVI and CANDLE monocytes had the highest relative expression of IFIT3 and LY6E, respectively. Preliminary studies in neutrophils have also shown that SAVI neutrophils have a greater induction of IRG transcription compared to CANDLE pts.
Conclusion: High expression of type-1 IFNs and IRGs in the PBMCs of SAVI pts. further demonstrate the role of these cells in the amplification of constitutive IFN signaling in this disease. Monocytes make a substantial contribution to the elevated IRG signature in peripheral blood found in both diseases and to a greater extent in SAVI. In addition, pts. with a SAVI phenotype and genotype but a negative IRG signature in whole blood may present an IRG transcription signature when investigating the PBMC fraction.
Funding for this study was provided in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. All patients were enrolled into an IRB-approved natural history protocol.
To cite this abstract in AMA style:Mitchell J, Alehashemi S, Marrero B, Huang Y, Torreggiani S, Bichell L, Montealegre Sanchez G, Goldbach-Mansky R, de Jesus A. Interferon Response Gene Expression Differs in Whole Blood, Peripheral Blood Mononuclear Cells, Monocytes, T Cells, B Cells, and NK Cells in Patients with the Autoinflammatory Interferonopathies, CANDLE and SAVI [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/interferon-response-gene-expression-differs-in-whole-blood-peripheral-blood-mononuclear-cells-monocytes-t-cells-b-cells-and-nk-cells-in-patients-with-the-autoinflammatory-interferonopathies-cand/. Accessed September 24, 2022.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interferon-response-gene-expression-differs-in-whole-blood-peripheral-blood-mononuclear-cells-monocytes-t-cells-b-cells-and-nk-cells-in-patients-with-the-autoinflammatory-interferonopathies-cand/