Characterization of Innate Immune Cells in Patients with the Interferon-Mediated Autoinflammatory Diseases Sting Associated Vasculopathy with Onset in Infancy (SAVI) and Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE)

Bernadette Marrero¹, Yin Liu², Katherine R. Calvo³, Angelique Biancotto⁴, Yan Huang¹, Adriana Almeida de Jesus¹, Gina A. Montealegre Sanchez¹ and Raphaela Goldbach-Mansky⁵, ¹National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, ²Scientific Review Branch, NIAMS, NIH, Bethesda, MD, ³Department of Laboratory Medicine, Hematology Section, National Institutes of Health Clinical Center, Bethesda, MD, ⁴Center for Human Immunology, Autoimmunity and Inflammation, NHLBI/NIH, Bethesda, MD, ⁵Translational Autoinflammatory Disease Studies, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Autoinflammatory Disease, interferons, phenotypes and vasculitis

Session Information

Date: Tuesday, November 15, 2016

Title: Pediatric Rheumatology – Pathogenesis and Genetics - Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: We recently described two rare autoinflammatory interferonopathies, STING Associated Vasculopathy with Onset in Infancy (SAVI) and Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE), caused by mutations in TMEM173/STING and in proteasome components, respectively which present with systemic inflammation and a strong IFN response gene signature. However the cellular source for Type I IFN remains unknown.

Methods: The cellular origin of Type I IFN was assessed in FACS sorted PBMCs (T, B, NK and monocytes) from SAVI (n=5) and CANDLE (n=6) patients compared to healthy controls (HC), and from lesional skin biopsies, n=3 for SAVI and for CANDLE. Type I IFN transcription and production and cell activation status were evaluated. Most CANDLE and SAVI pts were on JAK inhibitor treatment.

Results: Serum IFNa levels were increased in SAVI and CANDLE compared to HCs, IFNb is not reliably measured. SAVI pts’ monocytes had 481-fold [IQR 56-38,242] increased IFNB1 expression compared to HCs and CANDLE pts. However, during a CANDLE disease flare, monocyte IFNB1 transcription increased 4 and 51 fold. IFNA7/IFNA17 is constitutively 60 fold increased [IQR3-116] in SAVI but not in CANDLE. Monocyte depletion reduced the IFN message by 90% in the monocyte of PBMC/neutrophil fractions in SAVI pts., pointing to the presence of monocytes in the neutrophil fraction. Intracellular IFNa staining of monocytes confirmed that monocytes and not dendritic cells are the main source of IFNs for SAVI. The mean ratio of IFNB1 to IFNA7/17 was 1200:1 in SAVI and 1:1 in CANDLE monocytes. STING pathway activation with cGAMP in the presence of a blocker of translational elongation, cycloheximide (CHX), did not block IFNB1 transcription but blocked IFNA1,2,7,17,21 thus confirming constitutive IFNB1 transcription. A left-shift with a 2.3 and 1.5-fold increase of immature CD13lo CD16+ neutrophils in CANDLE and SAVI compared to HC was seen. Activation markers CD36+, CD64, were 87%, 65% on monocytes, and 26.1%, 60.3% on granulocytes in SAVI and CANDLE respectively, (HC 0.22%-5.32%). Morphologically, CANDLE monocytes had the highest content of cytoplasmic vacuoles with 6.4+/-2.1SD vacuoles/cell (V/C) compared to SAVI 3.5+/-2.5SD V/C (p>0.05) and HC 2.2+/-1.2SD V/C (p<0.004). CXCL10/IP-10 serum levels are equally high in CANDLE and SAVI patients and nanostring IP-10 counts were similar in CANDLE and SAVI (314+/-63SEM and 357+/-66SEM p=0.0007), (HC 91+/-14SEM, p<0.05); in skin IP-10 levels were 30-400 fold increased in CANDLE (81,803+/-28,605SEM) than SAVI (28,443+/-20,439SEM, compared to HC (28+/-20SEM, p>0.05).

Conclusion: In conclusion, the source for production of Type I IFNs varies in CANDLE and SAVI with constitutive transcription of IFNB1 in predominantly monocytes in the blood in SAVI pts. In CANDLE and SAVI lesional skin showed similar elevated transcription in IFNAs, and higher levels for IFNB1 in SAVI. IP-10 levels were highest in CANDLE skin samples. Understanding differences in intracellular signaling pathways activating IFN production and the IFN loop is needed to design targeted treatment approaches for the different interferonopathies.

Disclosure: B. Marrero, None; Y. Liu, None; K. R. Calvo, None; A. Biancotto, None; Y. Huang, None; A. Almeida de Jesus, None; G. A. Montealegre Sanchez, None; R. Goldbach-Mansky, None.

To cite this abstract in AMA style:

Marrero B, Liu Y, Calvo KR, Biancotto A, Huang Y, Almeida de Jesus A, Montealegre Sanchez GA, Goldbach-Mansky R. Characterization of Innate Immune Cells in Patients with the Interferon-Mediated Autoinflammatory Diseases Sting Associated Vasculopathy with Onset in Infancy (SAVI) and Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE) [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/characterization-of-innate-immune-cells-in-patients-with-the-interferon-mediated-autoinflammatory-diseases-sting-associated-vasculopathy-with-onset-in-infancy-savi-and-chronic-atypical-neutrophilic/. Accessed .

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