Background/Purpose: Many genetically defined autoinflammatory diseases (AID) are caused by innate immune dysregulation and present with “neutrophilic dermatoses”. This study systematically assesses immune-cell infiltrates, and interferon (IFN) scores in skin biopsies of 2 IFN-mediated AID: STING-Associated Vasculopathy with onset in Infancy (SAVI) and Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE) and 2 IL-1-mediated AID, Neonatal-onset Multisystem Inflammatory Disease (NOMID) and Deficiency of IL-1 Receptor Antagonist (DIRA). We hypothesize that histopathologic and immunologic features present in skin lesions can distinguish IFN- from IL-1-mediated disorders.

Methods: Tissue from skin lesions of patients with NOMID (n=4), DIRA (n=4), SAVI (n=3), CANDLE (n=5) and other interferonopathies (UIFN) (n=7) were stained with H&E. Immunohistochemistry with antibodies to Myeloperoxidase (MPO/Neutrophil), CD163 (macrophage), CD123 (plasmacytoid dendritic cell (pDC)), CD3 (T cell), CD19 (B cells) was performed. The presence of Neutrophil extracellular traps (NETs, citrullinated histone H4) and IFN-inducible protein (Mx1) were assessed by immunofluorescence. An RNA IFN score was obtained. Inflammatory cells in skin regions were semi-quantitatively scored: 0=absent, 1=scant, 2=moderate or 3=abundant.

Results:

Clinically, NOMID patients present with urticaria, DIRA with pustulosis, CANDLE with nodular rashes and SAVI with acral violaceous vasculitic plaques. Histochemically, dense MPO+ cells within intraepidermal microabscesses were seen only in DIRA. In CANDLE, MPO+ and CD163+ cells were noted predominantly in the deep dermis and sucutis. SAVI had intravascular thrombi, fibrinoid necrosis of vascular wall with abundant perivascular MPO+ and CD163+ cells. Nuclear debris was seen in SAVI and CANDLE. Mild CD123+ cells were seen in dermis and perivascular areas in SAVI and CANDLE; but not in DIRA and rarely in one NOMID sample. CD3+ cells were seen predominantly in dermis and perivascular areas in SAVI, and in periadnexal areas in CANDLE. Dermal CD19+ cells were noted only in a patient with long-standing SAVI. The presence of NETs was evident in NOMID, DIRA and CANDLE, but not in SAVI. SAVI and CANDLE samples have positive Mx-1 staining and high IFN-response gene scores, but not in NOMID and DIRA.

Conclusion: A distinct histologic pattern of neutrophil and macrophage infiltration characterizes SAVI, CANDLE, NOMID and DIRA skin biopsies, while Mx-1 staining and the IFN score distinguish IFN- and IL-1 mediated AID. Thus, the histologic and immunologic assessment of skin biopsies may guide the diagnosis and identify dysregulated immune pathways in AID. Furthermore the skin can serve as a tissue model to evaluate molecular pathways that lead to the skin manifestations in genetically defined and undefined inflammatory diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/histopathologic-features-and-tissue-interferon-response-gene-scoring-of-lesional-skin-samples-for-diagnosis-in-autoinflammatory-disorders/