Type I Interferon Response and Vascular Alteration in Chilblain-like Lesions During the COVID-19 Outbreak

Discussion

Beyond classical COVID-19 symptoms, several publications have reported CLL potentially associated with SARS-CoV-2 infection.^[2,17] The epidemiology and clinical features of CLL have been extensively studied and published; however, little is known about the pathophysiology of CLL. This study illustrates that both the immune system and endothelial cells play a critical role in the genesis of CLL.

The relationship between SARS-CoV-2 infection and CLL is still controversial; however, recurrence of previous chilblain lesions during the second wave of COVID-19 and peaks of CLLs concomitant with peaks of COVID-19 deaths in 2020^[18,19] strongly suggest that this disorder is closely related to SARS-CoV-2 infection.^[20] In our study, SARS-CoV-2 assays were almost all negative except for four serology results at day 0.

As described partially in other studies,^[21–23] the present study showed skin and systemic type I IFN polarization, which could be explained by a strong antiviral response towards SARS-CoV-2 in CLL or other viruses in SC, involving the type I IFN pathway. Histological aspects of CLL included vascular alterations such as lymphocytic infiltrates in vessel walls and microthrombi, but we did not observe true leucocytoclastic vasculitis as seen with SAVI.^[6] This is potentially related to lower IFN levels in CLL.

We also observed a strong cutaneous upregulation of genes related to cytotoxic T cells and natural killer cells. Interestingly, granzyme B has been shown to induce dysregulated angiogenesis and vascular permeability,^[24] and also IFN-γ release by skin keratinocytes.^[25] Altogether, these findings argue for the role of a type I IFN and cytotoxic axis, which has been previously shown to act in synergy^[26] and to be defective in critically ill patients with COVID-19.^[27] Moreover, our results suggest a common pathophysiology between CLL and SC. Even if some patients had positive ANA or low-level complement, none fulfilled at least four of the American College of Rheumatology revised criteria for systemic lupus erythematosus or had histologically ascertained cutaneous discoid lupus lesions.

Small-vessel vasculitis includes ANCA-related vasculitis, IgA-related vasculitis and cryoprotein-related vasculitis. These are characterized by cutaneous manifestations such as purpura, livedo or ulcers.^[28,29] In this study we found a low prevalence of cryofibrinogenaemia, inconsistently with a previous study.^[30] However, we found a high prevalence of ANCA of the IgA isotype, seen in 73% of patients with CLL and in 100% with SC, associated with vascular and interstitial IgA deposition. The association of systemic and local IgA activation could explain the cutaneous vasculitis with a possible postviral pathophysiology, in both CLL and SC. Indeed, IgA anti-SARS-CoV-2 is the first immunoglobulin detectable after SARS-CoV-2 infection,^[16] and several studies have highlighted COVID-19-related IgA manifestations.^[31–33]

The pathogenicity of IgA ANCA found in our patients with CLL remains unclear, but previous reports suggest their potential implication in erythema elevatum diutinum, skin vasculitis, ulcerative colitis and granulomatosis with polyangiitis.^[34,35] The vasculitis observed in our patient was mainly composed of lymphocytes, which is unusual. Indeed, IgA immune-complex vasculitis is usually associated with neutrophil infiltration, partially explained by the fact that IgA complexes can activate neutrophils via the IgA Fc receptor FcαRI (CD89), thereby inducing neutrophil migration and activation, which ultimately cause tissue damage.^[36] It has been shown that ANCA can recognize vascular endothelial cell-bound ANCA-associated autoantigens, such as myeloperoxidase, finally leading to complement activation and vascular injury.^[37]

Vascular and endothelial injury has been shown to be the hallmark of SARS-CoV-2 infection and could explain, at least in part, the pathophysiology of CLL. Our study confirms the increase of cutaneous histological and systemic markers (angiopoietin-1, angiopoietin-2 and VEGF-A) of endothelial dysfunction with normalization over time. The transcriptomic analysis revealed that both the complement pathway and angiogenesis seemed specifically activated in CLL compared with SC. We previously described an increase at admission in angiopoietin-2 and von Willebrand factor related to worsening of patients with COVID-19,^[10,38] which supports the role of microcirculatory dysfunction. Angiopoietin-2 is a regulator of angiogenesis that can be rapidly released by activated endothelium in the presence of thrombin or inflammatory cytokines, and participates in the responsiveness of endothelium to inflammatory, hyperpermeability apoptosis. This injury could be explained (i) by activation or apoptosis of endothelial cells by the immune system, notably cytotoxic molecules, or (ii) through complement-mediated microvascular injury.^[39]

In conclusion, our findings support an activation loop in the skin in CLL, which associates with endothelial alteration and immune infiltration of cytotoxic and type I IFN-polarized cells leading to clinical manifestation.

The British Journal of Dermatology. 2021;185(6):1176-1185. © 2021 Blackwell Publishing