Epidermodysplasia Verruciformis: Inborn Errors of Immunity to Human Beta-Papillomaviruses

Abstract

Epidermodysplasia verruciformis (EV) is an autosomal recessive skin disorder with a phenotype conditional on human beta-papillomavirus (beta-HPV) infection. Such infections are common and asymptomatic in the general population, but in individuals with EV, they lead to the development of plane wart-like and red or brownish papules or pityriasis versicolor-like skin lesions, from childhood onwards. Most patients develop non-melanoma skin cancer (NMSC), mostly on areas of UV-exposed skin, from the twenties or thirties onwards. At least half of the cases of typical EV are caused by biallelic loss-of-function mutations of TMC6/EVER1 or TMC8/EVER2. The cellular and molecular basis of disease in TMC/EVER-deficient patients is unknown, but a defect of keratinocyte-intrinsic immunity to beta-HPV is suspected. Indeed, these patients are not susceptible to other infectious diseases and have apparently normal leukocyte development. In contrast, patients with an atypical form of EV due to inborn errors of T-cell immunity invariably develop clinical symptoms of EV in the context of other infectious diseases. The features of the typical and atypical forms of EV thus suggest that the control of beta-HPV infections requires both EVER1/EVER2-dependent keratinocyte-intrinsic immunity and T cell-dependent adaptive immunity.

Cross-talk of cutaneous beta human papillomaviruses and the immune system: determinants of disease penetrance

“…There are several lines of evidence that host cellautonomous and extrinsic immunological conditions play an eminent role in the control of beta-HPVs in the general population. Studies in EV patients were seminal for this understanding [45]. Recent data strongly indicate that in these patients, the beta-HPV-specific keratinocyte-intrinsic restriction is lost owing to genetic mutation.…”

“…In such OTRs, the incidence of cSCCs is increased more than 100-fold, and infections with multiple beta-HPVs are observed with higher viral loads than in the general population [9,67]. Although OTRs generally do not present with symptoms of overt EV-like disease [45], actively replicating beta-HPV infection was demonstrated in actinic keratosis and epithelium adjacent to cSCCs of these patients [68]. Taken together, these studies strongly suggest that beta-HPVs are under strict control of host cell-autonomous as well as extrinsic, particularly T-cell-mediated, immunity.…”

Epidermodysplasia Verruciformis: Functional Role of E6 and E7 Oncoproteins as the Link between Viral Infection to Carcinogenesis

“…So in a way, the EVER/Zn-T complex regulates the activity of many transcription factors by modulating the zinc efflux and influx. 27 When the cell surface gets triggered, free zinc ions get released from the endoplasmic reticulum, causing a phenomenon called as the zinc wave followed by the binding of the zinc ions to the zinc finger. Zinc fingers are the cysteine-based protein domains to which the zinc ions bind to.…”

A CIB1 Splice-Site Founder Mutation in Families with Typical Epidermodysplasia Verruciformis

“…TO THE EDITOR Epidermodysplasia verruciformis (EV), an autosomal recessive genodermatosis, is characterized by persistent cutaneous infections of human papilloma viruses (HPVs) of the b-genus (de Jong et al, 2018a;Huang et al, 2018). The early clinical manifestations include thin, tinea versicolor-like lesions and flat warts that develop to protruding tumors.…”