Abstract
The study of inborn errors of immunity (IEI) provides unique opportunities to elucidate the microbiome and pathogenic mechanisms related to severe viral infection. Several immunological and genetic anomalies may contribute to the susceptibility to develop Human Papillomavirus (HPV) pathogenesis. They include different acquired immunodeficiencies, EVER1-2 or CIB1 mutations underlying epidermodysplasia verruciformis (EV) syndrome and multiple IEI. Whereas EV syndrome patients are specifically unable to control infections with beta HPV, individuals with IEI show broader infectious and immune phenotypes. The WHIM (warts, hypogammaglobulinemia, infection, and myelokathexis) syndrome caused by gain-of-CXCR4-function mutation manifests by HPV-induced extensive cutaneous warts but also anogenital lesions that eventually progress to dysplasia. Here we report alterations of B and NK cells in a female patient suffering from cutaneous and mucosal HPV-induced lesions due to an as-yet unidentified genetic defect. Despite no detected mutations in CXCR4, B but not NK cells displayed a defective CXCR4-dependent chemotactic response toward CXCL12. In addition, NK cells showed an abnormal distribution with an expanded CD56bright cell subset and defective cytotoxicity of CD56dim cells. Our observations extend the clinical and immunological spectrum of IEI associated with selective susceptibility toward HPV pathogenesis, thus providing new insight on the immune control of HPV infection and potential host susceptibility factors.
Highlights
More than 200 types of human papilloma virus (HPV) ordered into 5 genera have been recognized and classified as cutaneous or mucosal according to their tropism [1]
We explored the expression level of CCR7, a chemokine receptor controlling the homing to secondary lymphoid tissues of naïve T and B lymphocytes and CD56bright NK cells, as well as the expression level of CXCR5, controlling homing of B lymphocytes to follicular compartments on secondary lymphoid tissues [20, 21]
As compared with healthy donor (HD), CXCR4 was expressed at normal levels in patient’s CD4+ and CD8+ T lymphocytes, slightly reduced in NK cells yet it was increased in B lymphocytes
Summary
More than 200 types of human papilloma virus (HPV) ordered into 5 genera have been recognized and classified as cutaneous or mucosal according to their tropism [1]. The transwell migration assay showed that CD4+ and CD8+ T lymphocytes as well as NK cells derived from the patient’s blood displayed a normal chemotactic response towards CXCL12 (Figure 1C), despite the reduction of CXCR4 expression we observed on patient’s NK cells. The CCR7-dependent chemotactic response to CCL19 of these lymphocyte subsets was equivalent in patient- and HD-derived cells, despite the observed differences in relative CCR7 expression levels. For the patient-derived B lymphocytes, the CXCR4dependent chemotactic response was strongly reduced as compared to HD-derived cells, with a loss of chemotactic efficacy of 51 ± 7.6% and 80 ± 2.8% in response to 50 nM CXCL12 and 100 nM CXCL12, respectively (Figure 1C), in spite of increased expression levels of CXCR4 on B lymphocytes. Values are indicated as median (IQR, interquartlile range). *1.7(0.1-6) and 25(2.5-80) in CMV-seronegative and -seropositive subjects, respectively [22]. y, years
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