Interleukin-17 expression in the serum and exfoliated cervical cells of patients infected with high-risk oncogenic human papillomavirus.

Persistent infection by high-risk oncogenic human papillomavirus (HR-HPV) is the main cause of cervical cancer and its precursor lesions, and both the systemic and local immunological responses play an important role in eliminating or maintenance this infection. Th17 cells, as well as interleukin (IL)-17, are related to tumor growth and persistence of viral infection. Thus, this study aimed to quantify IL-17 in the serum and exfoliated cervical cells of HR-HPV-infected patients and healthy patients as well as identify CD4+IL17+ cells and IL-17 production in uterine cervix biopsies to better understand the behavior of this cytokine in HPV infections. IL-17 was quantified (pg/mL) in the serum and exfoliated cervical cells of 26 HR-HPV-infected patients, and in 18 healthy patients, using flow cytometry. Fifteen paraffin-embedded biopsy samples from the uterine cervix were subjected to immunohistochemistry to detect CD4+IL-17+ and IL-17+ cells. There was a significant increase in the concentration of IL-17 in HR-HPV-positive patients' serum when compared to that in samples of exfoliated cervical cells (p < 0.05). Likewise, when compared with that in healthy patients, the IL-17 concentration was still higher in HR-HPV-positive patients sera (p < 0.05). We did not find differences in the amount of CD4+IL-17+ cells and other IL-17-secreting cells between different histopathological lesions. Our results suggest that HR-HPV infection predominantly stimulates systemic IL-17 production along with less localized expression.

Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS).

Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10, whereas one patient showed additive loss-of-function mutations in PSMB8. Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.