RESUMEN
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.
Asunto(s)
Dermatitis , Complejo de la Endopetidasa Proteasomal , Humanos , Complejo de la Endopetidasa Proteasomal/genética , Síndrome , CitoplasmaRESUMEN
Persistent human papillomavirus (HPV) infection is closely associated with cervical carcinoma. Co-infection in the endocervical environment with other microorganisms, such as Chlamydia trachomatis, may increase the risk of HPV infection and neoplastic progression. While in some individuals, Chlamydia trachomatis infection is resolved with the activation of Th1/IFN-γ-mediated immune response, others develop a chronic infection marked by Th2-mediated immune response, resulting in intracellular persistence of the bacterium and increasing the risk of HPV infection. This work aimed to quantify cytokines of the Th1/Th2/Th17 profile in exfoliated cervix cells (ECC) and peripheral blood (PB) of patients positive for Chlamydia trachomatis DNA, patients positive for Papillomavirus DNA, and healthy patients. Cytokine levels were quantified by flow cytometry in ECC and PB samples from patients positive for C. trachomatis DNA (n = 18), patients positive for HPV DNA (n = 30), and healthy patients (n = 17) treated at the Hospital de Amor, Campo Grande-MS. After analysis, a higher concentration of IL-17, IL-6, and IL-4 (p <0.05) in ECC; INF-γ and IL-10 (p <0.05) in PB was found in samples from patients positive for C. trachomatis DNA compared to samples from healthy patients. When comparing samples from patients positive for HPV DNA, there was a higher concentration of cytokines IL-17, IL-10, IL-6, and IL-4 (p <0.05) in ECC and IL-4 and IL-2 (p <0.05) in PB of patients positive for C. trachomatis DNA. These results suggest that induction of Th2- and Th17 mediated immune response occurs in patients positive for C. trachomatis DNA, indicating chronic infection. Our results also demonstrate a high concentration of pro-inflammatory cytokines in ECC of patients positive for C. trachomatis DNA.
Asunto(s)
Infecciones por Chlamydia , Infecciones por Papillomavirus , Femenino , Humanos , Chlamydia trachomatis/genética , Virus del Papiloma Humano , Interleucina-10 , Interleucina-17 , Interleucina-6 , Interleucina-4 , Infección Persistente , Infecciones por Chlamydia/microbiología , Citocinas , Papillomaviridae/genéticaRESUMEN
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 (pâ¯<â¯0.05). Likewise, when compared with that in healthy patients, the IL-17 concentration was still higher in HR-HPV-positive patients sera (pâ¯<â¯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.
Asunto(s)
Cuello del Útero/patología , Cuello del Útero/virología , Interleucina-17/sangre , Oncogenes , Papillomaviridae/fisiología , Infecciones por Papillomavirus/sangre , Adulto , Biopsia , Antígenos CD4/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Infecciones por Papillomavirus/patología , Factores de RiesgoRESUMEN
ABSTRACT The HIV-1 initial viral infection may present diverse clinical and laboratory course and lead to rapid, intermediate, or long-term progression. Among the group of non-progressors, the elite controllers are those who control the infection most effectively, in the absence of antiretroviral therapy (ART). In this paper, the TH1, TH2 and TH17 cytokines profiles are described, as well as clinical and laboratory aspects of an HIV-infected patient with undetectable viral load without antiretroviral therapy. Production of IL-6, IL-10, TNF-α, IFN-γ, and IL-17 was detected; in contrast IL-4 was identified. Host-related factors could help explain such a level of infection control, namely the differentiated modulation of the cellular immune response and a non-polarized cytokine response of the TH1 and TH2 profiles.
Asunto(s)
Humanos , Femenino , Adulto , Infecciones por VIH/inmunología , Citocinas/inmunología , VIH-1 , Sobrevivientes de VIH a Largo Plazo , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/virología , Células Th2/inmunología , Células TH1/inmunología , Linfocitos T CD8-positivos/inmunología , Carga Viral , Terapia Antirretroviral Altamente Activa , Inmunidad Celular/inmunologíaRESUMEN
The HIV-1 initial viral infection may present diverse clinical and laboratory course and lead to rapid, intermediate, or long-term progression. Among the group of non-progressors, the elite controllers are those who control the infection most effectively, in the absence of antiretroviral therapy (ART). In this paper, the TH1, TH2 and TH17 cytokines profiles are described, as well as clinical and laboratory aspects of an HIV-infected patient with undetectable viral load without antiretroviral therapy. Production of IL-6, IL-10, TNF-α, IFN-γ, and IL-17 was detected; in contrast IL-4 was identified. Host-related factors could help explain such a level of infection control, namely the differentiated modulation of the cellular immune response and a non-polarized cytokine response of the TH1 and TH2 profiles.