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1.
Am J Physiol Cell Physiol ; 327(2): C423-C437, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38682236

RESUMEN

Sickle cell disease (SCD)-associated chronic hemolysis promotes oxidative stress, inflammation, and thrombosis leading to organ damage, including liver damage. Hemoglobin scavenger receptor CD163 plays a protective role in SCD by scavenging both hemoglobin-haptoglobin complexes and cell-free hemoglobin. A limited number of studies in the past have shown a positive correlation of CD163 expression with poor disease outcomes in patients with SCD. However, the role and regulation of CD163 in SCD-related hepatobiliary injury have not been fully elucidated yet. Here we show that chronic liver injury in SCD patients is associated with elevated levels of hepatic membrane-bound CD163. Hemolysis and increase in hepatic heme, hemoglobin, and iron levels elevate CD163 expression in the SCD mouse liver. Mechanistically we show that heme oxygenase-1 (HO-1) positively regulates membrane-bound CD163 expression independent of nuclear factor erythroid 2-related factor 2 (NRF2) signaling in SCD liver. We further demonstrate that the interaction between CD163 and HO-1 is not dependent on CD163-hemoglobin binding. These findings indicate that CD163 is a potential biomarker of SCD-associated hepatobiliary injury. Understanding the role of HO-1 in membrane-bound CD163 regulation may help identify novel therapeutic targets for hemolysis-induced chronic liver injury.


Asunto(s)
Anemia de Células Falciformes , Antígenos CD , Antígenos de Diferenciación Mielomonocítica , Biomarcadores , Hemo-Oxigenasa 1 , Hemoglobinas , Hemólisis , Receptores de Superficie Celular , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antígenos de Diferenciación Mielomonocítica/genética , Anemia de Células Falciformes/metabolismo , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/complicaciones , Antígenos CD/metabolismo , Antígenos CD/genética , Animales , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/genética , Humanos , Biomarcadores/metabolismo , Biomarcadores/sangre , Hemo-Oxigenasa 1/metabolismo , Hemoglobinas/metabolismo , Ratones , Masculino , Hígado/metabolismo , Hígado/patología , Femenino , Ratones Endogámicos C57BL , Adulto , Factor 2 Relacionado con NF-E2/metabolismo , Hemo/metabolismo , Hepatopatías/metabolismo , Hepatopatías/patología , Transducción de Señal , Haptoglobinas/metabolismo , Proteínas de la Membrana
2.
Front Immunol ; 12: 700045, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34539628

RESUMEN

We report a first in-depth comparison of immune reconstitution in patients with HIV-related lymphoma following autologous hematopoietic cell transplant (AHCT) recipients (n=37, lymphoma, BEAM conditioning), HIV(-) AHCT recipients (n=30, myeloma, melphalan conditioning) at 56, 180, and 365 days post-AHCT, and 71 healthy control subjects. Principal component analysis showed that immune cell composition in HIV(+) and HIV(-) AHCT recipients clustered away from healthy controls and from each other at each time point, but approached healthy controls over time. Unsupervised feature importance score analysis identified activated T cells, cytotoxic memory and effector T cells [higher in HIV(+)], and naïve and memory T helper cells [lower HIV(+)] as a having a significant impact on differences between HIV(+) AHCT recipient and healthy control lymphocyte composition (p<0.0033). HIV(+) AHCT recipients also demonstrated lower median absolute numbers of activated B cells and lower NK cell sub-populations, compared to healthy controls (p<0.0033) and HIV(-) AHCT recipients (p<0.006). HIV(+) patient T cells showed robust IFNγ production in response to HIV and EBV recall antigens. Overall, HIV(+) AHCT recipients, but not HIV(-) AHCT recipients, exhibited reconstitution of pro-inflammatory immune profiling that was consistent with that seen in patients with chronic HIV infection treated with antiretroviral regimens. Our results further support the use of AHCT in HIV(+) individuals with relapsed/refractory lymphoma.


Asunto(s)
Infecciones por VIH/inmunología , Infecciones por VIH/terapia , Trasplante de Células Madre Hematopoyéticas , Reconstitución Inmune/inmunología , Linfoma Relacionado con SIDA/terapia , Ensayos Clínicos Fase II como Asunto , Humanos , Trasplante Autólogo/métodos
3.
Front Oncol ; 10: 1723, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33102204

RESUMEN

Epstein-Bar virus (EBV) can directly cause lymphoproliferative disease (LPD), including AIDS-defining lymphomas such as Burkitt's lymphoma and other non-Hodgkin lymphomas (NHL), as well as human immunodeficiency virus (HIV)-related Hodgkin lymphoma (HL). The prevalence of EBV in HL and NHL is elevated in HIV-positive individuals compared with the general population. Rates of incidence of AIDS-defining cancers have been declining in HIV-infected individuals since initiation of combination anti-retroviral therapy (cART) use in 1996. However, HIV-infected persons remain at an increased risk of cancers related to infections with oncogenic viruses. Proposed pathogenic mechanisms of HIV-related cancers include decreased immune surveillance, decreased ability to suppress infection-related oncogenic processes and a state of chronic inflammation marked by alteration of the cytokine profile and expanded numbers of cytotoxic T lymphocytes with down-regulated co-stimulatory molecules and increased expression of markers of senescence in the setting of treated HIV infection. Here we discuss the cooperation of EBV-infected B cell- and environment-associated factors that may contribute to EBV-related lymphomagenesis in HIV-infected individuals. Environment-derived lymphomagenic factors include impaired host adaptive and innate immune surveillance, cytokine dysregulation and a pro-inflammatory state observed in the setting of chronic, cART-treated HIV infection. B cell factors include distinctive EBV latency patterns and host protein expression in HIV-associated LPD, as well as B cell-stimulating factors derived from HIV infection. We review the future directions for expanding therapeutic approaches in targeting the viral and immune components of EBV LPD pathogenesis.

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