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BACKGROUND: Estimated glomerular filtration rate (eGFR) calculated using creatinine and cystatin C often differ in older adults. We hypothesized that older adults with cystatin-based eGFR (eGFRcys) values significantly lower than creatinine-based eGFR (eGFRcr) values may have higher risk for aging-related adverse outcomes, independent of kidney function. METHODS: We conducted a longitudinal cohort study of adults ≥65 years old from the Health and Retirement Study, a cohort of older American adults, to determine the relationship between eGFR discordance and aging-related adverse outcomes. We calculated eGFRcr and eGFRcys using baseline creatinine and cystatin C measurements. A large eGFR discordance was defined as eGFRcys >30% lower than eGFRcr. We assessed four aging-related adverse outcomes over a two-year follow-up: falls, hip fractures, hospitalizations, and death. We fit separate multivariable regression models to determine the association between having a large eGFR discordance and each outcome adjusting for confounders including kidney function. RESULTS: Of 5574 older adults, 1683 (30%) had a large eGFR discordance. Those with a large eGFR discordance were more likely to be older, female, and White. The prevalence of a large eGFR discordance increased with age, from 20% among those 65-69 years to 44% among those 80 years and older. Over a two-year follow-up, there were 305 deaths (5.5%), 2013 falls (39.2%), 69 hip fractures (1.3%), and 1649 hospitalizations (32.2%). In adjusted analyses, large eGFR discordance was associated with a higher hazard ratio for death (HR 1.43, 95% CI 1.12-1.82) and significantly higher odds of falls (odds ratio [OR] 1.32, 95% CI 1.16-1.51) and hospitalizations (OR 1.32, 95% CI 1.15-1.51). A large eGFR discordance was not associated with hip fractures. CONCLUSION: In a large, nationally representative cohort of older adults, prevalence of eGFR discordance increased with age and was associated with higher risk of falls, hospitalization, and death, independent of kidney function.
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BACKGROUND: Guidelines for managing abnormal cervical cancer screening results are complex and adherence is challenging for clinicians. Previous studies have identified gaps in knowledge as a possible cause; few have explored the confidence clinicians have in their management decisions. Confidence in decision-making may influence management practices, particularly when guidelines are complex and evolving. OBJECTIVE: Assess whether confidence in decision-making is associated with making guideline-concordant recommendations for abnormal cervical cancer screening results. DESIGN: A clinician survey used vignettes to ask clinicians to make a management recommendation for different abnormal results and rate their level of confidence in their response. PARTICIPANTS: Physicians and advanced practice providers (APPs) at three diverse health systems in Washington, Texas, and Massachusetts. MAIN MEASURES: Correct response to each vignette based on either the 2012 or 2019 American Colposcopy and Cervical Pathology (ASCCP) management guidelines. KEY RESULTS: In total, 501 clinicians completed the survey between October and December 2020 (response rate 53.7%). Overall, most clinicians made guideline-recommended management decisions for two vignettes (73.2 and 73.7%), but fewer were confident in their selection (48.3% and 46.6%, respectively). Clinicians who reported high levels of confidence were more often correct than those who reported lower levels of confidence (85.8% vs. 62.2% and 87.5% vs. 60.7%, both p<0.001). After adjusting for clinician and practice characteristics, confidence remained significantly associated with selecting the correct answer. CONCLUSIONS: Clinician confidence in management decisions for abnormal cervical cancer screening results was significantly associated with knowing guideline-concordant recommendations. Given the complexity of cervical cancer management guidelines, solutions to improve clinician confidence in decision-making are needed.
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BACKGROUND: Follow-up of abnormal results is essential to cervical cancer screening, but data on adherence to follow-up are limited. We describe patterns of follow-up after screening abnormalities and identify predictors of guideline-concordant follow-up. METHODS: We identified the index screening abnormality (positive human papillomavirus test or atypical squamous cells of undetermined significance or more severe cytology) among women of ages 25 to 65 years at three US healthcare systems during 2010 to 2019. We estimated the cumulative incidence of surveillance testing, colposcopy, or treatment after the index abnormality and initial colposcopy. Logistic regressions were fit to identify predictors of guideline-concordant follow-up according to contemporaneous guidelines. RESULTS: Among 43,007 patients with an index abnormality, the cumulative incidence of any follow-up was 49.6% by 4 years for those with atypical squamous cells of undetermined significance/human papillomavirus-negative and higher for abnormalities warranting immediate colposcopy. The 1-year cumulative incidence of any follow-up after colposcopy was 70% for patients with normal results or cervical intraepithelial neoplasia I and 90% for patients with cervical intraepithelial neoplasia II+. Rates of concordant follow-up after screening and colposcopy were 52% and 47%, respectively. Discordant follow-up was associated with factors including age, race/ethnicity, overweight/obese body mass index, and specific types of public payor coverage or being uninsured. CONCLUSIONS: Adherence to the recommended follow-up of cytologic and histopathologic abnormalities is inconsistent in clinical practice. Concordance was poor for mild abnormalities and improved, although suboptimal, for more severe abnormalities. IMPACT: There remain gaps in the cervical cancer screening process in clinical practice. Further study is needed to understand the barriers to the appropriate management of cervical abnormalities.
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Colposcopía , Detección Precoz del Cáncer , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Persona de Mediana Edad , Adulto , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/estadística & datos numéricos , Estados Unidos/epidemiología , Anciano , Colposcopía/estadística & datos numéricos , Adhesión a Directriz/estadística & datos numéricos , Guías de Práctica Clínica como Asunto , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/virologíaRESUMEN
BACKGROUND: Fecal immunochemical test (FIT) is an effective colorectal cancer screening modality. Little is known about prevalence, reasons, and testing after unsatisfactory FIT, or a FIT that cannot be processed by the laboratory due to inadequate stool specimen or incomplete labeling. METHODS: Our retrospective cohort study examined unsatisfactory FIT among average-risk individuals aged 50-74 years in a large, integrated, safety-net health system who completed an index FIT from 2010 to 2019. We determined prevalence of unsatisfactory FIT and categorized reasons hierarchically. We used multivariable logistic regression models to identify factors associated with: (i) unsatisfactory FIT; and (ii) subsequent testing within 15 months of the unsatisfactory FIT. RESULTS: Of 56,980 individuals completing an index FIT, 10.2% had an unsatisfactory FIT. Reasons included inadequate specimen (51%), incomplete labeling (27%), old specimen (13%), and broken/leaking container (8%). Unsatisfactory FIT was associated with being male [OR, 1.10; confidence interval (CI), 1.03-1.16], Black (OR, 1.46; CI, 1.33-1.61), Spanish speaking (OR, 1.12; CI, 1.01-1.24), on Medicaid (OR, 1.42; CI, 1.28-1.58), and received FIT by mail (OR, 2.66; CI, 2.35-3.01). Among those with an unsatisfactory FIT, fewer than half (41%) completed a subsequent test within 15 months (median, 4.4 months). Adults aged 50-54 years (OR, 1.16; CI, 1.01-1.39) and those who received FIT by mail (OR, 1.92; CI, 1.49-2.09) were more likely to complete a subsequent test. CONCLUSIONS: One in ten returned a FIT that could not be processed, mostly due to patient-related reasons. Fewer than half completed a subsequent test after unsatisfactory FIT. IMPACT: Screening programs should address these breakdowns such as specimen collection and labeling to improve real-world effectiveness. See related In the Spotlight, p. 183.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Masculino , Femenino , Estudios Retrospectivos , Prevalencia , Medicaid , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Sangre Oculta , Tamizaje Masivo , ColonoscopíaRESUMEN
BACKGROUND: Despite national policy efforts to increase colorectal cancer (CRC) screening, rates in vulnerable populations remain suboptimal. Many types of interventions have been employed, but their impact on improving population-level rates of CRC screening over time is uncertain. OBJECTIVE: Assess the impact of 10 years of different in-reach and outreach strategies to improve CRC screening and identify factors associated with being screen up-to-date (SUTD). DESIGN: Observational cohort study. PARTICIPANTS: Patients aged 50-74 years from 12 community-based primary care clinics in an integrated, regional safety-net health system. INTERVENTIONS: Multiple system-level interventions were implemented over time (visit-based electronic health record [EHR] reminders, quality measurement, annual preventive service letters, and mailed fecal immunohistochemical stool tests [FIT]). MAIN MEASURES: CRC SUTD rates by calendar year among those with a primary care (PC) visit in the prior 1 and 3 years and their multivariable correlates. KEY RESULTS: The sample included 31,786-40,405 patients/year. In 2011, mean age was 58.9, 63.9% were women, 37.0% were Hispanic, 39.3% Black, 16.8% White, and 6.6% Asian/Other, and 60.5% were uninsured/Medicaid. Three-quarters of patients had ≥ 1 PC visit in the prior year. Lower-intensity interventions (EHR reminders, quality measurement, annual prevention letters) had limited impact on SUTD rates (2-3% rise). Implementing system-wide mailed FIT increased rates from 51.2 to 61.9% among those with a PC visit in the past year (40.5 to 46.8% with a PC visit ≤ 3 years). Stopping mailed FIT due to COVID wiped out these gains. Higher screening rates were associated with the following: older age; female; more comorbidities, PC clinic visits, and prior FITs; and better insurance coverage. Hispanics had the highest SUTD rates followed by Asians, Blacks, and Whites (p < 0.05). CONCLUSIONS: Implementation of a system-wide mailed FIT program had the greatest impact on SUTD rates. Lower-intensity interventions (EHR reminders, quality measurement, and patient letters) had limited effects.
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OBJECTIVE: To quantify the association between time to colposcopy and risk of subsequent cervical cancer. METHODS: A longitudinal analysis of patients aged 21-79 years with an abnormal cervical cancer test result from health care systems in Texas, Massachusetts, and Washington was performed. The outcome was a cervical cancer diagnosis 12 months or more after the abnormal result. The primary analysis compared receipt of colposcopy within 3 months (91 days or less) with receipt of colposcopy at 3-12 months (92-365 days) and no colposcopy within 12 months of the abnormal test result; post hoc analyses compared colposcopy within 12 months (365 days or less) with no colposcopy within 12 months. Associations were assessed with multivariable Cox proportional hazards regression controlling for age, risk status, result severity, and health care system. RESULTS: Of 17,541 patients, 53.3% of patients received colposcopy within 3 months, 22.2% received colposcopy in 3-12 months, and 24.6% had no colposcopy within 12 months. One hundred forty-seven patients were diagnosed with cervical cancer within 12 months and removed from subsequent analyses. Sixty-five patients (0.4%) were diagnosed with cervical cancer more than 1 year (366 days or more) after the abnormal Pap or human papillomavirus test result. The risk of cervical cancer detection more than 1 year after the abnormal test result was not different in patients who received colposcopy within 3-12 months (hazard ratio [HR] 1.07, 95% CI 0.54-2.12) and higher among patients with no colposcopy within 12 months (HR 2.34, 95% CI 1.33-4.14) compared with patients who had colposcopy within 3 months. Post hoc analyses showed that the risk of cervical cancer diagnosis was 2.29-fold higher among those without colposcopy within 12 months compared with those who received colposcopy within 12 months (95% CI 1.37-3.83); among patients with high-grade cytology results, the risk of cervical cancer detection among those without colposcopy within 12 months was 3.12-fold higher compared with those who received colposcopy within 12 months (95% CI 1.47-6.70). CONCLUSION: There was no difference in cervical cancer risk at more than 1 year between patients who received colposcopy within 3 months compared with those who received colposcopy within 3-12 months of an abnormal result. Patients who did not receive colposcopy within 12 months of an abnormal result had a higher risk of subsequent cervical cancer compared with those who received a colposcopy within 12 months.
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Colposcopía , Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Femenino , Humanos , Embarazo , Colposcopía/efectos adversos , Papillomaviridae , Infecciones por Papillomavirus/complicaciones , Displasia del Cuello del Útero/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/epidemiología , Frotis VaginalRESUMEN
In 2018, the US Preventive Services Task Force endorsed primary human papillomavirus testing (pHPV) for cervical cancer screening. We aimed to describe providers' beliefs about pHPV testing effectiveness and which screening approach they regularly recommend. We invited providers who performed 10 or more cervical cancer screens in 2019 in 3 healthcare systems that had not adopted pHPV testing: Kaiser Permanente Washington, Mass General Brigham, and Parkland Health; 53.7% (501/933) completed the survey between October and December 2020. Response distributions varied across modalities (P < .001), with cytology alone or cotesting being more often viewed as somewhat or very effective for 30- to 65-year-olds compared with pHPV (cytology alone 94.1%, cotesting 96.1%, pHPV 66.0%). In 21- to 29-year-olds, the pattern was similar (cytology alone 92.2%, 64.7% cotesting, 50.8% pHPV). Most providers were either incorrect or unsure of the guideline-recommended screening interval for pHPV. Educational efforts are needed about the relative effectiveness and recommended use of pHPV to promote guideline-concordant care.
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Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/prevención & control , Frotis Vaginal , Detección Precoz del Cáncer , Infecciones por Papillomavirus/diagnóstico , Papillomaviridae/genética , Atención a la SaludRESUMEN
Successful cervical cancer prevention requires screening and appropriate management of abnormal test results. Management includes diagnostic evaluation and treatment, if indicated, based on cervical cancer risk after most abnormal test results. There is little guidance on the optimal timing of diagnostic evaluation, and few data exist on factors associated with timely management. We quantified time-to-colposcopy within 12 months of an abnormal cervical cancer screening or surveillance test result from 2010 to 2018 across three diverse healthcare systems and described factors associated with timely colposcopy. Among 21-65 year-old patients with an abnormal test result for which colposcopy was indicated (n = 28,706), we calculated the proportion who received a colposcopy within 12 months of the abnormal test and used Kaplan-Meier methods to estimate the probability of colposcopy within 12 months. Across all systems, 75.3% of patients received a colposcopy within 12 months, with site-specific estimates ranging from 70.0 to 83.0%. We fit mixed-effects multivariable logistic regression models to identify factors associated with receipt of colposcopy within 12 months. The healthcare system and cytology result severity were the most important factors associated with of timely colposcopy. We observed that sites with more centralized processes had higher proportions of colposcopy completion, and patients with high-grade results were more consistently evaluated earlier than patients with low-grade results. Patient age also affected receipt of timely colposcopy, though this association differed by healthcare system and result severity. These data suggest opportunities for system-level interventions to improve management of abnormal cervical cancer test results.
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Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Femenino , Embarazo , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Colposcopía , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/prevención & control , Detección Precoz del Cáncer , Tamizaje Masivo , Frotis Vaginal , Prueba de Papanicolaou , Displasia del Cuello del Útero/diagnósticoRESUMEN
Non-Hodgkin lymphoma (NHL) is the most commonly diagnosed hematologic cancer of adults in the United States, with the vast majority of NHLs deriving from malignant B lymphocytes that express cell surface CD20. CD20 immunotherapy (rituximab) is widely used to treat NHL, even though the initial effectiveness of rituximab varies widely among patients and typically wanes over time. The mechanisms through which lymphomas initially resist or gain resistance to immunotherapy are not well established. To address this, a preclinical mouse model system was developed to comprehensively identify lymphoma transcriptomic changes that confer resistance to CD20 immunotherapy. The generation of spontaneous primary and familial lymphomas revealed that sensitivity to CD20 immunotherapy was not regulated by differences in CD20 expression, prior exposure to CD20 immunotherapy, or serial in vivo passage. An unbiased forward exome screen of these primary lymphomas was used to validate the utility of this expansive lymphoma cohort, which revealed that increased lymphoma galectin-1 (Gal-1) expression strongly correlated with resistance to immunotherapy. Genetically induced lymphoma Gal-1 expression ablated antibody-dependent lymphoma phagocytosis in vitro and lymphoma sensitivity to CD20 immunotherapy in vivo. Human NHLs also express elevated Gal-1 compared with nonmalignant lymphocytes, demonstrating the ability of this preclinical model system to identify molecular targets that could be relevant to human therapy. This study therefore established a powerful preclinical model system that permits the comprehensive identification of the dynamic lymphoma molecular network that drives resistance to immunotherapy.
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Antígenos CD20/genética , Resistencia a Antineoplásicos , Galectina 1/fisiología , Inmunoterapia/métodos , Linfoma de Células B/inmunología , Animales , Antineoplásicos/uso terapéutico , Modelos Animales de Enfermedad , Proteínas Fluorescentes Verdes/metabolismo , Hemicigoto , Humanos , Macrófagos/citología , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Fagocitosis , Rituximab/uso terapéuticoRESUMEN
B cells are known to instigate and promulgate immune responses by producing antibodies and presenting antigens to T cells. However, a rare but potent B-cell subset in both humans and mice is capable of inhibiting immune responses through the production of the anti-inflammatory cytokine IL-10. Regulatory B cells do not express any unique combination of surface markers but instead represent a small population of B cells that have acquired the unique ability to produce IL-10. This numerically rare B-cell subset is therefore functionally referred to as 'B10 cells' to reflect both their molecular program and the fact that their anti-inflammatory effects in models of autoimmunity, infection and cancer are solely attributable to IL-10 production. As with most B cells, B10 cell development and function appear to be predominantly, if not exclusively, driven by antigen-receptor signals. Once generated, B10 cells respond to both innate and adaptive immune signals, with a requirement for antigen-specific local interactions with T cells to induce IL-10 production and to provide optimal immune suppression in mouse models of autoimmune disease. B10 cells therefore provide an antigen-specific mechanism for delivering IL-10 locally to sites of immune activation and inflammation. The ability of B10 cells to regulate innate and adaptive immune responses makes them an ideal therapeutic target for the treatment of many immune-related disorders.
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Presentación de Antígeno , Linfocitos B Reguladores/inmunología , Dermatitis por Contacto/inmunología , Inmunidad Humoral , Interleucina-10/inmunología , Animales , Linfocitos B Reguladores/patología , Comunicación Celular , Dermatitis por Contacto/genética , Dermatitis por Contacto/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/inmunología , Humanos , Inmunidad Innata , Interleucina-10/genética , Ratones , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Transducción de Señal , Bazo/inmunología , Bazo/patología , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
B cells have diverse functions during immune responses, including antibody production, antigen presentation, and cytokine secretion. Multiple lymphomas and leukemias derive from malignant B cells, so therapies that deplete B cells are clinically important, particularly antibodies targeting the B cell-specific surface molecules CD19 and CD20. Macrophages are the principal mediators of CD19 and CD20 monoclonal antibody-dependent B-cell and lymphoma depletion in mice through Fcγ receptor-dependent phagocytosis. Thereby, the extent of CD19 or CD20 antibody-induced B cell and tumor depletion in vivo is influenced by molecular changes within tumors and genetic variations between individuals. In addition to Fcγ receptor polymorphisms, lymphoma- and regulatory B cell-derived cytokine production and macrophage localization and function within tumor microenvironments influence tumor clearance. Given the dynamic interactions of these factors, the identification of effector cell and tumor microenvironment genetic alterations will identify molecular targets that enhance immunotherapies for the treatment of human diseases.
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Anticuerpos Monoclonales/uso terapéutico , Antígenos CD19/inmunología , Antígenos CD20/inmunología , Antineoplásicos/uso terapéutico , Linfocitos B/inmunología , Inmunoterapia , Linfoma de Células B/tratamiento farmacológico , Rituximab/uso terapéutico , Microambiente Tumoral/inmunología , Animales , Humanos , Linfoma de Células B/inmunología , Macrófagos/inmunología , Ratones , Receptores de IgG/inmunologíaRESUMEN
B cells provide humoral protection against pathogens and promote cellular immunity through diverse nonclassical effector functions. To assess B cell function in promoting T cell homeostasis, mature B cells were either acutely or chronically depleted in mice using CD20 mAb. Acute B cell depletion in either 2- or 4-mo-old mice significantly reduced spleen and lymph node CD4(+) and CD8(+) T cell numbers, including naive, activated, and Foxp3(+)CD25(+)CD4(+) regulatory T cell subsets. The numbers of IFN-γ- and TNF-α-producing T cells were also significantly reduced. Chronic B cell depletion for 6 mo in aged naive mice resulted in a 40-70% reduction in activated CD4(+) and CD8(+) T cell numbers and 20-50% reductions in IFN-γ-producing T cells. Therefore, B cells were necessary for maintaining naive CD4(+) and CD8(+) T cell homeostasis for subsequent optimal T cell expansion in young and old mice. To determine the significance of this finding, a week of B cell depletion in 4-mo-old mice was followed by acute viral infection with lymphocytic choriomeningitis virus Armstrong. Despite their expansion, activated and cytokine-producing CD4(+) and CD8(+) T cell numbers were still significantly reduced 1 wk later. Moreover, viral peptide-specific CD4(+) and CD8(+) T cell numbers and effector cell development were significantly reduced in mice lacking B cells, whereas lymphocytic choriomeningitis virus titers were dramatically increased. Thus, T cell function is maintained in B cell-depleted mice, but B cells are required for optimal CD4(+) and CD8(+) T cell homeostasis, activation, and effector development in vivo, particularly during responses to acute viral infection.
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Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Homeostasis/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Enfermedad Aguda , Animales , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular , Citometría de Flujo , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Interacciones Huésped-Patógeno/inmunología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Subunidad alfa del Receptor de Interleucina-2/inmunología , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Recuento de Linfocitos , Depleción Linfocítica , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones , Ratones Endogámicos C57BL , Bazo/inmunología , Bazo/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
While B cells are traditionally regarded as promoters of the immune response via antibody secretion and pro-inflammatory cytokine production, recent studies have also confirmed an important role for B-cell-mediated negative regulation of immunity. Tremendous advances in the characterization of the mechanisms by which regulatory B cells function has led to the identification of a novel subset of regulatory B cells known as B10 cells, which regulate immune responses through the production of the anti-inflammatory cytokine interleukin-10 (IL-10). B10 cells are best defined by their functional ability to produce IL-10, as they are not confined to any particular phenotypic subset. B10 cells function in an antigen-specific manner that requires cognate interactions with T cells in vivo to regulate immune responses and have been demonstrated to be potent regulators of allergic and autoimmune disease, cancer, infection, and transplant rejection. Importantly, the recent discovery of human B10 cells has accelerated this field to the forefront of clinical research where the possibility of harnessing the regulatory potential of B10 cells for treatment of aberrant immune responses and diseases may become feasible.
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Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Interleucina-10/biosíntesis , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Autoinmunidad/inmunología , Linfocitos B Reguladores/inmunología , Linfocitos B Reguladores/metabolismo , Humanos , Inmunidad/fisiología , Inmunomodulación , Ratones , FenotipoRESUMEN
Balanced transmembrane signals maintain a competent peripheral B cell pool limited in self-reactive B cells that may produce pathogenic autoantibodies. To identify molecules regulating peripheral B cell survival and tolerance to self-antigens (Ags), a gene modifier screen was performed with B cells from CD22-deficient C57BL/6 (CD22(-/-[B6])) mice that undergo activation-induced cell death (AICD) and fail to up-regulate c-Myc expression after B cell Ag receptor ligation. Likewise, lysozyme auto-Ag-specific B cells in Ig(Tg) hen egg lysozyme (HEL) transgenic mice inhabit the spleen but undergo AICD after auto-Ag encounter. This gene modifier screen identified EndoU, a single-stranded RNA-binding protein of ancient origin, as a major regulator of B cell survival in both models. EndoU gene disruption prevents AICD and normalizes c-Myc expression. These findings reveal that EndoU is a critical regulator of an unexpected and novel RNA-dependent pathway controlling peripheral B cell survival and Ag responsiveness that may contribute to peripheral B cell tolerance.