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1.
NPJ Precis Oncol ; 8(1): 67, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461318

RESUMO

Genomic tumor testing (GTT) is an emerging technology aimed at identifying variants in tumors that can be targeted with genomically matched drugs. Due to limited resources, rural patients receiving care in community oncology settings may be less likely to benefit from GTT. We analyzed GTT results and observational clinical outcomes data from patients enrolled in the Maine Cancer Genomics Initiative (MCGI), which provided access to GTTs; clinician educational resources; and genomic tumor boards in community practices in a predominantly rural state. 1603 adult cancer patients completed enrollment; 1258 had at least one potentially actionable variant identified. 206 (16.4%) patients received a total of 240 genome matched treatments, of those treatments, 64% were FDA-approved in the tumor type, 27% FDA-approved in a different tumor type and 9% were given on a clinical trial. Using Inverse Probability of Treatment Weighting to adjust for baseline characteristics, a Cox proportional hazards model demonstrated that patients who received genome matched treatment were 31% less likely to die within 1 year compared to those who did not receive genome matched treatment (HR: 0.69; 95% CI: 0.52-0.90; p-value: 0.006). Overall, GTT through this initiative resulted in levels of genome matched treatment that were similar to other initiatives, however, clinical trials represented a smaller share of treatments than previously reported, and "off-label" treatments represented a greater share. Although this was an observational study, we found evidence for a potential 1-year survival benefit for patients who received genome matched treatments. These findings suggest that when disseminated and implemented with a supportive infrastructure, GTT may benefit cancer patients in rural community oncology settings, with further work remaining on providing genome-matched clinical trials.

2.
JCO Precis Oncol ; 7: e2200619, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37163717

RESUMO

PURPOSE: The Maine Cancer Genomics Initiative (MCGI) aimed to overcome patient- and provider-level barriers to using genomic tumor testing (GTT) in rural practices by providing genomic tumor boards (GTBs), clinician education, and access to comprehensive large-panel next-generation sequencing to all patients with cancer in Maine. This paper describes the successful implementation of the initiative and three key services made operative between 2016 and 2020. METHODS: A community-inclusive, hub-and-spoke approach was taken to implement the three program components: (1) a centralized GTB program; (2) a modular online education program, designed using an iterative approach with broad clinical stakeholders; and (3) GTT free of charge to clinicians and patients. Implementation timelines, participation metrics, and survey data were used to describe the rollout. RESULTS: The MCGI was launched over an 18-month period at all 19 oncology practices in the State. Seventy-nine physicians (66 medical oncologists, 5 gynecologic oncologists, 1 neuro-oncologist, and 7 pediatric oncologists) enrolled on the study, representing 100% of all practicing oncologists in Maine. Between July 2017 and September 2020, 1610 patients were enrolled. A total of 515 cases were discussed by 47 (73%) clinicians in 196 GTBs. Clinicians who participated in the GTBs enrolled significantly more patients on the study, stayed in Maine, and reported less time spent in clinical patient care. CONCLUSION: The MCGI was able to engage geographically and culturally disparate cancer care practices in a precision oncology program using a hub-and-spoke model. By facilitating access to GTT, structured education, and GTBs, we narrowed the gap in the implementation of precision oncology in one of the most rural states in the country.


Assuntos
Neoplasias , Criança , Humanos , Feminino , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Maine , Medicina de Precisão , Oncologia , Genômica
3.
BMC Cancer ; 21(1): 1273, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34823486

RESUMO

PURPOSE: Large-panel genomic tumor testing (GTT) is an emerging technology with great promise but uncertain clinical value. Previous research has documented variability in academic oncologists' perceptions and use of GTT, but little is known about community oncologists' perceptions of GTT and how perceptions relate to clinicians' intentions to use GTT. METHODS: Community oncology physicians (N = 58) participating in a statewide initiative aimed at improving access to large-panel GTT completed surveys assessing their confidence in using GTT, attitudes regarding the value of GTT, perceptions of barriers to GTT implementation, and future intentions to use GTTs. Descriptive and multivariable regression analyses were conducted to characterize these perceptions and to explore the relationships between them. RESULTS: There was substantial variability in clinicians' perceptions of GTT. Clinicians generally had moderate confidence in their ability to use GTT, but lower confidence in patients' ability to understand test results and access targeted treatment. Clinicians had positive attitudes regarding the value of GTT. Clinicians' future intentions to use GTT were associated with greater confidence in using GTT and greater perceived barriers to implementing GTT, but not with attitudes about the value of GTT. CONCLUSIONS: Community oncologists' perceptions of large-panel genomic tumor testing are variable, and their future intentions to use GTT are associated with both their confidence in and perceived barriers to its use, but not with their attitudes towards GTT. More research is needed to understand other factors that determine how oncologists perceive and use GTT in clinical practice.


Assuntos
Atitude do Pessoal de Saúde , Testes Genéticos/estatística & dados numéricos , Neoplasias/genética , Oncologistas/psicologia , Compreensão , Feminino , Previsões , Pesquisas sobre Atenção à Saúde/estatística & dados numéricos , Hematologia/estatística & dados numéricos , Humanos , Intenção , Maine , Masculino , Análise de Regressão , Serviços de Saúde Rural , Autoimagem , Incerteza
4.
Artigo em Inglês | MEDLINE | ID: mdl-34632254

RESUMO

Large-panel genomic tumor testing (GTT) is an emerging technology that promises to make cancer treatment more precise. Because GTT is novel and complex, patients may have unrealistic expectations and limited knowledge of its benefits. These problems may limit the clinical value of GTT, but their prevalence and associated factors have not been explored. METHODS: Patients with cancer enrolled in a large initiative to disseminate GTT in community oncology practices completed surveys assessing their expectations, knowledge, and attitudes about GTT. The study sample (N = 1,139) consisted of patients with a range of cancer types (22% gynecologic, 14% lung, 10% colon, 10% breast, and 46% other malignancies) and cancer stages (4% stage I, 3% stage II, 15% stage III, and 74% stage IV). Mean age was 64 years (standard deviation = 11); 668 (59%) were women; 71% had no college degree; 57% came from households with less than $50,000 US dollars household income; and 73% lived in a rural area. RESULTS: Generally, patients had high expectations that they would benefit from GTT (M = 2.81 on 0-4 scale) and positive attitudes toward it (M = 2.98 on 0-4 scale). Patients also had relatively poor knowledge about GTT (48% correct answers on an objective test of GTT knowledge). Greater expectations for GTT were associated with lower knowledge (b = -0.46; P < .001), more positive attitudes (b = 0.40; P < .001), and lower education (b = -0.53; P < .001). CONCLUSION: This research suggests patients have high expectations that they will benefit from GTT, which is associated with low knowledge, positive attitudes, and low education. More research is needed to understand the concordance between expectations and actual clinical outcomes.


Assuntos
Oncologia/métodos , Neoplasias/genética , Pacientes/psicologia , Idoso , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Oncologia/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Pacientes/estatística & dados numéricos , População Rural/estatística & dados numéricos , Inquéritos e Questionários
5.
Psychol Health Med ; 26(7): 805-817, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-32426996

RESUMO

Novel medical technologies, like large-panel genomic tumor testing (GTT), offer great promise but also substantial uncertainty regarding their clinical value and appropriate use. The goal of this study was to understand how clinicians' perceived uncertainty about GTT, and uncertainty tolerance (UT), a construct that describes trait-level differences in individuals' responses to uncertainty, influence attitudes and self-efficacy regarding GTT. Community-based oncologists participating in a study of large-panel GTT completed surveys assessing their perceptions of uncertainty about GTT, and their attitudes and self-efficacy regarding GTT. Multivariable regression analyses examined the relationship between oncologists' perceived uncertainty of GTT and their GTT-related attitudes and self-efficacy, and the potential moderating effect of individual differences in UT. Fifty-seven oncologists completed surveys. Greater perceived uncertainty about GTT was associated with more negative attitudes towards it. This association was moderated by UT, such that lower UT was associated with a stronger negative relationship between perceived uncertainty and attitudes. That is, oncologists who perceive GTT as uncertain, tended to have more negative attitudes, particularly if they were low in the trait of uncertainty tolerance. More research is warranted to understand how uncertainty and uncertainty tolerance influence clinicians' responses to GTT and other novel medical interventions.


Assuntos
Neoplasias , Autoeficácia , Atitude , Genômica , Humanos , Neoplasias/genética , Incerteza
6.
Patient Educ Couns ; 104(1): 3-11, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32690398

RESUMO

OBJECTIVE: To compare clinicians' and patients' preferences for disclosure of genomic tumor testing (GTT) results; to determine the sensitivity of these disclosure preferences to uncertainty about the actionability of results; and to explore factors associated with disclosure preferences. METHODS: Community-based oncology clinicians (n = 94) and patients (n = 1121) were surveyed about their preferences for disclosing GTT results with varying levels of uncertainty (Tiers 1, 2, 3). Descriptive and multivariable regression analyses were used to compare clinicians' and patients' disclosure preferences and their sensitivity to uncertainty, and to explore associations between disclosure preferences and sociodemographic, clinical, and psychological factors. RESULTS: Relatively more patients than clinicians preferred disclosure, and their preferences were less sensitive to the uncertainty of GTT results. For patients and clinicians, lower uncertainty sensitivity was associated with positive GTT attitudes; for patients it was also associated with greater uncertainty tolerance and knowledge of uncertainty in GTT. CONCLUSION: Relatively more cancer patients than clinicians prefer disclosure of GTT results, and their preferences are less sensitive to result uncertainty. Uncertainty sensitivity in disclosure preferences is associated with GTT-related attitudes and uncertainty tolerance. PRACTICE IMPLICATIONS: Differences in cancer patients' and clinicians' preferences for disclosure of uncertain GTT results warrant greater attention in cancer care.


Assuntos
Revelação , Neoplasias , Genômica , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Preferência do Paciente , Incerteza
7.
Eur J Immunol ; 41(6): 1742-53, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21469115

RESUMO

Alternatively activated macrophages are critical in host defense against parasites and are protective in inflammatory bowel disease, but contribute to pathology in asthma and solid tumors. The mechanisms underlying alternative activation of macrophages are only partially understood and little is known about their amenability to manipulation in pathophysiological conditions. Herein, we demonstrate that Src homology 2-domain-containing inositol-5'-phosphatase (SHIP)-deficient murine macrophages are more sensitive to IL-4-mediated skewing to an alternatively activated phenotype. Moreover, SHIP levels are decreased in macrophages treated with IL-4 and in murine GM-CSF-derived and tumor-associated macrophages. Loss of SHIP and induction of alternatively activated macrophage markers, Ym1 and arginase I (argI), were dependent on phosphatidylinositol 3-kinase (PI3K) activity and argI induction was dependent on the class IA PI3Kp110δ isoform. STAT6 was required to reduce SHIP protein levels, but reduced SHIP levels did not increase STAT6 phosphorylation. STAT6 transcription was inhibited by PI3K inhibitors and enhanced when SHIP was reduced using siRNA. Importantly, reducing SHIP levels enhanced, whereas SHIP overexpression or blocking SHIP degradation reduced, IL-4-induced argI activity. These findings identify SHIP and the PI3K pathway as critical regulators of alternative macrophage activation and SHIP as a target for manipulation in diseases where macrophage phenotype contributes to pathology.


Assuntos
Ativação de Macrófagos , Macrófagos/metabolismo , Neoplasias/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Animais , Arginase/genética , Arginase/metabolismo , Biomarcadores/metabolismo , Células Cultivadas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Inositol Polifosfato 5-Fosfatases , Interleucina-4/imunologia , Interleucina-4/metabolismo , Lectinas/genética , Lectinas/metabolismo , Ativação de Macrófagos/genética , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/imunologia , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/imunologia , RNA Interferente Pequeno/genética , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais/genética , Ativação Transcricional/genética , Transgenes/genética , beta-N-Acetil-Hexosaminidases/genética , beta-N-Acetil-Hexosaminidases/metabolismo , Domínios de Homologia de src/genética
8.
J Immunol ; 183(6): 3652-60, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19710468

RESUMO

There is a great deal of interest in determining what regulates the generation of classically activated (M1) vs alternatively activated (M2) macrophages (Mphis) because of the opposing effects that these two Mphi subsets have on tumor progression. We show herein that IL-3 and, to a lesser extent, GM-CSF skew murine Mphi progenitors toward an M2 phenotype, especially in the absence of SHIP. Specifically, the addition of these cytokines, with or without M-CSF, to adherence- or lineage-depleted (Lin(-)) SHIP(-/-) bone marrow (BM) cells induces high levels of the M2 markers, arginase I, and Ym1 in the resulting mature Mphis. These in vitro-derived mature Mphis also display other M2 characteristics, including an inability to enhance anti-CD3-stimulated splenic T cell secretion of IFN-gamma and low IL-12 and high IL-10 production in response to LPS. Not surprisingly, given that IL-3 and GM-CSF utilize STAT5 to trigger many downstream signaling pathways, this M2 phenotype is suppressed when STAT5(-/-) BM cells are used. Unexpectedly, however, this M2 phenotype is also suppressed when STAT6(-/-) BM cells are used, suggesting that IL-4- or IL-13-induced signaling might be involved. Consistent with this, we found that IL-3 and GM-CSF stimulate the production of IL-4, especially from SHIP(-/-) Lin(-) BM cells, and that neutralizing anti-IL-4 Abs block IL-3-induced M2 skewing. Moreover, we found that basophil progenitors within the Lin(-) BM are responsible for this IL-3- and GM-CSF-induced IL-4 production, and that SHIP represses M2 skewing not by preventing skewing within Mphis themselves but by inhibiting IL-4 production from basophils.


Assuntos
Basófilos/metabolismo , Diferenciação Celular/imunologia , Interleucina-3/farmacologia , Interleucina-4/biossíntese , Macrófagos/citologia , Monoéster Fosfórico Hidrolases/fisiologia , Animais , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Inositol Polifosfato 5-Fosfatases , Ativação de Macrófagos , Camundongos , Células-Tronco/citologia
9.
Proc Natl Acad Sci U S A ; 106(24): 9785-90, 2009 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-19497879

RESUMO

Cytolytic CD8(+) T cells (CTLs) kill virally infected cells, tumor cells, or other potentially autoreactive T cells in a calcium-dependent manner. To date, the molecular mechanism that leads to calcium intake during CTL differentiation and function has remained unresolved. We demonstrate that desmoyokin (AHNAK1) is expressed in mature CTLs, but not in naive CD8(+) T cells, and is critical for calcium entry required for their proper function during immune response. We show that mature AHNAK1-deficient CTLs exhibit reduced Ca(v)1.1 alpha1 subunit expression (also referred to as L-type calcium channels or alpha1S pore-forming subunits), which recently were suggested to play a role in calcium entry into CD4(+) T cells. AHNAK1-deficient CTLs show marked reduction in granzyme-B production, cytolytic activity, and IFN-gamma secretion after T cell receptor stimulation. Our results demonstrate an AHNAK1-dependent mechanism controlling calcium entry during CTL effector function.


Assuntos
Sinalização do Cálcio/fisiologia , Proteínas de Membrana/fisiologia , Proteínas de Neoplasias/fisiologia , Linfócitos T/metabolismo , Animais , Ensaio de Imunoadsorção Enzimática , Interferon gama/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase , Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia
10.
Trends Mol Med ; 15(5): 199-207, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19362058

RESUMO

Differentiation of naïve T cells leads to the generation of T-cell subsets, each possessing distinct cytokine expression profiles for serving different immune functions. Through the activation of separate signaling pathways, this process results in both differentiated helper T (Th) cells, termed Th1, Th2 and Th17, and induced regulatory T cells, which suppress Th cells. These different cells are important for combating infectious diseases and cancers; however, when aberrant, they can be responsible for chronic inflammatory diseases. One such disease is inflammatory bowel disease (IBD), in which each T-cell subset can have a role in disease. New studies highlight the importance of the recently identified Th17 subset in IBD. Therapeutics targeting these aberrant Th responses are already under development and hold promise for treating IBD and other chronic inflammatory diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular , Doenças Inflamatórias Intestinais/imunologia , Animais , Terapia Biológica/tendências , Linfócitos T CD4-Positivos/metabolismo , Citocinas/biossíntese , Tratamento Farmacológico/tendências , Humanos , Doenças Inflamatórias Intestinais/terapia , Ativação Linfocitária , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia
11.
Nat Rev Immunol ; 9(2): 116-24, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19165228

RESUMO

Interleukin-12 (IL-12) and IL-4 induce T helper 1 (T(H)1)- and T(H)2-cell differentiation, respectively, in vitro. However, not all T(H)1-cell responses require IL-12 in vivo, and T(H)2-cell responses are remarkably independent of IL-4-receptor signalling, suggesting that other polarizing signals must exist. Accumulating evidence indicates that Notch is a candidate receptor that might mediate these signals. However, contrasting roles for Notch have been proposed: some evidence shows that Notch promotes T(H)1-cell differentiation, whereas other evidence supports a prominent role for Notch in T(H)2-cell differentiation. In this Review, we discuss recent findings that help to reconcile this discrepancy and highlight the accumulating evidence for the role of Notch in T-cell-mediated diseases.


Assuntos
Linfopoese , Receptores Notch/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Asma/imunologia , Asma/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Humanos , Receptores Notch/metabolismo , Transdução de Sinais , Células Th1/metabolismo , Células Th2/metabolismo
12.
Immunity ; 27(1): 89-99, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17658279

RESUMO

CD4(+) T helper cells differentiate into T helper 1 (Th1) or Th2 effector lineages, which orchestrate immunity to different types of microbes. Both Th1 and Th2 differentiation can be induced by Notch, but what dictates which of these programs is activated in response to Notch is not known. By using T cell-specific gene ablation of the Notch effector RBP-J or the Notch1 and 2 receptors, we showed here that Notch was required on CD4(+) T cells for physiological Th2 responses to parasite antigens. GATA-3 was necessary for Notch-induced Th2 differentiation, and we identified an upstream Gata3 promoter as a direct target for Notch signaling. Moreover, absence of GATA-3 turned Notch from a Th2 inducer into a powerful inducer of Th1 differentiation. Therefore, Gata3 is a critical element determining inductive Th2 differentiation and limiting Th1 differentiation by Notch.


Assuntos
Diferenciação Celular/imunologia , Fator de Transcrição GATA3/metabolismo , Receptores Notch/fisiologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Sequência de Bases , Células Cultivadas , Fator de Transcrição GATA3/biossíntese , Fator de Transcrição GATA3/fisiologia , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/deficiência , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/citologia , Células Th2/imunologia , Células Th2/metabolismo
13.
J Immunol ; 171(7): 3435-41, 2003 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-14500638

RESUMO

A population of CD25(+)CD4(+) regulatory T cells (T regs) functions to maintain immunological self tolerance by inhibiting autoreactive T cell responses. CD25(+)CD4(+) T regs are present in low, but steady, numbers in the peripheral lymphoid tissues of healthy mice. Recent studies have shown that IL-2 is an essential growth factor for these cells. How this cytokine functions to regulate CD25(+)CD4(+) T reg homeostasis and prevent autoimmune disease remains unknown. In conventional CD4(+) T cells, IL-2 triggers signaling pathways that promote proliferation and survival by activating the STAT5 transcription factor and by increasing the expression of the antiapoptotic protein, Bcl-2. We show here that bcl-2 deficiency does not affect CD25(+)CD4(+) T reg homeostasis, and that ectopic expression of this molecule fails to rescue CD25(+)CD4(+) T reg numbers or to prevent the development of autoimmunity in IL-2-deficient mice. Furthermore, transient activation of STAT5 is sufficient to increase CD25(+)CD4(+) T reg numbers in IL-2-deficient mice. Our study uncovers an essential role for STAT5 in maintaining CD25(+)CD4(+) T reg homeostasis and self-tolerance.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proteínas de Ligação a DNA/fisiologia , Homeostase/imunologia , Proteínas do Leite , Receptores de Interleucina-2/biossíntese , Tolerância a Antígenos Próprios/imunologia , Transdução de Sinais/imunologia , Transativadores/fisiologia , Animais , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Homeostase/genética , Interleucina-2/deficiência , Interleucina-2/genética , Interleucina-2/fisiologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2/deficiência , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Fator de Transcrição STAT5 , Tolerância a Antígenos Próprios/genética , Transdução de Sinais/genética , Transativadores/deficiência , Transativadores/genética , Transativadores/metabolismo , Regulação para Cima/genética , Regulação para Cima/imunologia
14.
Immunity ; 19(2): 243-55, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12932358

RESUMO

A mouse strain was identified with a recessive genetic lesion, which spontaneously developed a lymphoproliferative autoimmune syndrome exhibiting features of systemic lupus erythematosus. Positional mapping of the disease-associated locus revealed a lesion in Rasgrp1 that prevented the translation of the RasGRP1 protein. T cells from these mice failed to activate Ras or proliferate vigorously following antigen encounter and showed defects in positive selection. Peripheral RasGRP1lag T cells spontaneously adopted a memory phenotype and were able to transfer disease to lymphopenic recipient mice. CD4+ T cells accumulated in the lymphoid tissues of older RasGRP1lag mice and were resistant to activation-induced cell death. RasGRP1lag B cells were functionally normal, but activated B cells were detected in older mice, as were autoantibodies directed against self-antigens. Our findings indicate that Ras signaling pathways are required to maintain T cell tolerance and to prevent autoimmune disease.


Assuntos
Autoimunidade/genética , Proteínas de Ligação a DNA/genética , Fatores de Troca do Nucleotídeo Guanina , Mutação , Animais , Apoptose , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Divisão Celular , Citocinas/biossíntese , Memória Imunológica , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Ativação Linfocitária , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Mutantes , Fenótipo , Tolerância a Antígenos Próprios/genética
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