Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
1.
Clin Exp Immunol ; 205(2): 169-181, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33864242

RESUMO

The impact of treatment on the risk of lymphoma in patients with rheumatoid arthritis (RA) is unclear. Here, we aimed to assess if the risk of lymphoma differs according to the type of tumor necrosis factor inhibitor (TNFi), comparing monoclonal anti-TNF antibodies to the soluble TNF receptor. We used B cell activating factor belonging to the TNF family (BAFF)-transgenic (Tg) mice as a model of autoimmunity-associated lymphoma. Six-month-old BAFF-Tg mice were treated with TNFi for 12 months. Histological examination of the spleen, assessment of the cellular composition of the spleen by flow cytometry and assessment of B cell clonality were performed at euthanasia. Crude mortality and incidence of lymphoma were significantly higher in mice treated with monoclonal anti-TNF antibodies compared to both controls and mice treated with the soluble TNF receptor, even at a high dose. Flow cytometry analysis revealed decreased splenic macrophage infiltration in mice treated with monoclonal anti-TNF antibodies. Overall, this study demonstrates, for the first time, that a very prolonged treatment with monoclonal anti-TNF antibodies increase the risk of lymphoma in B cell-driven autoimmunity. These data suggest a closer monitoring for lymphoma development in patients suffering from B cell-driven autoimmune disease with long-term exposure to monoclonal anti-TNF antibodies.


Assuntos
Anticorpos Monoclonais/imunologia , Artrite Reumatoide/imunologia , Fator Ativador de Células B/imunologia , Linfoma/imunologia , Camundongos Transgênicos/imunologia , Inibidores do Fator de Necrose Tumoral/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Linfócitos B/imunologia , Linhagem Celular , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia
2.
Lupus ; 27(13): 2029-2040, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30301439

RESUMO

INTRODUCTION: We examined the clinical relevance of urinary concentrations of B-cell-activating factor of the tumour necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) in systemic lupus erythematosus (SLE). METHODS: We quantified urinary BAFF (uBAFF) by enzyme-linked immunosorbent assay in 85 SLE, 28 primary Sjögren syndrome (pSS), 40 immunoglobulin A nephropathy (IgAN) patients and 36 healthy controls (HCs). Urinary APRIL (uAPRIL) and monocyte chemoattractant protein 1 (uMCP-1) were also quantified. Overall and renal SLE disease activity were assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000. RESULTS: uBAFF was detected in 12% (10/85) of SLE patients, but was undetectable in HCs, IgAN and pSS patients. uBAFF was detectable in 28% (5/18) of SLE patients with active nephritis vs 5/67 (7%) of those without ( p = 0.03), and uBAFF was significantly higher in active renal patients ( p = 0.02) and more likely to be detected in patients with persistently active renal disease. In comparison, uAPRIL and uMCP-1 were detected in 32% (25/77) and 46% (22/48) of SLE patients, respectively. While no difference in proportion of samples with detectable uAPRIL was observed between SLE, HCs and IgAN patients, both uAPRIL and uMCP-1 were significantly detectable in higher proportions of patients with active renal disease. CONCLUSIONS: uBAFF was detectable in a small but a significant proportion of SLE patients but not in other groups tested, and was higher in SLE patients with active renal disease.


Assuntos
Fator Ativador de Células B/urina , Lúpus Eritematoso Sistêmico/urina , Nefrite Lúpica/urina , Adolescente , Adulto , Idoso , Austrália , Biomarcadores/urina , Estudos de Casos e Controles , Quimiocina CCL2/urina , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/urina , Adulto Jovem
3.
Lupus ; 22(9): 873-84, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23846230

RESUMO

INTRODUCTION: The objective of this study is to determine whether serum concentrations of B cell activating factor from the tumour necrosis factor family (BAFF) and/or a proliferation-inducing ligand (APRIL) are associated with clinical manifestations of systemic lupus erythematosus (SLE). METHODS: BAFF and APRIL concentrations were quantified using a commercial ELISA in serum samples obtained at the time of clinical assessment in 98 patients, and on 245 samples from 75 of these patients followed prospectively. RESULTS: Serum BAFF was significantly increased, and APRIL decreased, in patients with either renal or central nervous system (CNS) lupus. In contrast, in cross-sectional analysis, there was no correlation between disease activity (SLEDAI-2k) and serum BAFF or APRIL. In longitudinal follow-up, there was no association between changes in serum BAFF or APRIL and changes in SLEDAI-2k, or between baseline serum BAFF or APRIL and subsequent changes in SLEDAI-2k. However, between-visit changes in BAFF were significantly different in patients with increases in SLEDAI-2k ≥ 4, compared to patients whose SLEDAI-2k did not change. CONCLUSIONS: Although neither serum BAFF nor APRIL correlated with disease activity in the overall population, elevated serum BAFF and reduced APRIL may be markers of renal and CNS disease in SLE patients.


Assuntos
Fator Ativador de Células B/sangue , Lúpus Eritematoso Sistêmico/fisiopatologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Adulto , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Lúpus Eritematoso Sistêmico/sangue , Nefrite Lúpica/sangue , Nefrite Lúpica/fisiopatologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/sangue , Vasculite Associada ao Lúpus do Sistema Nervoso Central/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença
4.
Intern Med J ; 43(3): 227-34, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23176380

RESUMO

The incidence and prevalence of autoimmune diseases such as rheumatoid arthritis, primary Sjögren syndrome, scleroderma and systemic lupus erythematosus (SLE) varies with geography and ethnicity. For example, SLE is reported to be more common in populations such as African-Caribbeans and Indigenous Australians (IA). As well as socio-economic status, variation in severity of disease may also show ethnic variability. The initial presentation of SLE in IA, in the context of a unique genetic background and distinctive environmental influences, is often florid with a recurring spectrum of clinical phenotypes. These clinical observations suggest a unique pathway for autoimmunity pathogenesis in this population. For instance, the high prevalence of bacterial infections in IA, particularly group A streptococcus, may be a potential explanation not only for increased incidence and prevalence of SLE but also the commonly florid acute disease presentation and propensity for rapidly progressive end organ threatening disease. This article will review the state of research in autoimmune disease of IA, consider key findings related to autoimmune disease in this population and propose a model potentially to explain the involvement of innate immunity and chronic infection in autoimmune disease pathogenesis. Ultimately, understanding of SLE at this level could affect management and result in personalised and targeted therapies to improve the health status of IA as well as better understanding of SLE pathogenesis per se.


Assuntos
Doenças Autoimunes/etnologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/etnologia , Havaiano Nativo ou Outro Ilhéu do Pacífico/etnologia , Austrália/etnologia , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Humanos , Imunidade Inata/imunologia , Lúpus Eritematoso Sistêmico/imunologia
5.
Leukemia ; 30(1): 163-72, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26139429

RESUMO

Interleukin (IL)-10-producing B cells (B10 cells) have emerged as important regulatory elements with immunosuppressive roles. Chronic lymphocytic leukemia (CLL) B cells also secrete IL-10 and share features of B10 cells, suggesting a possible contribution of CLL B cells to immunosuppression in CLL patients. Factors controlling the emergence of B10 cells are not known. B-cell-activating factor of the tumor necrosis factor (TNF) family (BAFF) is critical for B-cell maturation and survival, and is implicated in the development and progression of CLL. We sought to investigate the role of BAFF in the emergence of IL-10-producing regulatory B cells in healthy donors and CLL patients. Here, we report that BAFF signaling promotes IL-10 production by CLL B cells in a mouse model of CLL and in CLL patients. Moreover, BAFF-mediated IL-10 production by normal and CLL B cells is mediated via its receptor transmembrane activator and cyclophilin ligand interactor. Our work uncovered a major targetable pathway important for the generation of regulatory B cells that is detrimental to immunity in CLL.


Assuntos
Linfócitos B Reguladores/imunologia , Interleucina-10/biossíntese , Leucemia Linfocítica Crônica de Células B/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/fisiologia , Animais , Fator Ativador de Células B/sangue , Fator Ativador de Células B/fisiologia , Células Cultivadas , Humanos , Interleucina-10/sangue , Camundongos , Camundongos Endogâmicos C57BL , Receptor Toll-Like 9/fisiologia
6.
Leukemia ; 28(10): 2005-15, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24721775

RESUMO

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5(+)CD19(+) B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNα) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNα production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-ß and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immunocompetency in CLL.


Assuntos
Citocinas/metabolismo , Células Dendríticas/citologia , Regulação Leucêmica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Animais , Antineoplásicos/química , Ilhas de CpG , Progressão da Doença , Humanos , Interferon-alfa/metabolismo , Linfócitos/citologia , Camundongos , Receptor Toll-Like 9/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA