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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 JovemRESUMO
We use a Landau de Gennes free energy approach to model a diamond colloidal crystal immersed in a cholesteric liquid crystal. The pitch in our cholesteric is chosen in order to give rise to the most energetically favourable colloid-defect structure, commensurate with the diamond lattice. This structure corresponds to defect lines travelling along symmetry axes in the diamond crystal. By adding noise to the liquid crystal phase we are able to measure the phonon spectrum of our colloidal crystal, which we find to be consistent with a locally stable configuration. Therefore, although it may not correspond to the global minimum energy structure, once formed our diamond lattice should be stable against thermal fluctuations.
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We investigate the behavior of colloidal suspensions with different volume fractions confined between parallel walls under a range of steady shears. We model the particles using molecular dynamics (MD) with full hydrodynamic interactions implemented through the use of a lattice-Boltzmann (LB) fluid. A quasi-2d ordering occurs in systems characterized by a coexistence of coupled layers with different densities, order, and granular temperature. We present a phase diagram in terms of shear and volume fraction for each layer, and demonstrate that particle exchange between layers is required for entering the disordered phase.
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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 DoençaRESUMO
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/imunologiaRESUMO
Dietary factors influence male reproductive function in both experimental and epidemiological studies. However, there are currently no specific dietary guidelines for male preconception health. Here, we use the Nutritional Geometry framework to examine the effects of dietary macronutrient balance on reproductive traits in C57BL/6 J male mice. Dietary effects are observed in a range of morphological, testicular and spermatozoa traits, although the relative influence of protein, fat, carbohydrate, and their interactions differ depending on the trait being examined. Interestingly, dietary fat has a positive influence on sperm motility and antioxidant capacity, differing to typical high fat diet studies where calorie content is not controlled for. Moreover, body adiposity is not significantly correlated with any of the reproductive traits measured in this study. These results demonstrate the importance of macronutrient balance and calorie intake on reproductive function and support the need to develop specific, targeted, preconception dietary guidelines for males.
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Adiposidade , Carboidratos da Dieta , Animais , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Motilidade dos Espermatozoides , Dieta , Obesidade , Nutrientes , Gorduras na Dieta/farmacologia , Dieta Hiperlipídica/efeitos adversos , Proteínas AlimentaresRESUMO
BACKGROUND: Obesity and type 2 diabetes mellitus are characterized by insulin resistance and 'low-grade inflammation'; however, the pathophysiological link is poorly understood. To determine the relative contribution of obesity and insulin resistance to systemic 'inflammation', this study comprehensively characterized circulating immune cells in different grades of obesity. METHODS: Immune cell phenotypes and activation status were analysed by flow cytometry cross-sectionally in morbidly obese (n = 16, body mass index (BMI) 42.2 ± 5.4 kg/m2), overweight (n = 13, BMI 27.4 ± 1.6 kg/m2) and normal weight (n = 12, BMI 22.5 ± 1.9 kg/m2) subjects. RESULTS: Obese, but not overweight subjects, had increased activation marker expression on neutrophils, monocytes, T-lymphocytes and polarization of T helper cells towards a pro-inflammatory type 1-phenotype (Th1). Th1 numbers correlated positively with the degree of insulin resistance (homeostasis model assessment, p < 0.05). Lymphocytes from obese subjects showed reduced insulin-stimulated AKT-phosphorylation in vitro. Supra-physiological insulin concentrations did not affect T-cell differentiation, which under normal circumstances would promote an anti-inflammatory T helper type 2-phenotype. CONCLUSIONS: These results show that morbid obesity is characterized by circulating immune cells that are activated and insulin resistant, with the T-cell balance polarized towards a pro-inflammatory Th1 phenotype. The loss of insulin-induced suppression of inflammatory phenotypes in circulating immune cells could contribute to the systemic and adipose tissue inflammation found in morbid obesity.
Assuntos
Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Inflamação/imunologia , Resistência à Insulina , Células Secretoras de Insulina/imunologia , Obesidade Mórbida/complicações , Linfócitos T/imunologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Composição Corporal , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Citometria de Fluxo , Humanos , Inflamação/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Sobrepeso/imunologia , Sobrepeso/metabolismo , Linfócitos T/metabolismoRESUMO
Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine triggering cell responses through two distinct membrane receptors. Stimulation of leukocyte adhesion to the endothelium is one of the many TNF-alpha activities and is explained by the upregulation of adhesion molecules on the endothelial cell surface. Human umbilical vein endothelial cells (HUVEC) were isolated, cultured, and demonstrated to express both TNF receptor types, TNF-R55 and TNF-R75. Cell adhesion to HUVEC was studied using the HL60, U937, and MOLT-4 cell lines. HUVEC were activated by either TNF-alpha, binding to both TNF-R55 and TNF-R75, and by receptor type-specific agonists, binding exclusively to TNF-R55 or to TNF-R75. The TNF-alpha-induced cell adhesion to HUVEC was found to be controlled almost exclusively by TNF-R55. This finding correlated with the exclusive activity of TNF-R55 in the TNF-alpha-dependent regulation of the expression of the intercellular adhesion molecule type 1 (ICAM-1), E-selectin, and vascular cell adhesion molecule type 1 (VCAM-1). The CD44 adhesion molecule in HUVEC was also found to be upregulated through TNF-R55. However, both TNF-R55 and TNF-R75 upregulate alpha 2 integrin expression in HUVEC. The predominant role of TNF-R55 in TNF-alpha-induced adhesion in HUVEC may correlate with its specific control of NF-kappa B activation, since kappa B elements are known to be present in ICAM-1, E-selectin, and VCAM-1 gene regulatory sequences.
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Endotélio Vascular/citologia , Receptores de Superfície Celular/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Sequência de Bases , Adesão Celular/fisiologia , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Células Cultivadas , Endotélio Vascular/metabolismo , Humanos , Integrinas/metabolismo , Dados de Sequência Molecular , Oligonucleotídeos , Receptores do Fator de Necrose Tumoral , Regulação para CimaRESUMO
The transfer of lymphocytes into severe combined immunodeficiency (SCID) mice induces a series of histological changes in the spleen, including the appearance of mature follicular dendritic cells (FDCs). Studies were undertaken to clarify the role of lymphotoxin (LT) in this process. The results show that SCID mice have a small and partially differentiated white pulp containing marginal zone and interdigitating dendritic cells, but lacking FDCs. Transferred spleen cells can segregate into T and B cell areas shortly after their injection to SCID mice. This ability is dependent on signaling through LT-beta receptor (LT-betaR), since blocking ligand-receptor interaction in recipient SCID mice ablates the capacity of the transferred cells to segregate. A week after lymphocyte transfer, host-derived FDCs appeared in the reconstituted SCID mice. This induction of FDCs is dependent on LT-betaR signaling by B cells since LT-alpha-/- B cells are incapable of inducing development of FDCs in SCID mice, even after cotransfer of LT-alpha+/+ T cells. Therefore, LT plays at least two discrete roles in splenic organization. First, it appears that LT induces the differentiation of the white pulp to create sites for lymphocyte segregation. Second, LT expression by B cells drives the maturation of FDCs and the organization of B cell follicles.
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Linfócitos B/fisiologia , Células Dendríticas/metabolismo , Linfotoxina-alfa/fisiologia , Baço/fisiologia , Animais , Linfócitos B/metabolismo , Diferenciação Celular/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Imuno-Histoquímica , Receptor beta de Linfotoxina , Camundongos , Camundongos SCID , Microscopia Confocal , Fenótipo , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais/fisiologia , Baço/citologia , Linfócitos T/metabolismo , Transplante Isogênico/fisiologiaRESUMO
For more than a decade, the biological roles and the apparent redundancy of the cytokines tumor necrosis factor (TNF) and lymphotoxin (LT) have been debated. LT alpha exists in its soluble form as a homotrimer, which like TNF only binds the TNF receptors, TNF-R55 or TNF-R75. The cell surface form of LT exists as a heteromer of LT alpha and LT beta subunits and this complex specifically binds the LT beta receptor (LT beta-R). To discriminate the functions of the LT and TNF systems, soluble LT beta-R-immunoglobulin (Ig) or TNF-R-Ig fusion proteins were introduced into embryonic circulation by injecting pregnant mice. Exposure to LT beta-R-Ig during gestation disrupted lymph node development and splenic architecture in the progeny indicating that both effects are mediated by the surface LT alpha/beta complex. These data are the first to identify a cell surface ligand involved in immune organ morphogenesis. Moreover, they unambiguously discriminate the functions of the various TNF/LT ligands, provide a unique model to study compartmentalization of immune responses and illustrate the generic utility of receptor-Ig fusion proteins for dissecting/ordering ontogenetic events in the absence of genetic modifications.
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Membrana Celular/metabolismo , Tecido Linfoide/embriologia , Linfotoxina-alfa/metabolismo , Proteínas de Membrana/metabolismo , Animais , Imunoglobulina G/farmacologia , Linfonodos/embriologia , Receptor beta de Linfotoxina , Camundongos , Camundongos Endogâmicos BALB C , Morfogênese , Nódulos Linfáticos Agregados/embriologia , Receptores do Fator de Necrose Tumoral/imunologia , Receptores do Fator de Necrose Tumoral/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Baço/embriologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
B cell maturation is a very selective process that requires finely tuned differentiation and survival signals. B cell activation factor from the TNF family (BAFF) is a TNF family member that binds to B cells and potentiates B cell receptor (BCR)-mediated proliferation. A role for BAFF in B cell survival was suggested by the observation of reduced peripheral B cell numbers in mice treated with reagents blocking BAFF, and high Bcl-2 levels detected in B cells from BAFF transgenic (Tg) mice. We tested in vitro the survival effect of BAFF on lymphocytes derived from primary and secondary lymphoid organs. BAFF induced survival of a subset of splenic immature B cells, referred to as transitional type 2 (T2) B cells. BAFF treatment allowed T2 B cells to survive and differentiate into mature B cells in response to signals through the BCR. The T2 and the marginal zone (MZ) B cell compartments were particularly enlarged in BAFF Tg mice. Immature transitional B cells are targets for negative selection, a feature thought to promote self-tolerance. These findings support a model in which excessive BAFF-mediated survival of peripheral immature B cells contributes to the emergence and maturation of autoreactive B cells, skewed towards the MZ compartment. This work provides new clues on mechanisms regulating B cell maturation and tolerance.
Assuntos
Autoimunidade , Subpopulações de Linfócitos B/imunologia , Células-Tronco Hematopoéticas/imunologia , Proteínas de Membrana/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Fator Ativador de Células B , Subpopulações de Linfócitos B/citologia , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Células-Tronco Hematopoéticas/citologia , Camundongos , Modelos Imunológicos , Baço/citologia , Baço/imunologiaRESUMO
B cells undergo a complex series of maturation and selection steps in the bone marrow and spleen during differentiation into mature immune effector cells. The tumor necrosis factor (TNF) family member B cell activating factor of the TNF family (BAFF) (BLyS/TALL-1) plays an important role in B cell homeostasis. BAFF and its close homologue a proliferation-inducing ligand (APRIL) have both been shown to interact with at least two receptors, B cell maturation antigen (BCMA) and transmembrane activator and cyclophilin ligand interactor (TACI), however their relative contribution in transducing BAFF signals in vivo remains unclear. To functionally inactivate both BAFF and APRIL, mice transgenic for a soluble form of TACI were generated. They display a developmental block of B cell maturation in the periphery, leading to a severe depletion of marginal zone and follicular B2 B cells, but not of peritoneal B1 B cells. In contrast, mice transgenic for a soluble form of BCMA, which binds APRIL, have no detectable B cell phenotype. This demonstrates a crucial role for BAFF in B cell maturation and strongly suggests that it signals via a BCMA-independent pathway and in an APRIL-dispensable way.
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Linfócitos B/citologia , Proteínas de Membrana/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Fator Ativador de Células B , Antígeno de Maturação de Linfócitos B , Linfócitos B/fisiologia , Diferenciação Celular , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Receptores do Fator de Necrose Tumoral/genética , Proteína Transmembrana Ativadora e Interagente do CAML , Membro 13 da Superfamília de Ligantes de Fatores de Necrose TumoralRESUMO
Surface lymphotoxin (LT) is a heteromeric complex of LT-alpha and LT-beta chains that binds to the LT-beta receptor (LT-beta-R), a member of the tumor necrosis factor (TNF) family of receptors. The biological function of this receptor-ligand system is poorly characterized. Since signaling through other members of this receptor family can induce cell death, e.g., the TNF and Fas receptors, it is important to determine if similar signaling events can be communicated via the LT-beta-R. A soluble form of the surface complex was produced by coexpression of LT-alpha and a converted form of LT-beta wherein the normally type II LT-beta membrane protein was changed to a type I secreted form. Recombinant LT-alpha 1/beta 2 was cytotoxic to the human adenocarcinoma cell lines HT-29, WiDr, MDA-MB-468, and HT-3 when added with the synergizing agent interferon (IFN) gamma. When immobilized on a plastic surface, anti-LT-beta-R monoclonal antibodies (mAbs) induced the death of these cells, demonstrating direct signaling via the LT-beta-R. Anti-LT-beta-R mAbs were also identified that inhibited ligand-induced cell death, whereas others were found to potentiate the activity of the ligand when added in solution. The human WiDr adenocarcinoma line forms solid tumors in immunocompromised mice, and treatment with an anti-LT-beta-R antibody combined with human IFN-gamma arrested tumor growth. The delineation of a biological signaling event mediated by the LT-beta-R opens a window for further studies on its immunological role, and furthermore, activation of the LT-beta-R may have an application in tumor therapy.
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Apoptose , Interferon gama/farmacologia , Linfotoxina-alfa/fisiologia , Receptores do Fator de Necrose Tumoral/fisiologia , Transdução de Sinais , Adenocarcinoma/patologia , Animais , Anticorpos Monoclonais/farmacologia , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Humanos , Cinética , Receptor beta de Linfotoxina , Linfotoxina-alfa/imunologia , Camundongos/imunologia , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Células Tumorais CultivadasRESUMO
The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.
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Autoanticorpos/sangue , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Doenças Linfáticas/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Animais , Anticorpos Antinucleares/sangue , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Fator Ativador de Células B , Citometria de Fluxo , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Imunoglobulinas/metabolismo , Rim/imunologia , Rim/patologia , Cinética , Contagem de Leucócitos , Pulmão/imunologia , Doenças Linfáticas/genética , Doenças Linfáticas/patologia , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator Reumatoide/sangue , Linfócitos T/imunologiaRESUMO
Members of the tumor necrosis factor (TNF) family induce pleiotropic biological responses, including cell growth, differentiation, and even death. Here we describe a novel member of the TNF family, designated BAFF (for B cell activating factor belonging to the TNF family), which is expressed by T cells and dendritic cells. Human BAFF was mapped to chromosome 13q32-34. Membrane-bound BAFF was processed and secreted through the action of a protease whose specificity matches that of the furin family of proprotein convertases. The expression of BAFF receptor appeared to be restricted to B cells. Both membrane-bound and soluble BAFF induced proliferation of anti-immunoglobulin M-stimulated peripheral blood B lymphocytes. Moreover, increased amounts of immunoglobulins were found in supernatants of germinal center-like B cells costimulated with BAFF. These results suggest that BAFF plays an important role as costimulator of B cell proliferation and function.
Assuntos
Linfócitos B/imunologia , Proteínas de Membrana/fisiologia , Receptores do Fator de Necrose Tumoral/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Sequência de Aminoácidos , Animais , Fator Ativador de Células B , Linfócitos B/citologia , Sequência de Bases , Divisão Celular , Linhagem Celular , Mapeamento Cromossômico , Cromossomos Humanos Par 13/genética , Clonagem Molecular , Primers do DNA/genética , Células Dendríticas/imunologia , Humanos , Ligantes , Ativação Linfocitária , Proteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , Receptores do Fator de Necrose Tumoral/genética , Homologia de Sequência de Aminoácidos , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
The tumor necrosis factor (TNF) family member B cell activating factor (BAFF) binds B cells and enhances B cell receptor-triggered proliferation. We find that B cell maturation antigen (BCMA), a predicted member of the TNF receptor family expressed primarily in mature B cells, is a receptor for BAFF. Although BCMA was previously localized to the Golgi apparatus, BCMA was found to be expressed on the surface of transfected cells and tonsillar B cells. A soluble form of BCMA, which inhibited the binding of BAFF to a B cell line, induced a dramatic decrease in the number of peripheral B cells when administered in vivo. Moreover, culturing splenic cells in the presence of BAFF increased survival of a percentage of the B cells. These results are consistent with a role for BAFF in maintaining homeostasis of the B cell population.
Assuntos
Linfócitos B/imunologia , Ativação Linfocitária , Proteínas de Membrana/imunologia , Proteínas de Membrana/fisiologia , Receptores do Fator de Necrose Tumoral/imunologia , Receptores do Fator de Necrose Tumoral/fisiologia , Fator de Necrose Tumoral alfa , Animais , Fator Ativador de Células B , Antígeno de Maturação de Linfócitos B , Linhagem Celular , Sobrevivência Celular , Homeostase , Humanos , Imunoglobulina G/imunologia , Cadeias kappa de Imunoglobulina/genética , Cadeias kappa de Imunoglobulina/imunologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Tonsila Palatina/imunologia , Receptores do Fator de Necrose Tumoral/genética , Proteínas Recombinantes/imunologia , Baço/imunologia , TransfecçãoRESUMO
In scrapie-infected mice, prions are found associated with splenic but not circulating B and T lymphocytes and in the stroma, which contains follicular dendritic cells (FDCs). Formation and maintenance of mature FDCs require the presence of B cells expressing membrane-bound lymphotoxin-alpha/beta. Treatment of mice with soluble lymphotoxin-beta receptor results in the disappearance of mature FDCs from the spleen. We show that this treatment abolishes splenic prion accumulation and retards neuroinvasion after intraperitoneal scrapie inoculation. These data provide evidence that FDCs are the principal sites for prion replication in the spleen.
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Células Dendríticas Foliculares/patologia , Células Dendríticas Foliculares/virologia , Proteínas PrPSc/biossíntese , Baço/patologia , Baço/virologia , Replicação Viral/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Dendríticas Foliculares/metabolismo , Imunoglobulinas/genética , Receptor beta de Linfotoxina , Linfotoxina-alfa/antagonistas & inibidores , Linfotoxina-alfa/genética , Linfotoxina-alfa/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Proteínas PrPSc/administração & dosagem , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/imunologia , Proteínas Recombinantes de Fusão/administração & dosagem , Scrapie/imunologia , Scrapie/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Baço/imunologia , Baço/metabolismo , Replicação Viral/genéticaAssuntos
Células Dendríticas Foliculares , Doenças Priônicas/prevenção & controle , Receptores do Fator de Necrose Tumoral/uso terapêutico , Animais , Modelos Animais de Doenças , Imunoglobulinas/genética , Receptor beta de Linfotoxina , Camundongos , Receptores do Fator de Necrose Tumoral/genética , Proteínas Recombinantes de Fusão/uso terapêutico , Scrapie/prevenção & controleRESUMO
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/fisiologiaRESUMO
The cytokine, lymphotoxin [LT, tumor necrosis factor beta (TNF beta)] is a potent mediator of proinflammatory and tumoricidal activities. Soluble lymphotoxin is a complex of three LT alpha chains. Its receptors, TNF-R55 and TNF-R75, bind in clefts formed by adjacent identical LT alpha monomers. LT also exists as membrane anchored heterotrimers comprised of LT alpha and LT beta chains. The major and minor membrane forms, LT alpha 1 beta 2 and LT alpha 2 beta 1, respectively, bind a unique receptor, LT beta-R. As LT alpha 2 beta 1 expresses an LT alpha-alpha cleft, it also binds TNF-R. In this report we have compared the effects of ligand engagement of TNF-R and LT beta-R by evaluating the ability of soluble LT alpha beta complexes to initiate activities of human umbilical vein endothelial cells which are characteristically signalled by TNF. We recently reported that soluble LT alpha 1 beta 2 signals via LT beta-R to mediate cytotoxicity of a subset of gamma interferon (IFN-gamma) treated carcinomas. We now show that human LT alpha beta heterotrimers do not efficiently activate LT beta-R+, TNF-R+ human endothelial cells in vitro and only inefficiently mediates lethal toxicity in mice. We also show that neither LT alpha beta heterotrimer signals via TNF-R; in fact LT alpha 2 beta 1 trimers fail to activate NF-kappa B and rather inhibit ligand-induced TNF-R signalling supporting the role for aggregation in TNF-R signalling. Thus, the ability of LT alpha beta complexes to efficiently initiate tumoricidal but not inflammatory activities distinguishes the LT/LT beta-R from the LT/TNF-R pathways and suggest novel strategies for exploiting the LT ligands in tumor therapy and for inhibiting TNF-R-mediated inflammatory sequellae.