RESUMO
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies. However, the underlying cause of disease appears to relate to defects in T cell tolerance or T cell help to B cells. Transgenic (Tg) mice overexpressing the cytokine B cell-activating factor of the tumor necrosis factor family (BAFF) develop an autoimmune disorder similar to SLE and show impaired B cell tolerance and altered T cell differentiation. We generated BAFF Tg mice that were completely deficient in T cells, and, surprisingly, these mice developed an SLE-like disease indistinguishable from that of BAFF Tg mice. Autoimmunity in BAFF Tg mice did, however, require B cell-intrinsic signals through the Toll-like receptor (TLR)-associated signaling adaptor MyD88, which controlled the production of proinflammatory autoantibody isotypes. TLR7/9 activation strongly up-regulated expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which is a receptor for BAFF involved in B cell responses to T cell-independent antigens. Moreover, BAFF enhanced TLR7/9 expression on B cells and TLR-mediated production of autoantibodies. Therefore, autoimmunity in BAFF Tg mice results from altered B cell tolerance, but requires TLR signaling and is independent of T cell help. It is possible that SLE patients with elevated levels of BAFF show a similar basis for disease.
Assuntos
Fator Ativador de Células B/fisiologia , Fator 88 de Diferenciação Mieloide/fisiologia , Animais , Autoanticorpos/química , Fator Ativador de Células B/metabolismo , Diferenciação Celular , Separação Celular , Regulação da Expressão Gênica , Imunoglobulina A/metabolismo , Imunoglobulina M/metabolismo , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Fator 88 de Diferenciação Mieloide/metabolismo , Linfócitos T/metabolismoRESUMO
B-cell-activating factor of the TNF family (BAFF)/BLyS contributes to B-cell homeostasis and function in the periphery. BAFF is expressed as a membrane-bound protein or released by proteolytic cleavage, but the functional importance of this processing event is poorly understood. Mice expressing BAFF with a mutated furin consensus cleavage site, i.e. furin-mutant BAFF (fmBAFF), were not different from BAFF-deficient mice with regard to their B-cell populations and responses to immunization. It is however noteworthy that an alternative processing event releases some soluble BAFF in fmBAFF mice. Mild overexpression (â¼ 5-fold) of fmBAFF alone generated intermediate levels of B cells without improving humoral responses to immunization. Processed BAFF was however important for B-cell homeostasis, as peripheral B-cell populations and antibody responses were readily restored by administration of soluble BAFF trimers in BAFF-deficient mice. However, the rescue of CD23 expression in B cells of BAFF-deficient mice required both soluble BAFF trimers and fmBAFF, or a polymeric form of soluble BAFF (BAFF 60-mer). These results point to a predominant role of processed BAFF for B-cell homeostasis and function, and indicate possible accessory roles for membrane-bound BAFF.
Assuntos
Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Mutação , Sequência de Aminoácidos , Animais , Formação de Anticorpos , Fator Ativador de Células B/química , Fator Ativador de Células B/deficiência , Sequência de Bases , Sítios de Ligação/genética , Primers do DNA/genética , Furina/química , Células HEK293 , Homeostase , Humanos , Imunoglobulinas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Camundongos Transgênicos , Dados de Sequência Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Processamento de Proteína Pós-Traducional , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , SolubilidadeRESUMO
B cell activating factor belonging to the TNF family (BAFF or BLyS) is a critical B cell survival factor essential for B cell maturation. BAFF transgenic (Tg) mice develop autoimmunity resembling Systemic Lupus Erythematosus (SLE) in a T cell-independent but toll-like receptor (TLR) signalling-dependent manner, requiring TLR-induced innate B cell-derived pro-inflammatory autoantibody deposition in the kidneys. Importantly, neutralizing BAFF in the clinic shows efficacy in patients with SLE, confirming its critical role in the progression of this disease in both humans and mouse models. The specific B cell types that produce autoantibodies in BAFF Tg mice are TLR-activated innate marginal zone (MZ) B cells and B1 cells, but not follicular B cells. Interestingly, in BAFF Tg mice MZ-like B cells infiltrate salivary glands whereas B1 B cells infiltrate the kidneys. To ascertain the relevance of B1 and MZ-like B cells in the development of nephritis in BAFF Tg mice, we generated genetically asplenic as well as splenectomized BAFF Tg animals. BAFF Tg mice born without a spleen lack MZ B cells, have very reduced B1a B cell numbers but a normal B1b B cell compartment. Loss of these B cell subsets failed to protect BAFF Tg mice against nephritis indicating that B1b B cells are an important subset for the development of autoimmune nephritis in BAFF Tg mice. Thus the spleen is dispensable for the development of autoimmune nephritis in BAFF Tg mice and points toward a pathogenic role for innate B1 B cells. Identifying similar innate B cells in humans may offer the possibility of more targeted B cell therapies.
Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Fator Ativador de Células B/imunologia , Nefrite/imunologia , Animais , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Doenças Autoimunes/genética , Fator Ativador de Células B/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Humanos , Imunização , Linfonodos/imunologia , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Nefrite/genética , Vacinas Pneumocócicas/imunologia , Fator Reumatoide/imunologia , Fator Reumatoide/metabolismo , Baço/imunologia , Baço/patologia , Baço/cirurgia , EsplenectomiaRESUMO
B cell-activating factor belonging to the TNF family (BAFF) is a B cell survival factor required for B cell maturation. BAFF transgenic (Tg) mice develop autoimmune disorders characterized by autoantibody production, which leads to nephritis and salivary gland destruction (sialadenitis), features reminiscent of systemic lupus erythematosus and Sjögren's syndrome (SS), respectively. Disease in BAFF Tg mice correlates with the expansion of the marginal zone (MZ) B cell compartment and the abnormal presence of MZ-like B cells in the blood, LN and inflamed salivary glands, suggesting a role for these cells in BAFF-induced autoimmunity. Lymphotoxin-beta (LTbeta)-deficient mice show disrupted splenic architecture, lack MZ B cells and some peripheral LN, and are unable to mount T cell-dependent immune responses. BAFF Tg mice lacking LTbeta (LTbetaDelta-BTg) retained these defects, yet still developed nephritis associated with the presence of B-1 B cells in the kidneys. However, in contrast to old BAFF Tg mice, aging LTbetaDelta-BTg mice no longer developed sialadenitis. Thus, autoimmune disorders in BAFF Tg mice are possibly events coordinated by MZ and B-1 B cells at separate anatomical sites.
Assuntos
Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Proteínas de Membrana/imunologia , Nefrite/imunologia , Sialadenite/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Fator Ativador de Células B , Linfócitos B/citologia , Diferenciação Celular/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunoglobulina A/análise , Linfonodos/citologia , Linfonodos/imunologia , Linfotoxina-alfa/deficiência , Linfotoxina-beta , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/citologia , Baço/imunologia , Células-Tronco/citologia , Células-Tronco/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
B cell-activating factor belonging to the TNF family (BAFF; BLyS) is a critical regulator of B cell maturation and survival, and its overexpression in BAFF transgenic (Tg) mice results in the development of autoimmune disorders. BAFF also affects T cell function through binding to one of the BAFF receptors, BAFF-R. Using BAFF Tg mice, we examined a typical Th1-mediated response, the cutaneous delayed-type hypersensitivity reaction, and found a much greater degree of paw swelling and inflammation than in control mice. Importantly, delayed-type hypersensitivity scores correlated directly with BAFF levels in serum. Conversely, in a Th2-mediated model of allergic airway inflammation, BAFF Tg mice were largely protected and showed markedly reduced Ag-specific T cell proliferation and eosinophil infiltration associated with the airways. Thus, local and/or systemically distributed BAFF affects Th1 and Th2 responses and impacts on the course of some T cell-mediated inflammatory reactions. Our results are consistent with the idea that BAFF augments T cell as well as B cell responses, particularly Th1-type responses. Results in BAFF Tg mice may reflect the situation in certain autoimmune patients or virally infected individuals, because BAFF levels in blood are comparable.