RESUMO
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that is characterized by the over production of auto-antibodies against nuclear components. Thus, SLE patients have increased morbidity and, mortality compared to healthy individuals. Available therapies are not curative and are associated with unwanted adverse effects. During the last few years, important advances in immunology research have provided rheumatologists with new tools for designing novel therapies for treating autoimmunity. However, the complex nature of SLE has played a conflicting role, hindering breakthroughs in therapeutic development. Nonetheless, new advances about SLE pathogenesis could open a fruitful line of research. Dendritic cells (DCs) have been established as essential players in the mechanisms underlying SLE, making them attractive therapeutic targets for fine-tuning the immune system. In this review, we discuss the recent advances made in revealing the mechanisms of SLE pathogenesis, with a focus on the use of DCs as a target for therapy development.
Assuntos
Células Dendríticas/fisiologia , Tolerância Imunológica/imunologia , Lúpus Eritematoso Sistêmico/terapia , Humanos , Tolerância Imunológica/fisiologia , Imunidade InataRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple alterations affecting the normal function of immune cells, such as lymphocytes, dendritic cells (DCs) and monocytes. Although the understanding of autoimmunity has significantly increased, the breakthrough in effective therapies has been modest, making necessary the development of new therapeutic strategies. Here we propose that a new potential target for therapy is haem oxygenase-1 (HO-1), an enzyme that catalyses the degradation of the haem group into biliverdin, carbon monoxide (CO) and Fe(2+) . These products exhibit immunosuppressive and anti-inflammatory effects, which can contribute to improving tolerance during organ transplantation. Because HO-1 is highly expressed by immune cells involved in SLE pathogenesis, such as monocytes and DCs, we evaluated whether induction of HO-1 expression or the administration of CO could ameliorate disease in the FcγRIIb knockout (KO) mouse model for SLE. We found that CO administration decreased the expansion of CD11b(+) cells, prevented the decline of regulatory T cells and reduced anti-histone antibodies observed in untreated FcγRIIb KO mice. Furthermore, CO-treated animals and HO-1 induction showed less kidney damage compared with untreated mice. These data suggest that HO-1 modulation and CO administration can ameliorate autoimmunity and prevent the lupus symptoms shown by FcγRIIb KO mice, highlighting HO-1 as a potential new target for autoimmune therapy.
Assuntos
Monóxido de Carbono/administração & dosagem , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/terapia , Animais , Autoimunidade/efeitos dos fármacos , Antígeno CD11b/metabolismo , Modelos Animais de Doenças , Indução Enzimática/efeitos dos fármacos , Feminino , Heme Oxigenase-1/biossíntese , Rim/efeitos dos fármacos , Rim/enzimologia , Rim/patologia , Lúpus Eritematoso Sistêmico/enzimologia , Masculino , Proteínas de Membrana/biossíntese , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de IgG/deficiência , Receptores de IgG/genética , Baço/imunologia , Baço/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologiaRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple functional alterations affecting immune cells, such as B cells, T cells, dendritic cells (DCs) and monocytes. During SLE, the immunogenicity of monocytes and DCs is significantly up-regulated, promoting the activation of self-reactive T cells. Accordingly, it is important to understand the contribution of these cells to the pathogenesis of SLE and the mechanisms responsible for their altered functionality during disease. One of the key enzymes that control monocyte and DC function is haem oxygenase-1 (HO-1), which catalyses the degradation of the haem group into biliverdin, carbon monoxide and free iron. These products possess immunosuppressive and anti-inflammatory capacities. The main goal of this work was to determine HO-1 expression in monocytes and DCs from patients with SLE and healthy controls. Hence, peripheral blood mononuclear cells were obtained from 43 patients with SLE and 30 healthy controls. CD14(+) monocytes and CD4(+) T cells were sorted by FACS and HO-1 expression was measured by RT-PCR. In addition, HO-1 protein expression was determined by FACS. HO-1 levels in monocytes were significantly reduced in patients with SLE compared with healthy controls. These results were confirmed by flow cytometry. No differences were observed in other cell types, such as DCs or CD4(+) T cells, although decreased MHC-II levels were observed in DCs from patients with SLE. In conclusion, we found a significant decrease in HO-1 expression, specifically in monocytes from patients with SLE, suggesting that an imbalance of monocyte function could be partly the result of a decrease in HO-1 expression.
Assuntos
Células Dendríticas/enzimologia , Heme Oxigenase-1/metabolismo , Lúpus Eritematoso Sistêmico/enzimologia , Lúpus Eritematoso Sistêmico/imunologia , Monócitos/enzimologia , Adulto , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Feminino , Humanos , Receptores de Lipopolissacarídeos/biossíntese , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Monócitos/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de IgG/genética , Receptores de IgG/imunologia , Adulto JovemRESUMO
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by an excessive production of auto-antibodies against double-stranded DNA, nucleosomes, ribonucleoproteins and other nuclear components. Accumulation of self-reactive antibodies leads to immune complex deposition in blood vessels, activation of macrophages and complement, inflammation and subsequent tissue damage in several organs, such as the heart, kidneys, lungs and central nervous system. Although significant progress has been made in the past 30 years of research, no effective specific treatments are currently available. The course of this disease remains unpredictable and patients diagnosed with SLE face long-term treatments with the subsequent economic, social and health burden. From the immunological perspective, SLE is a genetic- and environment-controlled disease that involves almost every constituent of the immune system, including both innate and adaptive immunity. Therefore, several immune cell types and molecules could be susceptible for intervention and modulation to develop more effective and specific treatments. More importantly, such therapies are likely not to induce complete immunosuppression and show reduced side effects on patients. In this article we discuss recent work in the field of SLE pathogenesis with a focus on data that provide clues for therapy design and new treatments.
Assuntos
Células Dendríticas/imunologia , Lúpus Eritematoso Sistêmico/terapia , Linfócitos T/imunologia , Autoimunidade , Linfócitos B/imunologia , Humanos , Lúpus Eritematoso Sistêmico/imunologiaRESUMO
Autoimmune diseases, such as systemic lupus erythematosus (SLE), result from deficiencies in self-antigen tolerance processes, which require regulated dendritic cell (DC) function. In this study we evaluated the phenotype of DCs during the onset of SLE in a mouse model, in which deletion of the inhibitory receptor FcgammaRIIb leads to the production of anti-nuclear antibodies and glomerulonephritis. Splenic DCs from FcgammaRIIb-deficient mice suffering from SLE showed increased expression of co-stimulatory molecules. Furthermore, diseased mice showed an altered function of the nuclear factor-kappaB (NF-kappaB) transcription factor, which is involved in DC maturation. Compared with healthy animals, expression of the inhibitory molecule IkappaB-alpha was significantly decreased in mice suffering from SLE. Consistently, pharmacological inhibition of NF-kappaB activity in FcgammaRIIb-deficient mice led to reduced susceptibility to SLE and prevented symptoms, such as anti-nuclear antibodies and kidney damage. Our data suggest that the occurrence of SLE is significantly influenced by alterations of NF-kappaB function, which can be considered as a new therapeutic target for this disease.
Assuntos
Células Dendríticas/imunologia , Glomerulonefrite/imunologia , Lúpus Eritematoso Sistêmico/imunologia , NF-kappa B/imunologia , Receptores de IgG/imunologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Diterpenos/administração & dosagem , Diterpenos/farmacologia , Feminino , Glomerulonefrite/metabolismo , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Proteínas I-kappa B/agonistas , Proteínas I-kappa B/imunologia , Proteínas I-kappa B/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Rosiglitazona , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/farmacologiaRESUMO
The molecular bases responsible for the loss of T cell tolerance to myelin antigens leading to the onset of multiple sclerosis remain obscure. It has been shown that balanced signaling through activating and inhibitory receptors is critical for the maintenance of tolerance to self antigens in autoimmune disorders. However, although FcgammaR have been shown to influence experimental autoimmune encephalomyelitis (EAE) development, their role during pathogenesis remains controversial. Here we have evaluated whether relative expression of activating (FcgammaRIII) and inhibitory (FcgammaRIIb) FcgammaR can modulate myelin-specific T cell response, as well as the susceptibility to develop EAE in mice. While FcgammaRIIb(-/-) mice showed a significant increase in EAE severity, an FcgammaRIII deficiency protected mice from disease. In addition, FcgammaRIIb(-/-) mice showed enhanced activation of myelin-specific effector T cells, which were significantly more effective at causing EAE in adoptive transfer experiments than were T cells from wild-type mice. In contrast, FcgammaRIII(-/-) mice showed a significantly reduced activation of myelin-specific T cells and these cells failed to adoptively transfer EAE. Consistently, increased expansion of regulatory T cells (Treg) during EAE was observed only for FcgammaRIII(-/-) mice, which were able to suppress disease when adoptively transferred to recipient mice. These findings suggest that the balance between activating and inhibitory FcgammaR signaling can contribute to the maintenance of T cell tolerance to myelin antigens and modulate EAE progression.
Assuntos
Encefalomielite Autoimune Experimental/etiologia , Receptores de IgG/fisiologia , Linfócitos T/imunologia , Transferência Adotiva , Animais , Autoimunidade , Células Dendríticas/fisiologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas da Mielina , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito , Linfócitos T Reguladores/fisiologiaRESUMO
Autoimmune disorders develop as a result of deregulated immune responses that target self-antigens and cause destruction of healthy host tissues. Because dendritic cells (DCs) play an important role in the maintenance of peripheral immune tolerance, we are interested in identifying means of enhancing their therapeutic potential in autoimmune diseases. It is thought that during steady state, DCs are able to anergize potentially harmful T cells bearing T cell receptors that recognize self-peptide-major histocompatibility complexes. The tolerogenic capacity of DCs requires an immature phenotype, which is characterized by a reduced expression of costimulatory molecules. On the contrary, activation of antigen-specific naive T cells is enhanced by DC maturation, a process that involves expression of genes controlled by the transcription factor nuclear factor (NF)-kappaB. We evaluated the capacity of drugs that inhibit NF-kappaB to enhance the tolerogenic properties of immature DCs in the experimental autoimmune encephalomyelitis (EAE) model. We show that andrographolide, a bicyclic diterpenoid lactone, and rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist, were able to interfere with NF-kappaB activation in murine DCs. As a result, treated DCs showed impaired maturation and a reduced capacity to activate antigen-specific T cells. Furthermore, NF-kappaB-blocked DCs had an enhanced tolerogenic capacity and were able to prevent EAE development in mice. The tolerogenic feature was specific for myelin antigens and involved the expansion of regulatory T cells. These data suggest that NF-kappaB blockade is a potential pharmacological approach that can be used to enhance the tolerogenic ability of immature DCs to prevent detrimental autoimmune responses.