RESUMO
Siglec-G is a member of the sialic acid-binding Ig-like lectin (Siglec) family expressed on all B cells. Siglec-G-deficient mice show a large expansion of the B1 cell compartment, demonstrating the crucial role of Siglec-G as an inhibitory receptor on this cellular subset. Although Siglec-G-deficient mice did not develop spontaneous autoimmunity, mice double-deficient for Siglec-G and the related Siglec protein CD22 did show autoimmunity at an older age. In this study, we addressed the question of whether loss of Siglec G on its own affects disease severity in animal models of rheumatoid arthritis and systemic lupus erythematosus. Siglec-G-deficient mice showed moderately increased clinical severity and higher inflammation of the knee joints following collagen-induced arthritis, when compared with control mice. The Siglec-G-deficient mouse was also backcrossed to the autoimmune prone MLR/lpr background. Although both Siglec-G-deficient and control MRL/lpr mice developed a lupus-like disease, Siglec-G-deficient MRL/lpr mice showed an earlier occurrence of autoantibodies; a higher lymphoproliferation of B and T cells; and an earlier onset of disease, as shown by proteinuria and glomerular damage in the kidney. Moreover, Siglec-G-deficient female mice showed a significantly reduced survival compared with female control MRL/lpr mice. Thus, the loss of the inhibitory receptor Siglec-G led to a moderate exacerbation of disease severity and early onset in both collagen-induced arthritis and spontaneous lupus nephritis in MRL/lpr mice.
Assuntos
Artrite Experimental/imunologia , Lectinas/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Animais , Anticorpos Antinucleares/imunologia , Artrite Experimental/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Estimativa de Kaplan-Meier , Rim/imunologia , Rim/metabolismo , Rim/patologia , Lectinas/deficiência , Lectinas/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Receptores de Antígenos de Linfócitos B/deficiência , Receptores de Antígenos de Linfócitos B/genética , Índice de Gravidade de Doença , Fatores Sexuais , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Fatores de TempoRESUMO
Genetic variants of the inhibitory Fc receptor FcγRIIb have been associated with systemic lupus erythematosus in humans and mice. The mechanism by which Fcgr2b variants contribute to the development of autoimmunity is unknown and was investigated by knocking in the most commonly conserved wild mouse Fcgr2b promoter haplotype, also associated with autoimmune-prone mouse strains, into the C57BL/6 background. We found that in the absence of an AP-1-binding site in its promoter, FcγRIIb failed to be up-regulated on activated and germinal center (GC) B cells. This resulted in enhanced GC responses, increased affinity maturation, and autoantibody production. Accordingly, in the absence of FcγRIIb activation-induced up-regulation, mice developed more severe collagen-induced arthritis and spontaneous glomerular immune complex deposition. Our data highlight how natural variation in Fcgr2b drives the development of autoimmune disease. They also show how the study of such variants using a knockin approach can provide insight into immune mechanisms not possible using conventional genetic manipulation, in this case demonstrating an unexpected critical role for the activation-induced up-regulation of FcγRIIb in controlling affinity maturation, autoantibody production, and autoimmunity.
Assuntos
Autoimunidade/imunologia , Linfócitos B/metabolismo , Regulação da Expressão Gênica/imunologia , Variação Genética , Centro Germinativo/imunologia , Receptores de IgG/genética , Animais , Autoanticorpos/biossíntese , Autoimunidade/genética , Imunoprecipitação da Cromatina , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , ELISPOT , Citometria de Fluxo , Técnicas de Introdução de Genes , Centro Germinativo/citologia , Luciferases , Camundongos , Camundongos Endogâmicos C57BL , Mutagênese Sítio-Dirigida , Regiões Promotoras Genéticas/genética , Receptores de IgG/metabolismo , Análise de Sequência de DNA , Estatísticas não Paramétricas , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismoRESUMO
Autoantibodies are central to the pathogenesis of several autoimmune diseases including systemic lupus erythematosus. Plasma cells secrete these autoantibodies, but the anatomical sites of these cells are not well defined. Here, we found that although dsDNA-specific plasma cells in NZB/W mice were present in spleen and bone marrow, a large number were in the kidneys and their number correlated with the serum dsDNA-IgG titer. We observed renal plasma cells only in mice with nephritis, where they located mainly to the tubulointerstitium of the cortex and outer medulla. These cells had the phenotypic characteristics of fully differentiated plasma cells and, similar to long-lived bone marrow plasma cells, they were not in cell cycle. In patients with lupus nephritis, plasma cells were often present in the medulla in those with the most severe disease, especially combined proliferative and membranous lupus nephritis. The identification of the kidney as a major site of autoreactive plasma cells has implications for our understanding of the pathogenesis of lupus nephritis and for strategies to deplete autoreactive plasma cells, a long-standing therapeutic aim.
