RESUMO
The influence of complement receptor 1 and 2 (CR1/2) was investigated on the susceptibility to low-dose collagen-induced arthritis (CIA) in wild-type (WT) and CR1/2-deficient DBA/1 mice. Significantly enhanced CIA was observed in female CR1/2-deficient mice compared with WT female mice, while male mutant and WT mice showed similar arthritis development. The enhanced CIA was accompanied with higher complement levels and a prolonged IgM anti-collagen type II response. When investigating whether estrogen contributed to the different arthritis susceptibility, we found that ovariectomy rendered WT females more sensitive to low-dose CIA and to the same extent as CR1/2-deficient females, while CR1/2-deficient mice were unaffected by ovariectomy. Notably, the ovariectomized WT mice displayed reduced CR1(+) B220(+) B-cell numbers and CR1 expression compared with sham-operated WT mice, suggesting a stimulatory effect of estrogen on CR1. In accordance, a significant correlation was observed between reduced CR1 expression in B cells and increased age in healthy female blood donors but not in male donors. Our findings demonstrate an important role of CR1/2 in suppressing CIA in female mice under low-antigen conditions. The data suggest that estrogen promote CR1 expression in B cells. These findings provide insight to the increased frequency of rheumatoid arthritis in postmenopausal women.
Assuntos
Artrite Experimental/etiologia , Estrogênios/fisiologia , Receptores de Complemento 3b/deficiência , Receptores de Complemento 3d/deficiência , Adulto , Idoso , Animais , Artrite Experimental/imunologia , Artrite Experimental/fisiopatologia , Artrite Reumatoide/etiologia , Linfócitos B/imunologia , Sequência de Bases , Primers do DNA/genética , Feminino , Expressão Gênica , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Camundongos Knockout , Pessoa de Meia-Idade , Ovariectomia , Receptores de Complemento 3b/genética , Receptores de Complemento 3d/genética , Caracteres SexuaisRESUMO
Immune complex (IC) binding to Fc gamma receptors (FcgammaRs) is central for inflammatory reactions seen in autoimmune diseases. Consequently, a therapeutic agent with a possibility to interfere with binding of pathogenic IC to FcgammaRs would be valuable in autoimmune disorders such as rheumatoid arthritis (RA). Here we have explored the therapeutic effect of a recombinant soluble human FcgammaRIIb (sFcgammaRIIb) protein in collagen-induced arthritis (CIA). In vitro studies of the sFcgammaRIIb demonstrated binding to mouse IgG, suggesting that sFcgammaRIIb can absorb pathogenic IgG anti-collagen type II (CII) IC in vivo. Hence, administration of sFcgammaRIIb significantly reduced CIA severity compared to control treated mice. The sFcgammaRIIb treated mice had significantly less IgG anti-CII antibodies in serum and lower mRNA levels of inflammatory cytokines compared to control mice. In conclusion, sFcgammaRIIb treatment ameliorates CIA by reducing IC-stimulated inflammation and joint swelling. This suggests that recombinant sFcgammaRIIb may be useful as therapeutic agent in RA.
Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Receptores de IgG/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Relação Dose-Resposta Imunológica , Ensaio de Imunoadsorção Enzimática , Pé/patologia , Histocitoquímica , Humanos , Imunização , Imunoglobulina G/sangue , Masculino , Camundongos , Camundongos Endogâmicos DBA , RNA Mensageiro/química , RNA Mensageiro/genética , Proteínas Recombinantes/farmacologia , Ribonucleases/químicaRESUMO
Serglycin (SG) is a proteoglycan that is located predominantly in the secretory granules of hematopoietic cells. Previous studies have established a crucial role for SG in promoting the storage of various secretory granule compounds that are of importance in the immune defense system. Here, we show that mice lacking SG spontaneously develop enlargement of multiple lymphoid organs, including the spleen, Peyer's patches (PP), and bronchus-associated lymphoid tissue. In the spleen, the lack of SG resulted in a significant decrease in the proportion of CD4(+) cells as well as an increase of the CD45RC(+) leukocyte population, indicating an expansion of naïve lymphocytes. In the PP, the lack of SG resulted in a general increase in cellularity, without significant alterations in the proportion of individual leukocyte populations. The enlargement of lymphoid tissues was not accompanied by increased serum levels of inflammatory cytokines. The number of mast cells in the peritoneum was not affected by the lack of SG, as judged by surface staining for CD117 (c-kit). However, the intensity of c-kit staining was reduced significantly in SG null animals. Moreover, the number of peritoneal macrophages, defined by morphological criteria and by CD11b staining, was decreased markedly in older, SG-deficient animals. Finally, experiments in which airway inflammation was induced by bacterial LPS revealed a more pronounced inflammatory response in old, SG-deficient as compared with wild-type mice. Taken together, our data show that SG deficiency causes multiple, age-related effects on the lymphoid system.