RESUMEN
We have reported previously that naive T cells from relapsing-remitting multiple sclerosis (RRMS) patients have T cell receptor (TCR) repertoire shifts, but the basis of these TCR repertoire shifts was uncertain. Here, we questioned whether RRMS patients have altered naive CD4 and CD8 T cell homeostasis by studying homeostatic proliferation and thymic production in RRMS patients and healthy controls. We measured thymic production by quantifying signal joint T cell receptor excision circles (sjTRECs). Both naive T subsets from controls showed an age-associated decrease in sjTRECs, i.e. evidence of progressive thymic involution, but we detected no age-associated decrease in sjTRECs in RRMS patients. Instead, naive CD8 T cells from patients had lower sjTRECs (P = 0.012) and higher Ki-67 proliferation levels (P = 0.04) than controls. Naive CD4 T cell sjTRECs did not differ between patients and controls. However, in RRMS these sjTRECs correlated strongly with CD31, a marker expressed by newly generated CD4 T cells but not by naive CD4 T cells that have undergone homeostatic proliferation. HLA-DR2 positivity correlated negatively with naive CD4 T cell CD31 expression in RRMS (P = 0.002). We conclude in RRMS that naive T subsets have homeostatic abnormalities due probably to peripheral (non-thymic) mechanisms. These abnormalities could have relevance for MS pathogenesis, as naive T cell changes may precede MS onset.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Homeostasis/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Timo/inmunología , División Celular/inmunología , Reordenamiento Génico de Linfocito T/genética , Reordenamiento Génico de Linfocito T/inmunología , Genes Codificadores de los Receptores de Linfocitos T/genética , Genes Codificadores de los Receptores de Linfocitos T/inmunología , Antígeno HLA-DR2/análisis , Homeostasis/genética , Humanos , Inmunofenotipificación/métodos , Antígeno Ki-67/análisis , Esclerosis Múltiple Recurrente-Remitente/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Receptores Inmunológicos/inmunología , Reproducibilidad de los ResultadosRESUMEN
Components of the fibrinolytic system have been implicated in cell migratory events associated with tissue remodeling. Studies in plasminogen-deficient mice (PG(-/-)) indicated that skin wound healing is impaired, but is resolved with an additional fibrinogen deficiency. Plasminogen activator inhibitor-1 (PAI-1) expression by keratinocytes has been identified shortly after wound injury. PAI-1 expression could affect wound healing by regulating the fibrinolytic environment of the wounded area, as well as influencing events associated with cell attachment and detachment through interactions with matrix proteins. The present study directly assesses PAI-1 involvement in skin wound healing through analyses of a dermal biopsy punch model in PAI-1-deficient (PAI-1(-/-) mice. While the cellular events associated with the healing process are similar between wild-type (WT) and PAI-1(-/-) mice, the rate of wound closure is significantly accelerated in PAI-1(-/-) mice.