RESUMO
Thirty patients with clinically isolated syndromes (CIS) were evaluated at the onset of neurological symptoms and when they developed clinically definite MS (CDMS). Surface expression of LFA-1alpha, VLA-4 and intercellular adhesion molecule-1 (ICAM-1) on PBMC and CSF cells was evaluated using flow cytometry. Serum and CSF concentrations of soluble vascular cell adhesion molecules-1 (VCAM-1), ICAM-1 and E-Selectin, as well as MMP-9 and MMP-2 serum concentrations were assayed using ELISA. Surface expression of LFA-1alpha and VLA-4 molecules on peripheral blood and CSF T cells and monocytes from CIS and CDMS was significantly increased compared with control subjects. Moreover, LFA-1alpha and VLA-4 expression was significantly higher in patients who developed CDMS compared with those with CIS. Similar changes were observed in the serum levels of MMP-9. Furthermore, patients with CIS and CDMS had significantly higher levels of CSF sVCAM and s-E-Selectin than control subjects. These data suggest that VLA-4, LFA-1alpha and MMP-9 play a leading role in the evolution of inflammatory demyelinating lesions in patients with CIS who develop CDMS.
Assuntos
Moléculas de Adesão Celular/biossíntese , Metaloproteinases da Matriz/biossíntese , Esclerose Múltipla/enzimologia , Esclerose Múltipla/metabolismo , Adulto , Moléculas de Adesão Celular/sangue , Moléculas de Adesão Celular/líquido cefalorraquidiano , Membrana Celular/enzimologia , Membrana Celular/metabolismo , Feminino , Humanos , Integrina alfa4beta1/biossíntese , Integrina alfa4beta1/sangue , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/sangue , Molécula 1 de Adesão Intercelular/líquido cefalorraquidiano , Estudos Longitudinais , Antígeno-1 Associado à Função Linfocitária/biossíntese , Antígeno-1 Associado à Função Linfocitária/sangue , Antígeno-1 Associado à Função Linfocitária/líquido cefalorraquidiano , Masculino , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/sangue , Metaloproteinases da Matriz/sangue , Pessoa de Meia-Idade , Monócitos/enzimologia , Monócitos/metabolismo , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Solubilidade , Subpopulações de Linfócitos T/enzimologia , Subpopulações de Linfócitos T/metabolismo , Fatores de Tempo , Regulação para CimaRESUMO
We have recently reported that epidermal growth factor (EGF) modulates thymocyte development in fetal thymus organ cultures. Exogenously added EGF arrested thymocyte growth and differentiation, acting at the transition from the CD4-CD8- (double-negative (DN)) to the CD4+CD8+ (double-positive (DP)) phenotype. In this study, we further investigate some molecular aspects of this blockade. This inhibitory effect could be mimicked by tyrphostins, which are selective inhibitors of EGF receptor kinase activity. An attempt to use insulin (INS) as a synergizing effector resulted in partial restoration of lobe cellularity, leading to expansion of the CD44-CD25+ DN subset. However, INS did not overcome the EGF-driven blockade of the thymocyte DN --> DP transition. Analysis of CD45 phosphatase showed that this transition was preceded by a rise in CD45RB isotype expression. At the end of a 7-day culture, the remaining DN cells from both EGF- and EGF+INS-treated fetal thymus organ cultures showed a CD45RB- phenotype and were negative for the EGF-immunoreactive molecule described previously on the fetal thymocyte surface. This finding implies that neither molecule is related to the growth capability of cells at this early developmental stage; it is more likely that the molecules are related to subsequent events in the thymocyte pathway to the DP phenotype. Thus, our data support the concept that EGF receptor-related circuitry may be relevant in thymus ontogeny. Additionally, evidence is provided for the duality between growth and differentiation at this particular early stage of thymocyte development.