No abstract

Although T regulatory cells are abundant in inflamed thyroid tissue, they are apparently unable, in most cases, to downmodulate the autoimmune response and the tissue damage seen in AITD.

SummaryThe aim of this study was to assess the effect of Adalimumab on different immune parameters in patients with RA. Adalimumab was administered (40 mg every other week for 26 weeks) to eight patients with RA that were refractory to conventional drug therapy. Peripheral blood samples were obtained at days 0, 15 and 180 of Adalimumab therapy, and the following immune parameters were assessed: Number, phenotype, and function of regulatory T lymphocytes. The induction of apoptosis of immune cells and the in vitro and in vivo reactivity towards M. tuberculosis were also analysed. All patients responded to Adalimumab (ACR response 50-70), and a modest but significant increase in the number and function of regulatory T cells was observed at day 15 of anti-TNF-a a a a therapy. In addition, an increased percent of apoptotic cells was detected in the peripheral blood at day 15 of Adalimumab therapy. Unexpectedly, most of these effects were not further observed at day 180. However, two patients showed a persistent and marked reduction in the reactivity to M. tuberculosis . Although we have found that Adalimumab affects the number and function of regulatory T lymphocytes, and the apoptosis of immune cells, these effects are transient and its possible causal relationship with the therapeutic activity of this biological agent remains to be determined. Nevertheless, the down-regulatory effect of Adalimumab on the reactivity to M. tuberculosis could be related to an enhanced risk of tuberculosis reactivation.

Rho GTPases control many facets of cell polarity and migration; namely, the reorganization of the cellular cytoskeleton to extracellular stimuli. Rho GTPases are activated by GTP exchange factors (GEFs), which induce guanosine diphosphate (GDP) release and the stabilization of the nucleotide-free state. Thus, the role of GEFs in the regulation of the cellular response to extracellular cues during cell migration is a critical step of this process. In this report, we have analyzed the activation and subcellular localization of the hematopoietic GEF Vav in human peripheral blood lymphocytes stimulated with the chemokine stromal cell-derived factor-1 (SDF-1␣). We show a robust activation of Vav and its redistribution to motility-associated subcellular structures, and we provide biochemical evidence of the recruitment of Vav to the membrane of SDF-1␣-activated human lymphocytes, where it transiently interacts with the SDF-1␣ receptor CXCR4. Overexpression of a dominant negative form of Vav abolished lymphocyte polarization, actin polymerization, and migration. SDF-1␣-mediated cell polarization and migration also were impaired by overexpression of an active, oncogenic Vav, although the mechanism appears to be different. Together, our data postulate a pivotal role for Vav in the transmission of the migratory signal through the chemokine receptor CXCR4. IntroductionLeukocyte migration in and out of target tissues during homeostasis and inflammation is a finely regulated process mediated by many receptors, which regulate rolling, adhesion and/or detachment, and motility. Chemotactic receptors play an important role in the modulation of cell adhesion as well as in controlling the morphology of migrating leukocytes. 1 In particular, chemokines are chemotactic cytokines that, acting through heterotrimeric G-proteincoupled receptors (GPCRs), regulate cell adhesion through crosstalk with integrin receptors and also modulate the morphology of migrating leukocytes. 1,2 The chemokine stromal cell-derived factor-1 (SDF-1␣) is the most pleiotropic of chemokines, being involved in many processes, from migration of hematopoietic progenitors and most leukocytes to morphogenesis in mammals and lower organisms such as zebrafish. 3,4 SDF-1␣ interacts exclusively with the chemokine receptor CXCR4, the specificity of this pair being underscored by the similar phenotype of mice deficient for SDF-1␣ or CXCR4. [5][6][7] SDF-1␣ has been shown to modulate adhesion through the integrins very late activation antigen-4 (VLA-4, ␣ 4 ␤ 1 ) and leukocyte function associated antigen-1 (LFA-1, ␣ L ␤ 2 ), 8 although the intracellular mechanisms involved in such cross-talk are largely undefined. We and others have shown that SDF-1␣ induces profound morphological changes in adherent leukocytes and the acquisition of a bipolar shape with a front leading edge, in which chemokine receptors are clustered, 9-12 and a trailing edge or uropod that accumulates adhesion molecules such as ICAM-1, -3, or CD44 (Vicente-Manzanares and Sanchez-Madrid 1 ). CXCR4 trigge...