Expresión de L-selectina en linfocitos T y neutrófilos de niños infectados con HIV / L-selectin expression on T lymphocytes and neutrophils in HIV infected children

La capacidad de los leucócitos de abandonar la circulación y migrar hacia los tejidos es un paso crítica de la respuesta inmune. La L-selectina, selectina leucocitaria (CD62L), media la unión de linfócitos a las vênulas endoteliales altas de los ganglios linfáticos periféricos, y también participa en la adhesión de linfócitos, neutrófilos y monócitos al endotelio vascular activado en los sítios de inflamación. En este trabajo se estudiaron los niveles de expresión de L- selectina sobre los linfócitos T y polimorfonucleares neutrófilos en 25 niños HIV (+) sin tratamiento antirretroviral y 25 niños sanos HIV (-), avaluando además su comportamiento en 10 de los pacientes, luego de 6 meses de iniciada la terapéutica específica para el HIV. El número de linfócitos TCD3+, CD4+ y CD8+ que expresan CD62L se encontró significativamente disminuido en los niños HIV(+) con respecto al grupo control. El porcentaje de neutrófilos que expresan CD62L se encontro significativamente disminuido en los pacientes con mayor compromiso inmunológico. Se observó una correlación positiva entre los niveles de LTCD4+ y el porcentaje de neutrófilos que expresan CD62L. Luego de 6 meses de tratamiento antirretroviral no hubo câmbios significatios en los niveles de expresión de CD62L sobre LTCD4+ y LTCD8+ . La reducción en los niveles de expresión de L-selectina en estos tipos celulares sugiere que durante la infección por HIV las funciones leucocitarias tales como la migración y el asentamiento linfocitario son anormales, contribuyendo al progresivo deterioro inmune.

Losartan, a selective inhibitor of subtype AT1 receptors for angiotensin II, inhibits neutrophil recruitment in the lung triggered by fMLP.

We have shown that losartan, a selective inhibitor of AT1 receptors for angiotensin II (AII), inhibits the binding of [3H]fMLP to neutrophil receptors (FPR). Here, we analyze, in Wistar rats, the effect of losartan on neutrophil recruitment in the lung triggered by fMLP. We found that i.v. infusion of losartan (0.4-20.0 microg/kg/min) inhibits neutrophil recruitment induced by i.t. instillation of fMLP, without affecting the responses induced by other stimuli, such as aggregated human IgG (aIgG), precipitating immune complexes (IC), or zymosan. Histological evaluation of lungs as well as the analysis of lung hemorrhage indices showed that losartan prevents tissue injury partially in fMLP-challenged rats. We also analyzed the effect of losartan on lung-neutrophil recruitment triggered by i.t. instillation of Pseudomonas aeruginosa. Not only was there a marked decrease in neutrophil recruitment but also a significant increase in the survival of rats instillated with Pseudomonas aeruginosa, as a consequence of losartan treatment. Our results support the notion that losartan may be useful in the treatment of certain lung inflammatory disorders associated with bacterial infectious diseases.

Acidic pH increases the avidity of FcgammaR for immune complexes.

The interaction of immunoglobulin G (IgG) antibodies with FcgammaR constitutes a critical mechanism through which IgG antibody effector functions are mediated. In the current work we have examined whether human neutrophil FcgammaR exhibit pH dependence in their association with IgG. Binding assays were performed in culture medium adjusted to different pH values. It was found that the binding of either heat-aggregated human IgG (AIgG), soluble immune complexes (sIC) or IgG-coated erythrocytes (IgG-E) was markedly higher at pH 6.5 than at pH 7.3. This effect was not observed when saturation of FcgammaR was achieved, suggesting that acidic pH increases the avidity of FcgammaR for IC without modifying the total binding capacity. Similar results were observed for the binding of AIgG to either monocytes, natural killer (NK) or K562 cells, suggesting that acidic pH increases the avidity of both, FcgammaRII and FcgammaRIII. Additional experiments were performed to analyse whether the binding of IgG to FcgammaRI also showed pH dependence. To this aim, we employed interferon-gamma-treated human neutrophils and mouse inflammatory macrophages, previously incubated with blocking antibodies directed to FcgammaRII and FcgammaRIII. Acidic pH did not enhance the binding of AIgG nor monomeric IgG under these experimental conditions. Further studies are required to determine whether the enhancement of FcgammaR avidity for IC could be attributed to titration of histidine(s) residues on the Fc fragment of IgG.

Losartan, a selective inhibitor of subtype AT1 receptors for angiotensin II, inhibits the binding of N-formylmethionyl-leucyl-phenylalanine to neutrophil receptors.

Losartan, a selective antagonist of AT1 receptors for angiotensin II, is widely used clinically to manage hypertension. We report here that losartan markedly inhibits neutrophil shape change, adherence and chemiluminescence responses triggered by N-formylmethionyl-leucyl-phenylalanine (fMLP), without affecting responses induced by immune complexes, zymosan or concanavalin A. Neither saralasin, another antagonist of angiotensin II receptors, nor captopril, an angiotensin-converting enzyme inhibitor, reproduced the effects of losartan. It was also observed that neutrophil responses triggered by fMLP were not affected by exogenously added angiotensin II. The effect of losartan on the binding of fMLP was measured using [3H]fMLP. It was found that losartan inhibits the binding of [3H]fMLP to neutrophil receptors. As observed for neutrophils, studies performed with monocytes showed that losartan inhibits chemiluminescence emission triggered by fMLP, without affecting chemiluminescence responses triggered by immune complexes, zymosan or concanavalin A.

Inhibition of human neutrophil apoptosis by platelets.

In the absence of appropriate stimuli, polymorphonuclear neutrophils rapidly undergo characteristic changes indicative of programmed cell death or apoptosis. We report here that neutrophils cultured in the presence of platelets (neutrophil:platelet ratios of 1:50, 1:25, and 1:10) show a dramatic inhibition of apoptosis compared with neutrophils cultured alone. Similar degrees of apoptosis delay were induced by viable unstimulated platelets, fixed unstimulated platelets, or fixed activated (1 U/ml thrombin) platelets. Inhibition of apoptosis was associated with prolongation of the functional lifespan of the neutrophil, as indicated by the higher capacity of platelet-treated neutrophils to display chemiluminescence responses triggered by FMLP, immune complexes, and zymosan. The mechanism responsible for the inhibition of neutrophil apoptosis by platelets has not yet been defined. However, it seems that classical recognition systems such as those mediated by the interaction between platelet P-selectin (CD62) or glycoprotein IIb/IIIa complex and their counter-receptors expressed by neutrophils are not involved.

TRH receptor on immune cells: in vitro and in vivo stimulation of human lymphocyte and rat splenocyte DNA synthesis by TRH.

This work examined whether (1) immune cells express thyrotrophin releasing hormone (TRH) receptor mRNA and (2) TRH modulates lymphocyte activation. By Northern blot of RNA extracted from human peripheral blood mononuclear cells (PBMC) and rat splenocytes, a single TRH receptor mRNA band of about 3.8 kb (identical to that obtained from pituitary cells) was obtained, under both basal and stimulated conditions. A significant increase in DNA synthesis was observed in phytohemagglutinin-stimulated PBMC and concanavalin A (Con A) stimulated splenocytes when TRH (10(-6) M-10(-12) M) was added. After 5, 30, 60, 180 min and 24 h of TRH administration in vivo, a significant increase in the rat splenocyte proliferative response to Con A was observed. In vivo administration of anti-rat TSH antibody (1/1000) blocked the increase observed after 30 min of TRH administration on the Con A stimulated splenocyte response. TRH possess immunostimulatory functions directly via its receptor and indirectly via release of other immunostimulatory factors such as thyrotrophin.