An Eco RI polymorphic site in the human complement C4 gene distinguishes juvenile rheumatoid arthritis (JRA) susceptibility-bearing haplotypes

Susceptibility to acquire Juvenile Rheumatoid Arthritis (JRA) is linked to HLA-DR5 and DRw8 antigens in Caucasoid populations. However, the frequency of HLA-DR5 is too high in the normal Spanish population and JRA cannot thus be found to be associated with this antigen. It has been found a 14.3 kb-C4-Eco RI restriction fragment length polymorphism which correlates significantly with JRA and may be used as a marker for this disorder in Spaniards.     

Immunoresponses to Neisseria meningitidis epitopes: suppression of secondary response to phosphorylcholine is carrier specific

Results of our previous work have shown that Neisseria meningitidis serogroup B M986 can induce a phosphorylcholine (PC)-specific plaque-forming cell immunoresponse in mice. Also, a single injection of a relatively low dose of meningococci in NBF1 female mice induced a priming time-dependent suppression on subsequent meningococcus challenge. This suppression was not due to switching to another class of immunoglobulin nor to the presence of a capsule on N. meningitidis. In this study we show that suppression induced by meningococcus is carrier specific. Furthermore, we offer evidence suggesting that the structure(s) on meningococcus that trigger this suppression is heat labile and different from the antigenic structure(s) recognized by the suppressed B cells. In addition, we found that there is a gradual increase in antibody secretion rates of N. meningitidis-induced anti-PC plaque-forming cells that correlates with N. meningitidis priming time. Rather unexpected was the fact that pretreatment of mice with PC-keyhole limpet hemocyanin (thymus-dependent antigen) had a great influence on the subsequent PC-specific immunoresponses induced by N. meningitidis and PC-coupled heat-inactivated meningococcus [PC-(NMB)HI], as shown by (i) a striking decrease in T15 idiotype expression, (ii) concomitant direct anti-PC plaque-forming cells reduction, (iii) switching to immunoglobulin G (N. meningitidis-induced immunoresponse) or immunoglobulin G plus immunoglobulin A [PC-(NMB)HI-induced immunoresponse], and (iv) a significant increase in heterogeneity of plaque-forming cell secretion rates. The possibility that N. meningitidis, PC-(NMB)HI, and PC-KLH stimulate B lymphocytes pertaining to three different subpopulations embedded in distinct regulatory circuits is discussed, with emphasis on the interrelationships between T-dependent and T-independent lymphocyte compartments. We focus on the possibility of the existence of high-level regulatory circuits in which lymphocyte subpopulations or sets of lymphocyte subpopulations with different requirements of activation are connected.     

Impaired T cell signal transduction through CD28 in a patient with idiopathic thrombocytopenia.

We describe an infant whose peripheral blood mononuclear cells were unable to proliferate or synthesize IL-2 in response to a mitogenic combination of antibodies directed against CD2 and CD28. This peculiar defect, which has been stable to date, was attributed to an impairment in CD28-mediated T cell activation, because further comitogenic combinations containing anti-CD28 monoclonals also failed to induce normal proliferation of the patient's T cells. In contrast, proliferation after membrane stimulation (with anti-CD2, recombinant IL-2, or certain lectins) or transmembrane activation (with phorbol ester and calcium ionophore) was normal, suggesting that his lymphocytes did not have a general membrane or intracellular signalling impairment. A T cell line derived from the patient confirmed the existence of a severe defect in CD28-mediated T cell proliferation, but also showed a profound impairment in CD3-induced T cell proliferation. Other cell surface molecules like CD2 and CD25 were, in contrast, capable of transducing normal proliferation signals. As all relevant molecules were detectable by cytofluorography and immunoprecipitation, we conclude that the patient's lymphocytes had an intrinsic defect in the delivery of CD28-mediated signals which, in the absence of monocytes, also affected CD3-mediated proliferation. The study of this novel kind of immunodeficiency may help to unravel the complex interactions that take place among CD2, CD3 and CD28 during T cell activation. The presence of an idiopathic thrombocytopenia in the patient suggests the intriguing possibility of a role for CD28 in the maintenance of peripheral blood platelets levels, although alternative interpretations are not ruled out.     

Immunoresponses to Neisseria meningitidis epitopes: in vivo analysis of immunocompetent cells involved in suppression of secondary response to phosphorylcholine

The immune response to phosphorylcholine (PC) antigens has been extensively studied in recent years. Neisseria meningitidis serogroup B M986 (NMB) was recently reported to induce a PC-specific plaque-forming cell (PFC) immunoresponse in mice, a characteristic useful for the study of immunomodulating properties of N. meningitidis. With this technique, priming mice with low doses of NMB has been shown greatly to impair their ability, one month after priming, to mount an anti-PC response induced by NMB; this suppression is permanent, does not involve switching from IgM to another immunoglobulin class, transiently affects the T15 idiotype expression and is carrier specific. We report, based on an analysis of spleen cells from NMB-primed mice in an adoptive transfer model, that this suppression does not appear to be mediated by B lymphocytes nor does it seem to be under the direct control of T lymphocytes; rather, it involves radio-resistant cells. Additionally, our results show that NMB modulates the idiotype composition of the anti-phosphorylcholine response, probably by enhancing the expression of so called hapten-augmentable PFC. These results demonstrate that NMB can interfere effectively with the immune response in a variety of ways.Abbreviations BNF1 (BALB/c × CBA/N)F₁ hybrid mice - HI heterogeneity index - IFA incomplete Freund's adjuvant - KLH keyhole limpet hemocyanin - NBF1 (CBA/N × BALB/c)F₁ hybrid mice - NMB Neisseria meningitidis serogroup B M986 - PC phosphorylcholine - PC ₅₀ amount of PC-chloride that suppresses 50% of response - PC-KLH PC coupled to KLH - PC-(NMB)HI PC coupled to heat inactivated NMB - PFC plaque forming cell - TNP-Ficoll trinitrophenylated Ficoll     

Phenotypical and functional characterization of Herpesvirus saimiri-immortalized human major histocompatibility complex class ll-deficient T lymphocytes

Abstract: CD8⁺ T lymphocytes from two unrelated cases of MHC class II deficiency were immortalized in vitro using Herpesvirus saimiri. In both cases, a lack of expression of surface MHC class II molecules was ascertained, whereas variable defects were shown for MHC class I, CD74 (invariant chain) and LAG-3 (an MHC class II ligand). The functional analysis of both H. saimiri -immortalized T-cell lines revealed the existence of a proliferation impairment in response to anti-CD3 but not to other surface or transmem-brane stimuli. Further characterization of this functional defect indicated that it was not associated with impaired early activation events (like calcium flux) but, rather, with certain late events, like the induction of IL-2. H. saimiri '-immortalized T cells may be valuable in studying the biological role of MHC class II molecules in activated human T cells.     

Functional integrity of the CD28 co-stimulatory pathway in T lymphocytes from elderly subjects.

INTRODUCTION: the antigen CD28, expressed in most T cells, has co-stimulatory properties and plays a pivotal role in clonal T cell anergy mechanisms. METHODS: we have compared proliferative T cell responses after anti-CD3 or in phorbol myristate acetate activation with concomitant CD28 signal in peripheral blood mononuclear cells from healthy donors aged over 65 [elderly donors; ED] and young healthy donors (YD); mean age 30+/-2.7 years). RESULTS: no proliferative responses were observed in ED and YD with anti-CD28 monoclonal antibody alone. These responses both were defective in ED, particularly after anti-CD3 monoclonal antibody stimulus (7604 compared with 12,438 c.p.m. in YD, P=0.001) and were corrected when anti-CD28 monoclonal antibody was added to the culture (17,216 vs 18,536, not significant). Functional integrity of the CD28 co-stimulatory pathway was demonstrated by analysis of CD25 expression, interleukin-2 secretion and interleukin-2 gene expression on T cells from ED and YD. Age-associated phenotypic T cell changes were not crucial for an adequate CD28 response. CONCLUSION: these experiments demonstrate the integrity of the CD28 pathway in elderly people, and suggest that ageing does not affect different T cell activation pathways equally.     

Análisis de la eficacia y la seguridad de distintos balones liberadores de paclitaxel en un modelo animal

Introduction and objectives

Paclitaxel-eluting balloons have shown high antiproliferative efficacy in the treatment and prevention of restenosis. Nevertheless, not all available devices are equally effective, which makes it interesting to compare results in a preclinical model. Our objective was to assess the preclinical efficacy and safety of different devices.

Methods

We implanted 51 metallic stents (Architect^®, iVascular) in 17 domestic swine (mean, 25 [3] kg), inserting 1 stent per major coronary artery. Stent postdilatation was performed with different control balloons (n = 10) or paclitaxel-eluting balloons: paclitaxel-eluting balloon 1 (iVascular) (n = 15); paclitaxel-eluting balloon 2 (iVascular) (n = 16) and In.Pact Falcon^® (Medtronic) (n = 10). The restenosis rate (using angiography and histomorphometry) and vascular healing parameters (balloon-related vascular injury score, endothelialization rate, and fibrin and inflammation scores) were analyzed at 28 days.

Results

The distinct paclitaxel-eluting balloons showed a similar degree of stenosis at follow-up, which was significantly lower than that in the control group: diameter stenosis was 9% (12%) vs 34% (18%) by angiography (P < .0001) and was 22% (8%) vs 51% (18%) by histomorphometry (P < .0001). Scores for vascular injury (mean, 0.6 [0.5]) and inflammation (mean, 0.8 [0.3]) were uniformly low across all groups. Drug effect markers differed significantly between the paclitaxel-eluting balloons and control groups, with lower endothelialization rates (87% [10%] vs 99% [2%]; P = .0007) and higher fibrin scores (2.1 [0.7] vs 0.4 [0.5]; P < .0001) in the paclitaxel-eluting balloons groups. There were no differences between the different paclitaxel-eluting balloons.

Conclusions

In this preclinical model, the paclitaxel-eluting balloons studied significantly reduced in-stent restenosis compared with the control balloons. Although there were no findings of persistent vascular injury or inflammation, delayed endothelialization and fibrin aggregate suggest a drug deposition response.Full English text available from:www.revespcardiol.org/en     

Biliary lipid secretion during the prereplicative phase of rat liver regeneration.

The prereplicative phase-related changes in spontaneous and taurocholate-induced biliary lipid secretion were studied in anaesthetized male Wistar rats (250 g). Rats underwent two-thirds hepatectomy 1, 6 or 12 h before starting to collect bile samples. As compared with non-hepatectomized rats, biliary lipid secretion was increased at 1 h after hepatectomy and then restored to values similar to the control group up to 12 h after hepatectomy. In separate experiments, taurocholate was infused (200 nmol/min/g calculated liver weight) through the jugular vein over 80 min. Both taurocholate-induced bile flow and bile acid output were similar in control and hepatectomized rats, regardless of the time of the prereplicative phase considered. By contrast, taurocholate-induced lecithin and cholesterol outputs were markedly modified. The former was lowered throughout the prereplicative phase, whereas the latter increased at 6 h and decreased at 12 h. In summary, these results indicate that shortly after hepatectomy bile acid-induced biliary lipid secretion is profoundly modified, probably due to changes in the plasma membrane involved in preparing the hepatocyte to enter the cell cycle.     

Stomatococcus mucilaginosus septicemia in a patient with acute lymphoblastic leukaemia

A 16-year-old patient with acute lymphoblastic leukaemia which had relapsed for the third time developed clinical signs and symptoms of septicemia during a period of neutropenia. The patient had signs of oral mucositis, andStomatococcus mucilaginosus was isolated from blood cultures. The patient responded well to antibiotic therapy. The biochemical characteristics and antimicrobial susceptibility patterns of 68 other pharyngeal isolates ofStomatococcus mucilaginosus from immunocompromised patients are presented.     

T-lymphocyte dysfunctions occurring together with apical gut epithelial cell autoantibodies

Gut epithelial cell autoantibodies have been considered a hallmark of autoimmune enteropathy, a disorder occurring in children with protracted diarrhea of unknown etiology. Four patients (two male and two female) with such autoantibodies were studied. Immunofluorescence analysis showed two different disjunctive staining patterns: complement-fixing apical (three of four) and cytoplasmic (the remaining fourth one), which are shown to be directed against different structures. All three patients positive for complement-fixing apical gut epithelial cell autoantibodies had abnormal T-cell responses in vitro, one of them with an immunoglobulin G2 immunoglobulin deficiency and another with an immunoglobulin A deficiency. An immunoglobulin A deficiency without T-cell alterations was also diagnosed in the cytoplasmic gut epithelial cell autoantibody-positive patient. These findings suggest that different immunologic alterations (either a T-cell abnormality or immunoglobulin deficiency) may favor the appearance of gut epithelial cell autoantibodies (complement-fixing apical or cytoplasmic, respectively). Furthermore, these autoantibodies should not be considered a specific marker of autoimmune enteropathy, because they may not always be associated with such a disease: two patients with apical gut epithelial cell autoantibodies showed no signs of intestinal lesion or diarrhea.