Endogenous and exogenous antioxidants and the generation of antigenic epitopes in oxidatively-modified LDL.
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Animals↗
Biomedical subjects
E Maggi
Publications and source records attributed to E Maggi.
Opposite role for interleukin-4 and interferon-gamma on CD30 and lymphocyte activation gene-3 (LAG-3) expression by activated naive T cells.
Polarized human type 1 and type 2 T helper cells not only produce different sets of cytokines, but they also preferentially express certain activation markers, such as lymphocyte activation gene-3 (LAG-3) and CD30, respectively. In this study we have examined the LAG-3 and CD30 expression in relation to the lineage commitment of human naive CD4+ T cells, as assessed at the single-cell level of committed T cells. Purified CD45RA+ umbilical cord blood T lymphocytes were activated with phytohemagglutinin and interleukin (IL)-2 in the absence or presence of interleukin IL-4 or IL-12 and assessed for CD30 and LAG-3 expression, as well as for intracellular cytokine synthesis. Significant numbers of CD30+ cells were only found in CD4+ and CD8+ T lymphocytes of cultures primed with IL-4, which developed into cells able to produce IL-4 and IL-13 in addition to interferon (IFN)-gamma. By contrast, LAG-3 expression was strongly up-regulated in CD4+ and CD8+ T cells from cultures primed with IL-12, which developed into high numbers of IFN-gamma producers. The addition of a neutralizing anti-IFN-gamma antibody to IL-12-primed CD4+ T cell cultures virtually abolished the development of LAG-3-expressing CD4+ T cells. Taken together, these data suggest that CD30 expression is dependent on the presence of IL-4, whereas LAG-3 expression is dependent on the production of IFN-gamma during the lineage commitment of human naive T cells.
Antigens, CD↗
Circulating autoantibodies recognizing peroxidase-oxidized low density lipoprotein. Evidence for new antigenic epitopes formed in vivo independently from lipid peroxidation.
Oxidatively modified LDLs are antigenic and elicit the generation of autoantibodies often detected in plasma and within plaques of atherosclerotic patients. Although Cu(2+)-oxidized LDL and malondialdehyde (MDA)-modified LDL are usually used as antigens in immunoassays, other, still unrecognized epitopes may be formed in vivo during LDL oxidation and may induce antibody production. Antibodies recognizing LDL oxidatively modified by Cu2+, 2,2'-azobis-(2-amidino propane) hydrochloride (AAPH), and the combination of horseradish peroxidase and H2O2 (HRP) were detected in serum of a group of 90 unselected patients. HRP-oxidized LDL was the antigen that revealed the highest IgG titers, although the extent of LDL oxidation (evaluated as conjugated diene formation, loss of tryptophan fluorescence, production of fluorescent aldehydic adducts, and change in electrophoretic mobility) was comparable to that obtained with Cu2+ and AAPH. There was a highly statistically significant correlation between the IgG titers detected using Cu(2+)- and AAPH-oxidized LDLs as antigens, but no correlation was found between the IgG titers revealed by HRP and Cu2+ or AAPH. In addition, the antibody titers against MDA-modified LDL exhibited a significant correlation with those against Cu(2+)- or AAPH-oxidized LDL but did not correlate with those against HRP-oxidized LDL. Finally, immunocompetition experiments revealed that IgG recognizing HRP-oxidized LDL did not cross-react with Cu(2+)-oxidized LDL and vice versa. The possibility that lipid peroxidation-independent modifications could play a role in HRP-induced formation of antigenic epitopes in LDL was supported by two lines of evidence. First, in probucol-enriched LDL, despite the complete inhibition of lipid peroxidation, HRP, but not Cu2+ and AAPH, was still able to generate epitopes that were recognized by the same sera reacting with HRP-oxidized native (not probucol-enriched) LDL. In addition, the presence of autoantibodies against Cu(2+)- and AAPH-oxidized LDLs was negatively correlated with serum alpha-tocopherol concentration, whereas the titers against HRP-oxidized LDL did not exhibit any statistically relevant correlation with alpha-tocopherol levels. Together, these findings indicate that peroxidase(s)-dependent mechanisms can trigger peculiar lipid peroxidation-independent modifications of LDL in vivo.
Adult↗
Neonatal and maternal levels of lipid-soluble antioxidants.
Lipid peroxidation plays an important role in the pathogenesis of several neonatal complications. To improve the knowledge on the antioxidant lipid-soluble defenses in neonatal age, we investigated a group of healthy full-term infants and their mothers measuring by high-pressure liquid chromatography the levels of vitamin E and carotenoids. Our data demonstrate that neonatal levels of lipid-soluble anti-oxidants are lower than the maternal ones. Moreover we show that neonatal Vitamin E and carotenoid concentrations are respectively unrelated and strictly related to maternal levels of the same lipid-soluble anti-oxidants.
Adult↗
Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn's disease.
Crohn's disease (CD) is a chronic bowel inflammatory disorder in which the pathogenic role of immune alterations has been suggested, but the immunologic mechanisms responsible for the inflammatory reaction are still poorly understood. We investigated the profile of cytokine secretion by T-cell clones generated from gut tissue specimens of four patients with active CD, five patients with ulcerative colitis, and four patients with noninflammatory gut disorders (NIGDs). The great majority of CD4+ T-cell clones generated from the gut of patients with CD produced high levels of interferon-gamma (IFN-gamma) but low or undetectable amounts of interleukin-4 (IL-4), whereas substantial proportions of CD4+ T-cell clones derived from the gut of patients with either ulcerative colitis or NIGDs produced IL-4 in addition to IFN-gamma. The immunohistochemical analysis revealed high numbers of activated CD4+ T cells showing IFN-gamma but not IL-4 reactivity, as well as substantial proportions of IL-12-containing macrophages, in the intestinal lamina propria and muscularis propria of patients with CD, whereas these cells were very rare or undetectable in patients with NIGDs. Culturing T cells from gut biopsy specimens of a patient with CD in the presence of a neutralizing anti-IL-12 antibody down-regulated the development of IFN-gamma-producing CD4+ T cells. These findings suggest that a critical event in the initiation of bowel inflammatory lesions in CD may involve up-regulation of IL-12 production, resulting in conditions that maximally promote type 1 T-helper immune responses.
CD4-Positive T-Lymphocytes↗
In vivo CD30 expression in human diseases with predominant activation of Th2-like T cells.
CD30 is a member of the tumor necrosis factor (TNF) receptor family, originally described as a marker for Hodgkin and Reed-Sternberg cells in Hodgkin's disease, which has been found to be preferentially expressed by T cells producing Th2-type cytokines. The presence of CD30 expression was assessed by both immunohistochemistry and reverse transcriptase-polymerase chain reaction in the target organs of patients with Th1- or Th2-dominated disorders. CD30 expression was found in neither the gut of patients with Crohn's disease nor in the gastric antrum of Helicobacter pylori-infected patients, where there was high interferon-gamma (IFN-gamma) expression. In contrast, high CD30 expression in the apparent absence of IFN-gamma expression was observed in the skin of patients with systemic sclerosis or chronic graft versus host disease (GVHD), which can be considered Th2-dominated disorders. Moreover, high levels of soluble CD30 were found in the serum of both systemic sclerosis and GVHD patients but not in the serum of patients suffering from multiple sclerosis, a Th1-dominated disorder. Thus, CD30 expression appears to be preferentially associated with Th2-type responses not only in vitro but also in vivo.
Crohn Disease↗
Type 2 helper T-cell predominance and high CD30 expression in systemic sclerosis.
The pattern of cytokine production of skin-infiltrating T cells from patients with progressive systemic sclerosis was investigated. Most CD4+ T-cell clones generated from skin biopsy specimens showed a type 2 helper (Th2) cytokine profile (production of interleukin-4, but no interferon (IFN)-gamma). High interleukin-4 but little or no IFN-gamma mRNA expression was found by in situ hybridization in skin perivascular mononuclear cell infiltrates. The immunohistochemical analysis revealed CD30 expression by high numbers of CD4+ T cells in the same specimens. Finally, the great majority of patients with diffuse disease had elevated levels of soluble CD30 in their sera. These data suggest the existence in patients with progressive systemic sclerosis of a predominant activation of Th2-like T cells, which may account for the major alterations (endothelial cell injury, fibrosis, and autoantibody production) occurring in this disease.
Adult↗
Human CD8+ T lymphocyte subsets that express HLA class I-specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations.
A small percentage of human T lymphocytes, predominantly CD8+ T cells, express receptors for HLA class 1 molecules of natural killer type (NK-R) that are inhibitory for T-cell antigen receptor (TCR)-mediated functions. In the present study, it is demonstrated that the various NK-R molecules typically expressed by NK cells are also expressed on periheral blood T lymphocytes. These CD3+ NK-R+ cells have a cell surface phenotype typical of memory cells as indicated by the expression of CD45RO and CD29 and by the lack of CD28 and CD45RA. Furthermore, by the combined use of anti-TCR V beta-specific antibodies and a semiquantitative polymerase chain reaction assay, the TCR repertoire in this CD3+ NK-R+ cell subset was found to be skewed; in fact, one or two V beta families were largely represented, and most of the other V beta s were barely detected. In addition, analysis of recombinant clones of the largely represented V beta families demonstrated that these V beta s were oligoclonally or monoclonally expanded.
CD3 Complex↗
Effects of interferon-alpha on cytokine profile, T cell receptor repertoire and peptide reactivity of human allergen-specific T cells.
A large panel of T cell clones (TCC) specific for the recombinant form of Poa pratensis allergen (rKBG7.2 or Poa p9) were established from the peripheral blood of grass pollen-sensitive donor in the absence or presence of recombinant interferon-alpha (IFN-alpha) in bulk culture and their pattern of cytokine secretion, peptide reactivity and TCR V beta repertoire was examined. The majority of allergen-specific TCC derived in absence of IFN-alpha produced high amounts of interleukin-4 (IL-4) and IL-5 but not IFN-gamma (Th2 cells), while most of TCC derived in presence of IFN-alpha produced IFN-gamma but not, or limited amounts of, IL-4 and IL-5 (Th1 or Th0 cells). Of 24 TCC established in the presence of IFN-alpha, 22 were able to recognize a single allergen peptide, p26, while none of the clones established in the absence of IFN-alpha showed a similar specificity. The majority of both clones expressed the V beta 2 element regardless of whether they were established in the presence of INF-alpha, but the presence of IFN-alpha favored the expansion of V beta 2+, V beta 17+ and V beta 22+ Poa p9-specific T cells, whereas in the absence of IFN-alpha, other TCR V beta-bearing T cells (V beta 5, and V beta 6.7, and V beta 14) were expanded in addition to V beta 2+ T cells. None of V beta 2+ clones established in the absence of IFN-alpha reacted with p26, whereas all the V beta 2+ clones established in its presence in the absence of interferon-alpha reacted with p26, whereas all the V beta 2+ clones established in its presence reacted to this peptide. IFN-alpha also shifted the TCR V beta repertoire of both Poa p9- and Lolium perenne group 1 (Lol p1)-specific T cell lines generated from the same patient and from a different grass-sensitive individual. These data demonstrate that IFN-alpha modulates the development of allergen-specific T cells in vitro, and suggest that IFN-alpha may represent a useful tool for novel immunotherapeutic approaches in allergic disorders.
Allergens↗
Development in vitro of human CD4+ thymocytes into functionally mature Th2 cells. Exogenous interleukin-12 is required for priming thymocytes to produce both Th1 cytokines and interleukin-10.
Fresh postnatal thymocyte cell suspensions were directly cloned under limiting dilution conditions with either phytohemagglutinin or toxic shock syndrome toxin-1 (TSST-1), a bacterial superantigen. Cultures contained allogenic irradiated feeder cells and interleukin (IL)-2, in the absence or presence of exogenous IL-4, interferon (IFN)-gamma or IL-12. The resulting CD4+ T cell clones generated under these different experimental conditions were then analyzed for their ability to produce IL-2, IL-4, IL-5, IL-10, IFN-gamma and tumor necrosis factor (TNF)-beta in response to stimulation with phorbol 12-myristate 13-acetate (PMA) + anti-CD3 monoclonal antibody or PMA + ionomycin. Different from T cell clones generated from peripheral blood, virtually all CD4+ T cell clones generated from human thymocytes produced high concentrations of IL-2, IL-4 and IL-5, but no IFN-gamma, TNF-beta or IL-10. Moreover, after activation, these clones expressed on their surface membrane both CD30 and CD40 ligand, but not the product of lymphocyte activation gene (LAG)-3, and provided strong helper activity for IgE synthesis by allogeneic B cells. The Th2 cytokine pattern could not be modified by the addition of IFN-gamma. However, upon addition of exogenous IL-12, the resulting CD4+ thymocyte clones produced TNF-beta, IFN-gamma, and IL-10 in addition to IL-4 and IL-5. These results suggest that CD4+ human thymocytes have the potential to develop into cells producing the Th2 cytokines IL-4 and IL-5, whereas the ability to produce both Th1 cytokines and IL-10 is acquired only after priming with IL-12.
CD4-Positive T-Lymphocytes↗
Abnormal production of T helper 2 cytokines interleukin-4 and interleukin-5 by T cells from newborns with atopic parents.
T cell clones were generated from umbelical cord blood lymphocytes (UCBL) of nine newborns with atopic or nonatopic parents and their cytokine secretion profile was assessed. Both phytohemagglutinin-induced and Dermatophagoides pteronyssinus-specific T cell clones from newborns with atopic parents exhibited an enhanced ability to produce the Th2 cytokines interleukin (IL)-4 and IL-5, compared to T cell clones from newborns with nonatopic parents. In contrast, the ability to produce interferon-gamma by UCBL from the two groups of newborns was not different. Of the five children who could be followed up to 3 years after birth, four with atopic parents developed clinical and/or biological atopic manifestations, whereas one without atopic parents did not. Thus, the pronounced production of IL-4 and IL-5 by UCBL not only appears to be related to the atopic status of parents, but also associates with the subsequent development of atopy in childhood.
Allergens↗
Responsiveness to the major pollen allergen of Parietaria officinalis is associated with defined HLA-DRB1* alleles in Italian and Spanish allergic patients.
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Alleles↗
Role of type 2 T helper cells (Th2) in allergic disorders.
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Allergens↗
Role for CD30 in HIV expression.
CD30 is a member of the tumor necrosis factor (TNF)-receptor superfamily, whose ligand (CD30L) has been identified on B cells, activated macrophages and a subset of activated T cells. We show here that infection in vitro with human immunodeficiency virus (HIV) of CD4+ T-cell clones generated from HIV-seronegative individuals can enhance the expression of CD30, which often preceeds and is associated with the death of clonal T cells. Furthermore, cross-linking CD30 with an agonistic CD30-specific monoclonal antibody potentiated HIV replication induced by an insolubilized anti-CD3 antibody in T-cell lines generated from HIV-infected individuals. More importantly, paraformaldehyde-fixed CD8+ T-cell clones expressing CD30L enhanced HIV replication in anti-CD3-stimulated allogeneic or autologous HIV-infected CD4+ T-cell lines and such a potentiating effect was inhibited by an anti-CD30L antibody. The anti-CD30L antibody also exerted a suppressive effect on the spontaneous HIV replication occurring in lymph node cells, freshly derived from an HIV-seropositive patient showing CD30 expression in B cells and in a proportion of CD8+ T lymphocytes. Thus, CD30 triggering may play an important role in both HIV replication and the death of HIV-infected CD4+ T cells.
Antibodies, Monoclonal↗
Association of responsiveness to the major pollen allergen of Parietaria officinalis with HLA-DRB1* alleles: a multicenter study.
Parietaria, a plant belonging to the family of Urticaceae, is a major source of allergenic pollen in Europe. In the context of a multinational study, we investigated whether in allergic subjects antibody response towards Par o 1, the major allergen from P. officinalis, was associated with defined HLA-DRB1* alleles. The study population consisted of 234 allergic patients: 65 from Bulgaria, 30 from Israel, 99 from Italy, and 40 from Spain. In the Italian study group, the prevalence of ST positivity to Parietaria was 77%. In Parietaria ST-positive subjects, the prevalences of IgG and IgE serum Ab towards Par o 1 were 91% and 75%, respectively. HLA-DRB1*1101 and/or 1104 were significantly positively associated with the presence of IgG Ab and with high levels of IgE Ab towards this allergen (p = 0.0007 and p = 0.012, respectively). In the Spanish study group, the positive association of DR1100 with responsiveness to Par o 1 was confirmed (p = 0.02, RR = 4, and p = 0.002, RR = 7, for IgG and IgE Ab, respectively). None of the Bulgarian patients had IgE Ab to Par o 1, whereas IgG Ab response was observed in 7 out of 65 subjects and was positively associated with DRB1*1101 and/or 1104 (p = 0.025). In the Israeli study group, responsiveness to Par o 1 was not associated with specific HLA-DRB1* alleles. In conclusion, this study shows that in allergic patients from three European populations antibody response to the major allergen from the pollen of Parietaria is associated with HLA-DRB1*1101 and/or 1104. Our data suggest that this association is stronger in subjects monosensitized to Parietaria.
Adolescent↗
Expression and release of LAG-3-encoded protein by human CD4+ T cells are associated with IFN-gamma production .
The lymphocyte activation gene (LAG) -3 is a member of the immunoglobulin super-family that is selectively transcribed in human activated T and NK cells. In this work, the possibility that LAG-3 expression by human CD4+ T cells was preferentially related to one or another phenotype of cytokine secretion was investigated. Surface LAG-3 expression correlated with IFN-gamma, but not IL-4, production in antigen-stimulated T cells and it was up-regulated by IL-12. Most activated CD4+ T cell clones with established Th1 or Th0 profiles of cytokine secretion expressed LAG-3 on their surface, whereas the great majority of Th2 clones showed neither surface LAG-3 nor LAG-3 mRNA expression. After activation, the majority of CD4+ T cell clones also released soluble LAG-3-related peptides, and such a release correlated positively with the production of IFN-gamma and inversely with the production of IL-4. Thus, LAG-3 expression by activated CD4+ human T cells appear to be preferentially associated with the differentiation/activation pathway leading to the production of IFN-gamma.
Antigens, CD↗
Protective effects of carvedilol, a vasodilating beta-adrenoceptor blocker, against in vivo low density lipoprotein oxidation in essential hypertension.
Low density lipoprotein (LDL) oxidation plays a crucial role in the development and progression of atherosclerosis and is enhanced in patients with essential hypertension. This finding has stimulated a search for antihypertensive drugs with high intrinsic antioxidant properties. We investigated the antihypertensive and antioxidant effects of carvedilol, a new vasodilating beta-adrenoceptor blocking agent in a group of patients with mild to moderate essential hypertension after 4-month treatment. Carvedilol administration markedly increased the resistance to oxidation of LDL isolated from treated patients to values comparable to those of control, nonhypertensive subjects. This effect was achieved despite a significant loss in LDL-associated vitamin E. The increased resistance of LDL to oxidation promoted by carvedilol was not related to the normalization of previously increased blood pressure (BP). Indeed, the administration of other conventional antihypertensive drugs, capable of decreasing arterial BP but without high intrinsic antioxidant properties, to a control group of matched hypertensive patients failed to ameliorate LDL oxidation parameters. Carvedilol treatment also reduced the extent of in vivo LDL oxidation, as reflected by the decrease in antioxidized LDL autoantibody titer. This effect as well was detected only in the group of carvedilol-treated hypertensive patients and not after the simple reduction in BP obtained with antihypertensive drugs different from carvedilol.
Adrenergic beta-Antagonists↗
Immune mechanisms in the pathogenesis of inflammatory gastrointestinal disorders.
The cytokine secretion profile of T cells present in the gastric antrum of Helicobacter pylori-infected patients with peptic ulcer and in the gut of patients with Crohn's disease was investigated. A type 1 T helper (Th1)-dominated response was detected in the gastric antrum of Helicobacter pylori-infected subjects with peptic ulcer by both reverse transcriptase-PCR and immunohistochemistry. By using a T-cell cloning technique, it was shown that the majority of Th 1 cells were specific for Hp antigens. A Th1 predominance, which associated with high IL-12 expression, was also found, at both clonal and immunohistochemical level, in the gut of patients with Crohn's disease. These findings suggest that the Th1/Th2 paradigm may be useful to explain the inflammatory reactions involved in the pathogenesis of some gastrointestinal disorders.
Crohn Disease↗