Maria Grazia Giudizi

Role of interleukins in induction and regulation of human IgE synthesis

Studies of human IgE synthesis are summarized and provide further insight into the cellular and molecular mechanisms involved in IgE regulation, as well as in the alterations responsible for IgE disregulation in some pathological conditions. These include the demonstration that IL-4 is the essential factor for the induction of human IgE syntheses. Another T cell-derived lymphokine, IFN-gamma negatively regulated the IgE synthesis induced by IL-4. These two lymphokines can be produced by different T helper cells, as shown in mice, but they can also be the product of the same T cells clones. Additional cellular and/or molecular signals appear to be involved in the IL-4-induced IgE synthesis, but their precise role in this process is undetermined. Finally, alternations of one or more of these regulatory mechanisms can be detected in patients with pathological conditions characterized by hyperproduction of IgE. In particular, the increased prevalence of T cells clones able to produce IL-4 appears to be a distinctive feature of patients with common atopy whereas a reduction in the proportion of IFN-gamma-producing T cells seems to be peculiar of both patients with hyper-IgE syndrome and patients with AIDS.

Human TH1 and TH2 Subsets

Human CD4+ T cell clones secreting different patterns of cytokines similar to TH1 and TH2 cells described in mice have been demonstrated. These human TH1 and TH2 clones are produced in response to different antigens and exhibit distinct functional properties. TH1 clones are produced in response to intracellular bacteria and viruses, do not provide help for IgE production and possess cytolytic potential, whereas TH2 clones are produced in response to allergens and helminth components, provide optimal help for IgM, IgG, IgA and IgE synthesis, and lack cytolytic potential. The cytokine profile of ‘natural’ immunity evoked by intracellular parasites and viruses through the activation of macrophages and NK cells probably determines the phenotype of the subsequent specific immune (TH1) response. TH1 cells are not only involved in the protection against intracellular parasites but also play a role in the genesis of some organ-specific autoimmune diseases, such as Hashimoto’s thyroiditis. In contrast, TH2 cells are responsible for the initiation of the allergic cascade.

Activation of HIV expression by CD30 triggering in CD4+ T cells from HIV-infected individuals

CD30 is a member of the tumor necrosis factor receptor superfamily, preferentially expressed by T cells producing type 2 helper (Th2) cytokines, whose ligand (CD30L) has been identified on B cells, activated macrophages, and a subset of activated T cells. We show here that cross-linking CD30 with an agonistic CD30-specific monoclonal antibody, as well as with CD30L+ CD8+ T cell clones or CD30L+ B cells, enhanced HIV replication in CD4+ T cells from HIV-infected individuals, and such a potentiating effect was inhibited by anti-CD30L antibody. The anti-CD30L antibody also exerted a suppressive effect on spontaneous HIV replication occurring in lymph node cells from an HIV-sero-positive patient, showing CD30L expression by both B and CD8+ T lymphocytes. Thus, CD30 triggering by CD30L-expressing cells may plan an important role in the activation of HIV expression from latently infected CD4+ T cells.

Altered proportion of T mu-and T gamma-cell subpopulations in patients with Hodgkin's disease.

The ability of peripheral blood lymphocytes from patients with Hodgkins disease (HD) to form rosettes with ox red blood cells (ORBC) sensitized by anti‐ORBC purified rabbit IgM and IgG was investigated. The mean percentage of cells capable of forming rosettes with ORBC coated with IgM (EAIgM‐RFC) in the peripheral blood of either untreated or X‐ray‐treated patients with HD was significantly lower than that of normal individuals. In the same groups of patients with HD the mean percentage of T lymphocytes equipped with receptor for IgG (Tγ lymphocytes), evaluated by a mixed fluorescent rosette assay, was significantly higher than in normal controls. These data suggest that the altered proportion between Tμ‐ and Tγ‐cell subpopulations in patients with HD probably represents a disease‐related phenomenon.

Type 1 T Helper Cells Specific for Candida albicans Antigens in Peripheral Blood and Vaginal Mucosa of Women with Recurrent Vaginal Candidiasis

The cytokine profile of circulating and vaginal T cells specific for immunodominant mannoprotein antigens of Candida albicans was analyzed in patients with recurrent vaginal candidiasis (RVC). Peripheral blood mononuclear cells (PBMC) from patients with RVC proliferated more than those from healthy subjects and expressed higher type 1:type 2 T helper cell cytokine ratios in response to C. albicans stimulation. A higher number of C. albicans-specific T cells was generated in PBMC from patients with RVC than in PBMC from healthy donors. C. albicans-specific T cell clones from patients with RVC produced higher levels of interferon (IFN)-gamma and lower levels of interleukin (IL)-4 than clones from control women. More important, a higher proportion of C. albicans-specific T cell clones was generated from lesional mucosa of patients with RVC than from normal mucosa, all of which produced IFN-gamma but not IL-4. These findings provide direct evidence that RVC is characterized by a highly polarized local and circulating type 1 T helper cell-like response against C. albicans antigens.

Schnitzler's syndrome: what's new?

In 1972, Dr Liliane Schnitzler described a case of chronic nonpruritic urticaria associated with fever of unknown origin, bone pain, hyperostosis, increased erythrocyte sedimentation rate (ESR), and macroglobulinaemia.1 Subsequently, this syndrome was also reported by other groups.2,3 The eponym Schnitzler’s syndrome, was proposed in 1988 and 1989 by Saurat et al.4 and Janier et al.5 It is a rare and probably underdiagnosed condition: so far about 50 cases have been reported in the literature.6 Of note, most cases were found in Europe, mainly in France and Spain, but patients with the same syndrome have also been described in USA, Japan and Australia. The aetiology of this syndrome is unknown. The age at onset of Schnitzler’s syndrome ranges from 29 to 79 years and a slight prevalence was reported in males. Because of the variety of clinical signs, this syndrome is of concern to dermatologists, rheumatologists, haematologists and internists. A lot of patients consult all these specialists before the diagnosis is established and in most cases the diagnosis can be delayed by even more than 5 years.

Modified Adenine (9-Benzyl-2-Butoxy-8-Hydroxyadenine) Redirects Th2-Mediated Murine Lung Inflammation by Triggering TLR7

Substitute adenine (SA)-2, a synthetic heterocycle chemically related to adenine with substitutions in positions 9-, 2-, and 8- (i.e., 9-benzyl-2-butoxy-8-hydroxyadenine), induces in vitro immunodeviation of Th2 cells to a Th0/Th1 phenotype. In this article, we evaluate the in vivo ability of SA-2 to affect Th2-mediated lung inflammation and its safety. TLR triggering and NF-κB activation by SA-2 were analyzed on TLR-transfected HEK293 cells and on purified bone marrow dendritic cells. The in vivo effect of SA-2 on experimental airway inflammation was evaluated in both prepriming and prechallenge protocols by analyzing lung inflammation, including tissue eosinophilia and goblet cell hyperplasia, bronchoalveolar lavage fluid cell types, and the functional profile of Ag-specific T cells from draining lymph nodes and spleens. SA-2 induced mRNA expression and production of proinflammatory (IL-6, IL-12, and IL-27) and regulatory (IL-10) cytokines and chemokines (CXCL10) in dendritic cells but down-regulated TGF-β. Prepriming administration of SA-2 inhibited OVA-specific Abs and Th2-driven lung inflammation, including tissue eosinophilia and goblet cells, with a prevalent Foxp3-independent regulatory mechanism. Prechallenge treatment with SA-2 reduced the lung inflammation through the induction of a prevalent Th1-related mechanism. In this model the activity of SA-2 was route-independent, but adjuvant- and Ag dose-dependent. SA-2-treated mice did not develop any increase of serum antinuclear autoantibodies. In conclusion, critical substitutions in the adenine backbone creates a novel synthetic TLR7 ligand that shows the ability to ameliorate Th2-mediated airway inflammation by a complex mechanism, involving Th1 redirection and cytokine-mediated regulation, which prevents autoreactivity.

Anti-Ia reactivity in sera of untreated patients with active Hodgkin's disease.

The effect of sera from eight patients with Hodgkins disease on the autologous and allogeneic mixed lymphocyte response of normal individuals was examined. Sera from three patients with active disease caused marked inhibition of both autologous and allogeneic mixed lymphocyte reaction without inducing significant reduction of the phytohemagglutinin-induced proliferative response. The inhibitory activity of Hodgkins disease sera on the autologous mixed lymphocyte reaction was removed by adsorption with non-T, but not T, lymphocytes and it was correlated with the ability of such sera to block the binding of monoclonal anti-Ia antibody to Ia-positive target cells. Anti-Ia antibodies were detected in the same sera by double antibody radioimmunoassay and analysis on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, using 125I-labeled, partially purified, Ia antigens from two different human B-cell lines. This anti-Ia reactivity was strongly reduced or absent in sera taken from the same patients at the completion of multidrug chemotherapy.

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.

T cells specific for Candida albicans antigens and producing type 2 cytokines in lesional mucosa of untreated HIV-infected patients with pseudomembranous oropharyngeal candidiasis

Factors influencing the susceptibility to mucosal candidiasis in HIV-infected patients are not clearly understood. Since in animal models of candidiasis the T helper (Th)1- or Th2-responses are protective or non-protective, respectively, this study was aimed to evaluate the cytokine profile of T-cell response to Candida albicans in the blood and lesional tissues of human immunodeficiency virus (HIV)-infected individuals, suffering, or not, from pseudomembranous oropharyngeal candidiasis (POPC), of HIV-negative women suffering from recurrent vaginal candidiasis (RVC) and of healthy controls. Peripheral blood mononuclear cells from HIV-infected and RVC patients proliferated to C. albicans antigen more than controls. Upon antigen activation, T cells from HIV-infected patients produced low interferon (IFN)-gamma, while only T cells from patients with POPC displayed high interleukin (IL)-4 and IL-5 production. POPC-positive patients also showed higher serum IgE levels than POPC-negative patients. T-cell clones generated from the oral mucosa of one HIV-infected patient with POPC produced IL-4, but not IFN-gamma (Th2 phenotype), whereas clones obtained from vaginal mucosa from one RVC patient or one healthy donor showed a Th1 profile. These findings, showing a non-protective Th0/Th2 response to C. albicans antigen in the blood and lesional mucosa of HIV-infected patients with POPC, may explain the high susceptibility of candidiasis in these subjects.