Fabio Almerigogna

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.

Soluble E-selectin in essential hypertension: A correlate of vascular structural changes*

BACKGROUND Increased expression of the endothelial leukocyte adhesion molecule E-selectin is implicated in vascular disease and may accompany the development of hypertension. We evaluated plasma soluble (s) E-selectin to assess its relationship with endothelium-dependent and endothelium-independent vasodilation in patients with hypertension. METHODS Thirty-one previously untreated and uncomplicated essential hypertensive patients were compared with 16 normotensive controls for changes in forearm blood flow (by strain-gauge plethysmography) in response to brachial artery infusion of the endothelium-dependent vasodilator acetylcholine, and of the endothelium-independent vasodilator sodium nitroprusside. As an index of structural changes, minimal forearm vascular resistances were calculated as the ratio between maximal vasodilation after 13 min of ischemia and mean blood pressure. RESULTS Responses to acetylcholine were significantly lower and minimal forearm vascular resistances higher in hypertensives versus controls, whereas responses to nitroprusside were comparable. Baseline sE-selectin concentrations were (mean +/- SEM) 37.4 +/- 1.8 ng/mL in hypertensives and 27.8 +/- 0.7 ng/mL in normotensives (P < .001). In essential hypertensive patients, a significant (P < .01) correlation with the response to nitroprusside (r = -0.47) was found, but not with the response to acetylcholine or minimal forearm vascular resistances. sE-selectin was also positively correlated with age and LDL cholesterol. At multivariate analysis, sE-selectin remained significantly correlated with nitroprusside responses and LDL cholesterol. CONCLUSIONS In patients with essential hypertension, plasma levels of sE-selectin are higher than in normotensive controls and mostly related to structural vascular changes.

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.

Kounis syndrome (allergic acute coronary syndrome): different views in allergologic and cardiologic literature

The clinical picture of myocardial ischemia accompanying allergic reactions is defined in the cardiologic literature as Kounis syndrome (KS) or allergic angina/myocardial infarction. In PubMed, a search for “Kounis syndrome”, “allergic angina” or “allergic myocardial infarction” retrieves more than 100 results (among case reports, case series and reviews), most of which are published in cardiology/internal medicine/emergency medicine journals. In allergologic literature, heart involvement during anaphylactic reactions is well documented, but Kounis syndrome is hardly mentioned. Single case reports and small case series of angina triggered by allergic reactions have been reported for many years, and involvement of histamine and others mast cell mediators in the pathogenesis of coronary spasm has long been hypothesized, but the existence of an allergic acute coronary syndrome (ACS) is still questioned in the allergologic scientific community. Putative mechanisms of an allergic acute coronary syndrome include coronary spasm or heart tissue-resident mast cell activation (precipitating coronary spasm or inducing plaque rupture and coronary or stent thrombosis) due to systemic increase of allergic mediators, or heart tissue-resident mast cell activation by local stimuli. Indeed, the pathogenic mechanism of an ACS after an allergic insult might be related to direct effects of mast cell mediators on the myocardium and the atherosclerotic plaque, or to exacerbation of preexisting disease by the hemodynamic stress of the acute allergic/anaphylactic reaction. Which of these mechanisms is most important is still unclear, and this review outlines current views in the cardiologic and allergologic literature.

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.

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.

Rosette formation with protein A-coated erythrocytes: A method for detecting both IgG-bearing cells and another subset of human peripheral blood B lymphocytes

Abstract Human peripheral blood lymphocytes were tested for ability to form rosettes with human red blood cells (HRBC) coated with staphylococcal protein A (SpA-HRBC). Purified T lymphocytes did not form rosettes, but in T-cell-depleted suspensions the number of cells forming rosettes with SpA-HRBC was significantly greater than in unfractionated suspensions. When non-T-cell suspensions were depleted of Ig-bearing lymphocytes, cells forming rosettes with SpA-HRBC were no longer detectable. The number of cells forming rosettes with SpA-HRBC in either unfractionated or T-cell-depleted suspensions was significantly higher than the number forming rosettes with HRBC coated with anti-human γ chain immunosorbent-purified rabbit antibodies. Membrane components reacting with SpA-HRBC were not passively adsorbed on the cell surface and could be actively synthesized by lymphocytes. The SpA-reacting membrane components present on some B lymphocytes were sensitive to treatment with low concentrations of pronase, but other B cells maintained ability to form rosettes even after treatment with higher pronase concentrations. Incubation of T-cell-depleted lymphocyte suspensions with anti-human γ, and also with anti-human μ or anti-human δ chain F(ab′) 2 fragments induced significant reduction in the number of cells forming rosettes. After incubation of the same cell suspensions with a mixture of anti-γ, anti-μ and anti-δ (F(ab′) 2 fragments, virtually all the lymphocytes lost the ability to form rosettes with SpA-HRBC. These findings suggest that rosette formation with SpA-HRBC may be used as a method for detecting IgG-bearing cells but also to detect a subset of IgM- and/or IgD-bearing human B lymphocytes.

Natural killer cell deficiencies in a consecutive series of children with herpetic encephalitis.

Natural killer (NK) cells play a fundamental role in innate and early phases of adaptive immunity against viral infections, both in humans and in animal models. To date, NK cell deficiencies in patients with severe herpetic infections have been reported in single cases, and their role as predisposing factor is still controversial. Five children affected by herpetic encephalitis were consecutively admitted to the Anna Meyer Childrens Hospital in Florence (Italy) between 2003 and 2005. We therefore investigated the presence of NK cell deficiencies in a consecutive series of children with herpetic encephalitis. Five healthy children were included in the study as controls. Differential WBC counts, main Ig and IgE class serum analysis, cytofluorimetric analysis of circulating T, B and NK cells were performed on our study population. Sequencing of a selected region of CD16A gene transcript was carried out in two patients. All patients resulted to be affected by deficiencies related to NK cells in respect to controls. One patient was also affected by lymphopenia, while no other significant deficits of immunity were detected in the study population. To date, this is the first survey that demonstrates isolated NK cell deficiencies in a cohort of consecutive patients affected by severe herpes simplex infections. These findings suggest a role for NK cell deficiencies as a predisposing factor for increased susceptibility and severe course of disease in these patients.

Role of HLA class I and class II antigens in activation and differentiation of B cells

The monoclonal antibodies (MoAb) CR10-214, CR11-115, and Q1/28 to distinct monomorphic determinants of HLA class I antigens, the MoAb CL413 and PTF29.12 recognizing monomorphic determinants of HLA-DR antigens, the anti-HLA-DQw1 MoAb KS11, the anti-HLA-DPw1 MoAb B7/21, and the anti-HLA-DR,DP MoAb CR11-462 were tested for their ability to modulate human B-lymphocyte proliferation and maturation to IgM-forming cells. Purified tonsillar B cells were stimulated with Staphylococcus aureus bacteria of the Cowan first strain (SAC) or anti-human mu-chain xenoantibodies, as well as in growth factor- or T-cell-dependent activation cultures. The B-cell proliferative responses induced by SAC or by mitogenic concentrations of anti-mu-chain xenoantibodies were inhibited by some of the anti-HLA class I and anti-HLA class II monoclonal antibodies tested. The same antibodies were effective inhibitors of the proliferation of B cells stimulated with interferon-gamma (IFN-gamma) or interleukin-2 (IL-2) and with submitogenic concentrations of anti-mu-chain xenoantibodies. The proliferation induced by IL-2 of SAC-preactivated B cells was inhibited by some of the anti-HLA class II monoclonal antibodies, but not by the anti-HLA class I monoclonal antibodies tested. This inhibition appeared to reflect at least in part a direct effect on later events of the B-cell activation cascade, since some anti-HLA class II monoclonal antibodies still exerted considerable inhibitory activity when added together with IL-2 to SAC-preactivated B cells after the third day of culture. Anti HLA-DR, DQ, and DP monoclonal antibodies consistently inhibited the IgM production induced in B cells by T cells alone, T cells plus pokeweed mitogen (PWM), SAC plus IL-2, or IL-2 alone. In contrast, two of the three anti-HLA class I monoclonal antibodies tested inhibited the IgM production in cultures stimulated with SAC plus IL-2 and one the IgM production induced by IL-2 alone, but none of them had inhibitory effects on T-cell dependent IgM production. The results reported herein indicate that HLA class II molecules directly participate in different phases of the B-cell activation cascade. In addition, our data also suggest that HLA class I molecules can be involved in the events leading to B-cell proliferation and differentiation into immunoglobulin-secreting cells.