Emanuele Fanales-Belasio

Immunologic aspects of hyperimmunoglobulinemia E–like syndrome in patients with AIDS

In this study we describe a series of nine patients affected by acquired immunodeficiency syndrome (AIDS) or AIDS-related complex who had hypereosinophilia and hyperimmunoglobulinemia E (hyper-IgE) with chronic dermatitis and recurrent staphylococcal infections. These patients had features similar to those present in hyper-IgE syndrome, a primary immunodeficiency disease. In addition, immunologic characterization of these patients with human immunodeficiency virus (HIV) infection, compared with 51 HIV-positive patients without hyper-IgE, both atopic and nonatopic, and three patients affected by the primary hyper-IgE syndrome, also revealed an increase in IgA and a severe decrease in B and CD4+ lymphocytes. Spontaneous in vitro synthesis of IgE by peripheral blood mononuclear cells was confirmed in both hyper-IgE conditions, together with increased levels of circulating eosinophil cationic protein. Serum-soluble CD23, usually increased in atopic conditions and hyper-IgE, was similar to that of normal control subjects in the HIV-positive patients with hyper-IgE. On the basis of our findings, we conclude that a hyper-IgE-like syndrome represents a distinct aspect of the clinical manifestations associated with HIV infection and that the immunologic mechanisms in this condition seem to differ from those known in primary hyper-IgE syndrome, because CD4+ TH2 type cells, which are currently believed to have a role in IgE production, are severely depleted in HIV-positive patients.

Serum Eosinophil Cationic Protein in Patients with Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin, frequently associated with a family history of atopy, raised serum IgE levels and other immunological abnormalities. Both eosinophils and their basic proteins have been detected in the skin lesions of AD patients. We measured the levels of eosinophil cationic protein (ECP) in sera of 24 children with AD and found them to be increased, compared to nonatopic controls, both children and adults. High ECP values were also obtained in 3 patients with the hyper-IgE syndrome. However, no direct relationship between IgE and ECP serum levels could be established. We found no correlation between serum ECP and the number of circulating eosinophils, suggesting that part of ECP was produced by cells infiltrating the tissues. Measurement of ECP might represent a noninvasive tool to assess the activity of AD in relation to eosinophil involvement in this disease.

Immunodeficiency with hyperimmunoglobulinemia M in two female patients is not associated with abnormalities of CD40 or CD40 ligand expression

The immunologic defect in X-linked immunodeficiency and hyperimmunoglobulinemia M (HIM) are related to defective expression of the CD40 ligand (CD40L). We have studied two female patients with HIM to evaluate the role of CD40/CD40L in the pathogenesis of impaired immunoglobulin switching. In addition to recurrent infections characteristic of humoral immunodeficiencies, the two patients had chronic hepatitis caused by type C virus. Phenotypic characterization of peripheral blood mononuclear cells showed a similar picture in both patients, with a reduction in the absolute numbers of CD4 cells and increased numbers of CD8 and CD3/DR cells. B cells (CD19+) were reduced in one patient, but CD40 was expressed on all CD19+ cells in both patients. The expression of CD40L was normal on peripheral blood mononuclear cells from the two patients with HIM on both resting and stimulated cells. The combination of anti-CD40 and cytokines (interleukin-2, interleukin-4, and interleukin-10) was able to restore proliferative capacity to anti-IgM. Peripheral blood mononuclear cells from the two patients with HIM showed a high spontaneous production of IgM in vitro and no production of IgG or IgE. Our data suggest that the defect of isotype switching in female patients with HIM is not related to defective expression of the CD40/CD40L receptor system. A possible role for chronic hepatitis C virus infection in the pathogenesis of the disease is suggested by the detection of specific production of anti-hepatitis C virus IgM.

Serum eosinophil cationic protein (ECP) in human immunodeficiency virus (HIV) infection

HIV infection is immunologically characterized by progressive decrease of CD4’ lymphocytes and hypergammaglobulinemia. 1 Clinically, it spans from asymptomatic infection to full-blown AIDS, divided into definite stages by the Center for Disease Control classification.* A high incidence of atopic manifestations has been reported in HIV seropositive individuals3* ’ with increased serum levels of IgE.5 Recently, the rise of serum IgE has been related to the decrease of CD4+ cells.6 We selected 22 HIV seropositive subjects at different stages of disease, who presented allergic symptoms either for the first time or as a reexacerbation of previous atopic disease. In their sera, we measured the levels of total IgE, allergen-specific IgE, and ECP, a basic protein with cytotoxic properties released by EOSs, which is increased in sera and secretions of atopic patients.‘.’ As control subjects, we chose 25 healthy nonatopic subjects, 20 patients with acute recurrent infection (both bacterial and viral), and 29 HIV seropositive cases without history or present symptoms of atopy. Care was taken to match the HIV groups for age, sex, and disease stages. Detailed data on the composition of the groups are reported in Table I. Additional tests in HIV-positive subjects were white blood cell count, EOS count, both by standard methods, CD4’ lymphocyte count, with direct immunofluorescence with monoclonal anti-CD4 (OKT4, Ortho Diagnostic Systems, Raritan, N . J .) and read by flow cytometry (Cytoron, Ortho Diagnostic Systems), and serum levels of IgG, IgA, and IgM by nephelometry with a TDX analyzer (Abbott Diagnostics, Irving, Texas). Results of serum levels of IgE, mea-

Increased IL-6 gene expression and production in patients with common variable immunodeficiency.

We have studied IL‐6 gene expression and production by in vitro stimulated peripheral blood mononuclear cells (PBMC) isolated from common variable immunodeficiency (CVI) patients. A strong hybridization signal for the IL‐6 probe was observed in mRNA extracted from phyto‐haemagglutinin (PHA)‐ and PH A/phorbol myristate acetate (PMA)‐stimulated PBMC from most of 12 CVI patients analysed. IL‐6 production by PHA‐stimulated PBMC from 28 CVI patients was evaluated in ELISA and found to be significantly (P < 0.0001) higher than in normal controls. IL‐6 production, however, did not correlate with the lymphocyte populations examined, nor with the absolute number of monocytes. We have also showed that IL‐6 was able to increase IgM secretion by several Epstein Barr virus (EBV)‐transformcd cell lines derived from both normal donors and CVI patients, but it failed to modify substantially the amounts of IgM and IgG produced in vitro by PBMC derived from CVI patients and activated with pokeweed mitogen (PWM) or anti‐IgM. Our data indicate that IL‐6 gene expression and production is increased in CVI, but CVI cells do not respond to IL‐6 with increased production of immunoglobulin.